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Tebuconazole - Denial of Application to Register 3/05

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

March 4, 2005 CERTIFIED MAIL

Ms. Janice Jennings
Regulatory Specialist
Bayer Advanced/A Business Unit of Bayer Crop Science, LP
31 Inverness Center Parkway, Suite 425
Birmingham, Alabama 35242

Dear Ms. Jennings:

Re: Denial of Application to Register Bayer Advanced Garden Disease Control for Roses, Flowers, and Shrubs Concentrate (EPA Reg. No. 72155-14). Chemical Code: 128997

    The New York State Department of Environmental Conservation (Department) has evaluated your application and data packages received on 07/17/03; 09/22/03; 04/21/04; and 12/16/04 for the registration of the above-referenced product. The Department has completed the technical review of the submitted materials and finds the product unacceptable for homeowner use in New York State. The potential repetitive handling and use of the concentrate and diluted product, coupled with the detection of noncancer effects and developmental toxicity at relatively low doses of the active ingredient, raise concerns with this Department for the use of this product by homeowners. Therefore, your application to register the above-referenced product has been denied.

    The subject product contains 2.9% of the active ingredient tebuconazole and is registered in New York State for agricultural use, commercial tree injection, and commercial wood preservation use. The current product application is a major change in labeled use pattern (MCL) as it is designated for use by homeowners on ornamental plantings.

    The application was originally received by this Department on 7/17/2003, as a routine application for a product which contains an active ingredient currently registered in New York State for the labeled use pattern. The Department notified Bayer Advanced by letter dated 7/18/2003 of the additional data that would be required for a MCL review. The additional information was submitted by Bayer Advanced on 09/23/2003. The application package was declared incomplete on 11/12/2003 for lack of a homeowner exposure and risk assessment and acute toxicity data evaluation reviews (DERs) for the formulated product. Bayer submitted the required information on 4/21/2004 and the application package was declared complete for technical review on 6/4/2004.

    Pursuant to the review time frame specified in ECL 33-0704.2, a registration decision date of November 1, 2004 was established. Please note that the registration decision date was waived by mutual agreement of both parties in an attempt to resolve issues which obstructed registration of the product. The Department notified Bayer Advanced by letter dated 9/17/2004 that the product could not be registered unless certain concerns raised by the New York State Department of Health (NYSDOH) could be resolved. Bayer Advanced responded to these concerns via letter received 12/17/2004. This letter did not effectively address NYSDOH concerns as restated below. A nontarget organism and environmental fate review were not required after initial screening of the application materials.

Human Health Technical Review:

    To evaluate the acute toxicological properties of the Bayer Advanced product (which contains 2.9% tebuconazole), the United States Environmental Protection Agency (USEPA) permitted the registrant to use data from the acute toxicity studies conducted on a similar product which contains 4.35% tebuconazole since the Bayer Advanced product is simply a water dilution of that product. On an acute basis, the surrogate product was not very toxic to laboratory animals by the oral, dermal or inhalation routes of exposure. It also was neither very irritating to eyes or skin (tested on rabbits) nor did it cause dermal sensitization (tested on guinea pigs).

    In the past, NYSDOH reviewed the toxicological properties of the active ingredient tebuconazole in the pesticide product Elite 45. In that review, tebuconazole was not very toxic to laboratory animals following acute exposures. However, it caused a variety of effects in laboratory animals in chronic studies at relatively low doses and also produced some developmental effects. The USEPA Office of Pesticide Programs derived an oral reference dose (RfD) of 0.03 milligrams per kilogram body weight per day (mg/kg/day) for tebuconazole, based on a no-observed-effect-level (NOEL) of 3 mg/kg/day from a chronic dog study combined with an uncertainty factor of 100. The USEPA used this same value and basis as a Chronic Population Adjusted Dose (cPAD) for evaluating chronic dietary risks. For evaluating acute dietary risks, USEPA used an Acute Population Adjusted Dose (aPAD) of 0.01 mg/kg/day based on a NOEL of 10 mg/kg/day from a mouse developmental toxicity study and an uncertainty factor of 1,000 (100 to account for inter- and intra-species differences and an additional 10-fold factor for Food Quality Protection Act concerns for greater sensitivity of fetuses and children). Tebuconazole caused liver tumors in a chronic mouse study and is structurally similar to other triazole pesticides that also cause liver tumors. The USEPA's Carcinogenicity Peer Review Committee classified tebuconazole as a Group C (possible human) carcinogen and for the purpose of cancer risk assessment recommended that the RfD approach be used to estimate human risk. A current search of the toxicological literature did not find any significant new information on the toxicity of tebuconazole.

    The registrant submitted the results of an exposure risk assessment for the labeled uses of the Bayer Advanced Garden Disease Control Concentrate product. This assessment used several conservative assumptions including that homeowners wore shorts and a T-shirt with no gloves (whereas the Bayer Advanced product label requires the use of long-sleeved shirt, long pants and rubber gloves), and that dermal absorption would be 50% (the data suggest that actual absorption from the product would be lower). For determining margins of exposure (MOEs), dermal exposure estimates (inhalation exposures were determined to be negligible in comparison to dermal exposures) were compared to NOELs of 10 mg/kg/day from an oral developmental toxicity study in mice (for short-term exposures) and 3 mg/kg/day from a one-year dog feeding study (for long-term exposures). For homeowners involved in mixing, loading and application of the product, MOEs for short-term dermal exposures ranged from about 200 to 3,000, and for long-term exposures ranged from about 1,100 to 15,000. For post-application dermal exposures (cutting of flowers), MOEs for adults ranged from about 400 (short-term) to 2,600 (long-term), and for children the MOEs ranged from about 700 (short-term) to 38,000 (long-term). Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate protection. However, a MOE of 1,000-fold or greater may be a more appropriate criterion to use when evaluating risks from acute exposures to children and women of child-bearing age to account for developmental and reproductive concerns as the USEPA has done in evaluating dietary risks (Federal Register, 66: 15,437-15,443, March 19, 2001).

    The Bayer Advanced Garden Disease Control Concentrate product was neither very toxic following acute exposures, nor very irritating to eyes or skin and was not a dermal sensitizer. However, tebuconazole caused several noncancer effects at relatively low doses in chronic animal feeding studies, and also caused developmental toxicity. Also, tebuconazole caused liver tumors in mice following lifetime exposures. While the homeowner exposure and risk assessment provided by the registrant suggests that risks are relatively low in some cases, we have concerns for registering this type of product (homeowner use) given the toxicological properties of tebuconazole.

    The Bayer Advanced product as labeled also raises several concerns given that it is intended for homeowner use. The product contains 32 fluid ounces of concentrate that makes up to 42 gallons of diluted spray. These are substantial quantities for a homeowner product and could pose storage and disposal issues. In addition, the frequency of application in some cases (i.e., for protection of flowers) is as much as two to three times per week, thus creating considerable exposure potential from mixing, loading and application especially if the homeowner does not adhere to the label directions for wearing protective clothing and rubber gloves.

CONCLUSION: The toxicological properties of tebuconazole (especially those that would potentially impact reproduction and development), the low MOEs (below 1,000) for some exposures, the relatively large product package size/quantity, and the frequency of some recommended applications, raise concerns for use of Bayer Advanced Garden Disease Control Concentrate by homeowners. When used as labeled, this product could cause unreasonable adverse effects to humans. The Department hereby denies the application to register Bayer Advanced Garden Disease Control for Roses, Flowers, and Shrubs Concentrate (EPA Reg. No. 72155-14).

    You are reminded that the application fee is nonrefundable. If you wish to reapply, you must submit a complete new application for registration with all required documents and new application fee to register the above-mentioned product.

    Requirements and application forms can be found on our website, the address is noted in our letterhead. 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 regarding this matter, please contact Paula McBath, of my staff, at (518) 402-8768.


Maureen P. Serafini
Bureau of Pesticides Management

cc: Charles Boyd, Bayer Environmental Science
N. Kim/D. Luttinger - NYS Dept. of Health
R. Zimmerman/R. Mungari - NYS Dept. of Ag. & Markets
W. Smith - Cornell University, PSUR