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Flumioxazin
Registration of Valor Herbicide Containing the New Active Ingredient Flumioxazin 12/03

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

Bureau of Pesticides Management, 9th Floor
625 Broadway, Albany, New York 12233-7254
Phone 518-402-8788 FAX 518-402-9024
Website: http://www.dec.state.ny.us/website/dshm/pesticid/pesticid.htm

December 5, 2003

CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Mr. Dan Fay
Manager, Registration & Regulatory Affairs
Valent U.S.A. Corporation
1333 North California Boulevard
Suite 600
P.O. Box 8025
Walnut Creek, California 94596-8025

Dear Mr. Fay:

Re: Registration of the Valor Herbicide (EPA Reg. No. 59639-99) Containing the New Active Ingredient Flumioxazin

The New York State Department of Environmental Conservation (Department) has completed its technical review of your application and data packages submitted in support of the registration of Valor Herbicide. Valor Herbicide (EPA Reg. No. 59639-99) contains the new active ingredient flumioxazin, not previously registered in New York State. The product is labeled for control of susceptible weeds in peanuts and soybeans, and can also be used as part of an early preplant burn down program in cotton, field corn, rice, sorghum, sunflowers, and wheat. The Department has registered this product for labeled use on the above-listed crops in New York State.

Flumioxazin is a light-dependent peroxidizing herbicide (LDPH), which acts by blocking heme and chlorophyll biosynthesis resulting in an endogenous accumulation of phototoxic porphyrins. This class of herbicides are known to have a phototoxic mode of action in plants and possibly in fish. The formulated product contains 51% flumioxazin in a water soluble granule. The product is applied as a foliar spray at a maximum application rate of three ounces per acre per year, or 0.0956 lb. active ingredient/acre/year.

The United States Environmental Protection Agency (USEPA) issued a conditional registration for Valor Herbicide on April 12, 2001. The USEPA accepted a label amendment to add aerial application on July 31, 2002. The product labeling that has been registered for use in New York State neither allows aerial application nor application through any type of irrigation equipment. The label "Environmental Hazards" section warns of toxicity to nontarget plants and aquatic invertebrates and warns against contamination of surface waters. Product effectiveness is contingent on soil moisture and weather conditions.

The Valor Herbicide new active ingredient (NAI) application was received on January 13, 2003. The Department notified Valent USA Corporation of an incomplete application via letter dated March 5, 2003. Valent USA Corporation submitted three data packag es, received by the Department on the following dates: April 18, 2003; April 23, 2003; and June 12, 2003 to complete their application for a new active ingredient review of Valor Herbicide. The Valor Herbicide application package was declared complete as per Department letter dated June 25, 2003.

Pursuant to the review time frame specified in ECL §33-0704.2, a registration decision date of November 21, 2003 was established. Valent USA Corporation requested an extension of 30 days in order for the Department to evaluate supplemental information that Valent USA Corporation submitted on November 13, 2003. A new registration decision date of December 21, 2003 was established. The Department conducted the following technical reviews with regard to the registration of Valor Herbicide for impacts to human health, nontarget organisms, and the environment. Review summaries are provided below:

HUMAN HEALTH SUMMARY:

The New York State Department of Health (DOH) reviewed the application and supporting data submitted by Valent USA Corporation to register the pesticide product Valor Herbicide (EPA Reg. No. 59639-99) in New York State. This product contains the new active ingredient flumioxazin (2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione) and is labeled for control of susceptible weeds in peanuts and soybeans, and can also be used as part of an early preplant burn down program in cotton, field corn, rice, sorghum, sunflowers, and wheat.

Neither flumioxazin nor Valor Herbicide was very toxic in acute oral or dermal exposure studies in laboratory animals, nor were they very irritating to the eyes or skin (tested on rabbits). Also, neither the active ingredient nor the formulated product was a dermal sensitizer (tested on guinea pigs). In acute inhalation studies, neither flumioxazin nor Valor Herbicide was very toxic, but the formulated product caused some laryngeal lesions in the higher dose groups.

Flumioxazin caused some toxicity in chronic animal feeding studies. In a chronic feeding/oncogenicity study in rats, flumioxazin caused kidney damage in males at a dose of 18.0 milligrams per kilogram body weight per day (mg/kg/day) and in females caused anemia at 21.8 mg/kg/day; the respective no-observed-effect levels (NOELs) were 1.8 and 2.2 mg/kg/day. No effects were noted in mice at doses up to 754 mg/kg/day in males and 859 mg/kg/day in females, the highest doses tested. In dogs, an increase in liver weights and alkaline phosphatase activity was reported at 1,000 mg/kg/day; the NOEL was 100 mg/kg/day. The USEPA Office of Pesticide Programs established a reference dose (RfD) of 0.02 mg/kg/day based on a NOEL of 2.2 mg/kg/day in the chronic feeding/oncogenicity study in rats and an uncertainty factor of 100. This RfD has not yet been adopted by the USEPA's Integrated Risk Information System (IRIS).

Flumioxazin caused some developmental toxicity in the offspring of pregnant rats. In a rat oral developmental toxicity study, an increase in the incidence of cardiovascular effects (especially ventricular septal defects), rib abnormalities, fetal resorptions and a decrease in the number of viable fetuses were observed at ten mg/kg/day; the NOEL was three mg/kg/day. No maternal toxicity was observed at the highest dose tested, which was 30 mg/kg/day. In a second rat developmental toxicity study, but with dermal administration of flumioxazin, cardiovascular abnormalities were reported at 100 mg/kg/day; the NOEL was 30 mg/kg/day. Again, no maternal toxicity was observed at up to the highest dose tested (300 mg/kg/day). In a rabbit oral developmental toxicity study, no developmental effects were reported at doses up to 3,000 mg/kg/day. However, at this dose, some maternal toxicity, characterized by a decrease in body weight and food consumption was reported. In a multigeneration reproduction study in rats, flumioxazin caused a decrease in the number of liveborn pups and pup body weight at 12.7 mg/kg/day; the NOEL was 6.3 mg/kg/day. Parental toxicity characterized by an increase in mortality and liver effects in females was reported at 22.7 mg/kg/day, with a NOEL of 15.1 mg/kg/day.

Flumioxazin did not cause oncogenic effects in either rat or mouse chronic feeding studies. It also was negative in a number of genotoxicity studies. The USEPA classified flumioxazin as "not likely" to be carcinogenic to humans.

The USEPA established tolerances for flumioxazin residues in or on peanuts and soybean seed each at 0.02 parts per million (ppm). The chronic population adjusted dose (cPAD) for flumioxazin is 0.002 mg/kg/day based on the RfD of 0.02 mg/kg/day and an additional uncertainty factor of ten to account for the greater sensitivity of the fetus in the rat developmental and reproductive toxicity studies. The USEPA estimated that chronic dietary exposure to flumioxazin residues would be 0.5% of the cPAD for the general U.S. population and 2.3% for infants less than one year old. This chronic exposure analysis is based on the conservative assumption that 100% of crops are treated and contain tolerance level residues.

The USEPA conducted a risk assessment for dermal and inhalation exposure of workers to flumioxazin from its use on peanuts and soybeans. For mixer/loaders/applicators, margins of exposure (MOEs) were estimated to be 1,200 and above. For these estimates, it was assumed that workers wore long pants, long-sleeved shirt, but did not use gloves or a respirator (the label requires pants, shirt and gloves, but not a respirator). The NOELs used for estimating these MOEs were 30 mg/kg/day from the rat dermal developmental toxicity study (for comparing to short- and intermediate-term dermal exposures), three mg/kg/day from the rat oral developmental toxicity study (for comparing to short-term inhalation exposures), and two mg/kg/day from the rat chronic feeding/oncogenicity study (for comparing to intermediate-term inhalation exposures). For post-application occupational activities (i.e., irrigation, scouting, hand weeding), the estimated MOEs ranged from 700 to 11,000. Generally, the USEPA considers MOEs of 100-fold or greater to provide adequate worker protection.

DOH concluded that the labeled use of Valor would not pose significant direct risks to workers or the general public. However, DOH requested that the registrant clarify how an issue was resolved with the USEPA. The issue revolved around an acute inhalation toxicity study in rats which indicated that the formulated product caused lesions in the larynx of these animals. As a result of these findings, the USEPA reviewers of this study recommended that the product label require that handlers use a dust-filtering respirator. This requirement was apparently waived later in the federal review of this product, but no documentation for how the issue was resolved was provided.

Although the registrant was not able to supply any documentation from the USEPA regarding this matter, they submitted a risk assessment calculation for workers exposed to the active ingredient flumioxazin from the handling of Valor Herbicide based on the results of the acute inhalation study in rats. In making this calculation, the registrant assumed that the cause of lesions in the larynx of rats was due to the active ingredient. Results from this study indicate, however, that the cause of these lesions was instead the other ingredients in the product, not the active ingredient, as similar effects on the larynx were reported in studies using only the "inert" ingredients. Thus, in estimating a margin of exposure (MOE), the registrant should have compared the no-observed-effect air exposure level for the "inert" ingredients alone (expressed in terms of dose as 1.46 milligrams per kilogram body weight per day) with the corresponding estimate of worker inhaled dose (0.00021 milligrams per kilogram body weight per day) for these ingredients. When this comparison is made, the estimated MOE from inhalation exposure to the "inert" ingredients in the Valor product is approximately 7,000. This MOE, although about two-fold less than the registrant's estimated MOE, is still well within the range that the USEPA generally considers as providing adequate worker protection.

There are no chemical specific federal or State drinking water/groundwater standards for flumioxazin. 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).

Human Health Review Summary:

The available information on flumioxazin and Valor Herbicide indicates that overall the active ingredient and formulated product are not very acutely toxic in laboratory animal studies. The results of the above risk assessment analysis addressed our concern regarding respiratory protection for workers in lieu of documentation from the USEPA regarding this issue. Although data from chronic and developmental/reproductive studies on flumioxazin showed that this chemical has the potential to cause some toxicity, the expected exposure from the labeled uses of Valor Herbicide should not pose a significant risk to workers or the general public.

NONTARGET ORGANISM SUMMARY:

The New York State Department of Environmental Conservation Bureau of Habitat reviewed the application and supporting data submitted by Valent USA Corporation to register the pesticide product Valor Herbicide (EPA Reg. No. 59639-99) in New York State. Flumioxizan exhibited low toxicity to birds and mammals. It is somewhat more toxic to fish and aquatic invertebrates. It is very toxic to all aquatic plants, macrophytes and algae that were tested.

The freshwater aquatic invertebrate test was declared unacceptable and unrepairable by the USEPA. The study was deemed unacceptable due to some of the doses tested, exceeding the solubility (1.79 mg/L), and forming a precipitate, thus the actual content of the test solution was not accurately evaluated. However, the USEPA apparently did not require the study be redone.

Flumioxazin has a relatively short life in the environment. In water, it degrades quickly by photolysis and hydrolysis, with half-lives measured in hours. Two degradation products, 6-Amino-7-fluoro-4-(2-propynyl)-1,4,-benzoxazin-3(2H)-one (APF) and 3,4,5,6-tetrahydrophthalic acid (THPA) accounted for 42% and 48% of the parent flumioxazin degraded by hydrolysis. The toxicity of these degradation products was not described, but they did appear to be more soluble and persistent than the parent flumioxazin.

On soil, flumioxazin was broken down between three and 12 days by microbial metabolism and photolysis. APF and THPA were very minor degradates from fate processes in soil.

Model Parameters:

Pesticide Screening System (PSS) models were run using data extracted from the data support package supplied by the applicant using standard parameters. Because of the flumioxazin KOW of 354.8, the PONDTOX model selected values of one percent, three percent and five percent as appropriate estimates of the percentage of pesticide active ingredient that could be removed by runoff.

Model Results:

Both the MAMTOX and AVTOX models showed no acute or chronic adverse impacts to mammal and bird populations that were likely to result from consumption of vegetation that was treated with flumioxazin at the maximum labeled application rate.

The PONDTOX model similarly showed no acute or chronic adverse impacts to fish, aquatic invertebrates, or marine/estuarine organisms from flumioxazin transported to water via runoff, using runoff rates as high as five percent. However, at all runoff levels, from 0.25% to one percent and above, impacts to both aquatic macrophytes and Anabena flos-aquae, the most sensitive algae species tested, were evident. At one percent runoff, the Lemna gibba EC50 and NOEC were exceeded in all three pond depths (one, three, and six feet). The magnitude of exceedances as measured by Risk Quotients (RQs), ranged from 1.1 (EC50 in six-foot pond) to 8.8 (NOEC in one-foot pond). For Anabena flos-aquae, the EC50 was exceeded in the one- and three-foot ponds, with RQs of 2.3 and 1.1, indicating only marginal exceedances. The Anabena flos-aquae NOEC was exceeded in all three pond depths by a considerable margin, with RQs ranging from 23.5 in the six-foot pond to 87.6 in the one-foot pond.

When a runoff percentage of 0.25% was used, adverse impacts to aquatic life were still predicted, but at a much lower magnitude. No EC50s were exceeded. The Lemna gibba NOECs were marginally exceeded (RQs = 2.2 and one) in the one- and three-foot ponds. The Anabena flos-aquae NOECs were exceeded in all three pond depths with RQs ranging from 5.9 to 21.9.

Model Analysis:

The PONDTOX model clearly predicts the potential for significant impacts to aquatic plants, both algae and macrophytes from flumioxazin residue in runoff water. Because, as would be expected from an herbicide, these species were very sensitive to flumioxazin, a separate analysis was run using all of the algae and macrophyte data available. This analysis showed that at one percent runoff, all five of the plant species for which data were available showed some level of impact. For Skeletonema costatum, a marine diatom, the no effects concentration was exceeded in the one-foot pond only. For Lemna gibba, a freshwater macrophyte, both the EC50 and NOEC were exceeded in all three pond depths. At 0.25% runoff, no EC50s were exceeded. There were no toxicity thresholds exceeded at all for Skeletonema costatum or Selenastrum capricornutum, a freshwater green algae. For the others, the RQs ranged from one to 21.9.

Risk Assessment:

The PONDTOX models clearly show that Valor, when applied as labeled, has the potential to be harmful to aquatic plants, both macrophytes and algae, when transferred to water bodies via runoff.

Mitigation:

The PONDTOX model does not take into consideration either the terrestrial or aquatic degradation of pesticides. The rate of degradation can significantly impact the volume of pesticide available for runoff. Valor is applied one time only per season. It is also applied very early in the growing season, because it is used as either a preemergence herbicide or to burn off weeds as part of a preplant control program. Valor degrades fairly quickly on land, by both photolysis and microbial degradation with an average half-life of around three to 12 days. Also, Valor degrades very rapidly by hydrolysis and photolysis in water, with half-lives measured in minutes to hours, depending upon the ambient water pH.

The aquatic plant toxicity tests were five-day tests, with the exception of the Lemna gibba test, which was a 14-day study. In all likelihood, most flumioxazin would degrade before it could have a serious impact on exposed nontarget aquatic vegetation. Valor begins degrading shortly after being applied, continuously decreasing the amount of flumioxazin that is available to be washed off the soil in runoff. Once in the water, it will degrade very rapidly.

The formation of two persistent, soluble degradates was documented during aqueous hydrolysis studies, APF and THPA. The toxicity of these degradates is unknown. However, hydrolysis is a slower fate process than photolysis in water, and these degradates are formed at much lower rates during daylight. They are also only minor (i.e., < ten percent of parent) in terrestrial degradation. The formation of significant concentrations of these degradates is only likely to occur during hours of darkness. APF and THPA do degrade, both in water and on soil, albeit much more slowly.

Nontarget Organism Review Summary:

Because of the rapid fate processes that actively reduce the flumioxazin concentration both on land and in water, it is unlikely that a large enough concentration of flumioxazin is likely to exist in water long enough to harm aquatic plants. The use of Valor Herbicide should not impact wildlife, birds, or aquatic species when used as labeled in New York State.

ENVIRONMENTAL FATE SUMMARY:

The Department reviewed the application and supplemental data packages for impact to groundwater resources in New York State. All but two data evaluation records (DERs) were submitted. The main Environmental Fate & Groundwater Branch (EF&GWB) review memorandum was not submitted; however, a shorter memorandum dated July 21, 1993 that discussed several studies was submitted.

Hydrolysis: The DER for this study was not submitted. However, according to the USEPA memorandum dated July 21, 1993, this study was acceptable. Flumioxazin (or V-53482) had average calculated half-lives of 3.4 to 5.1 days, 21.4 to 24.6 hours and 14.6 to 22.0 minutes in solutions with pH of 5, 7, and 9 , respectively. Two degradates were found in the phenyl-labeled ring study--7-fluoro-5[(2-carboxy-cyclohexenoyl)amino]-4-(2-propynyl)-1,4-benzoxazin-2(2H)-1 or 482-HA, reached a maximum of 5.4 in the pH 5 solution, 60.2 in pH 7 solution, and 100% in pH 9 solution. The second degradate, 6-amino-7-fluoro-4-(2-propynyl)-1,4-benzoxazin-3(2H)-1 or APF, reached 90% in the pH 5 solution, 82.2% in the pH 7 and was ND in the pH 9. In the tetrahydrophthalimido ring-labeled study, three degradates were found. First, 482-HA at 6.7 % in pH 5 solution, 70.3% in the pH 7 solution and 98% in the pH 9 solution. Second, 3,4,5-6 tetrahydrophthalic acid or THPA as 96.6% in pH 5 solution, 84.2% in the pH 7 solution, and ND in the pH 9 solution. The third degradate, 3,4,5,6-tetrahydrophthalic acid anhydride or 1 -TPA, reached 8.8% in pH 5 solution, 8.7% in pH 7 solution, and ND in the pH 9 solution.

Aqueous Photolysis: This study did not meet Subdivision N Guidelines. The registrant-calculated half-life was 20.9 hours in a sterile pH 5 aqueous buffer solution. The reviewer-calculated half-life was 25.4 hours. Two unidentified major degradates were found. Unknown one reached 74.6% and Unknown three reached 16.8%. USEPA required that these studies be repeated and data submitted by April 12, 2003.

Soil Photolysis: USEPA found this study partially acceptable. In the phenyl ring-labeled study, flumioxazin had a half-life of 3.2 days on a sandy loam soil. Five minor degradates were found. In the THP ring-labeled study, flumioxazin had a half-life of 8.4 days on a sandy loam soil. Five minor degradates were found. 1-TPA reached 21.6% of applied, and THPA reached 12.9% of applied.

Aerobic Soil Metabolism: This study did not meet Subdivision N Guidelines. Degradates were not determined. Flumioxazin had a half-life in sandy loam, clay loam, sand and loam of 5.0 days, 18.6 days, 18.9 days and 15.6 days, respectively.

Anaerobic Aquatic Metabolism: This study did not meet Subdivision N Guidelines. In the phenyl ring-labeled study, flumioxazin had a half-life of 4.2 hours on a sandy loam soil. In the water phase, major degradate 482-HA reached 45.4% and SAT-482-HA-2 reached 16.2%. In the THP ring-labeled study, flumioxazin had a half-life of 4.3 hours on a sandy loam soil. In the water phase, major degradate 482-HA reached 52.8% and SAT-482-HA-2 reached 15.7%. USEPA required that these studies be repeated and data submitted by April 12, 2003.

Adsorption/Desorption: This study did not meet Subdivision N Guidelines. The Kocs of flumioxazin in sand, sandy loam, silt loam and clay loam were 265-277, 105-118, 675-1705 and 497-816, respectively. No degradates were noted.

Mobility and Aged Leaching: No DER was submitted for the phenyl-labeled ring study, but in the July 21, 1993 memorandum, USEPA indicated that this study was scientifically sound and partially acceptable. USEPA also had concerns about the length of time of the aging of the soil. However, no major degradates were noted, so no additional data was required for the aged leaching study. The DER for the TPA-ring labeled study indicated the half-life was 17.5 days with no major degradates.

Terrestrial Field Dissipation: MRID44295045 - This study did not meet Subdivision N Guidelines because the registrant did not analyze for degradates. USEPA believed the registrant calculated half-life of 10.3 days was questionable for many reasons.

MRID44295047 - This study was partially acceptable. The registrant calculated half-life was 4.8 days on a loam soil. Only minor degradates were found.

MRID44295043 - This study was partially acceptable. The registrant calculated half-life was 27 days in a loamy sand soil. Only minor degradates were found.

MRID44295046 - This study did not meet Subdivision N Guidelines because the registrant did not analyze for degradates. The registrant calculated half-life was 42 days in a silt loam soil.

MRID44295044 - This study did not meet Subdivision N Guidelines because the registrant did not analyze for degradates. USEPA believed the half-life was questionable. The registrant calculated half-life was 12.5 days in a silt loam soil.

Modeling: Staff modeled flumioxazin on Riverhead soil (to simulate upstate aquifers as well as Long Island) using a Koc of 105 (the lowest for sandy loam), a half-life of 18.9 days (the longest) and the maximum application rate of 0.0956 lb ai/a/yr. The model projected several peaks, all less than 0.015 ppb.

Environmental Fate Summary:

There appear to be no major degradates of Flumioxazin formed during its breakdown in the environment. Although a low Koc is typically an indicator of mobility and contamination of groundwater, Flumioxazin has a short half-life. Coupled with the very low application rate, the registration of this product for use as labeled will have no significant impact to groundwater resources.

REGISTRATION SUMMARY:

The Department will register Valor Herbicide for use as labeled in New York State. Enclosed for your record is a copy of the stamped accepted label and the Certificate of Registration for Valor Herbicide (EPA Reg. No. 59639-99). Please note that a proposal by Valent USA Corporation or any other registrant, to register a product that contains flumioxazin, and whose labeled uses 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.

Please contact our Pesticide Product Registration Section, at (518) 402-8768, if you have any questions.

Sincerely,

Maureen P Serafini

Maureen P. Serafini
Director
Bureau of Pesticides Management

cc: w/enc. - N. Kim/D. Luttinger - NYS Dept. of Health
R. Zimmerman/R. Mungari - NYS Dept. of Ag. & Markets
W. Smith - Cornell University, PSUR