Document ID: EPA-HQ-OPP-2015-0382-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-09-09T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Venus Eagle (PM 01), 703-308-8045. 
Arysta LifeScience North America, LLC 
Petition #5F8364 

Summary of Petition 
EPA has received a pesticide petition (5F8364) from Arysta LifeScience North America Corporation, 15401 Weston Parkway, Suite150, Cary NC 27513 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by amending the existing tolerance for residues of 3-dodecyl-1,4-dihydro-1,4-dioxo-2-naphthyl acetate and its metabolite 2-dodecyl-3-hydroxy-1,4-naphthoquinone expressed as acequinocyl equivalents in or on Hop, dried cones from 4.0 to 15.0 parts per million (ppm). EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry 
1. Plant metabolism. The nature of the residues of acequinocyl in plants is adequately understood as studies have been conducted on three crops; apples, oranges and eggplant. The major residue in all plant metabolism studies is acequinocyl. A minor but significant metabolite is acequinocyl-OH (2-dodecyl-3-hydroxy-1,4-naphthoquinone). The proposed tolerance expression is the parent, acequinocyl and its hydroxy metabolite, acequinocyl-OH.

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

3. Magnitude of residues.  The existing use of acequinocyl calls for a maximum of 2 applications per season at 0.3 lb a.i. per acre per application (maximum 0.6 lb a.i. per acre per season), with a 21-day interval between applications. The pre-harvest interval is 7 days. The established tolerance expressed as acequinocyl equivalents in/on Hops, dried cones is 4.0 ppm.  Arysta seeks to raise the tolerance to 15 ppm in order to match the tolerance values established in the European Union and Japan.

B. Toxicological Profile 
The complete toxicity profile of acequinocyl was previously published in the Federal Register of November 17, 2010 (73 FR 70143).  

1. Acute toxicity. Acequinocyl technical has low acute, dermal and inhalation toxicity in laboratory animals. The oral LD50 (M/F) in the rat and mouse was > 5000 mg/kg. The dermal LD50 (M/F) was > 2000 mg/kg. The inhalation LC50 was reported as > 0.84 mg/l. In the eye and dermal irritation studies, acequinocyl technical was not an eye or skin irritant to rabbits and was not a skin sensitizer in guinea pigs.

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

3. Reproductive and developmental toxicity. 
i. Rat teratology. Acequinocyl technical was administered by oral gavage to pregnant Sprague Dawley rats at dose levels of 0, 50, 150, 500 or 750 mg/kg/day. Common signs in the descendants included vaginal discharge, pallor, pale eyes, hypoactivity, piloerection, slow or irregular breathing, intra-uterine hemorrhage and blood stained stomach and/or intestinal contents. Maternal NOEL=150 mg/kg/day based on these signs. Developmental NOEL=500 mg/kg/day based on increase in certain skeletal variants that may be attributed to the observed maternal toxicity.
 ii. Rabbit teratology. Groups of New Zealand white rabbits received acequinocyl technical by gavage at doses of 0, 30, 60 or 120 mg/kg/day. Maternal NOEL=60 mg/kg/day based on reduction in maternal body weight and 5 females were sacrificed at 120 mg/kg/day. Fetal NOEL=60 mg/kg/day due to skeletal variations in the thoraco-lumbar ribs.
iii. Rat reproduction study. Acequinocyl technical was fed to two generations of male and female Sprague Dawley rats at dietary concentrations of 0, 100, 800, or 1500 ppm (0, 7.3, 59 or 111 mg/kg/day for males and 0, 8.7, 69 or 134 mg/kg/day for females). Systemic and pup NOEL=100 ppm (7.3 and 8.7 mg/kg/day). Systemic: Hemorrhage and swollen body parts were seen at 800 and 1500 ppm in F1 males . At 800 and 1500 ppm, treatment related clinical signs, hemorrhagic effects, subcutaneous bleeding on body parts and/or cranium and/or brain were seen in the F1 pups. At 800 and 1500 ppm toxicity seen in F2 pups included subcutaneous bleeding on body parts and/or cranium and/or brain at weaning.

4. Subchronic toxicity. 
i. Rat feeding study. Fischer rats received acequinocyl technical at dietary concentrations of 0, 100, 400, 1600 or 3200 ppm (0, 7.57, 30.4, 120, 253 mg/kg/day, respectively for males and 0, 8.27, 32.2, 129, 286 mg/kg/day, respectively for females) for 13 consecutive weeks. Treatment related yellow brown urine in all animals of both sexes at 400 ppm suggested the presence of the metabolite of the test material. Macroscopic examination on the surviving animals revealed no treatment related abnormalities. At 3200 and 1600 ppm, macroscopic and microscopic examination of the mortalities revealed hemorrhaging of muscle and other organs. NOEL=400 ppm (30.4 mg/kg/day for males and 32.2 mg/kg/day for females). 
ii. Mouse feeding study. Groups of CD-1 (ICR) BR mice received acequinocyl technical by oral route at concentrations of 0, 100, 500, 1000 or 1500 ppm (0, 16, 81, 151, 295 mg/kg/day respectively for males and 0, 21, 100, 231, 342 mg/kg/day respectively for females) for 13 weeks. At 100 ppm, there were hepatic histopathological lesions and an increase in relative liver weight. A clear NOEL for both sexes was not determined.  
iii. Dog feeding study. Acequinocyl technical was administered via gelatin capsule to male and female beagle dogs at dose levels of 0, 40, 160, 640 or 1000 mg/kg/day once a day 7 days a week for 13 weeks.  At 40, 160 and 640 mg/kg/day colored feces were observed in both sexes. At 160 and 640 mg/kg/day, treatment related decrease in body weight gain in males and an increase platelet count for females was observed. Macroscopic and microscopic examinations on the surviving animals revealed no treatment related abnormalities. A clear NOEL was not determined.
iv. 28-day dermal toxicity. Groups of Sprague Dawley rats received daily dermal applications of acequinocyl technical at doses of 0, 40, 200 or 1000 mg/kg/day for 6 hours/day for 28 days followed by a 14 day treatment free period only in the high dose group. There were no macroscopic findings. Red staining occurred on the back of the animals and was only seen in the morning after dosing. There was no evidence of systemic toxicity. NOEL=1000 mg/kg/day.

5. Chronic toxicity. 
i. Dog feeding study. Beagle dogs were dosed by capsule at 0, 5, 20, 80 or 320 mg/kg/day for 1 year with acequinocyl technical. Minor disturbances in platelet counts were observed in both sexes at 80 and 320 mg/kg/day. There were no treatment related macroscopic histopathological findings. Colored feces and/or abnormally stained sawdust were observed for all treatment groups. Varying degrees of discoloration of the urine was observed for animals receiving 20 mg/kg/day or more. The discoloration was considered to be attributable to a colored metabolite of the test substance. NOEL=20 mg/kg/day.
ii Rat feeding/oncogenicity study. Groups of F344 rats received acequinocyl technical at dietary levels of 0, 50, 200, 800 or 1600 ppm (0, 2.25, 9.02, 36.4, 74.0 mg/kg/day for males and 0, 2.92, 11.6, 46.3, 93.6 mg/kg/day for females) for 2 years. NOEL=200 ppm (9.02 and 11.6 mg/kg/day for males and females respectively). Corneal abnormalities and hypertrophy of the eye were observed in 800 ppm and 1600 ppm males and 1600 ppm females. At 800 ppm and 1600 ppm, PT was observed to be longer in males and shorter in females and APTT longer in females. Reddish brown urine was observed in both males and females. There was no incidence of tumors.
iii. Mouse oncogenicity study. Acequinocyl technical was administered in the diet of Crl:CD-1(ICR)BR mice at 0, 20, 50, 150 or 500 ppm for 80 weeks. NOEL=20 ppm (lowest dose tested equal to 2.7 and 3.5 mg/kg/day in males and females respectively), based on brown pigmented cells. At 50 and 500 ppm in both sexes, there was an increase incidence of fatty hepatocytes. Other associated findings were increased liver weight, slight increase in pale livers or pale areas within livers. Glomerular amyloidosis was statistically increased in the 150 and 500 ppm males. Yellow brown urine was consistently found in both sexes at high dose. There was no increase in the incidence of tumors.

6. Animal metabolism. Sprague Dawley rats were dosed orally with acequinocyl labeled 14C-phenyl or 14C-dodecyl. Both labels were used in the single low dose (10 mg/kg) study. The high dose (500 mg/kg) and 14-day repeat dose studies (10 mg/kg/day) were conducted with 14C-phenyl acequinocyl only. Excretion was rapid, with most of the dose in the feces. Less than 15% of the radioactivity was found in the urine. Absorption was about 25-42% based on the bile duct cannulation studies, which found 20-33% of the administered dose in bile, plus 5-9% in urine plus cage wash. Acequinocyl was not detected in urine and was only a minor component (1-2%) in the feces. The major fecal metabolite (12-36%) was the 2-hydroxy-3-dodecyl-1,4-naphthalenedione (acequinocyl-OH or designated R1). Subsequent oxidation of the dodecyl chain yielded butanoic and hexanoic acids, the only measurable identified urinary metabolites. 2-(1,2-dioxotetradecyl)-benzoic acid comprised 19-40% of the radioactivity in the feces. There were no remarkable differences in metabolite disposition due to gender and no effect of pre-dosing for 2 weeks. The large dose slowed transit time and reduced absorption.

7. Metabolite toxicology. NA-Remove.

8. Endocrine disruption. A standard battery of toxicity tests have been conducted on acequinocyl. No effects were seen to indicate that acequinocyl has an effect on the endocrine system.

9. Immunotoxicity. NA-Remove.

C. Aggregate Exposure 
1. Dietary exposure. 
i. Food. Tolerance-level residues and 100% CT data were used in the chronic dietary assessment.  DEEM default processing factors were used with the exception of those for grape juice and raisins.  As residues were reduced in both grape juice (<0.02x) and raisin (0.15x), separate tolerances are not required for these commodities.  The DEEM ver. 7.81 default processing factors for juice and raisin were set to "1" as concentration was shown not to occur (Levy et al, 2011).  The chronic dietary assessment was based on the most recent dietary risk assessment for acequinocyl (Levy et al, 2011).  
Permanent tolerances are currently established under 40 CFR §180.599(a) for the combined residues of acequinocyl and its metabolite, acequinocyl-OH, expressed as acequinocyl equivalents, in/on a number of plant and livestock commodities.  Tolerances for plant commodities range from 0.02 ppm (tree nuts and pistachios) to 30 ppm (citrus oil), and tolerances for livestock commodities are established at 0.02 ppm in the fat and liver of cattle, goat, horse, and sheep.
As cowpea forage and hay are significant feedstuff for livestock (dairy cattle only), the maximum reasonable balanced diet (MRBD) for acequinocyl was recalculated by EPA in 2011 using the Agency's most recent guidance on constructing reasonably balanced livestock diets (Science Advisory Council for Chemistry (ChemSAC) memo, 30-JUN-2008).  The beef cattle MRBDs did not need to be recalculated as cowpea forage and hay are not beef feed items.  The feeding study data indicate that the currently established tolerance level of 0.02 ppm for residues in cattle, goat, horse, and sheep fat is appropriate.  Furthermore, the 0.02 ppm residue level is sufficient to cover residues of the additional metabolite (AKM-15) of concern in ruminant liver and kidney.  The established 0.02 ppm residue level in cattle, goat, horse, and sheep liver are appropriate; however, the commodity definition should be changed to "meat byproducts" rather than "liver."  

ii. Drinking water. There are no drinking water monitoring data available for acequinocyl or its metabolite acequinocyl-OH (R1), the residues of concern.  Groundwater estimated drinking water concentrations (EDWCs) were generated by EPA for acequinocyl using the Screening Concentration in Ground Water (SCI-GROW) Model.  Surface water EDWCs were generated using the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) model for all proposed uses except cranberry.  Since cranberry harvesting may involve field flooding and PRZM/EXAMS is not currently capable to assess this type of scenario, cranberry was assessed using the provisional cranberry model.  The most conservative EDWC value was 6.69 ppb (0.00669 ppm) derived via the surface water Approach #1 for the use pattern in cherries and grapes.  The upper-bound value of 6.69 ppb was used in the DEEM-FCID model for "water, direct, all sources" and "water, indirect, all sources" (Levy et al, 2011).

2 Non-dietary exposure. 
i. Residential Handler:  Acequinocyl is currently registered for use on landscape ornamentals in and around residences, businesses, public property, schools, interiorscapes, and other non-production areas by commercial applicators and homeowners.  Therefore, there is the potential for residential handler exposure when applying to landscape ornamentals and ornamental or fruit trees.  Based upon the proposed use pattern, the following two residential handler scenarios were assessed by EPA (Lowe, 2007):

      (1) mixing/loading/applying liquids with low pressure handwand 
      (2) mixing/loading/applying liquids with hose-end sprayer 

Because no chemical-specific data were available with which to assess potential exposure to pesticide handlers, the estimates of exposure were based upon surrogate study data from the ORETF and PHED.   

New residential handler exposure and risk assessments were conducted using the EPA 2012 Residential SOPs which contain updated surrogate unit exposures and input parameters.  As in 2007, homeowner handler assessments are based on the assumption that individuals are wearing shorts, short-sleeved shirts, socks, and shoes.  Residential handler exposure scenarios are considered to be short-term only, due to the infrequent use patterns associated with homeowner products.  

Table 1 presents the exposure/risks for residential short-term dermal and inhalation exposures.  Based on the residential handler assessment, there are no risks of concern for residential handlers (i.e., MOEs > 100).

Table 1:  Residential Handler Exposure and Risks 

                                  Dermal and
                    Inhalation Unit Exposures (mg/lb ai)[1]
                               Application Rate 
                               (lb ai/gallon)[2]
                       Amount Handled Daily[1] (gallons)
                             Doses (mg/kg/day)[3]
                                    MOEs[4]
          Mixer/Loader/Applicator  -  Manually Pressurized Handwand 
                                    Dermal
                                      63
                                    0.00125
                                       5
                                    Dermal
                                    0.00492
                                    Dermal
                                    40,635
                                  Inhalation
                                    0.0018
                                       
                                       
                                  Inhalation
                                    1.4E-06
                                  Inhalation
                                   4.27E+07
                  Mixer/Loader/Applicator  - Hose-End Sprayer
                                    Dermal
                                      58 
                                    0.00125
                                      11
                                    Dermal
                                    0.00997
                                    Dermal
                                    20,000
                                  Inhalation
                                    0.0014 
                                       
                                       
                                  Inhalation
                                    2.4E-06
                                  Inhalation
                                    2.49E+08
[1]From 2012 EPA Residential SOPs
[3]Application rate is the maximum application rate determined from the label for acequinocyl
      [2]Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/gal) x Amount Handled (gal/day) x  % Absorption (100%) /Body weight (80 kg) 
[4]MOE = NOAEL/Dose; where the short-term dermal NOAEL = 200 mg/kg/day and short-term inhalation NOAEL = 60 mg/kg/day

ii.  Residential Post-Application:  With respect to residential post-application exposures, new HED policy (2012 Residential SOPs) specifies that there is potential for post-application dermal exposure following applications to residential landscape ornamentals and trees, either by adults or children between the ages of 6 and 11; therefore, a new residential post-application assessment was conducted.
Using the input parameters provided in Table 2-3 of the 2012 Residential SOPs, dermal re-entry exposure for adults and children to treated ornamentals and treated trees was calculated.  The exposures were compared to the dermal NOAEL of 200 mg/kg/day to generate a margin of exposure.  All margins of exposure exceed 100, indicating acceptable risk.

Table 2:  Residential Post-Application Dermal Risks
                                 Use Scenario
                             Application Rate[1] 
                                   (lb ai/A)
                                  TC (cm2/hr)
                              Exposure Time (hr)
                          Dermal Dose (mg/kg/day)[2]
                                    MOE[3]
                                    Adults
                                Garden re-entry
                                     0.21
                                     8400
                                      2.2
                                    0.1359
                                     1,470
                                 Tree re-entry
                                       
                                     1700
                                      1.0
                                    0.0125
                                     2,148
                         Children (6 to <11 years)
                                Garden re-entry
                                     0.21
                                     4600
                                      1.1
                                    0.0931
                                    15,986
                                 Tree re-entry
                                       
                                      930
                                      0.5
                                    0.00855
                                    23,378
[1]Application rate = 0.00125 lb ai/gallon x 5 gallons/day / 0.03 A (spot treatment)
[2]Daily dose = DFR x TC x ET / BW (80 kg adults; 32 kg children)  DFR = 25% of the application rate
[3]MOE = NOAEL/Dermal Dose where the short-term dermal NOAEL = 200 mg/kg/day 

D. Cumulative Effects 
There is no information available to indicate that toxic effects produced by acequinocyl are cumulative with those of any other compound.  Arysta LifeScience North America, LLC will submit information, if necessary, for EPA to consider concerning potential cumulative effects of fluoxastrobin consistent with the schedule established by EPA at 62 Federal Register 42020 (Aug. 4, 1997) and other EPA publications pursuant to the Food Quality Protection Act.

E. Safety Determination 
1. US Population.
 i. Short-Term Aggregate Risk: Short-term aggregate risk is made up of average dietary exposures from food and drinking water sources, and dermal and inhalation residential exposures.  Since acequinocyl has a residential use on ornamentals, adult residential handler exposure and post-application exposure is possible.  In addition, there is potential for children between the ages of 6 and 11 to come into dermal contact with foliar residues.  Based on the chronic dietary exposure, the "total US population" is the highest exposed adult population and can be considered protective of the other adult subgroups; therefore, this population was chosen for the aggregate risk assessment along with children, ages 6 to 12, as this most closely matches the subgroup that has potential for residential exposure through dermal post-application activities.  The results of the short-term aggregate risk assessment are shown in Table 3.

Dietary (food and drinking water) exposure is based on a Tier 1 (unrefined) chronic dietary exposure assessment (see Table 2).  Residential exposure estimates are conservative estimates due to the standard assumptions that were built into the calculations.  Residential exposure estimates were taken from Tables 1 and 2.  The short-term aggregate risk calculations for the general U.S. population and children, 6 to 12 years old, are shown below in Table 3.  Both aggregate MOEs are greater than 100 and therefore are not of concern.  

Table 3:  Short-Term Aggregate Risk Calculations.
                                  Population
                                Dietary MOE[1]
                           Residential Dermal MOE[2]
                         Residential Inhalation MOE[2]
                                   Aggregate
                                    MOE[3]
                                U.S. Population
                                    16,211
                                     1,370
                                   4.27E+07
                                     1,263
                            Children, 6 to 12 years
                                    12,002
                                     2,148
                                      NA
                                     1,822
[1]  Dietary MOE = short-term oral NOAEL (60 mg/kg/day)  chronic dietary exposure.
[2]  Residential MOEs are from Tables 3 and 4.  The "hose-end sprayer" scenario was used for the general US population as the MOE for this scenario is lower (more conservative) than the "manually pressurized handwand" MOE; the hose-end sprayer dermal dose was added to the garden reentry dose.  For children, the garden reentry dermal dose was used as the MOE for this scenario is lower than for tree reentry.
[3]  Aggregate MOE (dietary and residential) = 1((1MOEdietary)+(1MOEdermal)+(1MOEinhalation)); LOC = 100.

ii. Intermediate-Term Aggregate Risk:  Intermediate-term aggregate risk was not calculated since the use pattern is not expected to result in residential handler or post-application exposure of more than 30-day duration.  

iii. Long-Term Aggregate Risk:  Chronic (long-term) aggregate risk is made up only of dietary sources; therefore, the chronic exposure estimates provided in the chronic dietary exposure analysis (see Table 4) represents chronic aggregate exposure.

Table 4.  Summary of Tier 1 Estimates of Exposure and Risk from Chronic Dietary Exposure to Acequinocyl

                                  Population 
                                   Subgroup

                                  Chronic[1]
                                       

                               Dietary Exposure
                                  (mg/kg/day)

                                    % cPAD

Total U.S. Population 
                                   0.003701
                                     13.7

All Infants (< 1 year)
                                   0.006237
                                     23.1

Non-Nursing Infants (< 1 year old)
                                   0.007788
                                     28.8

Children (1-2 years)
                                   0.015713
                                     58.2

Children (3-5 years)
                                   0.010992
                                     40.7

Females (13-49 years)
                                   0.002698
                                     10.0

Youths (13-19 years)
                                   0.002610
                                      9.7

Adults (20-49 years)
                                   0.002795
                                     10.4

Adults  (50+ years)
                                   0.002699
                                     10.0

[1]The chronic dietary cPAD of 0.027 mg/kg/day applies to the general U.S. population and all population subgroups.

2. Infants and children. The short-term aggregate risk calculations for the general U.S. population and children, 6 to 12 years old, are shown below in Table 3.  Both aggregate MOEs are greater than 100 and therefore are not of concern.  

F. International Tolerances
Codex maximum residue levels (MRLs) are not yet established for acequinocyl.