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

COMPANY NOTICE OF FILING EPA Registration Division contact: Sidney Jackson , 703 - 305 - 7 610 Interregional Research Project Number 4 (IR - 4) and Arysta LifeScience North America LLC PP# 9E7598 EPA has received a pesticide petition ( 9E7598 ) from Interregional Research Project Number 4 (IR - 4) , 500 College Road East, Suite 201 W, Princeton, NJ 08540 , in cooperation with Arysta LifeScience North America LLC, 15401 Weston Parkway, Suite l50, Cary, N.C., 27513 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR p art 180 .599 by revising the tolerance expression to read tolerances are established for the residues of the insecticide acequinocyl, including its metabolites and degradates. Compliance with the tolerance levels specified is to be determined by

m easuring only

the sum of acequinocyl 2 - (acetyloxy) - 3 - dodecyl - 1,4 - naphthalenedione , and its metabolite 2 - dodecyl - 3 - hydroxy- 1,4 - naphthoquinone, calculated as the stoichiometric equivalent of acequinocyl and by establishing a tolerance for the residues of acequinocyl, including its metabolites and degradates in or on fruiting , vegetables , group 8 at 0.7 parts per million (ppm), okra at 0.7 ppm, bean, edible podde d at 0.25 ppm and hop , dried cone at 3.5 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the sufficiency

of the submitted data at this time or whether the data support granting of the petition. Additional data may

be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The nature of the residues of acequinocyl in plants is adequatel y understood based on three crops; apples, oranges and eggplant. The major residue in all plant metabolism studies is acequinocyl. A minor but significant metabolite is acequinocyl - OH (2 - dodecyl - 3 - hydroxy- l,4 - naphthoquinone). The proposed tolerance expression is the parent, acequinocyl and its hydroxy metabolite, acequinocyl - OH. 2. Analytical method. The anal ytical method to quantitate residues of acequinocyl and acequinocyl - OH in/on fruit crops utilizes high pressure liquid chromatography- mass spectrometry/mass spectrometry ( HPLC - M S/MS) detection for fruiting vegetables crop group 8 (tomatoes and peppers ) and LC/MS/MS for snap - bean, edible podded and hop, dried cones . The lowest level for method validation (LLMV) was 0.01 ppm for acequinocyl and 0.025 ppm for acequinocyl - OH. 3. Magnitu de of residues. The proposed use of acequinocyl calls for a maximum of 2 applications per season at 0.3 lb a.i. per acre per application (maximum 0.6 lb a.i. per acre per season), with a 21 - day

i nterval between applications. The pre - harvest interval is 7 days. The maximum residue for each commodity is shown in the following table.1

Sam ple Type Acequinocyl

Maximum Residue (ppm) Acequinocyl - OH Maximum Residue (ppm) Tomato Fruit 0.20 < 0.025 Tomato Paste 0.05 < 0.025 Tomato Puree 0.04 < 0.025 Non- Be ll Peppers 0.2950 0.0429 Bell Peppers 0.564 0.0430 Snap Beans 0.19 0.03 Hops 2.53 0.735 The crop field trial data are adequate to support the proposed tolerance s requested in Section F of the petition . B. Toxicological Profile 1. Acute toxicity. Acequi nocyl technical has low acute, dermal and inhalation toxicity in laboratory

animals. The oral lethal dose ( LD ) 50 male/female (M/F) in the rat and mouse was > 5000 milligram per kilogram (mg/kg) . The dermal LD50 (M/F) was > 2000 mg/kg. The inhalation lethal concentration ( LC ) 50 was reported as > 0.84 mg/1. Inthe eye and dermal irritation studies, acequinocyl technical was not an eye or skin irritant to rabbits and was not a skin sensitizer in guinea pigs. 2. Genotoxicty. Acequinocyl was found to be negative in the Ames reverse mutation, mouse ly

mphoma, Chinese hamster lung (CHL) chromosome aberration and mouse micronucleus assays. 3. Reproductive and developmental toxicity. i. Rat teratology . Acequinocyl technical was administered by

oral gavage to pregnant Spragu e Dawley rats at dose levels of 0, 50,150, 500 or 750 mg/kg/day on gestation days 7 - 17 . Common signs in the descendants included vaginal discharge, pallor, pale eyes, hy poactivity, piloerection, slow or irregular breathing, intra-uterine hemorrhage and blo od stained stomach and/or intestinal contents. Maternal no - observed adverseeffect level (NO AEL) =150 mg/kg/day b ased on these signs. Developmental NO AEL=500 mg/kg/day

b ased on an increase in certain skeletal variants that may b e attributed to the observed maternal toxicity .

2 ii. Rabbit teratology . Groups of New Zealand white rabbits received acequinocyl technical by gavage at doses of 0, 30, 60 or 120 mg/kg/day . Maternal NO AEL=60 mg/kg/day based on reduction in maternal body weight and 5 females were sacrificed at 120 mg/kg/day . Fetal NO AE L=60 mg/kg/day

due to skeletal variations in the thorac ic - lumbar ribs. iii. Rat reproduction study . Acequinocyl technical was fed to two generations of male and female Sprague Dawley

rats at dietary

concentrations of 0,100, 800, or 1500 ppm (0, 7.3, 59 or 111 mg/kg/day

for males and 0, 8.7, 69 or 134 mg/kg/day for females). S ys temic and pup NO AEL=100 ppm (7.3 and 8.7 mg/kg/day). S ys temic: Hemorrhage and swollen body parts were seen at 800 and 1500 ppm in Fl males. At 800 and 1500 ppm, treatment related clinical signs, hemorrhagic effects, subcutaneous bleeding on body parts and/or cranium and/or brain were seen in the Fl pups. At 800 and 1500 ppm toxicity seen in F2 pups included subcutaneous bleeding on body parts and/or cranium and/or brain at weaning. 4. Subchronic toxicity. i. Rat feeding study . Fischer rats received acequinocyl technical at dietary c oncentrations of 0, 100, 400, 1600 or 3200 ppm (0, 7.57 , 30.4, 120, 253 mg/kg/day, respectivel y for males and 0, 8.27, 32.2,129, 286 mg/kg/day, respectively f or females) for 13 consecutive weeks. Treatment related yellow brown urine in all animals of both sexes at 400 ppm suggested the presence of a metabolite of the test material. Macroscopic examination on the surviving animals revealed no treatment related abnormalities. At 3200 and 1600 ppm, macroscopic and microscopic examination of the mortalities revealed hemorrhaging of muscle and other organs. NO AEL = 400 ppm (30.4 mg/kg/day for males and 32.2 mg/kg/day for female s) . ii. Mouse feeding study . Groups of CD - I (ICR) BR mice received acequinocyl technical by

o ral route at concentrations of 0, 100, 500, 1000 or 1500 ppm (0,16,81,151, 295 mg/kg/day

respectivel y for males and 0, 21, 100, 231, 342 mg/kg/day respectively

f o r females) for 13 weeks. At 100 ppm, there were hepatic histopathological lesions and an increase in relative liver weight. A clear NO AEL for both sexes was not determined. iii. Dog feeding study . Acequinocyl technical was administered via gelatin capsul e to male and female beagle dogs at dose levels of 0, 40, 160, 640 or 1000 mg/kg/day once a day 7 days a week for 13 weeks. At 40, 160 and 640 mg/kg/day c olored feces were observed in both sexes. At 160 and 640 mg/kg/day, treatment related de crease in body weight gain in males and an increase platelet count for females was observed. Macroscopic and microscopic examinations on the surviving animals revealed no treatment related abnormalities. A clear NO AEL was not determined.iv. 28 - day dermal toxicity . Groups of Sprague Dawley rats received daily

dermal applications of acequinocyl technical at doses of 0, 40, 200 or 1000 mg/kg/day f or 6 hours/day

f or 28 days followed by

a 1 4 day treatment free period only in the high dose group. There were no macroscopic findings. Red staining occurred on the back of the animals and was only seen in the morning after dosing. There was no evidence of systemic toxicity . NO AEL=1000 mg/kg/day . 3 5. Chronic toxicity. i. Dog feeding study . Beagle dogs were dosed by c apsule at 0,5,2 0, 80 or 320 mg/kg/day

f or 1 ye ar with acequinocyl technical. Minor disturbances in platelet counts were observed in both sexes at 80 and 320 mg/kg/day . There were no treatment related macroscopic histopathological findings. Colored feces and/or abnormally stained sawdust were observed for all treatment groups. Varying degrees of discoloration of the urine was observed for animals receiving 20 mg/kg/day o r more. The discoloration was considered to be attributable to a colored metabolite of the test substanc e. NO AEL = 20 mg/kg/day . ii Rat feeding/oncogenicity s tudy . Groups of F344 rats received acequinocyl technical at dietary levels of 0, 50, 200, 800 or 1600 ppm (0, 2.25, 9.02, 36.4, 74.0 mg/kg/day for males and 0, 2.92, 11.6, 46.3, 93.6 mg/kg/day for females) for 2 ye ars. The NO AEL = 200 ppm (9.02 and 11.6 mg/kg/day

f or males and females , respectively). Corneal abnormalities and hy pertrophy of the eye were observed in 800 ppm and 1600 ppm males and 1600 ppm females. At 800 ppm and 1600 ppm, PT was observed to be longer in males and shorter in females and APTT longer in females. Reddish brown urine was observed in both males and females. There was no incidence of tumors. iii. Mouse oncogenicity study . Acequinocyl technical was administered in the diet of Crl:CD l(ICR)BR mice at 0, 20, 50, 150 or 500 ppm for 80 weeks. NO AEL=20 ppm (lowest dose tested equal to 2.7 and 3.5 mg/kg/day in males and females respectivel y), based on brown pigmented cells. At 50 and 500 ppm in both sexes, there was an increase inciden ce of fatty hepatocy tes. Other associated findings were increased liver weight, slight increase in pale livers or pale areas within livers. Glomerular amyloidosis was statistically increased in the 150 and 500 ppm males. Yellow brown urine was consistently found in both sexes at high dose. There was no increase in the incidence of tumors. 6. Animal metabolism. Sprague Dawley rats were dosed orall y with acequinocyl labeled 14C -phenylo r 14C - dodecyl. Both labels were used in the single low dose (10 mg/kg) study . The high dose (500 mg/kg) and 14 - day repeat dose studies (10 mg/kg/day) were conducted with 14C -phenyl acequinocyl only . Excretion was rapid, with most of the dose in the feces. Less than 15% of the radioactivity w as found in the urine. Absorption was about 25 - 42% based on the bile duct cannulation studies, which found 20 - 33% of the administered dose in bile, plus 5 - 9% in urine plus cage wash. Acequinocyl was not detected in urine and was only a minor component (1 - 2%) in the feces. The major fecal metab olite (12 - 36%) was the 2 - hydroxy- 3 - dodecyl - l, 4 - naphthalenedione (acequinocyl - OH or designated Rl). Subsequent oxidation of the dodecyl chain yi elded butanoic and hexanoic acids, the only m easurable identified urinary

m etabolites. 2 - (l, 2 - dioxotetradecyl) -benzoic acid comprised 19 - 40% of theradioactivity in the feces. There were no remarkable differences in metabolite disposition due to gender and no effect of pre - dosing for 2 weeks. The large dose slowed transit time and reduced absorption. 4

7. Endocrine disruption. A standard battery o f toxicity

t ests have been conducted on acequinocyl. No effects were seen to indicate that acequinocyl has an effect on the endocrine system. C. Aggregate Exposure 1. Dietary exposure. The tolerance of 0.7 ppm for fruiting ve getables crop group 8 (tomatoes and peppers) and okra , 0. 2 5 ppm for edible podded beans and 3.5 ppm for hops along with the previously

e stablished tolerances for acequinocyl were incorporated into the aggregate exposure results presented below. An aggregate risk assessment was conducted to include the potential chronic dietary

exposure from applications of acequinocyl o n these crops . This chronic risk assessment was conducted to assess dietary exposures from acequinocyl in food using DEEM FCID TM and the fol lowing input parameters: tolerance level residues; consumption data from the USDA 1994 - 1996 and 1998 Continuing Survey of Food Intakes by

Individuals (CSFII); 100 percent crop treated for all commodities; default processing factors for all commodities , if applicable ; and a chronic toxicological endpoint of 2.7 mg/kg body weight(bw) (NOAEL); 0.027 mg/kg bw (chronic reference dose ( c RfD ) ) from the chronic mouse study . Tolerance values used in the new Tier I DEEM anal ys is for current registered uses were obtained from the most recent EPA human health assessments (FR Notice, April 2, 2008). Please note that EPA has determined that there is no endpoint of concern attributable to a single dose and, therefore, an acute reference dose (aRfD) was not established. Therefore, no acute exposure assessment is necessary (FR, Vol. 69, No. 139, 7/21/04, page 43528). i. Food. The previous chronic dietary f ood exposure estimates to acequinocyl were all less than 100% of chronic RfD. When the previous risk assessment is revis ed to include tomatoes, peppers, okra, snap -beans, and hops , the chronic dietary f ood exposure estimates to acequinocyl are still not a concern for the US population as a whole or for any population subgroup. The new chronic dietary exposure estimate for the US population is 12.4% of the cPAD, indicating that there is plenty of room in the risk cup even with the addition of these proposed new crops. The previous DEEM analysis without these new proposed IR - 4 uses indicated 7.4% of the cPAD for the total US population (Levy, 2007) . The most highly exposed population subgroup is children aged 1 - 2 ye ars old at 52.6% of the cPAD; this compares to 41% of the cPAD without the addition of the new proposed IR - 4 uses. In order to determine which of the registere d and proposed commodities were driving the revised dietary risk assessment, a critical commodity c ontribution analysis was conducted for two subpopulation groups, children 1 - 2 ye ars old and children 3 - 5 ye ars old. This analysis identified (a) crop groups with greater than 5% of the total exposure contribution; and (b) those foods orfood- forms within the crop groups contributing more than 1% of the total exposure. F or both of

these subpopulations, the grape crop group (includes fresh grapes, grape juice and raisins) was the largest contributor. F or children 1 - 2, this food group contributed 33.7% of the total exposure; for children 3 - 5, the contribution was 30.5% of the total exposure. The next highest contributor to the 1 - 2 year olds was the pome fruit grouping, with apple juice being the highest Individual c ontributor. The pome fruit group contributed 31.8% and 26.9% of total exposure for children aged 1 - 2 and 3 - 5, respectivel y. The third highest crop group contributor was the fruiting vegetables, with fresh tomatoes, tomato sauce, and tomato puree being the highest individual food contributors within that crop group. This group accounted for 21.9% and 28.3% of total exposure for children aged 1 - 2 and 3 - 5, respectively . i i. Drinking water. The avail able environmental fate data indicate that acequinocyl does not persist in the environment nor does it have the ability to leach into groundwater resources. Acequinocyl degrades rapidly in the environment. Aqueous photolyis , T l/2 = 14 minutes, soil photolyis , T l/2 = 2 days, aerobic soil metabolism (4 soils) T l/2 = <3 days, aerobic aquatic metabolism T l/2 = 0.39 day in water and sediment, hydrolysis T l/2 = 74 days (pH4 ) , = 2.2 days (pH7 ) , =1.3 hours (pH9 ) . Acequinocyl shows low soil mobility . Drinking water data was incorporated directl y into the DEEM dietary a ssessment under “drinking water” for both direct and indirect sources using the chronic concentration of parent - only ( acequinocyl ) residues modeled from surface water using PRZM - EXAMS by EPA and used in their revised human health risk assessment (Levy, S ., 2007). This was a very c onservative estimate because it was assumed that acequinocyl was stable to all routes of degradation. A s a result, this model produced the highest estimated drinking water concentration (EDWC), 2.73 part per billion (ppb ) , which was considered to be the most protective. Using these considerations, exposures to acequinocyl in drinking water do not pose a significant human health risk. iii. Non - dietary exposure. The proposed expansion of the registration for applications to fruiting vegetables crop group 8 (tomatoes, p eppers ) , okra, edible podded beans, and hops requires evaluation of occupational handler and postapplication exposures and dietary exposures for consumers. a. Occupational Handler Exposure: The following handler scenarios were evaluated: 1. Mix/load liquid open -pour for groundboom applications 2. Mix/load liquid open -pour for airblast applications 3. Application by

groundboom, open - cab 4. Application by

airblast, open - cab Exposure data from PHED were used to assess dermal and inhalation risks. All short - term and intermediate - term occupational risks were acceptable (margin of exposure (MOE ) s exceeded 100; short - term MOEs ranged from 4,866 to 51,330 and intermediate - term MOEs ranged from 20,700 to 291,300). Based on the anticipated occupational use patterns for acequinocyl products, long - term (several months to lifetime) exposures are not expected for occupational handlers of acequinocyl. b . Occupational Postapplication Exposure: Since re - entry activities occur after the sprays have dried, post - application inhalation exposures are not assessed. Post - application exposures to acequinocyl are expected to be of short - term duration only (1 to 30 days) based on the limite d use pattern. Short - term dermal post - application exposures were assessed against the NOAELfor short - term dermal exposures (200 mg/kg/day). F or fruiting vegetables, okra, edible poddedbeans and hops, the risks are not of concern (MOEs > 100) on day 0 f or all potential re - entry activities. A s such, the REIo f 12 hours is appropriatel y protective. The highest exposure potential is in hops with high contact activities such as training, stripping and harvesting; the margin of exposure associated with thes e high contact activities is 942, well above the level of concern of 100. 6 c . Residential Handler exposure: Residential handler risks were calculated by EPA in the 2007 Human Health Risk Assessment document (Levy, S., 2007). Two scenarios, mixing/loading and applying liquids by l ow - pressure hand- wand and mixing/loading and applying liquids with a hose - end sprayer, were identified and evaluated for short - term re sidential risks. B ased on the E PA residential handler assessment, there are no risks of concern for residential handlers (MOEs > 100). The lowest MOE, 2,900, was associated with dermal exposure when using the hose - end sprayer. d . Residential Postapplication exposures: Current EPA policy indicates that there is no significant post - application exposure to treated residential ornamentals; therefore, no residential re - entry risk assessment was performed. In summary, all residential and occupational exposure scenarios are associated with a reasonable certainty

of no harm for the US population and all subpopulations. D . Cumulative Effects There is no information available to indicate that toxic effects produced by a cequinocyl are cumulative with those of any other compound. E. Safety Determination 1. U.S. population. . The chronic dietary f ood and drinking water exposure (including all current and proposed uses) to acequinocyl was estimated at 12.4% of the cPAD for the total US population. The calculated chronic dietary risks included contributions of modeled residues from drinking water (direct and indirect , all sources). The groundwater EDWC for acequinocyl was estimated to be 0.0036 ppb, while surface water EDWCs were estimated to be 0.37 and 2.73 ppb, using two different approaches (Levy, 2007). The most conservative value, 2.73 ppb, was chosen for use in the chronic dietary a ssessment. Acequinocyl concentrations in the source surface water are not expected to exceed 2.73 ppb in chronic scenarios due to the conservative high - end assumptions used in the model. The Tier 1 chronic dietary risk assessment to ok into account tolerance - level residues, 100% crop treated, and a drinking water modeled concentration of 2.73 ppb. The result of this assessment indicated exposures to the general US population were not of concern. 2. I nfants and children. The chronic dietary food exposure to acequinocyl was estimated at 22.5% of cPAD for all infants (<1 ye ar), and 52.6% of cPAD for children 1 - 2 ye ars (most highl y exposed). The calculated chronic dietary risks included contributions of modeled residues from drinking water ( direct and indirect, all sources). The most conservative value, 2.73 ppb obtained from PRZM - EXAMS surface water model, was chosen for use in the chronic dietaryassessment. Acequinocyl concentrations in the source surface water are not expected to exceed

the EDWC of 2.73 ppb in chronic scenarios due to the conservative high - end assumptions used in the model. The Tier 1 chronic dietary risk assessment took into account tolerance - level residues, 100% crop treated, and a drinking water modeled concentration of 2.73 ppb. The result 7 of this assessment indicated exposures to the most exposed subpopulation, children aged 1 to 2 ye ars, were not of concern. F. International Tolerances To date, no Codex, Canadian or Mexican tolerances exists for acequinocyl. REFERENCES: 1. Levy, Sarah. Amendment to PP#s 6F7040 and #7F176. Human Health Risk Assessment for the Proposed Uses of Acequinocyl on Grapes, the Tree Nut Crop Group, and Residential Sites (Ornamentals). December 12, 2007.8