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Mesotrione - Registration of Callisto Herbicide 6/02

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

June 10, 2002


John D. Abbott, Ph.D.
State Regulatory Affairs Team Leader
Syngenta Crop Protection, Inc.
P.O. Box 18300
Greensboro, North Carolina 27419-8300

Dear Dr. Abbott:

    Re: Registration of the New Active Ingredient Mesotrione, Contained in the Pesticide Product Callisto Herbicide (EPA Reg. No. 100-1131)

    The New York State Department of Environmental Conservation (the Department) has reviewed your application, received December 7, 2001, to register the above-mentioned product in New York State. The product contains the new active ingredient mesotrione (chemical code 122990).

    The application was deemed complete for purposes of review on January 31, 2002 and a registration decision is due by June 28, 2002.

    Callisto Herbicide (EPA Reg. No. 100-1131) is labeled as a preemergence and postemergence herbicide for control of annual broadleaf weeds in field corn, production seed corn, and corn grown for silage. The maximum application rate is 0.34 pound mesotrione per acre per season.

    Callisto was determined to be a reduced risk pesticide in 1999 by the United States Environmental Protection Agency (USEPA). The metabolites are MNBA (4-(methylsulfonyl)-2-nitrobenzoic acid) and AMBA (2-amino-4-(methylsulfonyl)benzoic acid). Mesotrione belongs to a class of chemicals called triketones, and has a different mode of action than that of previously registered broadleaf herbicides. It inhibits amino acid conversion and carotenoid biosynthesis, which results in the plant not protecting the chlorophyl from decomposition by sunlight. Mesotrione provides effective control of triazine, sulfonylurea and other ALS resistant weeds.

    The Department has reviewed the information supplied to date in support of registration of the new active ingredient mesotrione contained in the pesticide product Callisto Herbicide (EPA Reg. No. 100-1131).

    The New York State Department of Health (DOH) stated that neither mesotrione nor the formulated Callisto Herbicide product was very toxic in acute oral, dermal or inhalation exposure studies in laboratory animals. Mesotrione was mildly irritating to eyes, but not to skin, whereas Callisto Herbicide was slightly irritating to both skin and eyes (tested on rabbits). The active ingredient was not a dermal sensitizer, but the formulated product was mildly sensitizing to guinea pigs.

    Mesotrione 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 mesotrione as "not likely to be carcinogenic to humans."

    Mesotrione's mode of action as an herbicide is through the inhibition of the enzyme p-hydroxyphenylpyruvate dioxygenase (HPPD) which is involved in carotenoid pigment synthesis that protects chlorophyll from decomposition by sunlight. In mammals, HPPD is involved in the catabolism of the amino acid tyrosine. The registrant conducted a series of studies to demonstrate that the spectrum of toxicological effects reported in the animal studies results from elevated tyrosine levels in part caused by mesotrione's inhibition of HPPD. These studies also indicated that another enzyme involved in tyrosine catabolism, tyrosine aminotransferase (TAT), accounts for species differences in tyrosine levels and, therefore, their sensitivity to mesotrione. Because TAT activity in humans and mice is relatively high compared to that of the rat, rendering them less sensitive to mesotrione-mediated effects, data from mouse studies are believed to be more suitable for assessing risks to humans than are rat data. The USEPA, Office of Pesticide Programs established a reference dose (RfD) of 0.007 mg/kg/day based on a lowest-observed-effect level (LOEL) of 2.1 mg/kg/day in the mouse multi-generation reproduction study and an uncertainty factor of 300. An uncertainty factor of 100 was used to account for species extrapolation and human variability and an additional uncertainty factor of 3 to account for using a LOEL instead of a NOEL. This RfD has not yet been adopted by the USEPA's Integrated Risk Information System (IRIS).

    The USEPA established a tolerance of 0.01 parts per million (ppm) for mesotrione residues in or on field corn, production seed corn, and corn grown for silage. The USEPA estimated that chronic dietary exposure to these residues would be 1.8 percent of the chronic population adjusted dose (cPAD) of 0.0007 mg/kg/day for the general U.S. population, 4.2 percent for children one to six years old, and 4.3 percent for all infants less than one-year old. This chronic exposure analysis is based on the assumption that 100 percent of crops are treated and contain tolerance level residues. Actual residues and resulting exposure levels are expected to be less than this assessment estimates.

    The USEPA reported the results of an occupational risk assessment for dermal and inhalation exposures to mesotrione from use on corn. It was assumed that mesotrione was mixed, loaded for, and sprayed on between 80 and 1,200 acres per day depending on application methods. For determining margins of exposure (MOEs), the USEPA compared estimated short-term dermal and inhalation exposures combined to a LOEL of 100 mg/kg/day from the developmental toxicity study in rats. A 25 percent dermal absorption rate was assumed. For commercial handlers and applicators, MOEs were estimated to be 3,000 and above. These estimates assumed that workers wore gloves and long-sleeved shirt and pants as per label requirements. The MOE for post-application occupational exposures (scouting activities) was estimated to be 14,000. Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate worker protection.

    There are no chemical specific federal or State drinking water/groundwater standards for mesotrione or its degradates. Based on their chemical structure, mesotrione and the MNBA and AMBA degradates fall under the 50 microgram per liter (µg/L) New York State drinking water standard for "unspecified organic contaminants" (10 NYCRR Part 5, Public Water Systems). The New York State drinking water standard for the sum of "unspecified organic contaminants" and "principal organic contaminants" is 100 µg/L. If one uses the cPAD derived for the general United States population (0.0007 mg/kg/day) and procedures for deriving ambient water quality standards and guidelines based on non-oncogenic effects (6 NYCRR Part 702.5), a value of 5 µg/L can be calculated. This value could be used to derive a screening value for comparison to estimated impacts to groundwater and surface water.

    The available information on mesotrione and Callisto Herbicide indicates that they are not very acutely toxic in laboratory animal studies. Data from animal developmental and reproductive studies indicate that mesotrione affects offspring through delayed ossification and ocular effects. These effects, as well as those in the liver and kidney, appear to be secondary to tyrosinemia that, in part, results from the inhibition of the enzyme HPPD. Although mesotrione has the potential to cause tyrosinemia, humans have a capacity to regulate tyrosine levels (due to a relatively high TAT activity level). In addition, the expected exposure from the labeled use of Callisto is rather low and should not pose a significant risk to the general public or to workers.

    The Department's Division of Fish, Wildlife & Marine Resources' Bureau of Habitat (BOH) stated that technical mesotrione has a solubility of 160 ppm in unbuffered water. It has low vapor pressure, 4.3x10-8 mmHg, and volatilization will not contribute significantly to dissipation. Its bioaccumulation potential is low enough with an octanol/water partition coefficient, KOW, of 1.3, that the requirement for a fish accumulation study was waived by the USEPA. Soil organic carbon sorption coefficients, KOC, for 17 soils was pH dependent ranging from 16.5 mL/g at pH 7.7, to 390 mL/g at pH 4.6, geometric mean = 80.5, indicating the potential for mobility with precipitation once applied.

    Mesotrione is practically non-toxic to mammals on an acute basis but can be toxic with chronic exposure. It is practically non-toxic both acutely and chronically to birds, fish, and aquatic invertebrates except marine mysid shrimp for which it is moderately toxic. Mesotrione was not toxic to three invertebrate species not required by USEPA testing guidelines (earthworm, carabid beetle, and parasitic wasp) at concentrations that exceed likely field residue levels. Toxicity tests were conducted with the two primary mesotrione degradation products MNBA and AMBA. Both degradates are practically non-toxic to mammals, freshwater fish, and freshwater invertebrates.

    Mesotrione dissipates relatively rapid in the environment primarily through microbial metabolism. It is stable to hydrolysis. Its mean laboratory aqueous photolysis half-life, T1/2, is 84 days, mean soil surface photolytic T1/2 is approximately 15 days. All of the metabolism and field dissipation studies were lacking in some aspect. They did not meet USEPA guidelines and would not, taken individually, satisfy their respective data requirements. When the results are considered in total, however, mesotrione degradation is described with a reasonable degree of certainty. Aerobic soil metabolism data for 18 separate soils was submitted, T1/2's ranged from 4.6 days to 31.5 days with a geometric mean of 13.4 days. The mean aerobic aquatic metabolism T1/2 was 5 days in a British water/sediment system. This study was classified as supplemental because it was not conducted with a U.S. water or sediment. Anaerobic aquatic metabolism mean T1/2 (two studies) is 4 days. All three terrestrial field dissipation studies reported in this data package were seriously flawed. All that can be stated is that parent mesotrione "disappeared" fairly rapidly in each case. The parent compound 50% dissipation times, DT50, were 2, 9, and 14 days, the mean was 6.3 days.

    An aerobic soil metabolism study of the mesotrione metabolite AMBA in three different soils yielded T1/2's of 16, 27, and 20 days in clay, silt loam, and sandy loam soils, respectively.

    Use of Callisto as labeled is not likely to impact fish or wildlife resources as mesotrione degrades fairly rapidly in the environment making extended exposures unlikely and the described adverse effects take time to develop.

    The Department's groundwater staff stated the following:

Hydrolysis: Mesotrione was found to be stable at pHs 5, 7, and 9.

Aqueous Photolysis: The phenyl ring-labeled [14C] mesotrione degraded with a half life of 86.8 days. The cyclohexane ring-labeled [2-14C] mesotrione degraded with a half-life of 80.5 days.

Aerobic Soil Metabolism: The cyclohexane ring-labeled [2-14C] mesotrione degraded with a half-life of 13.5 days. MNBA accounted for 7.6% of applied and AMBA accounted for up to 9.7% of applied. Another study (MRID 45196006) had no Data Evaluation Record (DER), but was written up in the DER for MRID 4437351. A half-life of approximately 18 days was estimated by the reviewer. In another study, three soils were studied; a sandy loam from the United States, a loam from France and a clay loam from England. The phenyl ring-labeled [14C] mesotrione degraded with a half-life of 12 days in sandy loam, 5.9 days in loam and 4.6 days in clay loam. In the sandy loam soil, MNBA accounted for 12.7% of applied and AMBA accounted for up to 4.2% of applied. In the loam soil, MNBA accounted for 46.8% of applied. In the clay loam soil, MNBA accounted for 4.7% of applied and AMBA accounted for up to 4.2% of applied.

Anaerobic Aquatic Metabolism: The phenyl ring-labeled [14C] mesotrione degraded with a reviewer calculated half-life of 3.9 days in a flooded silt loam. AMBA in the aqueous phase was 66%. In the soil phase, AMBA was 49%. In another study, the cyclohexane ring-labeled [2-14C] mesotrione degraded with a half-life of 4.2 days in a flooded silt loam.

Parent Adsorption/Desorption: One study indicated that mesotrione had a sorption Koc of 58 in sandy loam, 19 in loam, 48 in silt loam, and 29 in clay loam. Mesotrione had a desorption Koc of 130 in sandy loam, 33 in loam, 61 in silt loam, and 50 in clay loam. No degradates were mentioned in this study. Another study indicated that mesotrione had a sorption Koc of 47 in silt loam, 25 in sandy loam, 171 in silty clay loam, 70 in clay and 14 in loam soil. Mesotrione had a desorption Koc of 67 in silt loam, 56 in sandy loam, 198 in silty clay loam, 86 in clay and 32 in loam soil. No degradates were mentioned in this study.

Degradate Adsorption/Desorption: MNBA had a sorption Koc of 3.2 in silt loam, and 6.1 in silty clay loam; estimated values were less than 20 in the sandy loam, 6 in clay and 10 in loam soils. MNBA had a desorption Koc of 13.3 in silt loam, and 15.6 in silty clay loam; estimated values were less than 20 in the sandy loam, clay and loam soils. AMBA had a sorption Koc of 44.9 in silt loam, 22.7 in sandy loam, 122.1 in silty clay loam, and 51 in clay soil and 17.7 in loam soil. AMBA had a desorption Koc of 68.9 in silt loam, 37.9 in sandy loam, 155.9 in silty clay loam, and 109.3 in clay soil and 50.2 in loam soil.

Degradate Field Dissipation: The half-life of AMBA was approximately 16 in clay soil (English soil), 27 in silt loam soil (Wisconsin), and 20 in sandy loam soil (English soil).

Surface Water Advisory: The label contains a surface water advisory that addresses drift, runoff, poorly draining soils and erosion controls.

Prospective Groundwater Monitoring Study: Two PGW studies at a site in Michigan are being performed. It appears that these studies are being done voluntarily by the registrant. Two interim reports have been submitted; the USEPA has not reviewed any reports yet.

Computer Modeling: Computer modeling, performed by our groundwater staff, projected cyclic peaks of parent mesotrione ranging from about 0.002 to 0.015 parts per billion. Very conservative modeling of the degradates indicated cyclic peaks of about 0.05 to 0.25 ppb. The model projects cyclic peaks because of the short half-lives for this pesticide; the product applied each year will degrade before the next year's application.

    Our groundwater staff concluded that this product, when used as labeled, should not leach significantly to groundwater on sandy Long Island soils due to the very short half life and low application rate.

    The Department concludes that Callisto Herbicide should 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.

    Therefore, the Department hereby accepts for general use registration in New York State Callisto Herbicide (EPA Reg. No. 100-1131) which contains the new active ingredient mesotrione.

    Enclosed is your Certificate of Registration and New York State stamped "ACCEPTED" label.

    Syngenta Crop Protection, Inc. is reminded that if New York State registration is requested for this product or for any other product which contains mesotrione 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.


Maureen P. Serafini
Bureau of Pesticides Management

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