Acequinocyl Human - Health Risk Assessment D P# 368425

Page 1 of 35 UNITED STA

TES ENVIRONMENTA L PROTECTION A GENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION MEMORANDUM Date : 2 6 - AUG - 2010 SUBJECT: Acequinocyl; Human - Health Risk Assessment for Proposed Section 3 Uses on

Fruiting Vegetables, Hops, Okra, and Edible - Podded Beans . PC Code: 006329 DP Barcode: D 368425 Decision No.: 417967 Re gistration No. : 66330 - 38 Petition No . : 9E7598 Regulatory Action: Section 3 Risk A ss essment Type : Single C hemical/Aggregate Case No.: 7621 T XR No.: NA CAS No.: 57960 - 19 - 7 MRID No . : NA 40 CFR: §180.599 FROM: Sarah J. Levy , Chemist

Anwar Y. Dunbar , Ph.D., Pharmacologist Allison Now o tarski , Biologist Registration Action Branch 1 (RAB1) Health Effects Division (HED) (7509 P ) THROUGH: Dana M. Vogel, Branch Chief

George F. Kramer, Ph.D., Branch Senior Chemist RAB1/HED (7509P) TO: B. Madden/S. Jackson , Risk Manager ( RM0 5)

Registration Divi sion (RD) (7505 P ) 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 f ruiting v egetables, h ops, o kra, and e dible - p odded b eans . A summary

of the estimat ed 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 charact erization was provided by Anwar Dunbar, the occupational /residential exposure assessment was provided by Allison Nowotarski (RAB1), and the drinking water exposure assessment was provided by Iw ona Maher of the Environmental Fate and Effects Division (EFED) .Acequinocyl Human - Health Risk Assessment D P# 368425

Page 2 of 35 Recommendation for Tolerances and Registration Pending submission of revised Sections B and F, and submission of analy tical reference standards to the EPA National Pesticide Standards Repository , there are no residue chemistry issues that would preclud e granting a permanent registration for the requested uses of acequinocyl or establishment of tolerances for residues of acequinocyl and acequinocyl - OH as follows: Vegetable, fruiting, group 8 ................................ ............................. 0.70 ppm Okra ................................ ................................ ................................ .. 0.70 ppm Bean, edible podded ................................ ................................ ......... 0.25 ppm Hop, drie d cones ................................ ................................ .............. 4.0 ppm Registration should be conditional pending resolution of the following deficienc ies : Toxicology  An Immunotoxicity

Study .  Acute and Subchronic Neurotoxicity Stud ies.  A 28 - Day

Inhalation Study . Note to PM: According to HED’s Interim Guid ance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression for acequinocyl should be revised to state: “Tolerances are established for residues of acequinocyl , including i t s metabolites and degradates, in or on the commodities in the tab le 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 stoich iometric equivalent of acequinocyl, in or on the commodity .Acequinocyl Human - Health Risk Assessment D P# 368425

Page 3 of 35 

### TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY ................................ ................................ ................................ ... 4 2.0 PHYSICAL/CHEMICAL PROPERT IES 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 Endocrine Disruption ................................ ................................ .............................. 14 3.5 Recommendation for Aggregate Exposure Risk Assessments ............................. 15 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION ................................ ......... 15 4.1 Summary of Proposed Uses ................................ ................................ ..................... 16 4.2 Dietary Exposure/Risk Pathway ................................ ................................ ............. 17 4.2.1 Residue Profile ................................ ................................ .......................... 17 4.3 Water Exposure/Risk Pathway ................................ ................................ ............... 19 4.4 Dietary Exposure Analyses ................................ ................................ ..................... 20 4.4.1 Chronic Dietary Exposure Analysis ................................ ........................ 21 4.5 Residential/Non - Occupational Exp osure Pathway ................................ ............... 21 4.5.1 Residential Handler Exposure/Risk ................................ ........................ 22 4.5.2 Residential Post - application Exposure/Risk ................................ .......... 23 4.5.3 Spray Drift ................................ ................................ ................................ . 24 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION ............. 24 5.1 Acute Aggregate Risk ................................ ................................ .............................. 24 5.2 Short - Term Aggregate Risk ................................ ................................ .................... 25 5.3 Intermediate - Term Aggregate Risk ................................ ................................ ....... 25 5.4 Long - Term Aggregate Risk ................................ ................................ ..................... 25 5.5 Cancer Risk ................................ ................................ ................................ .............. 25 6.0 CUMULATIVE RISK ................................ ................................ ................................ ......... 25 7.0 OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT ................................ ........ 26 7.1 Occupational Handler Exposure/Risk ................................ ................................ ... 26 7.2 Post - application Exposure/Risk ................................ ................................ .............. 28 7.3 REI ................................ ................................ ................................ ............................ 31 8.0 RESIDUE CHEMISTRY AND TOXICOLOGY DEFICIENCIES ................................ 31 8.1 Residue Chemistry ................................ ................................ ................................ ... 31 8.2 Toxicology ................................ ................................ ................................ ................. 31 8.3 Occupational a nd Residential Exposure ................................ ................................ 31 APPENDIX: Toxicity Profile Tables and Metabolites. ................................ .......................... 32Acequinocyl Human - Health Risk Assessment D P# 368425

Page 4 of 35 1.0 EXECUTIVE SUMMARY Acequinocyl is a quinoline - ty pe miticide that is curr ently registered for use on greenhouse, shadehouse, ornamental, floral, foliage, nursery crops , grapes, tree nuts, pome fruits, citrus fruits, pistachios, and strawberries , as well as for use on landscape ornamentals in and around residences, businesses, p ublic property , schools, interiorscapes, and other non - production areas by commercial applicators and homeowners . Acequinocyl i s currently registered to Ary sta Li fescience North America Corporation as a 15% suspension - concentrate (SC) formulation . Under PP# 9E7598 , the Interregional Research Project No.4 (IR - 4), on behalf of the Agricultural Experiment Station of AZ, CA, CO, FL , I D, NC, NJ, NY, OK, OR, TN, TX, VA, and WA, is requesting for the establishment of tolerances for the combined residues of the in secticide acequinocyl, 2 - (acetyloxy ) - 3 - dodecyl - 1,4 - naphthalenedione, and its metabolite, 2 - dodecyl - 3 - hydroxy - 1,4 - naphthoquinone, expressed as acequinocyl equivalents in/on the following commodities: Vegetable, fruiting, group 8 ................................ ............................. 0.70 ppm Okra ................................ ................................ ................................ .. 0.70 ppm Bean , edible podded ................................ ................................ ......... 0.25 ppm Hop, dried cones ................................ ................................ .............. 3.5 ppm The end - use product proposed for use on f ruiting vegetables, hops, okra and snap beans is Kanemite TM 15 SC Miticide, a 1.25 pounds per gallon ( lb/gal ) SC formulation. Up to two foliar applications are proposed for a maximum seasonal rate of 0.6 lb active ingredient per acre (ai/A ) , with a 7 - day

preharvest interval (PHI ), except for okra for which a 1 - d ay PHIis proposed. Hazard Assessment: Acequinocyl has low acute toxicity via the oral, dermal, and inhalation routes ( T oxicity C ategories I II and IV) . No ocular or dermal irritation was noted. Acequinocyl is not a dermal sensitizer. Acequinocyl is a known Vitamin K antagonist; there fore, it is thought to produce its adverse effects by disrupting the blood coagulation sy stem as indicated by increased prothrombin time, increased activated partial thromboplastin time, and internal hemorrhages. Ina subchronic oral toxicity study , a 28 - day

dermal toxicity

study , and a chronic feeding/oncogenic ity

study (all in the rat), acequinocyl increased prothrombin and activated partial thromboplastin times. Although clotting factors were not measured in some stud ies ( i. e., rat/rabbit developmental toxicity study , m ouse 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 enzy

mes. In both rat and rabbit developmental toxicity studies , a cequinocyl increased the number of resorptions. Developmental effects ( i.e., resorptions) occurr ed 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 offspr ing that were n o t observed in adults including swollen body parts, protruding eyes, clinical signs, delay s in pupil development and increased mortality occurring mainly after weaning. A clear no - observable - adverse - effect level (NOAEL ) was observed for the se effects.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 5 of 35 There was no evidence of carcinogenic potential in either the rat or mouse carcinogenicity study , indicating that acequinocyl is "not likely " to be carcinogenic to humans. There was no concern for mutagenic activity

as indicated by

several mutagenicity

studies . Dose- Response Assessment and FQPA Decision: The HED Hazard I dentification 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 Commi ttee recommended the Food Quality Protection Act (FQPA) S afety F actor (SF) for increased susceptibility

of infants and children be reduced to 1 X because there are no residual uncertainties for pre - and/or post - natal tox icity . InApril 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 rationa le, see Section 3.3. Dietary Exposure (Food + Drinking Water) : The HED Metabolism Assessment Review Committee (MARC) determined that the residues of concern in the dietary exposure and risk assessment are acequinocyl and acequinocyl - OH ( also referred to as R1) for both tolerance expression and risk assessment purposes. In addition, for liver and kidney , 2 - hydroxy - 3 - hexanoic acid - 1,4 naphthalenedione (AKM - 15) was also included , but for risk assessment purposes only . For the aquatic exposure modeling, both parent and metabolite (acequinocyl - OH) concentrations were estimated in the surface and ground water to address the toxicity concerns associated with the acequinocyl - OH degradate. The 1 - in - 10 - ye ar peak concentrations of acequinocyl ranged from 0.18 (CA citrus) to 5.57 (FL nursery plants except roses) ppb. The 60 - day concentrations of acequinocyl ranged from 0.04 to 1.26 ppb. A chronic aggregate dietary (food and drinking water) exposure and risk assessment was conducted for acequinocyl using the Diet ary Exposure Evaluation Model (DEEM - FCI D TM ), Version 2.03 , which use s food consumption data from the U.S. Department of Agriculture’s (USDA’s) Continuing Survey s of Food Intakes by Individuals (CSFI I) from 1994 - 1996 and 1998. Tolerance - level residues, DEEM  ver. 7.76 default processing factors, a nd 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 referenc e 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 h ave risk estimates which were not of concern to HED. The chronic dietary risk assessment shows that the chronic dietary risk estimates do not exceed HED ’s level of concern [(L OC) i.e., <100% of the chronic population - adjusted dose (cPAD)]. For the genera l U.S. population, the exposure for food and water utilized 9.8% of the cPAD. The chronic dietary risk estimate for the highest exposed population subgroup, children 1 - 2 years old, is 45% of the cPAD. Residential Exposure

/Risk : Acequinocyl is currently registered for use on landscape ornamentals in and around residences, businesses, public property , schools, interiorsc a pes, and other non - production areas by commercial applicators and homeowners . All risks for residential handlers are above the target MO E of 100 and do not exceed HED’s LOC . Post - application exposure is not anticipated with the proposed uses.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 6 of 35 Occupational Exposure Estimates: Occupational handler and postapplication exposure is expected from the proposed uses of acequinocyl. No chemic al - specific handler exposure data were submitted in support of this Section 3 registration. It is the policy of the HED to use data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure Guide (8/98) to a ssess handler exposures for regulatory actions when chemical - specific monitoring data are not available (HED Science Advisory Council for Exposure (ExpoSAC) Draft Standard Operating Procedure (SOP) #7, dated 1/28/99). All risks for occupational handlers are above the target margin of exposure ( MOE ) of 100 with the use of gloves , and do not exceed the LOC as the proposed labels already require the use of protective gloves as personal protective equipment. There are no risks of concern for all occupational post - application activities associated with the proposed uses. Acequinocyl is classified in Toxicity Category I II for acute dermal and acute inhalation. It is classified in Toxicity

Category IV for primary

eye irritation and primary skin irritation and it is not a dermal sensitizer. Therefore , the Worker Protection Standard (WPS) interim restricted entry interval (REI ) of 12 hours is adequate to protect agricultural workers from post - application exposures to acequinocyl. Aggregate Exposure Assessmen t: A cute 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 postappli cation exposure of more than 30 - day duration. A chronic aggregate exposure r isk 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 aggr egate risk is not of concern for these populations. An a ggregate risk assessment w as performed for short - term aggregate exposure (food + drinking water + residential exposure) because there are residential uses . Short - term aggregate exposures and risk es timates were calculated for adults and the aggregate MOEs are > 100 and are, therefore, not of concern to HED. Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this human - health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - In come 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. Inline 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 CSFI I and are used in pesticide risk asse ssments for all registered food uses of a pesticide. These data are analy zed and categorized by

subgroups based on age, season of theAcequinocyl Human - Health Risk Assessment D P# 368425

Page 7 of 35 ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, speciali zed 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 adu lts entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by stan ders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. Review of Human Research: Past acequinocyl risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed t o a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED , the Outdoor Residential Exposure Task Force (ORETF) Database , and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi - pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory

barrier to continued reliance on these studies. Recommendation for Tolerances and Registration: Pending submission of revised Sections B and F, and submission of analy tical reference standards to the EPA National Pesticide Standard s Repository , there are no residue chemistry issues that would preclude granting a permanent registration for the requested uses of acequinocyl or establishment of tolerances for residues of acequinocyl and acequinocyl - OH as follows: Vegetable, fruiting, group 8 ................................ ............................. 0.70 ppm Okra ................................ ................................ ................................ .. 0.70 ppm Bean, edible podded ................................ ................................ ......... 0.25 ppm Hop, dried cones ................................ ................................ .............. 4.0 ppm Registration should be conditional pending resolution of the following deficienc ies : Toxicology  An Immunotoxicity

Study .  Acute and Subchronic Neurotoxicity Stud ies .  A 2 8 - Day

Inhalation Study . Note to PM: According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner , 5/27/09 ), the tolerance expression for acequinocyl should be revised to state: “Tolerances are established for residues of acequinocyl , includin g i t s 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 metabol ite, 2 - dodecyl - 3 - hydroxy - 1,4 - naphthoquinone , calculated as the stoichiometric equivalent of acequinocyl, in or on the commodity .Acequinocyl Human - Health Risk Assessment D P# 368425

Page 8 of 35 2.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION Provided below are the phy sical/chemical properties for acequinocyl; they include product chemistry data. Most of this information was obtained from the acequinocy l “Pesticide Fact Sheet;” 9/ 26 / 03 ( http://www.epa.gov/opprd001/factsheets/acequinocy l.pdf ). 2 .1 Identification of Active Ingredient

Registrant: Ary sta L ifescience 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 Ty

pe: Miticide Chemical Family : Quinoline Target Pests: Tetranychus, Panonychus and Eutetranychus spp of mites Formulation: Product - Kanemite TM 15 SC; 1.25 lb ai/gal Ty pes of Formulations: Technical (96.8% ai) ; End - Use Product (15.8%) Empirical Formula: C 24 H 32 O 4 Molecular Weight: 384.5 2.2 Structural Formula of Acequinocyl and Acequinocyl - OH O

O C H 2 ( C H 2 ) 1 0 C H 3 O C O C H 3 O

O C H 2 ( C H 2 ) 1 0 C H 3

O H Acequinocyl Acequinocyl - OH 2.3 Physical and Chemical Properties of Acequinocyl These phy sical and chemical properties are for the end - use product unless otherwise noted. Appearance: Pale yellow Phy sical State: Li quid Suspension Vapor Pressure: 1.69 x 10 - 9 pascals at 25 0 C (technical) Water Solubility : 6.69 μg/Lat 20 0 C (technical) Octanol/Water Partition Coefficient (L og Kow):  6.2 (technical) Melting Point: 59.6  C (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.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 9 of 35 3.0 HAZARD CHARACTERIZATION/FQPA CONSIDERATIONS The existing toxicological database for acequinocyl is complete and supports the establishment of permanent tolerances for residues of acequinocyl in/on the raw agricultural commodi ties ( 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 Hazard Identific ation Assessment Review Committee (HIARC). Meeting Date: October 14, 2003. TXR No. 0052234. P. Terse; 11/ 13 / 04.  Acequinocyl. Report of the Hazard Identification Assessment Review Committee. Meeting Date: July 15, 2003. TXR No. 0052075. R. Fricke; 8/ 14 / 03. 3.1 Hazard Profile Acequinocyl binds to the Qo center at Complex I II in the mitochondria of mite cells and , thereby , exerts its miticidal action by inhibiting electron transfer. Acequinocyl possesses moderate activity against plant mitochondrial complex I II, in contrast to much higher activity against an insect mitochondrial complex I II. There is a lack of information regarding whether or not acequinocyl inhibits the mammalian mitochondrial electron transfer sy stem. Acequinocyl has low ac ute 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 mechan ism is supported by

effects observed in the database. Inthe 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 thro mboplastin time, increased prothrombin time, and internal hemorrhages . Inthe mouse subchronic oral toxicity

study , effects included p allor, sunken eyes, labored/irregular breathing, hunched posture, piloerection, weight loss, and hepatic vacuolization (b lood 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 reticulocy tes, 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 part ial prothromb oplastin time, increased fibrinogen levels, and increased heart weights (absolute and relative to the body weight) . Inthe 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 enzy

me levels (alanine and aspartate aminotransferase), increased liver weight, hepatocy te vacuolization, and hepatocy te fatty depositi on (blood clotting was not evaluated in this study ) . In the dog chronic toxicity study , effects included elevated prothrombin time, increased reticulocy te/platelet count , reduced body weight gain, and reduced food efficiency . Inthe rat prenatal devel opmental toxicity study , maternal toxicity

resulted in pale eyes, piloerection , red vaginal discharge, and internal hemorrhage at the lowest - observable adverseAcequinocyl Human - Health Risk Assessment D P# 368425

Page 10 of 35 effects level (L OAEL ; 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 ) . Inthe rat two - generation reproductive toxicity study , both the maternal and reproductive toxicity LOAEL s were not observed, however the LOAE L for parental males was 58.9/69.2 mg/kg/day based on hemorrhagic effects. T he offspring sy stem ic L OAEL 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, delay s in pupil development and increased mortality occurring mainly

after weaning. Previously , HED’s HIARC concluded that exposure to ace quinocyl 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 , HIAR C considered these as secondary because they

were observed at very high doses. In the 2 - generation reproduction study , significant reduction in startle response in F 2 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 day s post partum, an open field exploration test at 35 - 48 day s post partum and a water maze test with a learning phase and a memory phase at 35 - 48 day s 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 hunch ed 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 d ied 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 n o 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 ba cterial DNA damage or repair assay . Acequinoc yl 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 h ours 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 hydroly sis products and a glucuronide conjugate. There was no evidence for selective ti ssue accumulation or sequestration.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 11 of 35 In feces and the bile , th e components identified were : (1) parent compound ; (2) 2 - hydroxy - 3 - dodecyl - 1, 4 - naphthalenedione (acequinocyl - OH) ; (3) 2 - (1,2 - dioxotetradecyl) - benzoic acid (AKM - 18) ; (4) conjugated acequinocyl - OH; (5) 2 - hydroxy - 3 - butanoic acid - 1,4 - naphthalenedions ; and (AKM - 14) (6) 4 naphthalenedione (AKM - 15) . T he structures for these metabolites may

be found in the Appendix, Table A - 3 . The major urinary metabolites included: (1) 2 - hydroxy - 3 - hexanoic aci d - 1; 4 naphthalenedione (AKM - 15); and (2) 2 - hydroxy - 3 - butanoic acid - 1,4 - naphthalenedions (AKM - 14). Neither the parent compound nor the hydroxy metabolite ( acequinocyl - OH ) was observed in the urine. The major components detected in plasma were: (1) parent compound; (2) acequinocyl - OH ; (3) conjugated acequinocyl - OH ; (4) AKM - 14; and (5) AKM - 15. 3.2 FQPA Considerations HED’s RAB1 risk assessment team concluded that based on toxicological considerations and the residue assumptions used in the dietary and residential exposure analy ses, the FQPA SF may be reduced to 1 X . 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 neuro pathology

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 sy stemic effects in both studies. Therefo re, 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 a gency does not believe that conducting these studies will result in a lower point of departure ( POD ) than that currently use d for overall risk assessment, and therefore, a database uncertainty factor (UF DB ) is not needed to ac count for lack of these studies.  There is no evidence of increased susceptibility of rat or rabbit fetuses to in utero exposure to acequinocyl. Inthe 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 a cequinocyl does not show any evidence of treatment - related effects on the immune sy stem. The overall weight of evid ence suggests that this chemical does not directly

target the immune sy stem . An immuno toxicity 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 UF DB 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 inhalatio n risk was estimated by calculating exposure using the Agency's Residential SOPs. For chemicals with low vapor pressure (7.5 x 10 - 5 mmHg or below for outdoor uses at 20 - 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 conservativeAcequinocyl Human - Health Risk Assessment D P# 368425

Page 12 of 35 and is considered protective and the additional FQPA SF is not ne eded.  Since all calculated inhalation MOEs for residential handlers are significantly greater than HED’s LOC (MOE >100), the lack of an inhalation study will not impact the FQPA SF.  The dietary

food and drinking water exposure assessments will not underes timate 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 concentratio n 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 s 3. 3 .1 and 3. 3 .2 provide the toxici ty endpoints used in this risk assessment. Table 3.3.1 . Sum mary of Toxicological Doses and Endpoints for Acequinocyl for Use in Dietary , Occupational , and Residential Exposure Risk Assessm ents . 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 popu lation including infants and children is not required. Chronic Dietary (All Populations) NOAEL = 2.7

mg/kg/day UF A = 10x

UF H =10x FQPA SF = 1X cPAD = c RfD = 0.027 mg/kg/day 18 - month carcinogenicity study in mice; LOAEL = 7.0 mg/kg/day based on clinical chemistry and microscopic nonneoplastic lesions (brown pigmented cells and perivascular inflammatory cells in liver) . Short - (1 - 30 days) and Intermediate - (1 - 6 months) Term Dermal Dermal NOAEL

= 200 mg/kg/day UF A = 10x

UF H =10x LOC ( occupational/ residen tial) = MOE <100 28 - day dermal study in rats; LOAEL = 1000 mg/kg/day based on increased clotting factor times . Short - (1 - 30 days) Term Inhalation Oral

NOAEL=60 mg/kg/day (inhalation absorption rate=100%) UF A= 10x

UF H =10x LOC ( occupational/ r esidential) = 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, h emorrhaging uterus, fluid in the cecum, fur in the stomach, blood stained vaginal opening, blood stained urinary bladder contents/urine).Acequinocyl Human - Health Risk Assessment D P# 368425

Page 13 of 35 Intermediate - (1 - 6 months) Term Inhalation Oral NOAEL =

16 mg/kg/day (inhalation absorption rate=100%) UF A = 1 0x

UF H = 10x LOC ( occupational/ residential) = MOE <100 Subchronic toxicity in mice; LOAEL = 81 mg/kg/day based on hepatocyte vacuolation .

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans . ” 1 UF = uncert ainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), FQPA SF = FQPA Safety Factor, NOAEL = no observed - adverse - effect level, LOAEL = lowest - obs erved - 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, UF DB = database uncertainty factor, UF L = uncert a i nty factor for lack of a NO AEL . 2 15% Dermal - absorption factor

– d erived from dermal - penetration study. Acute Dietary Endpoint : The aRfD for the general population, including infants and children, was not established because an endpoint of concern attributable to a single dose w as not identified. Therefore, this assessment is not necessary . Chronic Dietary Endpoint : The chronic reference dose ( cRfD ) of 0.027 mg/kg/day was determined on the basis of the chronic carcinogenicity study in mice. An UF of 100 (10 - fold for interspec ies extrapolation and 10 - fold for intraspecies variability ) was applied to the NOAEL of 2.7 mg/kg/day

to derive the cRfD. The L OAEL of 7.0 mg/kg/day is based on clinical chemistry and microscopic non - neoplastic lesions (brown pigmented cells and perivascu lar inflammatory ce lls) in the liver. The FQPA SF of 1 X is applicable for chronic dietary risk assessment. Therefore, the cPAD is equal to the RfD and is 0.027 mg/kg/day . The lowest NOAEL in the database was derived from this study , and this study is thus appropriate for the chronic reference dose. It is also appropriate for both the expected duration of exposure and the route of exposure. Short- and Intermediate - Term Incidental Oral Endpoints: Since there are no residential uses under consideration i n the current risk assessment, where there may be potential short - or intermediate term incidental oral exposures, these risk assessments were not performed. Dermal Absorption: No dermal absorption factor was necessary for the short - and intermediate ter m 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 absorptio n values at the three doses at 168 hours (7 day s). Short- and Intermediate - Term Dermal Endpoints: The s hort - and intermediate - term dermal endpoints are based on increased clotting factor times seen in the rat 28 - day dermal toxicity

study at the L OAEL 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 day s and 1 - 6 months) , and it is consistent with the mechanism of action for this acti ve ingredient. The LOC for occupational exposure is for a MOE of <100. Short- Term Inhalation Endpoint: The s hort - term inhalation endpoint is based on the maternal NOAEL of 60 mg/kg/day in the developmental study in rabbits. The NOAELof 60 mg/kg/dayAcequinocyl Human - Health Risk Assessment D P# 368425

Page 14 of 35 wa s 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 L OAEL of 120 mg/kg/day . Because H IA RC 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 . Interm ediate - Term Inhalation Endpoint: The i ntermediate - term inhalation end point is based on hepatocy te vacuol iz ation seen in the 90 - day oral study

in mice observed at the L OAEL of 81 mg/kg/day (NOAEL = 16 mg/kg/day ). Because H IA RC selected an oral NOAEL for intermediate - term inhalation exposure assessment, a conservative 100% o ral equivalent inhalation absorption factor is assumed . This study is relevant for the duration of exposure (90 - day s). The LOC for occupational exposure is for a MOE of < 100. Long- Term Dermal and Inhalation Endpoint s : Since the uses under considerati on in the current risk assessment do not include long - term dermal or inhalation exposure s , long - term dermal and inhalation risk assessment s w ere not performed. Based on the available toxicity database and the Agency's current practices, the inhalation ris k 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 In secticide, Fungicide, and Rodenticide Act (FI FRA) Scientific Advisory Panel (SAP) i n 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 pro cess 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. I f any

new policies or procedures are develo ped, then the Agency may revisit the need for an inhalation toxicity study for acequinocyl and/or a re - examination of the inhalation toxicity

risk assessment. 3.4 Endocrine Disruption As required under FFDCA section 408(p), EPA has developed the Endocri ne Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocr ine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact w ith the estrogen, androgen, or thy roid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will det ermine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 15 of 35 Between October 2009 and February 2010, EPA issu ed te st orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Acequinocyl wa s not amon g the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly , EPA anticipates issuing future EDSP test orders/data call - ins for all p esticide active ingredients . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/ 3.5 Recommendation for Aggregate Exposure Risk Assessments S ince short - and intermediate - term inhalation endpoints are based on oral studies, dietary exposure will be aggregated to inhalation exposure for all populations/dur ations. 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION Please refer to the following documents for detailed considerations of the material summarized in this section:

 PP#: 9E7598 . Acequinocyl. Petition for Use on Fruiting Vegetables, Hops, Okra, an d Edible - Podded Beans. Summary of Analytical Chemistry and Residue Data . D369100 . S. Levy, 8/25/10 .  PP#: 9E7598. Acequinocyl. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action Use o n Fruiting Vegetables, Hops, Okra, and Edible Podded Beans. D369101. S. L e vy, 8/25/10.  Acequinocyl: Occupational and Residential Exposure/Risk Assessment for Proposed Use on Fruiting Vegetables Crop Group 8 (Tomatoes & Peppers), Edible Podded Beans, Hops, and Okra. DP Barcode: 369099. A. Now otarski. 6/10/10 .  Acequinocyl and its Degradate, Acequinocyl - OH (R1), Drinking Water Assessment in Support of IR - 4 New Uses Registration for Fruiting Vegetables (Crop Group 8), Okra, Edible Podded Beans, and Ho ps. D368426 and 368579 . I. Maher et al., 4/ 29 / 10 . Acequinocyl is a quinoline ty pe miticide registered for use in the U.S. on pome fruits, citrus fruits, grapes, tree nuts , pistachios, and strawberries for the control of various phy tophagous mite species. Under PP# 9E7598 , the Interregional Research Project No.4 (IR - 4), on behalf of the Agricultural Experiment Station of AZ, CA, CO, FL , I D, NC, NJ, NY, OK, OR, TN, TX, VA, and WA, is requesting for the establishment of tolerances for the combined residues of the insecticide acequinocyl, 2 - (acetyloxy ) - 3 - dodecyl - 1,4 - naphthalenedione, and its metabolite, 2 - dodecyl - 3 - hydroxy - 1,4 - naphthoquinone, expressed as acequinocyl equivalents in/on the following commodities: Vegetable, fruiting, group 8 ................................ ............................. 0.70 ppm Okra ................................ ................................ ................................ .. 0.7 0 ppmAcequinocyl Human - Health Risk Assessment D P# 368425

Page 16 of 35 Bean, edible podded ................................ ................................ ......... 0.25 ppm Hop, dried cones ................................ ................................ .............. 3.5 ppm 4.1 Summary of Proposed Uses The petitioner provided a draft label for Kanemite TM 15 SC Miticide ( EPA Reg. No. 66330 - 38) , a 1.25 lb/gal SC formulation of acequinocyl. The acequinocyl formulation , which is currently registered for use on several fruit and nut crops , is proposed for use on fruiting vegetables, okra, edible - podded beans and hops . Table 4.1.1 provides a summary of the proposed use patterns. Table 4.1 . 1. Summ ary of Proposed Directions for Use of Acequinocyl . Commodity Trade Name

(EPA Reg. No.) Application

Timing, Ty pe, Equipment Application

Rate (lb ai/A) Maximum

Number Applications Per Season Maximum

Seasonal Application Rate (lb ai/A) PHI 1

(days) Use Dire ctions and

Limitations 1 Fruiting vegetable crop group 8 (tomato and pepper) Kanemite TM

15 SC Ground 0.3 2 0.6 7 RTI: 21 days, min imum GPA: 100 Edible podded bean Hop Okra 1 1 PHI = preharvest interval, RTI = retreatment int erval, GPA = gallons of water volume per acre . General label restrictions include: (i) do not apply through any

ty pe of irrigation sy stem; (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 - mi xing the SC acequinocyl product with other miticide/insecticide products; a spray- mix compatibility and phy totoxicity trial under local conditions should first be conducted. A 12 - hour REIis specified. No rotational crop restrictions are specified on the label. The label requires applicators and other handlers to wear long - sleeved shirt and long pants, chemical - resistant gloves, and shoes plus socks. Conclusions: The proposed use directions are adequate to allow for evaluation of the submitted residue data relative to the proposed uses. T he proposed uses are generally supported by

the submitted field trial data; however, the data for fruiting vegetables supports a 1 - day PHIfor all fruiting vegetables. The petitioner may reduce the proposed PHI for fr uiting vegetables from 7 day s to 1 day , based on field trial data. The submitted fruiting vegetable data do support the 1 - day PHIproposed for okra. Furthermore, the submitted field trial data reflect a pplications made without the us e of a spray adjuvant . A revised Section B should be submitted incorporating an adjuvant - use re striction. An adequate confined rotational crop study was previously

submitted, reflecting the maximum proposed use pattern for rotated crops (fruiting vegetables and edible - podd ed beans).Acequinocyl Human - Health Risk Assessment D P# 368425

Page 17 of 35 These data support a 30 - day plant - back interval ( PBI ) for all non - labeled crop s. A revised Section B should be submitted incorporating the rotational crop restriction. 4.2 Dietary Exposure/Risk Pathway 4.2.1 Residue Profile Nature of the Residue-

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

Livestock: There are no livestock feedstuffs associated with the proposed crop uses addressed herei n. Therefore, no livestock metabolism data, enforcement methods, storage stability

data, or feeding studies are required to support this petition. Magnitude of the Residue- Plants : The submitted magnitude of the residue data for tomatoes, peppers, edible - podded beans, and hops are adequate. The field trials reflect the proposed use patterns and an adequate number of field trials were conducted in major crop growing regions. The submitted field trial data reflect a pplications made without the us e of a sp ray adjuvant . A revised Section B should be submitted incorporating an adjuvant - use re striction. The Agency ’s tolerance spreadsheet as specified by the Guidance for Setting Tolerances Based on Field Trial Data SOP (August 2009 version) was used to determ ine the appropriate tolerance levels. The field trial data will support tolerances of: 0.70 ppm for fruiting vegetables; 0.70 ppm for okra; 0.25 ppm for edible - podded beans; and 4.0 ppm for dried hop cones . Itis noted that the proposed PHI for fruiting vegetables is 7 day s whereas the field trials reflect a 1 - day PHI . Residue decline trials for tomato and pepper demonstrate that residues generally decline with later sampling intervals; therefore, the proposed/recommended tolerance will likely overestim ate anticipated residues of acequinocyl and acequinocyl - OH in/on fruiting vegetables. The available data support the proposed tolerances for fruiting vegetables, okra, and edible podded beans; however, the proposed tolerance for hop dried cones is too low . Magnitude of the Residue in Processed Food and Feed: An adequate tomato processing study is available and supports the proposed use on fruiting vegetables . The tomato processing study is adequate. The results indicate that residues of acequinocy l and acequinocyl - OH did not concentrate in paste and puree processed from tomato fruits bearing quantifiable residues of acequinocyl. No tolerances are required for tomato processed matrices. Residue Analytical Method for Crops: There are adequate residue analy tical methods for enforcing tolerances for acequinocyl residues of concern in/on the proposed/registered plant commodities. These methods include two high - performance liquid chromatography methods with tandem mass - spectroscopy detection ( HP LC /MS/MS) for determining residues in/on fruit and nut commodities (Morse Methods Meth - 133 , Revision #4 and Meth - 135 , Revision #3 )Acequinocyl Human - Health Risk Assessment D P# 368425

Page 18 of 35 (Memo, S. L evy , 8/25/10; DP#: 380302) . For each of these methods, residues are extracted with hexane or acetoni trile (ACN)/water and cleaned up by solvent partitioning, gel - permeation chromatography (GPC) and/or silica - gel solid - phase extraction (SPE ). Residue data from the current field trial and processing studies were obtained using the approved enforcement m ethods, Meth - 135 (tomato, pepper and hops) and Meth - 133 (snap beans) with minor modifications. The methods are adequate for data collection based on acceptable method validation and concurrent method recovery data for tomato and its processed matrices, pe pper, and snap beans. However, the data - collection method yielded consistently low recoveries (~53%) for acequinocyl - OH in dried hop cones; therefore, residues of the metabolite from the hop field trials were corrected for low recoveries. The validated l imit of quantitation (L OQ) was 0.010 ppm for acequinocyl and 0.025 ppm for acequinocyl - OH in/on tomato and pepper; 0.020 ppm each for acequinocyl and acequinocyl - OH in/on edible - podded beans; and 0.10 ppm for acequinocyl in/on hop dried cones. The avail able analy

tical standards for acequinocyl and acequinocyl - OH at the EPA National Pesticide Standards Repository ( personal communication with Dallas Wright, ACB, 4/ 30 / 10) expired on 4/ 19 / 10 and 4/ 20 / 10, respectively . This is a deficiency. T he petitioner s hould either recertify the lot in the repository

and send in an updated certificate of analy sis (COA), or submit new standards (different lot #) if the previous lots w ill not be recertified. The data requirements for multiresidue (MRM) methods are fulfill ed. 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. L evy , 2/ 18 / 04; DP#: 298917). Storage Stability in Plants: The submitte d concurrent storage stability data for tomato, snap bean , and hops is adequate to support the storage intervals and conditions incurred by the field trial studies. In addition, the concurrent storage stability data for the parent acequinocyl is adequate to support the sample storage intervals and conditions for the pepper field trials and tomato processing studies. It is noted that zero - day data were not provided. IR - 4 is reminded that storage stability

studies should alway s include a zero - day sampling interval to establish the residue levels present at the time samples are placed into storage [see OPPTS 860.1380(d)(6)(i)]. The concurrent storage stability data indicate problems with the stability of acequinocyl - OH in peppers and processed tomato paste and puree. Because zero - day samples were not analy

zed, determination of residue levels present at the time samples were placed in frozen storage could not be made. In addition, an insufficient number of time points were analy zed in order to establish ho w much of the residue (acequinocyl - OH) was lost at various time points. However, because residues of acequinocyl - OH in the pepper field trial were <10% of the parent value or were <LOQ, correction for 51% decline would not affect the results. Furthermo re, in the tomato processing study , b ecause there were quantifiable residues of the parent in the RAC and residues of acequinocyl - OH in the RAC were nonquantifiable, HED believes that any concentration of acequinocyl - OH residues would not significantly inc rease the total residue level. Therefore, HED is not requesting additional storage stability data at this time. Confined Accumulation in Rotational Crops: An adequate confined rotational crop study was previously

submitted. These data reflect the maxi mum proposed use pattern for rotated cropsAcequinocyl Human - Health Risk Assessment D P# 368425

Page 19 of 35 (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 PBIfor all non - labeled crops. Proposed and Recomm ended Tolerances: The proposed and recommended tolerances for the combined residues of acequinocyl are listed below in Table 4.2 .1.1 ( a revised Section F should be submitted ). There are no established or proposed Codex, Canadian, or maximum residue limit s (MRL s) for acequinocyl. T he field trial data for tomato and pepper are considered adequate to support a crop group tolerance. The tomato, bell pepper and non - bell pepper datasets were separately entered into the tolerance spreadsheet (rev. 8/ 09) in the Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data ; see Appendix I . The proposed tolerance (0.70 ppm) for the fruiting vegetable group 8 is appropriate. No tolerances are required for tomato paste or puree. Okra has been recommended to be added as a member of the fruiting vegetable group 8; however, until okra has been officially added to the crop group, a separate tolerance is required. The tomato and pepper field trial data will support the proposed tolerance (0.70 ppm) for okra. The snap bean and hop dried cone data are adequate, and were entered into the tolerance spreadsheet to determine the appropriate tolerances; see Appendix I . The proposed tolerance (0.25 ppm) for edible - podded beans is appropriate; however, the tol erance proposed for hop dried cones is too low and should be increased to 0.40 ppm. The proposed and HED - recommended tolerances are listed in Table 4.2.1.1 . Table 4.2.1.1 . Tolerance Sum ma ry for Acequinocyl . Commodity Proposed Tolerance (ppm) HED - Recomm ended

Tolerance (ppm) Comments;

Correct Commodity Definition Vegetable, fruiting, group 8 0.70 0.70 Okra 0.70 0.70 Bean, edible podded 0.25 0.25 Hop, dried cones 3.5 4.0 4.3 Water Exposure/Risk Pathway Environmental Fate Assessment: Acequinoc yl appears to undergo fairly rapid transformation in most aquatic and terrestrial environments. It undergoes hydroly sis with a half - life of a few hours to less than 2 day s under neutral and alkaline pH conditions. However, it is stable at acidic pH condit ions. 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 day s 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. Ace quinocyl 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 hydroly ze to formAcequinocyl Human - Health Risk Assessment D P# 368425

Page 20 of 35 hydroxy - acequinocyl (also known as OH - AKD 023, 2 - hydroxy - 3 - dodecyl - 1,4 - napthelenedione (HDNQ), and R - 1). Surface and Ground Water Estimated Drinking Water Concentrations ( EDWC s ) : There are no drinking water monito ring data available for acequinocyl or its metabolite acequinocyl - OH (R1), the residues of concern . Groundwater and surface water estimated drinking water concentrations (EDWCs) were generated for acequinocyl using the Screening Concentration in Ground Water (SCI - GROW) and Pesticide Root Zone Model/Exposure Analy sis Modeling Sy stem (PRZM/EXAMS) models, respectively . T wo approaches were used in performing the drinking water assessment for the proposed acequinocyl uses. In Approach #1, acequinocyl was cons ervatively

assumed to be stable to all routes of degradation to account for the uncertainties associated with the environmental fate data. In Approach #2, total (acequinocyl + acequinocyl OH) residues were modeled with the assumption that the metabolite a cequinocyl - OH (referred to as the R1 degradate in this assessment) is of toxicological concern. The highest PRZM - EXAMS surface water modeling estimates were obtained for the Pennsy lvania tomato scenario for the chronic values. The modeled EDWCs for groun d and surface water are summarized in Table 4.3.1 . Table 4.3.1 . Ground and Surface Water EDWCs for Acequinocyl. Approach #1 and #2 Groundw ater EDWC for Acequinocyl + R1 (ppb) Surface Water Approach #1 Acequinocyl Approach #2 Acequinocyl + R1 1 - in - 10 - Year Chronic Mean Concentration (ppb) 1 - in - 10 - Year Chronic Mean Concentration (ppb) 0.0036 2.45 0.29 Since the surface water EDWCs are higher than the groundwater EDWC, HED selected the surface water value for use in the chronic dietary assessment. The EDWC derived via Approach #1 represents the upper - bound value (2.45 ppb) while that derived via Approach #2 represents the lower - bound value (0.29) . The 2. 45 ppb value was used in the dietary modeling as this value assures a conservative assessment . 4.4 Dietary Exposure Analyses An acute dietary

assessment was not conducted for acequinocyl because an endpoint of concern attributable to a single dose was not identified; therefore, an aRfD was not established and an acute dietary

assessment is not nec essary . 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 - FCI DTM, Version 2.03 , which incorporates c onsumption data from USDA’s CSFI I, 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 day s. Foods “as consumed” ( i.e. , apple pie) are linked to EPA defined food c ommodities ( 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 analy sis of the 1994 - 96, 98 CSFI I 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:Acequinocyl Human - Health Risk Assessment D P# 368425

Page 21 of 35 the general U.S. population, all infants (<1 year old), children 1 - 2, children 3 - 5, children 6 - 12, yo uth 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 r esidue 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 - FCI D TM analy sis estimates the dietary exposure of the U.S. population and various population subgroups. The chronic dietary exposure assessment (using tolerance level residues and 100% CT information for all registered and proposed uses) was conducted for the general U.S. population and various population subgroups. Drinking water was incorporated directly into the dietary assessment using the chronic concentration for surface water generated by the PRZM/EXAMS model. The highest chronic surface water value ( i.e. , most conservative) of 2.45 ppb was used for this assessment. This assessment concludes that the chronic dietary exposure estimates are not of concern to HED for the general U.S. population (9.8% cPAD) and all population subgroups. The most highly exposed population subgroup is children 1 - 2 years old at 45% of the cPAD. The use of anticipated residues ( ARs ) , emp irical 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 . Sum ma ry of Dietary (Food and Drinking Water) Exposure and Risk for Acequinocyl. Population S ubgroup Chronic Dietary 1 Dietary Exposure (m g/kg/day) % cPAD U.S. Population (total) 0.002657 9.8 All Infants (< 1 year old) 0.005584 21 Children 1 - 2 years old 0.012193 45 Children 3 - 5 years old 0.008046 30 Children 6 - 12 years old 0.003657 14 Youth 13 - 19 years old 0.001855 6.9 Adults 20 - 49 years old 0.001758 6.5 Adults 50+ years old 0.001811 6.7 Females 13 - 49 years old 0.001808 6.7 1 Chronic dietary endpoint of 0.027 mg/kg/day applies to the general U.S. population and all population subgroups. The values for the highest exposed population for each type of risk assessment should be bolded. 4. 5 Residential/Non - Occupational Exposure Pathway Acequinocyl is currently

registered for use on landscape ornamentals in and around residences, businesse s, public property , schools, interiorscapes, and other non - production areas by commercial applicators and homeowners. The last residential exposure assessment was conducted in September of 2007 (Memo, K. L owe, 9 / 6 /0 7, D332006, 337473) and showed noAcequinocyl Human - Health Risk Assessment D P# 368425

Page 22 of 35 risks of concern to HED (i.e., MOEs >100). The assessment provided in this document reflects changes to the short - and intermediate - term dermal and inhalation endpoints. 4.5.1 Residential Handler Exposure/Risk There is potential for residential handler expos ure from the registered uses on landscape ornamentals in and around residences, businesses, public property , schools, interiorscapes, and other non - production areas by commercial applicators and homeowners. Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including mixing and loading (if needed), and application. Based upon the proposed use pattern, the following residential handler scenarios have been assessed: (1) Mixing/loading.applying liquids with low - p ressure handwand (ORETF - fruit trees and ornamentals); and (2) Mixing/loading/applying liquids with hose - end sprayer (ORETF - fruit trees and ornamentals). No chemical - specific data were available with which to assess potential exposure to pesticide handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data available from the ORETF. Homeowner handler assessments are based on the assumption that individuals are wearing shorts, short - sleeved shirts, socks, and shoes. Resident ial handler exposure scenarios are considered to be short - term only , due to infrequent use patterns associated with homeowner products. Daily dermal or inhalation handler exposures are estimated for each applicable handler task with the application rate, the area treated in a day , and the applicable dermal or inhalation unit exposure using the following formula: Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x Application Rate (lbs ai/gallon) x Amount Handled (gal/day) Where: Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount inhaled that is available for inhalation absorption; Unit Exposure = Unit exposure value (mg ai/lb ai) derived from August 1998 PHED data or from ORETF data; Application Rate = Normalized application rate (lb ai/gal); and Daily Area Treated = Normalized amount handled (gal/day). The daily dermal or inhalation dose is calculated by normalizing the daily

exposure by

body weight and adj usting, if necessary , with an appropriate dermal or inhalation absorption factor using the following formula: Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x (Absorption Factor (%/100) / Body Weight (kg) Where: Average Daily Dose = Abs orbed dose received from exposure to a pesticide in a given scenario (mg ai/kg bw/day);Acequinocyl Human - Health Risk Assessment D P# 368425

Page 23 of 35 Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount inhaled that is available for inhalation absorption; Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such as the skin or lungs (% of the total available absorbed); and Body Weight = Body w eight determined to represent the population of interest in a risk assessment (kg). Non - cancer dermal and inhalation risks for each applicable handler scenario are calculated using a MOE , which is a ratio of the NOAEL to the daily dose. All MOE values were calculated using the formula below:

MOE = NOAEL or LOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day) Table 4.5.1.1 presents the exposure/risks for residential handler short - term dermal and i nhalation exposures at baseline. Based on HED’s residential handler assessment, there are no risks of concern for resid ential handlers (i.e., MOEs >100). Table 4.5. 1 .1. Residential Handler Derm al and Inhalation Exposures and Risks. Derm al and Inhalation Unit Exposures (m g/lb ai) Application Rate

(lb ai/gallon) 1 Am ount H andled D aily (gallons) 2 Doses

(m g/kg/day) 3 MOEs 4 Mixer/Loader/Applicator

– Liquid with Low -Pressure Handwand (ORETF -- fruit trees and ornamentals) Dermal Baseline 5 : 56 0.00125 5 Dermal Baseline: 0.00 5 Dermal

Baseline: 40,000 Inhalation Baseline 6 : 0.0026 Inhalation Baseline: 2.3E - 07 Inhalation Ba seline: 2.6E8 Mixer/Loader/Applicator

– Liquid with Hose - End Sprayer (ORETF -- fruit trees and ornamentals) Dermal Baseline: 39 0.00125 100 Dermal Baseline: 0.07 Dermal

Baseline: 2,900 Inhalation Baseline: 0.0016 Inhalation Baseline: 2.9E - 06 Inhalation

Baseline : 2.1E7 1 Application rates are the maximum application rates determined from proposed labels for acequinocyl. 2 Amount handled per day values are HED estimates of acres treated per day based on Exp o SAC SOP #9 “Standard Values for Daily

Acr es Treated in Agriculture,” industry sources, a nd HED estimates. 3 Dose (mg/kg/day) = Unit exposure (mg/lb ai ) x A pp R ate (lb ai/gal) x Amount Handled (gal/day) x %Absorption (100% dermal and 1 00% i nhalation) / Body weight (70 kg) . 4 MOE = NOAEL /Dose ; wh ere the short - term dermal NOAEL = 200 mg/kg/day and short - term inhalation NOAEL = 60 mg/kg/day . 5 Baseline Dermal: short - sleeve shirt, short pants, and no gloves. 6 Baseline Inhalation: no respirator. 4.5. 2 Residential Post - application Exposure/Risk D ermal : With respect to the registered residential uses on landscape ornamentals, current HED policy (see ExpoSAC minutes from 8/19/99 and 10/11/01) spe cifies that no significant dermal post - application exposure is anticipated from landscape ornamentals, e ither by residents or professional applicators; therefore, no residential dermal post - application assessment was conducted.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 24 of 35 Inhalation : Based on the Agency's current practices, a quantitative residential post - application inhalation exposure assessment (i ncluding by stander exposure) was not performed for acequinocyl at this time . However, volatilization of pesticides may be a potential source of post application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the p rocess 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. I f new policies or pr ocedures are put into place, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for acequinocyl . 4.5 .3 Spray Drift Spray drift is alway s 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 L ead 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 T ask Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriately

apply the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERI ZATION Inaccordance 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 c oncern was not identified to quantify acute - dietary

risk to the general population or to any population subgroup. Since an acute dietary endpoint was not identified, an acute hazard does not exist and an acute aggregate assessment was not performed.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 25 of 35 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 u p of average dietary

exposures from food and drinking water sources, and dermal and inhalation residential exposures. T he adult 50+ years old population is the highest exposed adult population and can be considered protective of the other adult population s groups ; therefore, this sub - population is shown below in Table 5.2.1, as well as the general U.S. population . Dietary (food and drinking water) exposure is based on a Tier 1 (unrefined) chronic dietary exposure assessment (see Table 4. 4 .1.1 ). Residenti al 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 s hort - term aggregate risk calculations for both the general U.S. pop ulation and the adults 50+ years old sub - population are shown below in Table 5.2.1 and are not of concern to HED . Table 5. 2.1. Short - Term Aggregate Risk Calculations . Population Dietary MOE 1 Residential Dermal MOE 2 Residential Inhalation MOE 2 Aggregat e

MOE 3 U.S. Population 23,000 2,900 21,000,000 2,600 Adults 50+ years old 33,000 2,900 21,000,000 2,700 1 Dietary MOE = short - term oral NOAEL ( 60 mg/kg/day)  chronic dietary exposure . 2 Residential MOEs are from Table 4.5. 1 .1. The “l iquid with h ose - e nd s prayer handler” scenario w as used as the MOEs for this scenario are low er (i.e., more conservative) than the “l iquid with l ow - p ressure h andwand handler” scenario. 3 Aggregate MOE (dietary and residential) = 1  ((1  MOE dietary )+(1  MOE dermal)+(1  MOE inhal ati on); 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 appli cation exposure of more than 30 - day duration. 5 .4 Long - Ter m Aggregate Risk C hronic (long - term) aggregate risk is made up only of dietary

sources; therefore, the chronic exposure estimates provided in the chronic dietary exposure analy sis represent s chronic aggregate exposure. 5 .5 Cancer Risk Aggregate canc er 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 mec hanism of toxicity finding asAcequinocyl Human - Health Risk Assessment D P# 368425

Page 26 of 35 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 Fruiting Vegetables Crop Group 8 (Tomatoes & Peppers), Edible Podded Beans, Hops, and Okra. D P Barcode: 369099. A. Now otarski. 6/ 9 / 10 . 7.1 Occupational Handle r Exposure/Risk Potential occupational exposure scenarios include: 1) mixing/loading liquids in support of groundboom operations, and 2) ap plicators using open - cab ground boom equipment. Application through irrigation or aerial sy stems is prohibited. No chemical - specific data are available with which to assess potential exposure to pesticide handlers. The estimates of exposure to pesticide handlers are based upon surrogate study data available in PHED (8/ 1998). For pesticide handler s, it is HED standard practice to present estimates of dermal exposure for “baseline” ; that is, for workers wearing a single layer of work clothing consisting of a long - sleeved shirt, long pants, shoes plus socks , and no protective gloves , as well as for “baseline” and the use of protective gloves or other personal - protective equipment (PPE) as might be necessary . The proposed product label involved in this assessment directs applicators and other handlers to wear long - sleeved shirt and long pants, socks, shoes, and chemical - resistant gloves made of waterproof material . Daily handler exposures are estimated for each applicable handler task with the application rate, the area treated in a day , and the appli cable unit exposure using the following formula: Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x Application Rate (lbs ai/area) x Daily Area Treated (area/day) Where: Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation absorption; Unit Exposure = Unit exposure value (mg ai/lb ai) derived from August 1998 PHED data; Application Rate = Normalized application rate based on a logical unit treatment, such as acres; and Daily Area Treated = Normalized applicatio n area based on a logical unit treatment such as acres (A/day). The daily dermal or inhalation dose is calculated by normalizing the daily

exposure by

body weight and adjusting, if necessary , with an appropriate inhalation absorption factor using theAcequinocyl Human - Health Risk Assessment D P# 368425

Page 27 of 35 foll owing formula: Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x (Absorption Factor (%/100)) / Body Weight (kg) Where: Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg ai/kg body weight/day) ; Daily Exposure = Amount (mg ai/day) deposited on surface of skin that is available for dermal absorption, or the amount inhaled that is available for inhalation absorption; Absorption Factor = A measure of the amount of chemical that crosses a biolo gical boundary such as the skin or lungs (% of the total available absorbed); and Body Weight = Body w eight determined to represent the population of interest in a risk assessment (kg). Based on the use pattern and information provided on the labels, ( i. e., 2 applications per season and 21 - day

RTI ), short - and intermediate - term exposures are expected and were assessed . Lo ng term exposures are not expected ; therefore, a long - term assessment was not conducted. Non - cancer dermal and inhalation risks fo r each applicable handler scenario are calculated using an MOE , which is a ratio of the NOAEL to the daily dose. All MOE values were calculated using the formula below: MOE= NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day) Table 7.1.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers. An MOE ≥100 is adequate to protect occupational pesticide handlers. Since all the estimated MOE s are > 100 with baseline protection, the proposed uses are not of concern for HED.Acequinocyl Human - Health Risk Assessment D P# 368425

Page 28 of 35 1 Application rates are the maximum application rates determined from proposed labels for acequinocyl . 2 Amount handled per day values are HED estimates of acres treated per day based on ExpoSAC SOP #9 “S tandard Values for Daily

Acres Treated in Agriculture,” indus try sources, and HED estimates. 3 Baseline Dermal: L ong - sleeve shirt, long pants, and no gloves. 4 Bas eline Inhalation: no respirator. 5 Dose (mg/kg/day) = Unit exposure (mg/lb ai) x A pp R ate (l b ai/acre or lb ai/gallon) x Area Treated (acres/day) or Amount Handled (gallons) / Body weight (kg) . 6 MOE = NOAEL / d ose ; where the short - and intermediate - term dermal NOAEL = 200 mg/kg/day ; short - term inhalation NOAEL = 60 mg/kg/day; intermediate - term i nhalation NOAEL = 16 mg/kg/day . 7 Combined MOE = NOAEL (xx mg/kg/day) / Combined dermal + inhalation dose (mg/kg/day) . 7.2 Post - application Exposure/Risk Dermal : HED expects that post - application dermal exposure will occur since acequinocyl is applied as a foliar spray . Post - application exposure is expected to be short - term based on information provided on the proposed label. Inaddition, since the short and intermediate - term points of departure are the same, short - term risk estimates are protective o f intermediate term exposures. Post - application exposures have been assessed using dermal transfer coefficients (TCs) from HED’s ExpoSAC Policy Number 3.1 “Agricultural Transfer Coefficients” (August, 2000). Table 7.2.1 summarizes the scenarios assessed. Inaddition, the following assumptions were used in the calculations:

• Exposure Duration = 8 hours per day • Body

Weight = 7 0 kg • Dislodgeable Foliar Residue (DFR) = No DFR data are available for acequinocyl for the proposed uses. Therefore, this asse ssment uses HED’s default assumption that Table 7.1.1. Occupational Derm al and Inhalation Exposures and Risks. Crop or Target App.

Rate (lb ai/A) 1 Area

Treated Daily or Am ount Handled (A/ day) 2 Derm al and

Inhalation Unit Exposures (m g/lb ai) Short - and Interm ediate - term Doses (m g/kg/day) 5 MOEs 6 Com bined MOEs 7 Short term Int. -

term Short term Int. -

term Mixing/Loading Liquid Concentrates for Groundboom Applications (PHED) Fruiting vegetable crop group 8 (tomato and pepper) 0.3 80 Dermal Baseline 3 : 2.9 Dermal

Baseline: 0.15 Dermal Base line: 1300 1,300 1 , 300 Edible podded bean Inhalation Baseline 4 : 0.0012 Inhalation

Baseline: 0.00041 Inhal .

Baseline: 150 , 000 Inhal .

Baseline: 39 , 000 Hop Okra Applying Sprays via Groundboom Equipment Fruiting veg etable crop group 8 (tomato and pepper) 0.3 80 Dermal Baseline: 0.014 Dermal

Baseline: 0. 00 072 Dermal Baseline: 280,000 130,000 51,000 Edible podded bean Inhalation Baseline: 0.00074 Inhalation Baseline: 0.000 25 Inhal.

Baseline: 240 , 000 Inhal .

Baselin e: 63,000 Hop OkraAcequinocyl Human - Health Risk Assessment D P# 368425

Page 29 of 35 20 % of the application rate is available on Day 0 (i.e., 12 hours after application) and the residue dissipates at a rate of 10 % per day . Table 7.2.1. Anticipated Post - application Activities and Derm al TCs. Prop osed Crops Policy Crop Group Category Application

Rate (lb ai/A ) TCs (cm 2 /hr) Activities

Tom ato

Fruiting vegetable group 8 0.3 1000 Pruning (hand), staking, thinning, training, tying 700 Irrigation, scouting 500 Weeding (hand) Bell Pepper 0.3 10 00 Harvest (hand), staking, tying 700 Irrigation, scouting 500 Weeding (hand), thinning Chili Pepper 0.3 1000 Harvest (hand), pruning (hand), thinning 700 Irrigation, scouting 500 Weeding (hand)

Okra 0.3 1000 Harvest (hand), staking, tying 700 Irrigation, scouting, pruning

(hand) 500 Weeding (hand), thinning Hops Bunch/bundle 0.3 2000 Harvest (hand and mech), stripping, training 1300 Scouting 100 Irrigation, w eeding (hand) Edible - Podded Bean Field/ row crop, low

/ medium 0.3 2500 Harvest (hand) 1500 Irrigation, scouting 100 Weeding (hand), thinning Equations/Calculations: Daily dermal exposures were calculated on each post - application day after application using the following equation: Daily Dermal Dose t = [DFR t (μg/cm

2 ) x 0.001 mg/μg x TC (cm 2 /hr) x DA x ET (hrs)] / BW (kg) Where, DFR t = dislodgeable foliage residue on day "t" (ug/cm2 );Acequinocyl Human - Health Risk Assessment D P# 368425

Page 30 of 35 TC = transfer coefficient (cm 2 /hr); DA = dermal absorption factor (100%); ET = exposure time (8 hr/day); and BW = body weight (70 kg). Once daily

exposures are calculated, the calculation of daily absorbed dose and the resulting MOEs use the same algorithms that are described above for the handler exposures. These calculations are completed for each day o r appropriate block of time after application. HED has determined that short - term dermal risk estimates are not of concern (i.e., MOEs > 1 00) on the day

of treatment (i.e., Day

0) for all post - application exposure activities. Table 7.2.2 presents a summar

y of occupational dermal post - application risks associated with use of acequinocyl.

The information in the table is based on proprietary and non - proprietary data. 1 N OAEL/Daily Dose (Short - term N OAEL = 200 mg/kg/day) . Inhalation : Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment wa s not performed for acequinocyl at this time. However, there are multiple potential sources of postapplication inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatili zation 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 FI FRA SAP in December 2009. The Agency received the SAP’s fin al report on 3/2/10 ( http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available postapplication inhalation exposure data generated by

the Agricultural Reentry

Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational postapplication inhalation exposure into the Agency's risk assessments. I f new policies or procedures are put into p lace, the Agency may revisit the need for a quantitative occupational postapplication inhalation exposure assessment for acequinocyl . Table 7.2.2. Post - application Risk Estim ates for Acequinocyl. Crop Grouping Application

Rate (lb ai/A) TC

(cm 2 /hr) DFR

(ug/cm 2 ) Days After

Treatm ent MOE 1 Fruiting veg etable group 8 0.3 1000 0.67 0 (12 hours) 2600 700 3700 500 5200 Bunch/ bundle 0.3 2000 0.67 0 (12 hours) 1300 1300 2000 100 26000 Field/row crop, Low/ medium 0.3 2500 0.67 0 (12 hours) 1000 1500 1700 100 26000Acequinocyl Human - Health Risk Assessment D P# 368425

Page 31 of 35 7. 3 REI Acequinocyl is classified in Toxicity Category I II for acute dermal and acute inhalation. It is classified in Toxicity

Category IV for primary

eye irritation and primary skin irritation and it is not a dermal sensitizer. Therefore , the WPS interim REI is adequate to protect agricultural workers from post - application exposures to acequinocyl. 8.0 RESIDUE CHEM ISTRY AND TOXICOLOGY DEFICIENCIES 8.1 Residue Chemistry

 Revised Section F.  Revised Section B.  Analy tical reference standard s for the acequinocyl and acequinocyl - OH must be submitted to the EPA National Pesticide Standards Repository . 8.2 Toxicology

 An Immunotoxicity

Study .  Acute and Subchronic Neurotoxicity Stud ies .  A 28 - Day

Inhalation Study . 8.3 Occupational and Residential Exposure

 None.

c c: S. L evy (RAB1) ; A. Dunbar; A. Now o tarski RDI : RAB1 Branch ( 09 - JUN - 2010 ); RAB1 Chemist s ( 0 9 - JUN - 2010 ) S. L evy: S10953 : PY1:703 - 3 05 - 0783 ; 7509P:RAB1Acequinocyl Human - Health Risk Assessment D P# 368425

Page 32 of 35 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) 4 5435011 LD 50 > 5000 mg/kg IV 870.1200 (81 - 2) Acute Dermal 45435012 LD 50 > 2000 mg/kg III 870.1300 (81 - 3) Acute Inhalation 45435013 LC 50 > 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 vacuol iz ation .

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, 2 00, 1000 mg/kg/day Acceptable/Guideline Systemic NOAEL = 200 mg/kg/day; LOAEL = 1000 mg/kg/day based on increased clotting factor times (increased prothrombin time, increased activated partial prothromboplastin time, increased fibrinogen levels). Dermal NOAEL = 1000 mg/kg/day; LOAEL = not established . 870.3700a Prenatal Developmental in Rodents - RAT 45531908, 45651706 (1995); 0, 50, 150, 500, 750 mg/kg/day Acceptable/Guideline Maternal NOAEL = 150 mg/kg/day; LOAEL = 500 mg/kg/day based on signs of internal hemorrhage and increased incidence of clinical signs (pale eyes, piloerection, red vaginal discharge) . Developmental NOAEL = 500 mg/kg/day mg/kg/day; LOAEL = 750 mg/kg/day based on increased resorptions .Acequinocyl Human - Health Risk Assessment D P# 368425

Page 33 of 35 Table A - 2. Toxicity Profile for Acequinocyl . Guideline No.; Study Type MRID (year); Doses; Classification Results 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 outp ut, 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 / 13 3.5 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, protr

uding 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 inflamm atory 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 LO AEL (M/F) = 9.02/93.56 mg/kg/day based on enlarged eyeballs in male an d 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 ov er 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 .Acequinocyl Human - Health Risk Assessment D P# 368425

Page 34 of 35 Table A - 2. Toxicity Profile for Acequinocyl . Guideline No.; Study Type MRID (year); Doses; Classification Results 870.5375 Chromosome Aberration 4543 5103 (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 Th ere was no evidence of chromosome aberrations induced over background .

870.5395 Mammalian Erythrocyte Micronucleus Test in MICE 45435104 (1993); 0, 1250, 2500 or 5000 mg/kg body weight Acceptable/Guideline There was no statistically - significant increas e 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 gluc uronide conjugate. There was no evidence for selective tissue accumulation or sequestration of 2023 (acequinocyl) or its metabolites in rats . 870.7600 Dermal Penetration - RAT 45435106(2000); 0, 0.001, 0.01, 0.1, 1.0 mg/cm2 Acceptable/Guideline Percen t of dose absorbed decreased with exposure concentration indicating that saturation of absorption at/or about the high dose. Absorption at 168 hours was 12.23%, 19.75%, and 14.77% for the 0.1, 0.01 , and 0.001 mg/cm2 dose groups, respectively . Table A - 3. Structures of Acequinocyl and Its Metabolites . Com mo n Nam e/Code Chem ical Nam e Chem ical Structure Acequinocyl 2 - (acetyloxy) - 3 - dodecyl - 1,4 - naphthalenedione O

O C H 2 ( C H 2 ) 1 0 C H 3 O C O C H 3 Acequinocyl - OH (Metabolite R1) 2 - dodecyl - 3 - hydroxy - 1,4 - naphthalenedione O

O C H 2 ( C H 2 ) 1 0 C H 3 O H

AKM - 18 2 - (1,2 - diox otetradecyl) - benzoic acid O

O O O H ( C H 2 ) 1 1 C H 3Acequinocyl Human - Health Risk Assessment D P# 368425

Page 35 of 35 AKM - 15 2 - hydroxy - 3 - hexanoic acid - 1, 4 naphthalenedione O

O O H C O O H

AKM - 14 2 - hydroxy - 3 - butanoic

acid - 1,4 - naphthalenedions O O C H 2 O H ( C H 2 ) 9 C H 3 C H O H