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Famoxadone - Registration of DuPont Tanos Fungicide 1/05

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
Website: http://www.dec.state.ny.us/website/dshm/pesticid/pesticid.htm
E-Mail: ppr@gw.dec.state.ny.us

January 21, 2005

CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Ms. Miriam Carr
DuPont Crop Protection
Stine-Haskell Research Center
P.O. Box 30
Newark, Delaware 19714-0030

Dear Ms. Carr:

Re: Registration of DuPont Tanos Fungicide (EPA Reg. No. 352-604) Containing the Active Ingredients Famoxadone (Chemical Code 113202) and Cymoxanil (Chemical Code 129106)

    The New York State Department of Environmental Conservation (Department) has completed its technical review of your application and data package submitted on 11/21/2003 to register DuPont Tanos Fungicide. DuPont Tanos Fungicide (EPA Reg. No. 352-604) contains two active ingredients: cymoxanil at 25% and famoxadone at 25%. The active ingredient famoxadone is a new active ingredient (NAI) for New York State and the addition of new crop sites triggers a major change in labeling (MCL) review for cymoxanil in accordance with 6 NYCRR Part 326.16 and .17.

    DuPont Tanos Fungicide is labeled for use in commercial and/or farm plantings on cucurbits (including cantaloupe, cucumber, honeydew melon, muskmelon, watermelon, pumpkin, summer squash, and other cucurbits), head lettuce, peppers, potatoes and tomatoes. Cymoxanil is currently registered in New York State for use on potatoes as the sole active ingredient in DuPont Curzate 60 DF Fungicide (EPA Reg. No. 352-592).

    Famoxadone is an oxazolidinedione contact fungicide and affects susceptible fungal pathogens through inhibition of mitochondrial respiration. The maximum application rate is 72 ounces of product per acre per year (1.1 lb./acre/year of cymoxanil and 1.1 lb./acre/year of famoxadone). The initial application received on 11/21/2003 was declared incomplete on 01/20/2004. Your Company submitted a second information package on 05/26/2004 and an additional application package received by this Department on 07/07/2004. The application was determined to be complete for technical review on 08/24/2004 with the condition to submit requested analytical methods prior to registration of the product. This condition was met by your submittal on 09/24/2004. The Department has registered this product for sale, distribution, and use in New York State.

    Pursuant to the review time frame specified by New York State ECL §33-0704.2, a registration decision date of January 21, 2005 was established. The Department has conducted the following technical reviews with regard to the registration of DuPont Tanos Fungicide (EPA Reg. No. 352-604) for impacts to human health, nontarget organisms, and the environment. Review summaries are provided below for human health and environmental fate. The Department's Bureau of Habitat had no objection to registration of this product in regard to protection of nontarget organisms.

Human Health Review:

Famoxadone:

    Neither the new active ingredient famoxadone nor the formulated product DuPont Tanos Fungicide was very toxic in acute oral, dermal and inhalation toxicity studies. In dermal and eye irritation studies, the formulated product was both a mild skin and eye irritant (tested on rabbits), whereas famoxadone was moderately irritating to the eyes and mildly to moderately irritating to the skin. Neither the active ingredient nor the formulated product was a skin sensitizer (tested on guinea pigs).

    Famoxadone caused some toxicity in subchronic animal feeding studies. In a subchronic oral toxicity study with famoxadone in rats, mild hemolytic anemia in males and females was reported at 13.0 milligrams per kilogram body weight per day (mg/kg/day) and 16.6 mg/kg/day, respectively. The respective no-observed-effect levels (NOELs) were 3.3 and 4.2 mg/kg/day. In mice, mild hemolytic anemia and hepatotoxicity occurred at 534 mg/kg/day in males and 757 mg/kg/day in females, with respective NOELs of 62.4 and 79.7 mg/kg/day. In dogs, an increased incidence of cataracts was observed in males at 10 mg/kg/day, but not at 1.3 mg/kg/day. In females, this effect occurred at the lowest dose tested, which was 1.4 mg/kg/day.

    In a rat chronic oral toxicity study with famoxadone, slight hemolytic anemia and histopathological changes in the liver were reported at a dose of 16.8 mg/kg/day in males. Slight hemolytic anemia was observed in females along with decreased body weight gain at 10.7 mg/kg/day; the respective NOELs for male and female rats were 8.4 and 2.2 mg/kg/day. In male and female mice, chronic feeding of famoxadone resulted in slight hepatotoxicity at doses of 274 and 392 mg/kg/day, respectively; the respective NOELs were 96 and 130 mg/kg/day. In a dog chronic feeding study with famoxadone, cataracts were reported at dose levels of 8.8 and 9.3 mg/kg/day in males and females, respectively. A NOEL of 1.2 mg/kg/day was reported for these lesions in both males and females. According to the United States Environmental Protection Agency (USEPA), a NOEL could not reliably be determined for cataracts because of a fixation artifact that affected the quality of the histopathology sections of the eyes from all dogs in this study, including those in the 0.3 and 0.6 mg/kg/day dose groups. Consequently, the USEPA determined that the lowest dose at which cataracts were actually observed was 1.4 mg/kg/day in female dogs in the subchronic study. The USEPA Office of Pesticide Programs (OPP) established a reference dose (RfD) of 0.0014 mg/kg/day based on this lowest-observed-effect level (LOEL) of 1.4 mg/kg/day and an uncertainty factor of 1,000. An uncertainty factor of 1,000 was used to account for the use of a LOEL value obtained from a subchronic study rather than the use of a NOEL from a chronic study. This RfD has not yet been adopted by the USEPA's Integrated Risk Information System (IRIS).

    Famoxadone caused some developmental toxicity in the offspring of pregnant rabbits administered this compound during organogenesis at doses that also caused maternal toxicity. In a rabbit oral developmental toxicity study, abortions and equivocal increases in post-implantation loss and mean resorptions per dose were observed at 1,000 mg/kg/day; the NOEL was 350 mg/kg/day. In this study, maternal toxicity which was characterized by a decrease in food consumption, body weight and body weight gain was reported at a dose level of 1,000 mg/kg/day with a NOEL of 350 mg/kg/day. In a rat oral developmental toxicity study, no developmental toxicity effects were reported at 1,000 mg/kg/day, which was the highest dose tested. Maternal toxicity, characterized by a transient decrease in body weight gain and food consumption occurred at 500 mg/kg/day with a NOEL of 250 mg/kg/day. In a multigeneration reproduction study in rats, famoxadone caused a decrease in rat pup weights at 44.7 mg/kg/day; the NOEL was 11.3 mg/kg/day. Parental toxicity, characterized by hepatotoxic effects, and a decrease in body weight, body weight gain and food consumption was reported at doses of 44.7 and 53.3 mg/kg/day for male and female animals, respectively. The respective NOELs were 11.3 and 14.2 mg/kg/day.

    Famoxadone did not cause oncogenic effects in either rat or mouse chronic feeding studies. Although famoxadone gave positive results in two in vitro assays (induction of unscheduled DNA synthesis and a chromosomal aberration assay in human lymphocytes), this chemical was reported to be negative in other genotoxicity tests, including two additional unscheduled DNA synthesis assays, the Ames bacterial mutation assay, the mouse bone marrow micronucleus assay, and the Chinese hamster ovary assay. Based on the lack of evidence for carcinogenicity in rats and mice, the USEPA classified famoxadone as "not likely to be carcinogenic to humans."

    The USEPA established tolerances for famoxadone residues in or on head lettuce at 10.0 parts per million (ppm); potatoes (0.02 ppm); tomatoes (1.0 ppm); cucurbits (0.30 ppm) and fruiting vegetables except tomatoes (4.0 ppm). The chronic population adjusted dose (cPAD) for famoxadone is 0.0014 mg/kg/day and has the same basis as the RfD. The USEPA estimated that chronic dietary exposure to famoxadone would be 36% of the cPAD for the general U.S. population, 76% for children one to two years old and 68% for children three to five years old. This chronic exposure analysis is based on the conservative assumption that 100% of each crop is treated with famoxadone. Also used in estimating these exposures were anticipated residues based upon average field trial values.

    The USEPA conducted a risk assessment for dermal and inhalation exposure of workers to famoxadone from its use on fruiting vegetables, cucurbit vegetables, head lettuce and potatoes. For mixers/loaders, the combined margin of exposure (MOE) for short-term dermal and inhalation exposures was 2,700 and for applicators, the combined MOE was 33,000. For these estimates, it was assumed that these workers did not use personal protective equipment (PPE) and 350 acres were to be treated each day. For dermal exposure, the USEPA used a dermal adsorption factor of five percent and assumed 100% absorption for inhalation exposure. The NOEL used for estimating these MOEs was 10 mg/kg/day from a subchronic feeding study in dogs in which the toxicity endpoint was muscle twitches starting on day 21 of exposure to famoxadone. The USEPA considered MOEs of 100-fold or greater for this toxicity endpoint to provide adequate worker protection. For intermediate-term exposure, the estimated combined (dermal and inhalation) MOE for mixers/loaders (using single layer clothes and gloves) was 380 and for applicators (not using PPE) the estimated MOE was 4,500. For estimating these MOEs, the LOEL of 1.4 mg/kg/day from the dog subchronic feeding study was used in which the toxicity endpoint was cataracts of the eyes in female dogs. Since a LOEL from a subchronic toxicity study rather than a NOEL was used as a basis of comparison for estimating these intermediate-term MOEs, the USEPA considered MOEs of 300 or greater to provide adequate worker protection. For post-application occupational activities (e.g., irrigation, scouting, hand weeding) the estimated MOEs ranged from 430 to 10,000.

    There are no chemical specific federal or State drinking water/groundwater standards for famoxadone. 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). Based on the USEPA OPP RfD of 0.0014 mg/kg/day and DEC Water Quality Regulation procedures for deriving surface water and groundwater standards and guidance values from non-oncogenic effects (6 NYCRR Part 702.5), the ambient water quality value for famoxadone would be 10 micrograms per liter.

Cymoxanil:

    We previously reviewed the active ingredient cymoxanil in the currently registered product, Curzate 60 DF Fungicide. Cymoxanil was not very acutely toxic in laboratory animal studies, did not cause oncogenic effects and was generally negative in genotoxicity studies. Cymoxanil, however, caused some developmental effects in offspring of rats and rabbits exposed during organogenesis. A current search of the toxicological literature did not find any significant new information on the toxicity of cymoxanil.

    The USEPA originally calculated an RfD for cymoxanil of 0.013 mg/kg/day based on the NOEL from a rat chronic feeding/oncogenicity study (4.1 mg/kg/day) and an uncertainty factor of 300. The uncertainty factor of 300 was chosen because of neuropathology findings in the rat chronic feeding study and the absence of a developmental neurotoxicity study. Since that time, the rat developmental neurotoxicity study was completed and the USEPA decreased the uncertainty factor to 100. Therefore, the RfD for cymoxanil was increased from 0.013 mg/kg/day to 0.04 mg/kg/day.

    The USEPA established tolerances for cymoxanil residues in or on head lettuce, cucurbits, and fruiting vegetables at 4.0 ppm, 0.05 ppm and 0.2 ppm, respectively. The cPAD for cymoxanil is 0.04 mg/kg/day and has the same basis as the revised RfD. Using this cPAD, the USEPA estimated that chronic dietary exposure to cymoxanil residues would be 13% of the cPAD for the general U.S. population and all population subgroups. This chronic exposure analysis is based on the conservative assumption that 100% of crops are treated and that these crops contain tolerance level residues.

    No data were submitted on worker exposures to cymoxanil. However, given DuPont Tanos' relatively low application rate (57 grams cymoxanil per acre), the apparent low potency from dermal exposure (a 28-day dermal rat study did not report effects at doses as high as 1,000 mg/kg/day) and the relatively low exposure potential by inhalation compared to the dermal contribution, worker risks from exposure to cymoxanil should not be significant.

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

    In summary, the available information on famoxadone, cymoxanil and DuPont Tanos Fungicide indicates that neither the two active ingredients nor the formulated product are very acutely toxic in laboratory animal studies. Furthermore, neither famoxadone nor cymoxanil was carcinogenic in mice or rats. Although data from subchronic, chronic and developmental/reproductive studies showed that these two chemicals have the potential to cause some toxicity, the estimated risks to workers from use of DuPont Tanos Fungicide are within the range that is generally considered acceptable. Also, dietary exposure of the general public to both famoxadone and cymoxanil residues on currently labeled crops is not expected to pose significant health risks.

Environmental Fate Review:

Solubility: Famoxadone is highly insoluble, with a solubility of 0.052 ppm.

Hydrolysis: USEPA found this study acceptable. Famoxadone had calculated half-lives in pH 5, 7, and 9 of 31 days, 2.7 days and 1.8 hours, respectively. Major degradates include IN-JL856 (_-hydroxy-_-methyl-4-phenoxybenzene-acetic acid-s-phenylhydrazide) at 24.4%, IN-JS940 (_-hydroxy-_-methyl-4- phenoxybenzeneacetic acid) at 51.7%, IN-H3310 (1-(4-phenoxyphenyl) ethanone) at 11.9%, IN-MN968 (1-carboxy-1-(4-phenoxyphenyl)ethyl 2-phenylhydrazine carboxylate monosodium salt) at 39.3%, catechol (1,2-benzendiol) at 16.4%, phenol at 10.9% and benzene (volatile) at 28.7%. IN-JL856 degrades into IN-JS940, IN-MN968 degrades to IN-JS940, and IN-JS940 and IN-H3310 are stable.

Aqueous Photolysis: USEPA found this study acceptable. Half-lives for the two 14C labeled rings were 2.6 days and 4.6 days. IN-JL856 was found at 11%, IN-JS940 was found at 21.7%, and IN-H3310 was found at 39.3%.

Soil Photolysis: USEPA found this study acceptable. Half-lives for the two 14C labeled rings were 9.5 days and 16.1 days. IN-KF015 (5-methyl-4-(4-phenoxyphenyl)2,4-oxazolidinedione) was found at 21.5%, IN-H3310 was found at 26.6%, IN-MN468 (5-methyl-3-[(4-nitrophenyl) amino]- 5-(4-phenoxyphenyl)-2,4-oxazolidinedione) was found at 13.4% and IN-MN467 (5-methyl-3-{(2-nitrophenyl)amino]-5-(4-phenoxyphenyl)-2,4-oxazolidinedione) was found at 18.3%.

Aerobic Soil Metabolism: USEPA found these studies acceptable. The first four results are from Study ID 44946339, and the last result is from Study ID 44946402.

Soil Type
% OC
Soil pH
Aerobic
Half-life
Major Degradates
Madison loamy sand 1.1 7.1 9 days  
Milton sandy loam 2.9 7.4 11 days IN-KZ007 16.2%
Matapeake silt loam 1.9 5.3 3 days IN-JS940 11.1%
Nambesheim silt loam 1.9 8.0 2 days  
Speyer sandy loam 1.4 7.2 7.6/8.9 days  

Degradate IN-KF015 had a half-life in Speyer sandy loam of 1.2 and four days. The half-life of IN-JS940 was 20.4 hours in sandy clay loam, 24 hours in loam, and five hours in sandy loam. The half-life of IN-KZ007 (5-[4-(4-hydroxyphenoxy)phenyl-5-methyl-3-(phenylamino)-2,4-oxazolidine dione) was 2.5 days in a sandy clay loam, 18.3 days in loam and 11.8 days in sandy loam. USEPA did not find either degradate study acceptable, but did not believe that additional work needed to be done.

Aerobic Aquatic Metabolism: USEPA found this study acceptable. In the flood water, half-lives in two 14C labeled systems were 0.4 days at pH 7.1, and 0.02 and 0.06 days at pH 7.7. In the sediment, the half-lives were 1.8 days at pH 7.1, and 1.7 and 13.6 days at pH 7.7. In the whole system, half-lives were 1.2 days at pH 7.1, and 1.4 and 3.5 days for pH 7.7. IN-JS940 was found at 24.7%. The half-lives for IN-JS940 were 3.8 days at pH 7.1 and 5.9 days at pH 7.7.

Aerobic Aquatic Metabolism: USEPA found this study acceptable. Reviewer calculated half-lives were 33.5 days and 36.1 days. IN-JS940 was found at 27.8%.

Aged Leaching: USEPA did not find this study acceptable. Only one soil was utilized rather than four. Additional studies must be submitted. No mobility was presented.

Adsorption/Desorption: USEPA did not find these studies acceptable. Further information was required.

Soil Type
% OC
Soil pH
Adsorption
Koc Parent
Adsorption IN-JS940*
Adsorption IN-KF015*
Speyer sand 2.29 5.9 3890    
Speyer sandy loam 1.34 6.6 3300 33  
Donna sandy clay loam 0.58 8.0 4030 515  
Matapeake loam 1.2 5.2   591  
Nijmegen loam 1.4 7.0   179  
Fargo Silty Clay Loam 3.3 7.8     130
Madison loamy sand 1.1 7.1     210
Matapeake silt loam 1.9 5.3     1300
Milton sandy loam 2.9 7.4     380
*USEPA did not find these studies acceptable, but did not require additional work.

Even though USEPA is requiring further studies, the Kocs are so high that the chemical will probably still be considered immobile once the new studies are completed.

Terrestrial Field Dissipation: Famoxadone degraded with a reviewer-calculated half-life of 26.4 days in a clay loam, 10.1 days in a sand, 19.7 days in a loam, 30.5 days in a sandy loam, 12.5 days in a loamy sand, and 32.9 days in a gravelly fine sandy loam. In studies done on a silt loam, sand and silty clay loam, famoxadone and cymoxanil were applied, but analyses did not include the cymoxanil and the degradates of both. The registrant calculated half-life for famoxadone was six, 12 and 11 days, respectively. USEPA did not find any of these studies acceptable, and further information was be required to upgrade them.

Modeling: Staff modeled famoxadone on Riverhead soil (to simulate upstate aquifers as well as LI) using a Koc of 3300 a half-life of 8.9 days and the maximum application rate of 1.12 lb. ai/a/yr. The model projected no leaching at all.

Technical Review on Cymoxanil:

Hydrolysis: Cymoxanil had a hydrolysis half-life in pH 5, 7 and 9 of 148 days, 34 hours, and 31 minutes, respectively. There were two major degradates at pH 7: IN-U3204 at 52.7%, and IN-KP533 at 57%.

Soil Photolysis: Cymoxanil had a half-life of 37.3 days in a sandy loam soil. In another study, the half-life was 25.3 days. The major degradates were CO2, and IN-JX915 at 10.8%.

Aqueous Photolysis: The aqueous photolysis summary (no DER provided) indicated half-lives in irradiated samples of 1.8 days and 5.2 hours at pH 5 and 7. Major degradates were IN-R3273, IN-U3204 and KP-533 at greater than ten percent, but the actual amount was not given in the summary.

Aerobic Metabolism: The half-life of the radio-labeled cymoxanil was 0.75 days (18 hours), with radio labeled CO2 reaching a maximum of 60.4%.

Anaerobic Metabolism: The half-life was 1.6 hours in an anaerobic sediment-water system of loamy sand. The major degradates were: M1a at 28%; M3 (JX915 and M3a) at 25%; and CO2 at 30%.

Adsorption/Desorption: The adsorption/desorption study was not acceptable, but USEPA was not requesting any additional data. No mobility data was provided for the parent. The degradates are very mobile-the Kocs for three degradates, R3273, KQ960, and JX915 ranged from 0 to 50.

Terrestrial Field Dissipation: The terrestrial field dissipation study indicated a half-life of < one day in a silt loam, and 8.7 days in a loam. Additional field studies were carried out using European soils had half-lives ranged from < one to two days.

Computer Modeling: Staff could not model cymoxanil because no Kocs were given. However, with a half-life of 18 hours, the model would predict no leaching.

USEPA Label Text for Tanos: USEPA required the following Surface Water Advisory placed on the label:

This product may contaminate water through drift of spray in wind. This product has a potential for runoff for several months or more, after application. Poorly draining soils and soils with shallow water tables are more prone to produce runoff that contains this product. A 25-foot buffer strip is required between areas to which this product is applied and permanent surface water features including lakes; rivers; streams, marshes and ponds; springs; estuaries and commercial fish farm ponds to reduce the potential for contamination of water from rainfall-runoff. Runoff of this product will be reduced by avoiding applications when rainfall is forecasted to occur within 48 hours. Sound erosion control practices will reduce this product's contribution to surface water contamination.

It appears that USEPA required this text to be placed on the label because famoxadone binds very tightly to the soil and this soil could be carried along during runoff events. The active ingredient would remain bound to the soil, however, and not be available to contaminate the surface water.

    In Summary, the review of the environmental fate data indicates that these two chemicals are immobile and do not have the characteristics of those chemicals that are known to contaminate groundwater.

Registration Summary:

    Enclosed for your record is a copy of the stamped accepted label and the Certificate of Registration for DuPont Tanos Fungicide (EPA Reg. No. 352-604). Please note that a proposal by DuPont Crop Protection, or any other registrant, to register a product that contains famoxadone or cymoxanil for 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 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