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Zoxamide - Registration of Gavel 75DF Agricultural Fungicide 9/03

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
E-Mail: ppr@gw.dec.state.ny.us

September 12, 2003

CERTIFIED MAIL
RETURN RECEIPT REOUESTED


Raymond S. Brinkmeyer, Ph.D.
State Regulatory Leader
Regulatory Success - Americas Dow AgroSciences LLC
9330 ZionsvilleRoad
Indianapolis, Indiana 46268-1054

Dear Dr. Brinkmeyer:

Re: Registration of One New Pesticide Product, Gavel 75DF Agricultural Fungicide (EPA Reg. No. 62719-441), Which Contains the New Active Ingredient Zoxamide

    The New York State Department of Environmental Conservation (Department) has reviewed your application, received November 21, 2001, and additional information, received March 15, 2002, August 29, 2002, and March 5, 2003, to register one new pesticide product, Gavel 75DF Agricultural Fungicide (EPA Reg. No. 62719-441), in New York State. The product contains the currently registered active ingredient mancozeb and the new active ingredient zoxamide (chemical code 10 1702).

    The application was deemed complete for purposes of review on April 22, 2003 and a registration decision is due by September 19, 2003.

    Gavel 75DF Agricultural Fungicide (EPA Reg. No. 62719-441) is labeled as a broad-spectrum protectant fungicide for disease control in potatoes, cucurbits, and tomatoes. The product is applied foliarly via ground and aerial application. The maximum application rate for potatoes is 8 pounds of mancozeb and 1 pound of zoxamide per acre per crop, and the maximum application rate for tomatoes and cucurbits is 10.67 pounds of mancozeb and 1.33 pounds of zoxamide per acre per crop.

    The Department has reviewed the information supplied to date in support of registration of the new product Gavel 75DF Agricultural Fungicide (EPA Reg. No. 62719-441) in New York State.

HEALTH EFFECTS:
    The New York State Department of Health (DOH) stated that neither zoxamide nor the formulated Gavel 75DF product was very toxic in acute oral, dermal or inhalation exposure studies in laboratory animals. Both the active ingredient and the formulated product were moderate eye irritants (tested on rabbits). Zoxamide was not a skin irritant, but the formulated product was slightly irritating (tested on rabbit skin). Both zoxamide and Gavel 75DF were strong dermal sensitizers (tested on guinea pigs).

    Both acute and subchronic neurotoxicity studies were conducted on zoxamide. No effects were reported in the acute oral neurotoxicity study at dose levels up to 2,000 milligrams per kilogram body weight (mg/kg). No signs of neurotoxicity were noted in a 90-day oral rat neurotoxicity study at zoxamide doses up to 1,509 mg/kg/day in males and 1,622 mg/kg/day in females, the highest doses tested.

    Zoxamide caused some toxicity in subchronic dermal and feeding studies in laboratory animals. In a 28-day dermal study in rats, zoxamide caused dermal effects (scabbing, hyperplasia, hyperkeratosis and inflammation) at 150 mg/kg/day, the lowest dose tested. No systemic effects were reported at up to the highest dose tested (1,000 mg/kg/day). In a 90-day feeding study in dogs, an increase in liver weight, hepatocellular hypertrophy, and a decrease in albumin and albumin/globulin ratios were reported in males at a dose level of 1,139 mg/kg/day; the no-observed-effect level (NOEL) was 322 mg/kg/day. Zoxamide caused increased liver weights in females at 322 mg/kg/day; the NOEL was 55 mg/kg/day. No effects were noted in a 90-day feeding study in mice at doses up to 1,666 mg/kg/day.

    Zoxamide was also evaluated in chronic animal feeding studies. In a one-year dog feeding study, zoxamide caused decreased body weight, increased liver and thyroid weight, and increased alkaline phosphatase at a dose of 255 mg/kg/day in males and 278 mg/kg/day in females; the NOELs were 50 mg/kg/day and 48 mg/kg/day, respectively. Zoxamide did not cause any effects at doses up to 1,289 mg/kg/day in a chronic feeding/oncogenicity study in mice, or at 1,058 mg/kg/day in a chronic feeding/oncogenicity study in rats, which were the highest doses tested. The United States Environmental Protection Agency (USEPA), Office of Pesticide Programs established a reference dose of 0.48 mg/kg/day for zoxamide based on the NOEL of 48 mg/kg/day from the chronic dog feeding study and an uncertainty factor of 100. This same value was used as a chronic population adjusted dose (cPAD) for evaluating dietary risks. This RfD value has not yet been placed in USEPA's Integrated Risk Information System (IRIS). Zoxamide did not cause oncogenic effects in rat or mouse chronic feeding studies. This compound was also negative in a number of genotoxicity studies. The USEPA classified zoxamide as "not likely" to be a human carcinogen.

    Zoxamide did not cause developmental effects in offspring of either pregnant rabbits or rats administered this compound during organogenesis at doses up to 1,000 mg/kg/day. No maternal toxicity was observed in either study as well. In a two-generation reproduction study in rats, no reproductive effects were reported at 2,091 mg/kg/day in males and 2,239 mg/kg/day in females, which were the highest doses tested. Parental toxicity consisted of decreased body weight and body weight gain in females at 1,624 mg/kg/day; the NOELs were 409 mg/kg/day in females and 1,474 mg/kg/day in males.

    The USEPA reported the results of an occupational risk assessment for inhalation exposures to zoxamide from use on potatoes. The USEPA did not identify an appropriate toxicity endpoint for dermal exposure (no systemic effects were noted in the 28-day dermal study in rats), so this exposure pathway was not considered in the occupational risk assessment. It was assumed that zoxamide was mixed, loaded, and applied to between 160 and 990 acres per day, depending on application methods. For determining margins of exposure (MOEs), the USEPA compared estimated short- and intermediate-term inhalation exposures to a NOEL of 48 mg/kg/day from the chronic dog feeding study. For commercial handlers and applicators, the MOEs for inhalation exposure ranged from 27,000 (for mixing/loading a dry flowable formulation for aerial/chemigation application) to 370,000 (for applying sprays with a fixed-wing aircraft with an enclosed cockpit). Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate worker protection. Post-application exposures, were not evaluated because dermal endpoints were not identified by the USEPA for this potential exposure pathway.

    Although occupational risks from dermal exposure were not evaluated by USEPA, this aspect should be considered. The exposure assessment indicates that mixer/loader/applicators applying Gavel 75 DF by ground boom to 160 acres of potatoes per day would have dermal exposures to zoxamide of 0.034 mg/kg/day. This exposure assessment assumed that mixer/loaders wore long-sleeved shirt, long pants and gloves, and that applicators wore long-sleeved shirt, long pants, but no gloves. In the 28-day dermal exposure study in rats, dermal effects were noted at the lowest dose tested, 150 mg/kg/day. Comparing the lowest-observed-effect level (LOEL) in the rat study to the estimated exposure yields an MOE of about 4,400. MOEs are ordinarily calculated using NOELs, not LOELs, and the above MOE may not be valid given that an appropriate NOEL was not available for this study and it is not possible to determine how much lower a NOEL would be for these effects. The lack of a NOEL is of particular concern as it cannot be determined from the information provided whether the dermal effects in the rat study were simple irritation resulting from repeated skin contact or if they were from a sensitization reaction. If the effects represent a sensitization reaction, the actual NOEL could be substantially lower than the LOEL identified in the study. Consequently, MOEs for sensitized workers would be substantially lower than those calculated above. Also, given the fact that dermal exposure and dermal effects are at issue, evaluating risks on a mg/kg/day basis may not be the most appropriate form of comparison. It may be more appropriate to evaluate risks on the basis of the amount of zoxamide applied per square centimeter of skin in the rat study compared to dermal contact levels in exposed workers using the same measurement.

    There are no chemical specific federal or State drinking water/groundwater standards for zoxamide. Based on its chemical structure, zoxamide falls under the 50 microgram per liter New York State drinking water standard for "unspecified organic contaminants" (10 NYCRR Part 5, Public Water Systems).

    The available information on zoxamide and Gavel 75DF Agricultural Fungicide indicates that they are not very acutely toxic in laboratory animal studies, but both zoxamide and Gavel were dermal sensitizers. Zoxamide was not neurotoxic, oncogenic or genotoxic, and did not cause reproductive/developmental effects. Zoxamide did not cause effects in rodents, even at the highest doses tested in subchronic and chronic feeding studies, but caused some liver and thyroid toxicity in dogs. Risks to the general public from Gavel use are expected to be low as there are no labeled residential uses and estimated dietary exposure to zoxamide from treated food commodities is minimal. However, the sensitizing nature of the active ingredient and formulated product pose a concern for workers. This concern is partially mitigated by the label requirement for personal protective equipment (long-sleeved shirt, long pants, chemical-resistant gloves, shoes plus socks) and the precautionary label statement that "This product is a dermal sensitizer," but it is not possible to determine whether adequate MOEs exist for dermal sensitization. Moreover, the DOH has concerns for zoxamide being a potential inhalation sensitizer. The USEPA also apparently had this concern and required as a condition of federal registration that an inhalation sensitization study be conducted and that the registrant monitor instances of inhalation and dermal sensitization from Gavel use.

ECOLOGICAL EFFECTS:
    The Department's Division of Fish, Wildlife & Marine Resources' Bureau of Habitat (BOH) reviewed the information submitted in support of registration of Gavel 75DF Agricultural Fungicide and stated that they have no objection to registration.

ENVIRONMENTAL FATE AND GROUNDWATER IMPACTS:

    The Department's groundwater staff stated the following:

Hydrolysis: Zoxamide (RH-117281) had a half-life of 15.5, 15.7 and 8.1 days in pHs 4,7 and 9 respectively. The following degradates were found: RH-150721 at 38%, RH-24549 at 31%, RH-141288 at 22% and RH-129151 at 25%.

Aqueous Photolysis: Zoxamide had a half-life of 14 days in a pH 4 buffer solution. The following degradates were found: RH-150721 at 11%, RH-24549 at 28%, and RH-139432 at 42%. Soil Photolysis: Zoxamide had a corrected half-life of 78 days. The following degradates were found: RH-24549 at 22%, RH-129151 at 4%, and RH-127450 at 11%.

Aerobic Soil Metabolism: Zoxamide had a half-life of 37.5 and 38.1 days. No major degradates were found. The following minor degradates were found: RH-24549 at 7%, RH-127450 at 6%, RH-129151 at 1.6%, and RH-139432 at 1%.

Anaerobic Soil Metabolism: Zoxamide had a half-life of 14.6 days in a pH 7.2 sandy loam. The following degradates were found: RH-24549 at 17%, RH-127450 at 13%, RH-141288 at 0.7%, RH-129151 at 0.9%, and RH-139432 at 0.5%.

Aerobic Aquatic Metabolism: Zoxamide had a half-life of 3.6 and 7.6 days in a pH 7 to 8 soil and water system. The following degradates were found: RH-150721 at 11%, RH-127450 at 20%, and RH-163353 at 13%.

Adsorption/Desorption: The results of batch equilibrium studies suggest low mobility of zoxamide in terrestrial and aquatic environments. KocS were 815, 1196, 1294, 1385, 1431 on a loam, sandy loam, silty clay loam, sandy loam and silty loam, respectively. Further studies are required on aged zoxamide in order to assess the mobility of the degradates.

Field Dissipation: Zoxamide had half-lives of 11.5 days, 15 and 17.7 days and 9.4, 14.2, and 68.8 days on bare ground plots in California, New York and Canada respectively. The registrant did not attempt to identify any degradates that were less than 10% in the lab studies. The field dissipation study results are difficult to interpret because of the lack of adequate information on the frozen storage stability of zoxamide.

Computer Modeling: Running LEACHM using the Riverhead sandy profile, a Koc of 1196, a half-life of 37 days and an application rate of 1 lb ai/a/yr, the model predicted cyclic peaks ranging up to .0000006 ppb.

    Groundwater staff stated that given the moderate Koc, the short aerobic and field half-life, and fairly low application rate, use of this product as labeled should not impact the groundwater resources of New York State.

    Dow AgroSciences LLC submitted additional information, on September 8, 2003, in response to Department concerns pertaining to worker exposure, dermal sensitization, and pulmonary sensitization.

    In regards to worker protection and exposure, Dow AgroSciences LLC stated that additional protective measures appear on the label under "Agricultural Use Requirements." For potatoes, workers must be notified prior to entering a field that the area was treated with a possible skin sensitizer and that they must report any reaction via the phone number on the label. There is a 48 hour restricted entry interval (REI) on the label, even though normal cultural practices used in growing potatoes indicate that it is highly unusual for a worker to need to reenter a field.

    For tomatoes and cucurbits, there is actually double notification. The USEPA has required that workers are verbally warned about potential skin sensitization, and signs must be posted at the entrances to treated areas. Signs must be posted for 4 days after treatment.

    Therefore, the combined safety elements are:
  1. Verbal warning to workers prior to entry
  2. 48 hour REI
  3. Printed warning sign
  4. A four day posting requirement for warning sign
  5. Protective clothing
    Dow AgroSciences LLC stated that a delayed contact hypersensitivity study in guinea pigs was completed and submitted to the USEPA in February 2002. Based on the results of the study, Gavel 75DF produced mild to moderate contact hypersensitivity under study conditions. To date, the USEPA has not responded to the results of this study. The USEPA required as a condition of federal registration that Dow AgroSciences LLC give workers the ability to notify the company of any complaints regarding sensitization. Also, a survey was conducted of laboratory workers, production personnel, formulators, and field cooperators who had worked with and/or used Gavel or the active ingredient zoxamide. No adverse sensitizations were reported.

    The Department has determined that Gavel 75DF Agricultural Fungicide should be classified as a restricted use product in New York State due to the concerns regarding exposure and sensitization. The restricted use classification of the product may be revisited when more information and data is available for submission and review by the Department. The Department concludes that Gavel 75DF Agricultural Fungicide will not have an adverse effect on the health of workers or the general public, the fish and wildlife resources, or the ground and surface water of New York State when used as labeled and all additional protective measures are followed.

    Therefore, the Department hereby accepts for restricted use registration the new product Gavel 75DF Agricultural Fungicide (EPA Reg. No. 62719-441).

    The pesticide product is classified as "restricted use" in New York State according to rules and regulations 6NYCRR 326.23(e). Please note the "YES" under the "restriction" column on the enclosed Certificate of Pesticide Registration and the "classified for restricted use in New York State" stamp on the enclosed product label.

    As such this product is restricted in its purchase, distribution, sale, use and possession in New York State. Furthermore, this product may only be purchased and used by a certified applicator in New York State.

    According to New York State Department of Environmental Conservation Regulations 6NYCRR 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." Should you require information to obtain a commercial permit, please contact the Pesticide Certification Section at (518) 402-8748.

    The Pesticide Reporting Law (PRL) in the Environmental Conservation Law Article 33 Title 12 requires all certified commercial pesticide applicators to report information annually to the Department regarding each pesticide application they make. Commercial pesticide retailers are required to report all sales of restricted pesticide products and sales of general use pesticide products to private applicators for use in agricultural crop protection. If no sales are made within New York State, a report still must be filed with the Department indicating this is the case.

    If you need information relating to the Pesticide Reporting Law, or annual report forms, please visit the Department's website or call 1-888-457-0110 (toll free within New York State). Out-of-State callers may contact the Pesticide Reporting Section at (518) 402-8765. Enclosed are your New York State stamped "ACCEPTED" label and a copy of the Certificate of Registration.

    Dow AgroSciences LLC is reminded that if New York State registration is requested for this product or for any other product which contains zoxamide with an increased application rate and/or expanded use sites, the product will be considered a Major Change in Labeling and the Department will require an extensive review.

    If you have any questions, please contact Mr. Samuel Jackling, Chief of our Pesticide Product Registration Section, at (518) 402-8768.

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