## Proposed Registration of Fenazaquin on Ornamentals, Christmas Tree Plantations, Non-Bearing Tree Fruits and Nuts, and Established Ornamental Landscape Plantings

for the Control of Mites and Insects

February 18, 2010

U.S. Environmental Protection Agency Office of Pesticide Programs Registration Division2/18/2010



### Proposed Registration of Fenaza quin on Ornamentals, Christmas Tree Plantations, Non-Bearing Tree Fruits and Nuts, and Established Ornamental Landscape Plantings for the Control of Mites and Insects

Regulatory Rationale

The Agency is proposing to grant the first registrati ons of the active i ngredient, fenazaquin, formulated as a technical and an end-use produc t, for application to greenhouse and shadehouse ornamentals, established ornamental landscap e plantings, Christmas tree plantations, and nonbearing fruit and nut trees to control mites and in sects. Previously, the Agency had established import tolerances for fenazaquin for apples, pears, and citrus fruits.

1. Human Health Risk

Following repeated oral doses rats, hamste rs and dogs exhibited non-specific effects characterized by decrease in body weight, body wei ght gain, food intake, and food efficiency.

These effects occurred at the hi ghest tested doses and did not pr ogress in severity with time. There was no evidence of developmental or reproductive toxicity, mutagenicity or carcinogenicity. Although neurotoxic ity, immunotoxicity, and dermal toxicity studies are needed to complete the database, there are no concerns for neurotoxicity or i mmunotoxicity based on the results of the existing studies a nd a Point of Departure to assess risk from dermal exposure was extrapolated from an acceptable oral study.

a. Toxicological End Points

1. Acute : EPA established an acute reference dose (a RfD) and an Acute Population Adjusted Dose (aPAD) of 0.1 mg/kg/day for the genera l population including in fants and children and females 13+ years of age, based on a rat develo pmental toxicity study. The maternal LOAEL = 40 mg/kg/day, based on findings (as early as GD 6-9) of decreased body weight gain, food intake, and food efficiency supporte d by clinical signs of acute toxi city in the acute oral study. There was no evidence of a single dose effect on the developing fetus.

2. Chronic Dietary : EPA established a chronic reference dose (cRfD) and a Chronic Population Adjusted Dose (cPAD) of 0.05 mg/kg/day for all populations, based on a rat two-generation toxicity study. The LOAEL = 25 mg/kg/day base d on excessive salivation and decreased body weight/weight gain and food intake.

3. Short-Term Dermal and Inhalation : EPA established a Level of Concern (LOC) for the Margin of Exposure (MOE) of 100, based on a rat developmental toxicity study. The maternal LOAEL = 40 mg/kg/day, based on decreased body weight gain, f ood intake, and food efficiency.

24. Intermediate-Term Dermal and Inhalation : EPA established a Level of Concern (LOC) for the Margin of Exposure (MOE) of 100, based on a 90 Day Feeding Study (Dogs). The LOAEL = 15 mg/kg/day, based on decreased body weight ga in, body weight gains, food consumption, and food efficiency.

5. Cancer : EPA has classified fenazaquin as “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

b. Occupational Risk

Short-term occupational handler exposure is poss ible via the dermal and inhalation routes, and short-/intermediate-term postappl ication exposure may occur via the dermal route based on the proposed use pattern.

Handler Exposure and Risk : For all exposure s cenarios (except “Mixin g/Loading Liquid and Applying with High-Pressure Handwand”), the MOEs range from 320 to 4800 and thus provide a margin of protection greater than the Agency’s level of co ncern (LOC=100), provided handlers wear personal protective equipment (PPE, i.e. "b aseline" clothing, which includes: long sleeve shirt, long pants, shoes and sock s) and gloves. For the one ex ception, the addition of coveralls provides greater protection such that the estimat ed MOE of 89 increases to 140. The estimated

MOE of 89 is based on the conservative a ssumption of 100% dermal absorption and an extrapolated PoD from an oral dose study. Data from a 28-day route-specific dermal toxicity study would provide additional certainty in the es timated risk from dermal exposures. The label

will reflect the additional PPE for this scenario.

Occupational Postapplication Exposure and Risk : Occupational postapplication exposure is possible for workers entering trea ted areas to tend ornamentals in nurseries, greenhouses, and landscapes. Short- /intermediat e-term postapplication exposure ma y occur via the dermal route based on the proposed use pattern. The activitie s evaluated include hand pruning, harvesting, and burlapping containerized ornamentals. The s hort- and intermediate-term dermal MOEs for occupational postapplication are greater than the LOC of 100 on the day of application (indicating a Re-Entry Interval of 12 hours, the shortest interval for re-entry of treated areas); and therefore, are not of concern.

c. Residential Risk

An emulsifiable concentrate liq uid (GWN-1708) is proposed for us e as a single application per cropping season to established ornamental plantings in residentia l areas and recreational sites such as golf courses and parks. When determin ing the potential for re sidential exposure, the Agency considers foliar residues, leaf to skin residue transfer and expos ure time. In the case of fenazaquin, exposure potential to adults and children would be negligible for the following reasons: 1) Activities such as pruning or thinning ornamentals or playing in and around ornamentals when residues may be present on the day of the single a pplication per cropping season are unlikely to co-occur; 2) if present, leaf to skin residue transfer would be negligible because of the minimal frequency and duration of contact. Based on the frequency of application and unlikely postapplication exposure, there are no re sidential risk concerns for this use pattern.

3d. Aggregate (Food + Drinking Water) Risk

Acute : The acute dietary analysis (food a nd drinking water) made at the 95 th percentile indicate

risk estimates are below the 100% of the aPAD threshold level of concern for each population subgroup. For the most highly exposed population subgroup, children 1-2 years of age, acute dietary risk was estimated to be 24% of the aPAD with an exposure of 0.023546 mg/kg/day.

Chronic : The chronic dietary analysis (food and dr inking water) yielded risk estimates well

below 100% of the cPAD threshold level of co ncern for each population subgroup. For the most highly exposed population subgroup, ch ildren 1-2 years of age, chr onic dietary risk estimate was

13% of the cPAD with an e xposure of 0.006251 mg/kg/day.

Aggregate : Because residential exposure to fen azaquin from its proposed use on ornamentals in residential areas is expected to be negligible, shor t-, intermediate-, and long-term aggregate risk assessments considering background expos ure from food and water pathways were not conducted. Therefore, the components of aggr egate risk are residue s in food and drinking water only.

2. Environmental Risk

a. Environmental Fate and Exposure

Fenazaquin is moderately persistent in soil with a half-life of approximately 8 weeks. It has a very high K

oc and thus will adsorb strongly to soils and sediments. Its low vapor pressure and Henry’s Law Constant suggest th at volatilization from soil and water is not likely. However, particulates adsorbed to soil could move off-site by soil erosion to adjacent water bodies. Fenazaquin has a low solubility in water of approximately 0.1 mg/L. Though fenazaquin has a high log K

ow , available bioaccumulation data do not dem onstrate a potential to bioaccumulate in

fish.

Persistence : Fenazaquin persists in abiotic aqueous solutions for at least one month, except at pH 5 (half-life 9.6 days). Although fenazaquin has the potential to undergo direct photolysis in abiotic aqueous media, direct photolysis is slow (estimated half-life approximately 30 days). The half-life of fenazaquin in a single soil inc ubated under aerobic condi tions was estimated to be 51 days.

Transport : Fenazaquin adsorbs strongly to so ils as indicated by the Freundlich K

oc s ranging from 15,800 in sand to 101,083 in clay loam soils. Its low vapor pressure (1.9E-5 Pa at 25°C) and Henry’s Law Constant (4.25E-008 Atm-m 3 mole -1 ) suggest that volatilization of fenazaquin

from soil and water is not likel y a dissipation route. However, particulates adsorbed to soil could move off-site by soil erosion to adjacent areas and/or by atmospheric tran sport of particulates.

Bioaccumulation : Based on the Log K

ow of 5.7, fenazaquin has the potential to bioaccumulate in aquatic organisms. However, a fish bioaccumu lation study indicated BCF factors ranging from 390x to 1400x with rapid removal of accumulated residues. Thus, bioaccumulation is not expected.

4b. Fish and Aquatic Invertebrate Risk

Risk Associated with Acute Exposure

1. Freshwater Fish

Acute toxicity testing indi cates that technical fenazaquin is very highly toxic to freshwater fish. Available data on the propionic acid metabolite and the 2-(4-tert-buthyl phenyl) ethanol degradate indicate that they are less toxic than the parent. Risk quotients based on a screening

level risk assessment were calc ulated to be: turf (0.04-0.17); ornamentals/nursery (0.05-0.3); residential (0.04); fruit/n ut trees (0.04 - 0.28).

2. Freshwater Invertebrates

Acute toxicity testing in dicates that technical fenazaquin is very highly toxic to freshwater invertebrates. Risk quotients based on a screeni ng level risk assessment were calculated to be: turf (0.03 -0.12); ornamentals/nursery (0.03-0.21); residential (0.03); fru it/nut trees (0.03-0.19).

3. Marine/Estuarine Fish

No ecotoxicity studies on estuarine/marine fi sh were available. Therefore, a quantitative

estimation of risk cannot be conducted. Based on risk to freshwater fish, there is potential acute

risk to estuarine/marine fish. Preliminar y findings from an ongoing study with sheepshead minnow, which has not yet been reviewed by the Agency, reportedly indicate that marine/estuarine fish would not be expected to be more sensitive to fenazaquin than freshwater

fish.

4. Marine/Estuarine Invertebrates (mollusks)

A shell deposition study conducted with the eastern oyster indicates that technical fenazaquin is very highly toxic to marine/e stuarine invertebrates (mollusk s). Risk quotients based on a screening level risk assessment were calculated to be: turf (0.04-0.17); ornamentals/nursery (0.05-0.3); residential (0.04); frui t/nut trees (0.04-0.28). Preliminary findings from an ongoing study with mysid shrimp which has not yet been reviewed by the Ag ency reportedly indicate that

marine/estuarine invertebrates w ould not be expected to be more sensitive to fenazaquin than

freshwater invertebrates.

Risk Associated with Chronic Exposure

1. Freshwater Fish

A screening level assessment using the chronic endpoint from an early life-stage study with technical fenazaquin on rainbow trout and th e estimated 60 day aver age aquatic EEC was

conducted. No levels of concern fo r freshwater fish were exceeded.

52. Freshwater Invertebrates

No acceptable chronic studies on freshwater in vertebrates are available. Therefore, a quantitative estimation of risk cannot be c onducted. A non-guideline 28-day study conducted on the benthic organism, midge ( Chironomus riparius ) was reviewed. Using a maximum pore

water concentration of 0.25 μ g/L; the chronic RQ for benthic freshwater invertebrates is 0.09, suggesting no chronic risk.

3. Estuarine/Marine Fish and Invertebrates

No chronic toxicity studies on marine/estuarine fi sh were available to assess the chronic risk to

estuarine/marine fish and invertebrates.

Aquatic Risk Characterization

The aquatic ecotoxicology data base for fen azaquin is limited but additional studies are underway. Acute toxicity data show that technical fenazaquin is ve ry highly toxic to freshwater fish and aquatic invertebrate s. Based on a screening leve l assessment with conservative assumptions, the risk quotients ranged from 0.03 - 0.3. The potential estimated risks are considered to be conservative and likely overes timate risk based on these assumptions for the following reasons:

o Conservative assumptions on environmen tal fate parameters include: Using

results from one aerobic soil metabolism study, a 51-day half-life was multiplied by 3 to estimate the degradation input parameter for exposure modeling (as per the Agency’s standard approach for calcu lating input parameters when data are limited).

o In the absence of aquatic metabolism da ta, the 153-day half-life in soil was multiplied by 2 to estimate the half-life in aquatic systems.

o Thus, the Estimated Environmental Concen trations (EECs) are considered an upper bound estimate and most likely will be lower with additional environmental

fate data to refine the risk assessment.

In an aquatic microcosm study, EL-436, an 18% emulsifiable concentrate of fenazaquin, was applied through simulated spray drift and runoff to an artificial pond. The test animals were bluegill sunfish and daphnia. The peak water concentration of fenazaquin in the microcosm study was 0.52 μg a.i./L, and decreased 97% after 14 days. As expected based on the laboratory toxicity studies conducted with bluegill sunfish and daphnia, and the exposure profile simulated in the microcosm study, there were no observe d effects in the microcosm study. In fact,

concentrations measured in the microcosm st udy were lower than those for which no effects were observed in the laboratory studies.

In interpreting these results, it is also informativ e to compare the exposure profile achieved in the microcosm study with the expected environmenta l concentrations predicted by the exposure modeling done for the ecological ri sk assessment. Model-estimated fenazaquin concentrations in water used in the risk assessment were 1.16 μg /L (peak), 0.49 μg/L (21-day average), and 0.34

6μg/L (60-day average); concentrations that are i ndeed higher than those m easured in the artificial pond study, both in terms of a peak concentration and al so longer term exposures. It is expected that, once submitted, the additional environmental fate data will provide confirmatory evidence that the aquatic risk assessment is conservative and that exposure concentrations are most likely lower than predicted by the aquatic exposure modeling.

A new aquatic invertebrate life-c ycle study (Daphnia magna) is n eeded to address uncertainties regarding risk to freshwater invertebrates. The submitted study with Daphnia magna had

excessive variation in concentra tion levels and significant effects detected between the negative and solvent control grou ps, indicating possible adverse effe cts from the solvent in the study.

c. Risk to Aquatic Plants

There are no risk concerns fo r listed aquatic non-vascular plants. The RQ for non-listed nonvascular plants was not estimated because no effects were observed at the highest concentration tested, 208 μg a.i./L. Therefore, the EC 50 would be greater than 208 μg /L. This concentration is higher than the solubility of fen azaquin in water. There is an un certainty with the estimated risk for non-vascular plants because it is based on the re sults of one species. Aquatic vascular plants were not tested. Therefore, there is an uncertain ty associated with aqua tic vascular plants as well, although limited due to the effect on non-vasc ular plants (green al gae) and the mode of action for this pesticide, which is not expected to affect plants.

d. Avian Risk

Acute Risk

No acute risk to birds is predicted.

Chronic Risk

No chronic risk to birds is predicted.

e. Mammalian Risk

Acute Risk

The acute RQs varied from 0.20 to < 0.01; theref ore acute risk to mammals is predicted

. For piscivorous (fish-eating) mammals, the acute RQs varied from 0.197 to 0.014, also suggesting risk concerns through this route of exposure.

Chronic Risk

The chronic RQs varied from 1.09 to 0.01. Ther e are no chronic concerns for mammals on a dietary basis. On a dose basis, the RQ great er than 1 for small mammals eating short grass suggests risk concerns. However, since the RQ is only slightly above the concern level and the NOAEL is based on no effects at the highest dos e tested, chronic risk to mammals is not expected.

For piscivorous (fish-eating) mammals, the chro nic RQs varied from 1.06 to 0.077. Chronic risk

7to piscivorous mammals is not expected, as th e NOAEL is based on no effects at the highest dose tested and RQs estimated by the KABAM m odel may be conservative as the model underestimated the rate of depuration, by an order of magnitude, as compared with the depuration rate determined in the fish accumulation study.

f. Terrestrial Invertebrates

1. Honey Bee

The 48-hour contact LD 50 is 1.21 μ g ai/bee with a NOAEC if 0.375 μ g ai/bee and a LOAEC of 0.75 μg/bee based on mortality. Based on this toxici ty data, fenazaquin is classified as ‘highly toxic’ to honeybees on an acute contact basis. Thus, direct contact with fenazaquin is likely to

result in adverse effects to bene ficial terrestrial insects. This would be expected because fenazaquin is a miticide/insecticide. Risk to honeybees and other pollinators is expected to be greatest for direct application of this product to blooming crops, w eeds, and ornamental plants or through spray drift to these areas. There is un certainty about risk to pollinators from extended residual toxicity following application of fenazaquin because a honey bee t oxicity of residues on foliage study has not been submitted.

2. Earthworm

In addition, the LD 50 from a 14-day study in the earthworm Lumbricus terrestris , is 1.93 mg ai/kg ww soil with a NOAEC of 0.044 mg ai/kg ww soil and a LOAEC of 0.386 based on mortality. The estimated concentration of fen azaquin in the top 15-cm of soil, based on the application rate of 0.2625 lbs a.i. /A, is 0.147 mg a.i./kg soil, is only 9.7 times lower than the 14- day LD 50 value for the earthworm and within the range of the NOAEC and LOAEC. The halflife for fenazaquin in soil is 51 days or longer. Therefore, it is possible that there may be some mortality for soil dwelling invertebrate s following fenazaquin application.

g. Plants

The RQs were all < 0.1 suggesting no risk for an y terrestrial monocots or dicots. In addition, risk to terrestrial plants is not anticipated due to fenazaquin’s mode of action; disruption of insect

mitochondria.

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### PROPOSED REGISTRATION DECISION

The Gowan Company of Yuma, Ariz ona, submitted applications for these first two registrations (Fenazaquin Technical and GWN- 1708 Miticide/Insecticide) on Ap ril 2, 2007. The requested application use is for the c ontrol of mites and whiteflie s on ornamentals (outdoor and greenhouse-grown), Christmas trees (plantations), established or namental landscapes (including interiorscapes and around residential premises ), and on non-bearing fruit and nut trees. The Agency published a Notice of Receipt for thes e first registrations on February 4, 2008 and

received no comments.

The human health risk assessmen t concluded that the databases are adequate for dietary and occupational assessment for registration of one technical and one end-use fenazaquin formulation. Since the applic ation for registration of fen azaquin was received by the Agency, EPA has added additional guidelin e requirements for toxicity te sting, for which sufficient time has not yet elapsed to generate data. These addi tional studies are proposed to be required within three years as a condition of the registration of fenazaquin:

• Acute Neurotoxicity Sc reening Battery (rat)

• 90 Day Neurotoxicity Screening Battery (rat)

• Immunotoxicity Study

In addition, the following studies are proposed to be required to provide additional certainty in the estimated risk from dermal and inhalation exposures.

• 28-Day Dermal Toxicity Study

• 28-Day Inhalation Toxicity Study

EPA has considered the entire fenazaquin toxi city data base for pot ential neurot oxic and immunotoxic effects. Although ther e are uncertainties in the abse nce of the required acute and subchronic neurotoxicity and im munotoxicity studies, EPA does not believe it necessary to assign a database uncertainty factor (UF db )for the lack of these data based on the following: 1) the NOAEL used for the acute dietary risk asse ssment is protective of the clinical signs indicative of neurotoxicity in the acute oral st udy and 2) based on the toxicity profile of this chemical, it is unlikely that th e results of an immunotoxicity study would result in a NOAEL lower than the point of departure used for chr onic, dermal and inhalation risk assessments.

The environmental fate and effects review conc luded that the database s are adequate for a screening level assessment. Howe ver, because of uncertainty rega rding risk to aquatic organisms and honey bees, EPA has determined additional data requirements are required to better

characterize risk. These studies are proposed to be required as a condition of the registration of fenazaquin:

• Acute toxicity estuarine/marine fish

• Acute toxicity estuarine/ma rine invertebrates (mysid)

• Aquatic invertebrate life-cycle

• Avian acute oral toxicity test (passerine species)

• Avian reproduction study (waterfowl)

9• Honey bee toxicity of residues on foliage

• Aerobic soil metabolism

• Aerobic aquatic metabolism

Pending submission of this data, EPA will require a 100-foot buffer around water bodies. This buffer zone reduces the RQs to below th e LOC for all aquatic organisms.

In order to protect bees, fenazaquin will be la beled with the restriction “Do not apply this product or allow it to drift to blooming crops, we eds or ornamentals while bees are visiting the treatment area.” Due to possible phytotoxicity, fe nazaquin may not be applied to roses which are attractive to bees. Fenazaquin is limited to one application per cropp ing cycle and aerial application is prohibited.

Public Interest

EPA believes that the registration of techni cal fenazaquin and the end use product, GWN-1708, are in the public interest. Fenazaquin is in th e quinazoline chemical class, which is a new class of pesticide chemistry in the U. S. The target pests, mites a nd whiteflies, are known for quickly developing resistance and controlling them has hist orically been challenging. According to the Agency’s Pesticide Registration Notice 2001-5; Guidance for Pestic ide Registrants on Pesticide Resistance Management Labeling, “the management of pesticide resistance development is an important part of sustainable pest management and this, in conjunction with alternative pest management strategies and Integrated Pest Ma nagement (IPM) programs, can make significant contributions to reducing risks to humans and the environment.”

The proposed label for GWN-1708 identifies fena zaquin as a “Group 21 A caricide” with the

mode of action stated on the label as mitochondr ial electron transport inhibition. As defined by

the Insecticide Resistance Acti on Committee Mode of Action Cla ssification, pesticides in Group 21 are “Mitochondrial complex I electron transp ort inhibitors,” and will affect energy metabolism in the target pests. Registra tion of GWN-1708 will provide growers with an

additional tool from a new chem ical class to use in manageme nt of mites and whiteflies. Additionally, fenazaquin is considered to be of low toxicity to hu man health across many endpoints.

For the proposed use sites, fe nazaquin may be used instead of some insecticides in the neonicotinoid class and the keto-enol class, and m iticides such as dicofol, etoxazole, avermectin

and clofentezine. In these cas es, fenazaquin may compare equally or more favorably in human toxicity and ecotoxicity risk.

10Proposed Decision

The Agency believes, in accordance with FI FRA 3(c)(7)(C), that use of fenazaquin on ornamentals, Christmas tree plantations and nonbearing fruit and nut trees while awaiting

conditional data will not cause any unreasonable adverse effect on the environment and that its use is in the public interest. Therefore, the Agency proposes to grant these conditional registrations.

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