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Pymetrozine - Registration of Fulfill and Endeavor Insecticides 1/01

New York State Department of Environmental Conservation
Division of Solid & Hazardous Materials
Bureau of Pesticides Management, Room 498
Pesticide Product Registration Section

50 Wolf Road, Albany, New York 12233-7254
Phone: (518) 457-7446 FAX: (518) 485-8990
Website: www.dec.state.ny.us/website/dshm/pesticid/pesticid.htm
E-Mail:ppr@gw.dec.state.ny.us


January 29, 2001

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Mr. Jerry Harrison
Manager, State Registration and Regulatory Support
Novartis Crop Protection, Inc.
PO Box 18300
Greensboro, NC 27419-8300

Dear Mr. Harrison:

Re: Registration of Two New Pesticide Products Fulfill Insecticide (EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No. 100-913), Which Contain the New Active Ingredient Pymetrozine

    The New York State Department of Environmental Conservation (the Department) has reviewed your application, received July 6, 2000, for registration of Fulfill Insecticide (EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No. 100-913) in New York State. The products contain the new active ingredient pymetrozine. The application was deemed complete for purposes of review September 1, 2000 and a registration decision is due by January 29, 2001.

    Fulfill Insecticide and Endeavor Insecticide are both water dispersible granules with 50% of the active ingredient pymetrozine. Fulfill Insecticide is labeled for control of certain aphids in cucurbit vegetables, fruiting vegetables, potatoes (and other tuberous and corm vegetables) and tobacco. The application rate is 0.086 lb. pymetrozine per acre per application, with a maximum application rate of 0.17 lb. pymetrozine per acre per year. Endeavor Insecticide is labeled "For Professional Use Only" for control of aphids and whiteflies on landscape ornamentals, container grown ornamentals, non-bearing fruit and nut trees in nurseries, Christmas trees, ground covers and ornamental plants in greenhouses, lath and shadehouses, and interiorscapes. The application rate is 0.3125 lb. pymetrozine per acre per application. The maximum application rate is 1.5 lbs. pymetrozine per acre per year outdoors and 3.125 lbs. pymetrozine per acre per year indoors.

    The Department has reviewed the information supplied to date in support of the pesticide product registration application for Fulfill Insecticide (EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No. 100-913).

    The New York State Department of Health (DOH), the Department's Division of Fish, Wildlife & Marine Resources' Bureau of Habitat and the Department's groundwater staff have reviewed the information submitted to date in support of the application for registration of Fulfill Insecticide (EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No. 100-913).

    The DOH stated that neither the active ingredient nor the formulated product was very toxic in acute oral, dermal or inhalation exposure studies in laboratory animals, nor were they very irritating to skin or eyes. The active ingredient, pymetrozine, demonstrated a slight dermal sensitization with an intradermal challenge, but not with an epidermal challenge. The formulated product did not produce sensitization with either challenge.

    In an acute neurotoxicity feeding study with pymetrozine in rats, neurotoxic effects (reduced body temperature, function observation battery changes, and decreased motor activity in males) were reported at 125 milligrams per kilogram per day (mg/kg/day) which was the lowest dose tested; the no-observed-effect level (NOEL) was less than 125 mg/kg/day. In a subchronic (13 week) neurotoxicity feeding study with pymetrozine in rats, neurotoxic effects (stereotypy in males and tiptoe gait in females) were reported at 201 mg/kg/day; the NOEL was 68 mg/kg/day.

    Pymetrozine also caused some toxicity in chronic animal feeding studies. In rats pymetrozine caused liver effects (hepatocellular hypertrophy) at 3.76 mg/kg/day in males and 46.26 mg/kg/day in females. The respective NOEL's were 0.377 and 4.48 mg/kg/day. In mice, increases in liver weight as well as hepatocellular hypertrophy and hemosiderosis (increase in storage of iron) were reported at a dose level of about 250 mg/kg/day; the corresponding NOEL was about 12 mg/kg/day. In dogs, intestinal myopathy (muscle disease) and anemia were reported at a dose level of 27.8 mg/kg/day; the NOEL was about 5.33 mg/kg/day. The United States Environmental Protection Agency (USEPA) established a chronic population adjusted dose (cPAD) of 0.0038 mg/kg/day for the general U.S. population and 0.0013 mg/kg/day for infants, children and females 13 years of age and older. These values were based on the NOEL from the rat chronic feeding study (0.377 mg/kg/day) and uncertainty factors of 100 and 300, respectively. These cPADs have not yet been placed as reference doses in the USEPA's Integrated Risk Information System.

    Developmental studies with pymetrozine were conducted in rats and rabbits. Maternal toxicity (decreased body weight gain and food consumption and efficiency) occurred in rats and rabbits at dose levels of 100 and 75 mg/kg/day, respectively; the respective NOELs were 30 and 10 mg/kg/day. In rats, the developmental toxicity lowest-observed-effect level (LOEL) was 300 mg/kg/day, based on increased incidence of skeletal abnormalities; the NOEL was 100 mg/kg/day. In rabbits, there was also an increased incidence of skeletal abnormalities at doses of 75 mg/kg/day; the NOEL was 10 mg/kg/day. Also, there were increased resportions and post-implantation losses and reduced litter sizes at 125 mg/kg/day. In a two-generation reproduction study in rats, parental toxicity was observed as increases in liver effects. The LOELs were 13.9-17.0 and 16.0-18.1 mg/kg/day for males and females, respectively. The parental NOEL was 1.4-1.7 mg/kg/day for males and 1.6-1.8 mg/kg/day for females. No reproductive effects were noted in either generation at the highest doses tested (136.9-179.0 mg/kg/day for males and 151.6-186.5 mg/kg/day for females). However, offspring systemic/developmental toxicity occurred as decreased pup weight and delay in eye opening in both generations. The LOEL was 136.9-179.0 mg/kg/day for males and 151.9-186.5 mg/kg/day for females. The respective NOELs were 13.9-17.0 and 16.0-18.1 mg/kg/day.

    Pymetrozine caused liver tumors in chronic rodent studies. In female rats, there were significant positive trends for hepatomas and combined hepatomas and/or carcinomas. There was also a significant pair-wise comparison for these tumors between the controls and the highest dose group, 148.3 mg/kg/day. The USEPA determined that the tumor incidence in male rats was within historical control range. In mice, both males and females had significant positive trends for liver carcinomas, hepatomas and combined hepatomas and/or carcinomas. There was also a significant pair-wise comparison between controls and the highest dose group (675.0 mg/kg/day) for liver carcinomas and combined hepatomas and/or carcinomas in males and for hepatomas and combined adenomas and/or carcinomas in females. The USEPA classified pymetrozine as a "likely human carcinogen" and calculated a cancer potency slope factor for this compound of 0.205 (mg/kg/day)-1. Pymetrozine, however, was negative in a number of genotoxicity tests.

    The USEPA established tolerances for residues of pymetrozine in or on curcurbit vegetables and fruiting vegetables at 0.05 parts per million (ppm) each, and for tuberous and corm vegetables at 0.02 ppm. The USEPA estimated that chronic dietary exposure from pymetrozine use on these crops would be 4.5 x 10-4 mg/kg/day for the general U.S. population and 9.6 x 10-4 mg/kg/day for children one to six years of age. These exposure estimates represent 12 percent and 74 percent of the respective chronic population adjusted doses. This chronic dietary exposure analysis was based on the assumption that 100 percent of all commodities for which tolerances are established are treated and that they contain tolerance level residues. The USEPA also did a more refined exposure analysis based on 20 percent crop treatment and anticipated residue levels. Based on a chronic dietary exposure estimate of 8 x 10-7 mg/kg/day for tuberous and corm vegetables only and the cancer potency slope factor of 0.205 (mg/kg/day)-1, an increased lifetime cancer risk of 1.7 x 10-7 was calculated for the general U.S. population.

    The USEPA also evaluated worker risks from the use of the Fulfill and Endeavor products. For mixer/loader/applicators of pymetrozine on potatoes, average daily exposures ranged from 1.8 x 10-6 to 3.6 x 10-5 mg/kg/day, and for pymetrozine on ornamentals and Christmas Trees, the average daily exposure estimates ranged from 1.9 x 10-7 to 5.6 x 10-6 mg/kg/day. When these exposure estimates are compared to a NOEL from the rat chronic feeding study (0.377 mg/kg/day), margins of exposure ranging from about 10,500 to 209,000 and 67,300 to 1,980,000, respectively, can be calculated. Generally, margins of exposure 100-fold or greater are considered adequate by the USEPA. The cancer risk estimates for mixer/loader/applicators of pymetrozine on potatoes, and ornamentals and Christmas trees ranged from 1.8 x 10-7 to 3.9 x 10-6; and 1.8 x 10-8 to 5.9 x 10-7, respectively. These values are within the general USEPA acceptable level of comparison (1 x 10-4 or less) for occupational exposures.

    There are no chemical specific federal or State drinking water standards for pymetrozine. Based on its chemical structure, pymetrozine falls under the 50 microgram per liter (ug/L) general New York State drinking water standard for "unspecified organic contaminants" (10 NYCRR Part 5, Public Water Systems). Using the USEPA cancer slope factor of 0.205 (mg/kg/day)-1 and 6 NYCRR Part 702.4 procedures for deriving ambient water quality standards and guidelines based on oncogenic effects, the value associated with a one in one million increased lifetime cancer risk is 1.4 ug/L for pymetrozine. Using the USEPA cPAD of 0.0013 mg/kg/day for infants, children and females and 6 NYCRR Part 702.5 procedures for deriving ambient water quality standards and guidelines based on non-oncogenic effects, a value of 9.1 ug/L can be calculated.

    Neither pymetrozine nor the formulated Fulfill/Endeavor products were very toxic following acute exposures in laboratory animal studies. The data indicate that pymetrozine caused developmental effects only at doses that also were parentally toxic. In addition, it was not genotoxic. However, pymetrozine did cause liver effects at relatively low doses, including the formation of liver tumors in mice and rats exposed over their lifetimes and the USEPA classified this chemical as a "likely human carcinogen." Both a dietary and occupational cancer risk assessment conducted by the USEPA indicated that the estimated increased lifetime cancer risk to the public and workers generally would not exceed USEPA acceptable levels and estimated non-cancer risks to the public and workers also are low.

    While the estimated risks posed by the Fulfill/Endeavor products are within the USEPA acceptable range, we generally have concerns for registering a pesticide product that has carcinogenic potential unless either the needs for the product are significant or it replaces products that pose greater risks. To address this issue, the registrant submitted a reduced risk rationale document for pymetrozine and its associated end-use products. This document compares the properties of pymetrozine to those of nine other active ingredients that have the same uses on certain crops. Of the possible alternatives to pymetrozine in this document, imidacloprid and acephate are the only other chemicals reported to have the "CAUTION" signal word. Other chemicals considered in this comparison (dimethoate, endosulfan, fenpropathrin, oxydemeton-methyl, methamidophos, oxamyl, and methomyl) have the signal words WARNING, DANGER or DANGER-POISON which indicate a greater acute toxicity or irritancy risk.

    Imidacloprid, a "CAUTION" signal word product, did not show oncogenic potential in laboratory animal studies and is classified by the USEPA as a Group E (evidence for non-carcinogenicity in humans) carcinogen; acephate, the other "CAUTION" signal word product, is classified as a Group C (possible human carcinogen). In total, six of the alternatives are reported to be Group E carcinogens, two are Group C carcinogens and one (oxydemeton-methyl) has not been classified. The USEPA Office of Pesticide Programs reference dose values for the alternative compounds range from 0.0002 to 0.057 mg/kg/day. The cPAD value for pymetrozine is either 0.0013 or 0.0038 mg/kg/day depending on the population group. These values for pymetrozine are about in the middle of the range for the alternate compounds. Acephate, dimethoate, oxydemeton-methyl, methamidophos, oxamyl, and methomyl are all cholinesterase inhibitors. Oxamyl and methomyl are classified as carbamates. Acephate, dimethoate, oxydemeton-methyl and methamidophos are organophosphates.

    The application rate of pymetrozine on potatoes (39 grams per acre) is about 4 to 12-fold less than those of the alternative active ingredients. Similarly, the tolerance for pymetrozine on potatoes (0.02 ppm) is reported to be between 5 and 40-fold lower than those for the other active ingredients. Consequently, pymetrozine use could reduce dietary exposure to insecticides on potatoes. Also, many of the other alternatives have physicochemical properties which, along with their environmental persistence in certain cases, raises some concern about potential impacts on groundwater/drinking water in areas where soils are permeable and the water table is shallow. Pymetrozine's environmental fate properties do not raise these concerns.

    Our groundwater staff stated that the pymetrozine parent has very high Kocs, and modeling indicated that there would be no leaching at the labeled rate. The major mode of degradation when used as labeled would be aerobic metabolism or photolysis from the foliage. The use of the products as labeled should not cause an impact to ground or surface water in New York State.

    The Bureau of Habitat reviewed the information submitted and indicated that there were no fish and wildlife concerns associated with the use of the products, when used as labeled.

    Pymetrozine is an insecticidal compound which belongs to a new chemical class known as pyridine azomethines. It exhibits a unique mode of action which can be characterized as neural inhibition of feeding behavior. Pymetrozine is a low use rate product which controls aphids at lower rates than most commonly used insecticide standards.

    Pymetrozine is an organophosphate alternative and has potential for utility in both integrated pest management (IPM) and resistance management programs because of its unique mode of action, its selectivity, and its safety to predators, parasites, and other beneficial mites and insects. Pymetrozine poses minimal risk to birds, bees, fish and aquatic invertebrates. The pymetrozine environmental fate profile indicates no major issues in the areas of soil mobility and fish bioaccumulation. Pymetrozine is not acutely toxic and is not a mutagen, neurotoxin or a teratogen. The labeled uses of Fulfill Insecticide and Endeavor Insecticide do not appear to pose a significant risk to workers or the general public.

    Therefore, the Department hereby accepts for registration Fulfill Insecticide (EPA Reg. No. 100-912) and Endeavor Insecticide (EPA Reg. No. 100-913).

    Endeavor Insecticide is labeled "For Professional Use Only" and is, therefore, classified as restricted use in New York State in accordance with rules and regulations 6 NYCRR 326.2(g). As such the product is restricted in its purchase, distribution, sale, use, and possession in New York State. According to the New York State Department of Environmental Conservation Regulations 6 NYCRR 326.3 (a): "It shall be unlawful for any person to distribute, sell, offer for sale, purchase for the purpose of resale, or possess for the purpose of resale, any restricted pesticide unless said person shall have applied for, and been issued a commercial permit."

    Furthermore, the product may only be purchased and used by certified applicators in New York State.

    Please contact the Pesticide Certification Section, at (518) 457-7482, if you require information concerning commercial permits or pesticide applicator certification.

    Enclosed are your New York State stamped "ACCEPTED" labels and a copy of the Certificate of Registration.

    If you have any questions, please contact Francis X. Hegener, Chief of our Pesticide Product Registration Section, at (518) 457-7446.


Sincerely,


Maureen P. Serafini
Director
Bureau of Pesticides Management

Enclosures

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