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

COMPANY NOTICE OF FILING

EPA Registration Division contact: Sidney Jackson, 703-305-7610

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 part 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 measuring only the sum of acequinocyl 2-(acetyloxy)-3-dodecyl-1,4-

naphthalenedione, and its metabolite 2-dodecyl-3-hydroxy-1,4-naphthoquinone, calculated as the 

stoichiometric equivalent of acequinocyl 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 podded 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 adequately 

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 analytical method to quantitate residues of acequinocyl and 

acequinocyl-OH in/on fruit crops utilizes high pressure liquid chromatography-mass 

spectrometry/mass spectrometry (HPLC-MS/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. Magnitude 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 interval between applications. The pre-harvest interval is 7 days. The 

maximum residue for each commodity is shown in the following table.
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Sample 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-Bell 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 tolerances requested in 

Section F of the petition.

B. Toxicological Profile

1. Acute toxicity. Acequinocyl 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. 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 on gestation days 7-17. 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 no-observed adverse 
effect level (NOAEL)=150 mg/kg/day based on these signs. Developmental NOAEL=500 

mg/kg/day based on an increase in certain skeletal variants that may be attributed to the 

observed maternal toxicity. 

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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 NOAEL=60 mg/kg/day based on 

reduction in maternal body weight and 5 females were sacrificed at 120 mg/kg/day. Fetal 

NOAEL=60 mg/kg/day due to skeletal variations in the thoracic-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 

NOAEL=100 ppm (7.3 and 8.7 mg/kg/day). Systemic: 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 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 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. NOAEL = 400 ppm (30.4 mg/kg/day for males and 32.2 mg/kg/day for

females).

ii. Mouse feeding study. Groups of CD-I (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 NOAEL 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 NOAEL 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. NOAEL=1000 mg/kg/day.

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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. NOAEL = 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. The NOAEL = 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:CDl(ICR)BR mice at 0, 20, 50, 150 or 500 ppm for 80 weeks. NOAEL=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-l, 4-naphthalenedione (acequinocyl-OH or designated Rl). Subsequent 

oxidation of the dodecyl chain yielded butanoic and hexanoic acids, the only measurable 

identified urinary metabolites. 2-(l, 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.

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7. 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.

C. Aggregate Exposure

1. Dietary exposure. The tolerance of 0.7 ppm for fruiting vegetables crop group 8

(tomatoes and peppers) and okra, 0.25 ppm for edible podded beans and 3.5 ppm for hops along 

with the previously established 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 on these crops. This chronic 

risk assessment was conducted to assess dietary exposures from acequinocyl in food using 

DEEM FCID

TM and the following 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 (cRfD)) from the chronic mouse study. Tolerance values used 

in the new Tier I DEEM analysis 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 food exposure estimates to acequinocyl were all 

less than 100% of chronic RfD. When the previous risk assessment is revised to include 

tomatoes, peppers, okra, snap-beans, and hops, the chronic dietary food 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 years 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 registered and proposed commodities were driving the revised 

dietary risk assessment, a critical commodity contribution analysis was conducted for two 

subpopulation groups, children 1-2 years old and children 3-5 years old. This analysis identified 

(a) crop groups with greater than 5% of the total exposure contribution; and (b) those foods or 
food-forms within the crop groups contributing more than 1% of the total exposure. For both of 

these subpopulations, the grape crop group (includes fresh grapes, grape juice and raisins) was 

the largest contributor. For 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 contributor. The pome fruit group contributed 31.8% and 26.9% of total exposure for 

children aged 1-2 and 3-5, respectively. 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.

ii. Drinking water. The available 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, Tl/2 = 14 minutes, soil 

photolyis, Tl/2 = 2 days, aerobic soil metabolism (4 soils) Tl/2 = <3 days, aerobic aquatic 

metabolism Tl/2 = 0.39 day in water and sediment, hydrolysis Tl/2 = 74 days (pH4), = 2.2 days

(pH7), =1.3 hours (pH9). Acequinocyl shows low soil mobility. Drinking water data was 

incorporated directly into the DEEM dietary assessment 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 conservative estimate because it was 

assumed that acequinocyl was stable to all routes of degradation. As 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, peppers), 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 limited 

use pattern. Short-term dermal post-application exposures were assessed against the NOAEL for

short-term dermal exposures (200 mg/kg/day). For fruiting vegetables, okra, edible podded 
beans and hops, the risks are not of concern (MOEs > 100) on day 0 for all potential re-entry 

activities. As such, the REI of 12 hours is appropriately protective. The highest exposure 

potential is in hops with high contact activities such as training, stripping and harvesting; the 

margin of exposure associated with these high contact activities is 942, well above the level of 

concern of 100.

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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 low-pressure hand-wand and mixing/loading and 

applying liquids with a hose-end sprayer, were identified and evaluated for short-term residential 

risks. Based on the EPA 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 acequinocyl 

are cumulative with those of any other compound.

E. Safety Determination

1. U.S. population. . The chronic dietary food 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 assessment. 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 took 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. Infants and children. The chronic dietary food exposure to acequinocyl was estimated 

at 22.5% of cPAD for all infants (<1 year), and 52.6% of cPAD for children 1-2 years (most 

highly 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 dietary
assessment. 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 

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of this assessment indicated exposures to the most exposed subpopulation, children aged 1 to 2 

years, 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.
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