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thiophanate-methyl NYS DEC Letter - Registration for Major Change in Label 6/04

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

Bureau of Pesticides Management, 9th Floor
625 Broadway, Albany, New York 12233-7254
Phone: (518) 402-8788     FAX: (518) 402-9024
Website: www.dec.state.ny.us

June 7, 2004

CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Mr. Timothy M. Formella
Manager, Product Registration
Cerexagri, Incorporated
630 Freedom Business Center, Suite
402 Wilmington, Delaware 19808

Dear Mr. Formella:

Re: Registration for the Major Change in Labeling of TopsinŽ M WSB (EPA Reg. No. 4581-408) Containing the Active Ingredient Thiophanate-methyl

    The New York State Department of Environmental Conservation (Department) has reviewed the referenced application received March 7, 2003, and additional information, received June 6, 2003; September 12, 2003; and April 13, 2004. The application was deemed complete for purposes of review on October 17, 2003.

    A waiver of the Registration Decision date was mutually agreed upon in order to allow Cerexagri, Inc., time to submit additional information for determining the comparative risks of alternate products as well as the demonstration of need to register Topsin for use on additional crops in New York State.

    Topsin M WSB, which is a 70% wettable powder packaged in one-pound water soluble bags, contains the active ingredient thiophanate-methyl (dimethyl [(1,2-phenylene)-bis (iminocarbonothioyl]bis[carbamate]) and is currently registered as a systemic fungicide for use on a large variety of crops. The registrant has requested that grapes, potatoes and pears be added to the labeled crops for this product.

    In the initial review of this major change in labeling for Topsin M WSB, it was determined that neither thiophanate-methyl nor Topsin M WSB was very toxic in acute oral, dermal and inhalation studies in laboratory animals, nor were they very irritating to the eyes or skin (tested on rabbits). Whereas the formulated product did not show skin sensitizing properties as tested on guinea pigs using the Buehler test, the active ingredient was a skin sensitizer when using the more sensitive Magnusson guinea pig maximization test.

    Thiophanate-methyl caused some toxicity in chronic animal feeding studies. In a chronic feeding/oncogenicity study in rats, thiophanate-methyl caused liver and thyroid gland hypertrophy and thyroid hyperplasia at a dose of 54.4 milligrams per kilogram body weight per day (mg/kg/day); the no-observed-effect level (NOEL) was 8.8 mg/kg/day. Liver hypertrophy also was observed in mice chronically fed thiophanate-methyl at a dose of 123 mg/kg/day; the NOEL was 23.7 mg/kg/day. In dogs, thyroid effects (thyroid hypertrophy and decreased thyroid hormone levels) and a decrease in body weight gains were reported at 40 mg/kg/day; the NOEL was eight mg/kg/day. The United States Environmental Protection Agency (USEPA) Office of Pesticide Programs established a reference dose (RfD) of 0.08 mg/kg/day for thiophanate-methyl based on a NOEL of eight mg/kg/day in the chronic dog feeding study and an uncertainty factor of 100. This RfD (at least numerically) has been adopted by the USEPA's Integrated Risk Information System (IRIS). It should be noted, however, that the IRIS RfD for thiophanate-methyl is based on a rat chronic feeding study which is different from that submitted by the registrant and discussed above. In both rat studies, the critical effect was on the thyroid.

    Thiophanate-methyl caused some developmental toxicity in the offspring of pregnant rabbits. In a rabbit oral developmental toxicity study, an increased incidence in supernumerary ribs and a decrease in fetal weights were observed at 40 mg/kg/day; the NOEL was 20 mg/kg/day. Maternal toxicity, characterized by a decrease in body weight and food consumption, was reported at 20 mg/kg/day, with a NOEL at ten mg/kg/day. In a rat oral developmental toxicity study, no developmental effects were reported at doses up to 163 mg/kg/day. However, some maternal toxicity, characterized by a decrease in food consumption, occurred at 85 mg/kg/day; the NOEL was 18 mg/kg/day. In a multigeneration reproduction study in rats, thiophanate-methyl caused a decrease in body weights of the offspring during lactation at 43.3 mg/kg/day; the NOEL was 13.7 mg/kg/day. Parental toxicity characterized by hypertrophy of the liver and thyroid gland, and hyperplasia of the thyroid, at 13.7 mg/kg/day (the lowest dose tested).

    Oncogenic effects were observed both in mice and rats in chronic feeding studies with thiophanate-methyl. In mice, statistically significant dose-dependent increases in hepatocellular adenomas were observed in males and females at the two highest doses tested (468 and 1,079 mg/kg/day for males, 558 and 1,329 mg/kg/day for females). In addition, the combined incidence of hepatocellular adenomas and carcinomas was increased in males. In rats, a statistically significant increased incidence of thyroid follicular cell adenomas was observed in males at 281 mg/kg/day, which was the highest dose tested. Although this dose was considered excessive by the USEPA's Health Effects Division, Cancer Assessment Review Committee (CARC), based on high mortality, the CARL concluded that the increased incidence of thyroid tumors was biologically significant since a dose-response was observed in both sexes. The CARC classified thiophanate-methyl as "likely to be carcinogenic to humans" based on the dose-dependent increase in liver tumors (combined incidence of adenomas and carcinomas) in male mice. Using this tumor incidence data, the USEPA calculated a cancer potency slope factor for thiophanate-methyl of 0.0138 (mg/kg/day)-1 Although two acceptable genotoxicity studies on this chemical were negative, "The CARC determined that additional genotoxicity testing should be provided to adequately assess direct mutagenicity of thiophanate-methyl."

    The USEPA established tolerances for thiophanate-methyl residues in or on grapes at 5.0 parts per million (ppm) and in or on potatoes and pears each at 0.1 ppm. The chronic population adjusted dose (cPAD) for thiophanate-methyl is 0.027 mg/kg/day based on the RfD of 0.08 mg/kg/day and an additional uncertainty factor of three to account for the absence of acute, subchronic and developmental neurotoxicity studies. The USEPA estimated that chronic dietary exposure to thiophanate-methyl residues from all food commodities for which there are tolerances is 0.8% of the cPAD for the general U.S. population, 1.6% for infants of less than one year of age, and 2.3% for children one- to six-years old. This chronic exposure analysis is based on average residues from field trial data and average percent crop treated estimates. The USEPA estimated that the increased lifetime cancer risk for the general U.S. population from exposure to thiophanate-methyl residues in food would be 8.5 x 10'. This risk level is slightly below USEPA's level of concern of l x 10-6 for carcinogenic risk.

    The USEPA reported the results of a risk assessment for dermal and inhalation exposure of workers to thiophanate-methyl for a variety of different handling and application scenarios. For determining margins of exposure (MOEs), estimated short- and intermediate-term dermal and inhalation exposures were compared to a NOEL of 100 mg/kg/day from a 21-day dermal toxicity study and to a NOEL of ten mg/kg/day (for inhalation exposure) for maternal toxicity from the rabbit developmental toxicity study. For some MOE determinations, it was assumed that workers wore long pants, long-sleeved shirt, but no gloves (as per the label requirements). While this level of personal protective equipment alone provided MOEs of 100-fold or greater for some mixing/loading and application methods on grapes, potatoes and pears, MOEs for other scenarios were less than 100-fold. Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate worker protection. When additional measures were considered, such as water-soluble packaging (the Topsin product is in water-soluble packets), MOEs exceeded 100-fold in all cases. In addition, the USEPA estimated that the corresponding increased cancer risks would range from about 3.0 x 10-7 to 2.6 x 10-6. These values are within what the USEPA generally considers to be acceptable (1 x 10-4 or less) for occupational exposures.

    There are no chemical specific federal or State drinking water/groundwater standards for thiophanate-methyl. 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 USEPA cancer potency slope factor of 0.0138 (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 2.5 micrograms per liter for thiophanate-methyl.

    Neither thiophanate-methyl nor Topsin M WSB was very toxic or irritating following acute exposures in laboratory animals. Thiophanate-methyl also did not cause developmental or reproductive effects except at doses in excess of those that caused maternal toxicity. However, this active ingredient caused oncogenic effects in mice and rats, and the USEPA classified thiophanate-methyl as "likely to be carcinogenic in humans." The information in the registration package indicates that adding grape, pear and potato crops to the labeled use of Topsin M WSB should not pose significant risks to workers or a significant dietary risk to the general public.

    However, the information in the registration package for Topsin M WSB did not provide an adequate basis for determining the need for nor the comparative risks of this product in New York State when used on grapes, pears and potato crops.

    In response to the request for comparative risk data (see correspondence from T. Formella to C. Crowley, April 12, 2004), the registrant submitted limited toxicological information on fungicide active ingredients currently registered in New York State for use on the same crops, namely pears, grapes and potatoes, that are the subject of this registration action for Topsin M WSB. This information indicates that many of the alternative active ingredients to thiophanate-methyl also have oncogenic potential. To supplement this information, a simple comparison was conducted of reference doses and their bases, as well as application rates, for the alternative active ingredients. This comparison indicates that thiophanate-methyl has a reference dose that is numerically higher than most of the alternatives (generally indicating lower toxicity) and is applied at rates within the range of the competing products.

    In regard to establishing a need for Topsin M WSB in New York State, the registrant provided what appears to be strong support from several professors of plant pathology and one Cornell Cooperative Extension educator. The letter from one of the professors (see correspondence from D. Rosenberger to S. Jackling, March 4, 2004), is also accompanied by results from a field research trial which "[C]learly show that New York pear growers need Topsin M fungicide to control a disease complex that cannot be controlled by other available fungicides." Taken collectively, these endorsements would indicate that the need for this pesticide product is significant when used on pears. In addition, a significant need for the Topsin product on grapes was conveyed by Professor Wayne Wilcox (see correspondence from W. Wilcox to S. Jackling, April 7, 2004), although no field research trial data accompanied this correspondence. No endorsements were provided for use of Topsin on potatoes.

    Thiophanate-methyl has some oncogenic potential and the Topsin product is currently registered for use on many food crops in the State. The additional proposed use of Topsin on grapes, potatoes and pears would potentially increase exposure and risk to the general public and workers. However, the estimated risks for this addition are within the range of what the USEPA considers acceptable. Also, a simple comparison of the application rates and some toxicological parameters for thiophanate-methyl and other fungicides with the same uses indicates that the Topsin product should not pose greater risks overall than the alternatives.

    Topsin M WSB is applied either aerially or by ground application. The maximum application rate is four lbs. product per acre per crop cycle for most crops. Cucurbits are '/z lb. prod/acre every seven days with no maximum application rate indicated. Conifers are six lb. prod/acre/year or 4.2 lb ai/a/yr. The inerts do not appear to be solvent carriers.

Solubility: Thiophanate-methyl has a solubility in water at 21.8 mg/1 at pH 7.

Aqueous Photolysis: The calculated half-life in a pH 5 buffer system was 2.17 days in natural sunlight. MBC (Methyl-2-benzimidazolycarbamate) was found at 49.7% and DX-105 (methyl-N-[2-(N'methoxycarbonylthio-ureido)phenylaminocarbonyl]-carbamate was found at 14.3%.

Soil Photolysis: The calculated half-life in a sandy loam Soil at pH 7.4 was 2.9-5.5 days in natural Sunlight. MBC and DX-105 were found, but no percentages were given.

Aerobic Soil Metabolism: Thiophanate-methyl has a half-life of < one day in a clay loam soil and two Sandy loam soils. One major degradate was found: MBC at 82.7%. There appeared to be an increase in Soil bound residue with increasing organic matter.

Anaerobic Aquatic Metabolism: Thiophanate-methyl degraded with a half-life in a Silt loam soil (pH 6.2) of < one day. Degradate MBC was found at 66.1%.

Adsorption/Desorption: USEPA found this study partially acceptable and Stated that there is a high uncertainty in the values because they were calculated for nonequilibrium conditions. The adsorption Kocs were found using Sandy loam (0.6% organic matter (OM)), loam,(1.2% OM), Sand (0.2% OM), clay loam (2.8% OM), loam and loamy sand (0.7% OM) soils. KocS were 188.6, 136.6, 225.0, 858.8, 358.5, and 117.7, respectively. The KocS for degradates DX-105, FH-432 (dimethyl[(phenylene)bis(iminocarbonyl]bis(carbamate) were similar to those of thiophanate-methyl; while the KocS for MBC were higher.

Terrestrial Field Dissipation: USEPA found this Study acceptable but it contributes to satisfying the USEPA guidelines. Thiophanate-methyl dissipated rapidly in a loamy Sand Soil to MBC and allophanate and could not be detected at day 0. The registrant calculated half-life is one day. In a Sandy loam Soil, the registrant calculated half-life was 4.2 days. MBC dissipated with a half-life of 22 days.

USEPA Comments: Based upon data from acceptable Studies, thiophanate-methyl is rapidly (less than one day) converted to MBC. Therefore, under most conditions, parent thiophanate-methyl per Se would not likely be found in groundwater as it is rapidly degraded to MBC. There may be some concern for contamination of Surface water through erosion of Soil particles or runoff containing the parent compound, but this is only a Short-term threat due to the rapid conversion to MBC in soils as well as rapid conversion to MBC through photodegradation.

Computer Modeling: The parent was not run through the model because the half-life is less than one day. Running the degradate MBC on Riverhead Soil, using a Koc of 300, a half-life of 22 days, and running the entire application amount of 4.2 lb ai, the model projected peaks of between 0.0005 to 0.004 ppb.

    Given the very Short half-life, this product will not have a significant negative impact on groundwater when used as labeled.

    The Department concludes that the additional uses for Topsin M WSB Should not have an adverse effect on the health of workers or the general public, or the ground and surface water of New York State, when used as labeled. If the registrant seeks additional crop uses for Topsin or thiophanate-methyl in the future, a more thorough analysis of comparative risks may be required than was conducted for this registration action.

    Therefore, the Department hereby accepts for general use registration in New York State Topsin M WSB (EPA Reg. No. 4581-408), which contains the active ingredient Thiophanate-methyl, for the additional use on grapes, pears and potatoes.

    Enclosed is your New York State stamped "ACCEPTED" label.

    If you have any questions, please contact 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