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Flonicamid
NYS DEC Letter - Registration of Technical flonicamid and F1785 GH 50 WG Insecticide (EPA Reg. No. 279-3264) Containing the Active Ingredient Flonacimid 6/04

New York State Department of Environmental Conservation
Division of Solid & Hazardous Materials

Bureau of Pesticides Management
Pesticide Product Registration Section
625 Broadway, Albany, New York 12233-7257
Phone 518-402-8768     FAX 518-402-9024
Website: http://www.dec.state.ny.us/website/dshm/pesticid/pesticid.htm
E-Mail: ppr@gw.dec.state.ny.us

June 9, 2004

CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Mr. Michael Peplowski
Manager, Product Registrations
ISK Biosciences Corporation
7470 Auburn Road, Suite A
Concord, Ohio 44077

Mr. Michael Zucker
Senior Registration & Label Specialist
FMC Corporation - Agricultural Products Group
1735 Market Street - Rm 2298
Philadelphia, Pennsylvania 19103

Dear Messrs. Peplowski and Zucker:

Re: Registration of Technical Flonicamid Insecticide (EPA Reg. No. 71512-7) and F1785 GH 50 WG Insecticide (EPA Reg. No. 279-3264) Containing the Active Ingredient Flonicamid

    The New York State Department of Environmental Conservation (Department) has completed its technical review of ISK Biosciences Corporation (ISK) application and data package submitted on 12/08/03 to register Technical Flonicamid Insecticide and FMC Corporation (FMC) application and data package submitted on 12/12/03 to register F1785 GH 50 WG Insecticide (EPA Reg. No. 279-3264). The active ingredient, flonicamid, is a low dosage pyridine insecticide for control of aphids and other sucking and chewing insects. The formulated product is labeled for use in commercial greenhouses and interiorscapes. The Department has registered these products for sale, distribution, and use in New York State, in accordance with the enclosed approved labeling.

    The new active ingredient (NAI) review on F1785 GH 50 WG Insecticide (EPA Reg. No. 279-3264) was conducted concurrently with the review on the Technical Flonicamid Insecticide (EPA Reg. No. 71512-7) manufacturing use product (MUP) application. The MUP contains 98.4% flonicamid while FMC's formulated product contains 50% flonicamid and is applied at a maximum use rate of 120 grams of product (0.134 lb. flonicamid) per 100 gallons of water. A volume of 200 gallons/acre may be applied to plants greater than six feet in height (maximum use rate = 0.268 lb. active ingredient per acre). The product may be reapplied every seven to 28 days as necessary. To limit pest resistence to this product, it is recommended that the user rotate to a different chemistry after two consecutive applications of this product. The label also states that a NPDES permit is required if water containing flonicamid is discharged into the waters of the State. Flonicamid was registered by the United States Environmental Protection Agency (USEPA) as a potential organophosphate replacement product.

    Pursuant to the review time frame specified by New York State ECL §33-0704.2, registration decision dates of July 2, 2004 (ISK) and August 20, 2004 (FMC) were established. The Department has conducted the following technical reviews with regard to the registration of both products for impact to human health, nontarget organisms, and the environment. Review summaries are provided below:

Human Health Review:
    Neither the active ingredient flonicamid nor the formulated product was very toxic in acute oral, dermal or inhalation toxicity studies in laboratory animals. Also, neither material was a skin irritant (tested on rabbits) nor a skin sensitizer (tested on guinea pigs). The active ingredient was not an eye irritant (tested on rabbits), but the formulated product showed severe eye irritation properties.

    Several subchronic toxicity studies were conducted on flonicamid. In a 90-day rat feeding study, histopathological changes (hyaline deposition) in the kidneys of males and females were reported at 60 and 340 milligrams per kilogram body weight per day (mg/kg/day), respectively. Also, liver effects (centrilobular hypertrophy) were observed in female rats at a dose of 340 mg/kg/day. The no-observed-effect levels (NOELs) for males and females were 12.1 and 72.3 mg/kg/day, respectively. In a subchronic neurotoxicity feeding study in rats, no neurotoxic effects were observed either in males or females at doses up to 625 and 722 mg/kg/day, respectively (the highest doses tested). Mice fed flonicamid for 90 days had increased liver and spleen weights, and showed histopathological changes in bone marrow, spleen and kidney at a dose of 154 mg/kg/day in males and 192 mg/kg/day in females. The respective NOELs were 15.3 and 20.1 mg/kg/day. In a 90-day dog study, oral administration of flonicamid resulted in increased adrenal weights and decreased thymus weights in males at 20 mg/kg/day. In females, lower red blood cell counts and an increase in kidney tubular vacuolations were observed at 50 mg/kg/day. The respective NOELs for males and females were eight and 20 mg/kg/day.

    Because the formulated product is labeled for nonfood use only, the USEPA did not require chronic feeding/oncogenicity studies, a multigeneration reproduction study or a rabbit developmental toxicity study for its registration. Several genotoxicity studies were required, in which flonicamid yielded negative results. In the required rat developmental toxicity study, some evidence of developmental effects, characterized by increased fetal skeletal variations, was reported in rats at a dose (500 mg/kg/day), which also caused maternal toxicity. Observed maternal effects included increased liver weight, hypertrophy of centrilobular liver cells and vacuolation of proximal tubular cells of the kidneys. The reported NOEL for both developmental and maternal toxicity was 100 mg/kg/day.

    Even though chronic feeding/oncogenicity studies and some developmental/reproduction toxicity studies were not required for the labeled nonfood use of flonicamid in the formulated product F1785 GH 50 WG Insecticide, a summary of these toxicity studies was presented in the Federal Re ister (Vol. 68, May 23, 2003; pages 28, 218-28, 222). In regard to these studies, no developmental toxicity was observed in rabbits at the highest dose of flonicamid tested, which was 25 mg/kg/day. In addition, no effects on reproductive performance was reported in rats, also at the highest doses tested of 197 and 402 (mg/kg/day)-1 for males and females, respectively. In chronic rodent feeding studies, flonicamid caused some toxicity including liver and hematological effects in mice and rats at doses of about 30 and 37 mg/kg/day, respectively. The NOEL was 7.3 (mg/kg/day)-1 for rats. No NOEL was observed in the mouse chronic feeding/oncogenicity study. In a chronic oral dog study, reduced body weights in females and effects on circulating red blood cells were reported at 20 mg/kg/day; the NOEL was eight mg/kg/day.

    Flonicamid did not cause oncogenic effects in the rat chronic feeding study. In mice, however, a statistically significant increase in the incidence of lung (alveolar/bronchiolar) adenomas occurred in all three dose groups (30, 89 and 264 mg/kg/day) of both sexes. Lung carcinomas were only significantly increased in the high dose female mice. Although the USEPA did not calculate a cancer potency slope factor for flonicamid, the registrant using data on lung tumors in mice, calculated a value of 0.031 (mg/kg/day)-1.

    The registrant conducted an occupational risk assessment for dermal and inhalation exposure of workers exposed to flonicamid in the handling and application of the formulated product in greenhouses. For estimating exposures, it was assumed that workers wore personal protective equipment (long-sleeved shirt and long pants, shoes plus socks, protective eyewear, waterproof gloves) as required by the product's label. Inhalation exposures were estimated assuming 100% absorption of flonicamid, whereas for dermal exposures, the estimated percent of active ingredient absorbed was either 1.2 or six percent. Using the registrant's derived cancer potency slope factor of 0.031 (mg/kg/day)-1 and estimated dermal and inhalation exposures, an increased lifetime cancer risk of about 2.5 x 10-5 can be calculated. This value is within the range of what USEPA generally considers to be acceptable (1 x 10-4 or less) for occupational exposures. For post-application exposures of greenhouse workers, the highest increased lifetime cancer risk estimated was 5 x 10-6. Comparing the same occupational exposure estimates to a NOEL of 7.3 (mg/kg/day)-1 from the rat chronic feeding/oncogenicity study, margins of exposures (MOEs) for handling/application of flonicamid in greenhouses and for post-application exposure were 9,000 and 46,000, respectively. Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate worker protection.

    There are no chemical specific federal or State drinking water/groundwater standards for flonicamid. Based on its chemical structure, this compound falls under the 50 microgram per liter New York State drinking water standard for "unspecified organic contaminants" (10 NYCRR Part 5, Public Water Systems). Using the cancer potency slope factor for flonicamid of 0.031 (mg/kg/day)-1 and 6 NYCRR Part 702.4 procedures for deriving ambient water quality standards and guidelines based on oncogenic effects, the ambient water quality value associated with a one in one million increased lifetime cancer risk is 1.1 micrograms per liter for flonicamid.

    The available information indicates that neither flonicamid nor F1785 GH 50 WG Insecticide is very acutely toxic. Although the formulated product can cause severe eye irritation, the use of protective eyewear, as required by the product label, should mitigate this potential effect. Flonicamid caused limited developmental toxicity, but only at doses that also caused maternal toxicity. Chronic feeding/oncogenicity studies in rodents indicate that flonicamid caused lung tumors in both male and female mice, but did not cause oncogenic effects in rats. The USEPA noted "[T]hat the lung effects are unique to the mouse and are not likely to translate to other species including the rat." Nevertheless, the registrant conducted an occupational cancer risk assessment for greenhouse exposure to flonicamid. This assessment showed that the occupational health risks, both cancer and noncancer, posed by using the formulated product, are within the USEPA acceptable range. Overall, the weight of evidence indicates that flonicamid should not pose a significant risk to workers or the general public. However, given that flonicamid appears to have some oncogenic potential, the Department would require a reanalysis of risks and a comparison to other products also registered for those same uses if a registrant seeks to add use of flonicamid on food crops.

Nontarget Organism Review:
    The USEPA either waived many ecological data requirements or did not require certain studies because of the indoor use pattern. Many other studies were classified as supplemental. From the limited data that were provided, flonicamid appears to exhibit relatively low toxicity to fish, aquatic organisms, birds, or mammals. It is stable to photolysis and hydrolysis in water or soil. The primary fate process is microbial metabolism. The half-life for this fate process was 3.1 days.

Modeling: AVTOX and MAMTOX models could not be run because no residue data were provided. Aquatic modeling was run with PONDTOX. The model showed that a direct application of flonicamid at the highest labeled rate to a one-acre pond 0.5 feet deep would not exceed toxicity thresholds or NOECs for rainbow trout, bluegill, green algae (Selenastrum capricornutum) or Daphnia magna.

Nontarget Organism Review Summary: Flonicamid appears to be relatively nontoxic to fish and wildlife. Used as labeled, i.e., commercial greenhouses and interior plantscapes, this insecticide is not likely to have adverse ecological effects. However, flonicamid must not be registered for outdoor uses in New York State unless the product is reviewed again with a comprehensive data support package to justify proposed outdoor uses.

Environmental Fate Review:
Hydrolysis: This study was found to be acceptable. At 25° C, flonicamid was stable in pH 5 and 7 aqueous buffer solutions. The half-life was estimated to be 204 days in a pH 9 buffer solution. In the pH 9 solution, the major degradate TFNG-AM (N-(4-trifluoromethyl-nicotinoyl)glycinamide) at 30.5% at 120 days was found and the minor degradate TFNG [N-(4-trifluoromethylnicotinoyl) lycine] averaged < 3%.

Aqueous Photolysis: USEPA found this study to be acceptable. At pH 7, flonicamid had a half-life of 534 days. No major transformation products were noted.

Soil Photolysis: This study was found to be acceptable. In a loamy sand soil, flonicamid had a calculated half-life of 22.4 days. TFNG-AM and TFNG were both minor transformation products. Aerobic Soil Metabolism: This study was found to be supplemental. In a loamy sand, the half-life was 3.1 days. Major transformation products were 4-trifluoromethyl nicotinic acid (TFNA) at 36.9%; 6-hydroxy-4-trifluoromethyl nicotinic acid (TFNG-OH) at 21.8%; TFNG-AM at 10.3%; and CO2. Minor transformation products were 4-trifluoromethylnicotinamide (TFNA-AM) at eight percent and TFNG three percent.

Adsorption/Desorption: These studies were found to be acceptable. Kocs ranged from 7.9 to 34.9 in various UK or German loamy sands and sandy loams, treated with either five mg/kg or 12 mg/kg of parent and with or without 0.01 % HgCl.

Computer Modeling: Modeling was done using Riverhead sand, an application rate of 0.067 ai/a/app (the application rate of one- to two-foot high plants), a Koc of 34.9, and an aerobic half-life of 3.1 days. The label allows an application every seven to 28 days, with no more than two consecutive applications before switching to another insecticide. Assuming two applications per month, and assuming the greenhouse runs all year around, 24 applications were applied. The model projected one peak of approximately 0.4 ppb.

Environmental Fate Summary: Flonicamid has very low Kocs and is very mobile. It also has a very short half-life under environmental conditions coupled with low application rates. These two factors limit accumulation of the chemical to well below the level of concern to human health as reported by the Department's Human Health Review. Modeling indicates that use of F1785 GH 50 WG Insecticide as labeled, should not negatively impact groundwater.

Registration Summary:
    Enclosed for your record is a copy of your stamped accepted label and the Certificate of Registration for your product. Please note that a proposal by ISK/ FMC, or any other registrant, to register a product that contains flonicamid for outdoor use, use on food crops, or any other labeled uses that are likely to increase the potential for significant impact to humans, nontarget organisms, or the environment, would constitute a major change in labeled (MCL) use pattern. Such an application must be accompanied by a new application fee and meet the requirements listed in Appendix 1.B. of "New York State Pesticide Product Registration Procedures" (August 1996). Such information, as well as forms, can be accessed at our website as listed in our letterhead. Please note that any application for outdoor use will require review of additional analytical methodology for soil and water matrices.

    Please be aware that any unregistered product may not be sold, offered for sale, distributed, or used in New York State.

    If you have any questions on this matter, please contact our Pesticide Product Registration Section, at (518) 402-8768.

Sincerely,

Maureen P. Serafini
Director
Bureau of Pesticides Management

Enclosure
cc: w/enc. - N. Kim/D. Luttinger - NYS Dept. of Health
R. Zimmerman/ R. Mungari - NYS Dept. of Ag. & Markets
W. Smith - Cornell University, PMEP