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 51 8-402-9024 Website: http://ww.dec.nv.~ov E-Mail: ppr@gw.dec. state.ny.us Alexander B. Gmnnis Commissioner CERTIFIED MAIL RETURN RECEIPT KEOUESTED Ms. Melinda Bowman Registration & Regulatory Affairs Valent U.S.A. Corporation P.O. Box 8025 Walnut Creek, California 94596-8025 Dear Ms. Bowman: Re: Registration of the New Pesticide Product Chateau Herbicide WDG @PA Reg. No. 59639-119) and Registration of Supplemental Labeling for the Currently Registered Pesticide Product Chateau Herbicide SW @PA Reg. No. 59639-99) Which Represent a Major Change in Labeling for the Active Ingredient Flnmioxazin I The New York State Department of Environmental Conservation (Department) has completed it's review of your applications, received October 24,2006, and additional information received May 4,2007, August 3,2007 and December 4,2007, to register Chateau Herbicide WDG @PA Reg. No. 59639-1 19) and supplemental labeling for Chateau Herbicide SW @PA Reg. No. 59639-99) which contain the active ingredient flurnioxazin (chemical code 129034). I The applications were determined to be complete for the purposes of a technical review on December 14,2006 and the original registration decision date was May 14,2007. However, due to techmcal issues discovered during the review process, the registration decision date was waived. Flumioxazin is currently registered in New York State for weed controvsuppression and vegetation burn-down in field corn, soybeans, peanuts, cotton and other crops, non-crop land, orhamentals and trees. The new proposed uses of flumioxazin on strawberries, pome f i t and stone hit, as specified on the Chateau Herbicide S W and Chateau Herbicide WDG labels, represent a major change in use pattern for tbis active ingredient in New York State. Chateau Herbicide SW (EPA Reg. No. 59639-99) and Chateau Herbicide WDG (EPA Reg. No. 59639-1 19) are identical in formulation. The active ingredient, flurnioxazin, 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.
I 1 Ms. Melinda Bowman 2. I I The Department has reviewed the information supplied to date in support of registration of Chateau Herbicide WDG (EPA Reg. No. 59639-1 19) and registration of the supplemental labeling for Chateau F'lrrhiclde SW (EPA Reg. No. 59639-99) and concludes that when used as labeled these products should not have an adverse effect on the health of applicators or the general public, the fish and wildlife resources, or the ground and surface water of New York State. HUMAN HEALTH RISK ASSESSMENT The New York State Department of Health @OH) stated that the Chateau Herbicide products are identical in formulation to Valor Herbicide, whch the DOH previously reviewed. In that review, the DOH noted that the available information indicated that overall Valor Hdicide and its active ingredient flumioxazin were not very acutely toxic in laboratory animal studies. Flumioxazin did not cause oncogenic effects in either rat or mouse chronic feeding studies and was negative in a number of genotoxicity studies. Based on these results, the U.S. Environmental Protection Agency (U.S. EPA) classified flumioxazin as "not likely" to be carcinogenic to humans. Data from chronic and developmental/reproductive toxicity studes in animals showed that this chemical has the potential to cause some toxicity, notably kidney damage and anemia (chronic toxicity study in rats) and cardiovascular and skeletal abnormalities (developmental toxicity studies in rats). A current search of the toxicological literature did not find any significant new information on the toxicity of flumioxazin The U.S. EPA originally calculated am oral reference dose (m) for flumioxazin of 0.02 milligrams per kilogram body weight per day (mgkdday) based on the no-observed-effect level (NOEL) fiom the rat chronic feedingloncogenicity study (2.2 mgkglday) and an uncertainty factor of 100. For the purpose of evaluating dietary risks fiom exposure to flumioxazin through. crops treated with this chemical, a chronic population adjusted dose (cpad) of 0.002 m&g/day was used. This value was based on the RfD of 0.02 mg/kg/day and an additional uncertainty factor of 10 to account for the greater sensitivity of the fetus in the rat developmental and reproductive toxicity studies. In a more recent evaluation of the toxicological data base for ffumioxazin, the U.S. EPA concluded that because the toxicity endpoints of concem fiom these studies are well characterized with a we11 defined dose response curve for the observed cardiovascular effects, the additional uncertainty factor of 10 can be removed, which in turn increased the cpad to 0.02 mg/kg/day. The U.S. EPA established tolerances for fldoxazin residues in or on strawberries at 0.07 parts per million (ppm); and pome fruit and stone hit, each at 0.02 ppm. Using the revised cpad of 0.02 mgflrglday, the U.S. EPA estimated that chronic dietary exposure to flumioxazin residues fiom all the registered crop uses of this active ingredient would be less than 6 percent of the cpad for the general U.S. population, less than 18 percent for infants less than one-year old and less than 11 percent for children one to two years old. This chronic exposure analysis is based on the conservative assumptions that 100 percent of crops are treated and that they contain tolerance level residues. In the DOH'S review of Valor Herbicide, they reported the results of a U.S. EPA risk assessment for dermal and inhalation exposure of workers to flumioxazin fiom its use on peanuts and soybeans. For mixers/loaders/app~icators, margins of exposure (MOEs) were estimated to be 1,200 and above. Generally, the U.S. EPA considers MOEs of 100-fold or greater to provide adequate worker protection. Because the application rate for flumioxazin on strawberries, using a Chateau Herbicide product, is the same (43.5 grams per acre) as it was for the Valor product, it
Ms. Melinda Bowman 3. is reasonable to expect that the estimated MOEs from use on strawberries, would also be 1,200 and above. Accordingly, because the application rate on pome h it and stone fnut is two to fourfold greater than on strawberries, the estimated MOEs would be about 300 and above. Using this same reasoning for post-application occupational activities (i.e., irrigation, scouting, hand weeding), the estimated MOEs are expected to be about 700 and above for strawberries and about 175 and above both for pome and stone hit. The available information on flumioxazin and Chateau Herbicide indicates that overall the active ingredient and formulated product are not very acutely toxic in laboratory animal studies. Although data from chronic and developmental/reproductive studies on flumioxazin showed that this chemical has the potential to cause some toxicity, the expected exposure h m the labeled uses of Chateau Herbicide should not pose a si@cant risk to workers. However, the DOH had some concerns about the characterization of dietaryrisks. That is, while dietary risks evaluated using the newer cpad did not indicate a significant concern, risks estimated using the old cpad would indicate a potential concern. It was not clear from the information provided why the ten-fold uncertainty factor to address Food Quality Protection Act requirements was eliminated during the development of the new cpad since the same study data appeared to be used during the development of both cpads. To address this concern, three options were presented to the registrant: (1) provide additional documentation on U.S. EPA's basis for removing the 10-fold uncertainty factor in the specific case of flumioxazin; (2) use the U.S. EPA guidance documents on the appropriate use of the FQPA uncertainty factors to explain why the agency changed the cpad, or (3) conduct a more refined analysis of dietary exposure to flumioxazin residues from all food commodities for which there are tolerances. In response to the DOH'S request, the regisirant submitted additional infomation that discussed the above three options. Regarding the first option, the registrant indicated that there are no other documents that can be obtained from the U.S. EPA that specifically discuss removing the additional 10-fold uncertainty factor for flumioxazin. The removal of the 10-fold factor appears to have resulted fiom a philosophical change at the U.S. EPA. In this regard, the registrant quoted a U.S. EPA guidance document (developed between the first and second cpad determinations), which states "...the presence of pre-or post-natal toxicity, by itself, is not regarded as determinant as to the size of the children's safety factor. Rather the U.S. EPA stresses the importance of evaluating all the data under a weight of evidence approach focusing on the safety of infants and children. This attention on the overall database also indicated a shift in emphasis for the U.S. EPA's implementation of the children's safety factor provision as previous decisions had often treated a finding of increased sensitivity in the young as almost necessitating some additional safety factor." To address the third option, the registrant submitted a refined dietary exposure analysis. In this dietary exposure assessment, the registrant used field trial residue data, percent crop treated data and food processing factors. This assessment estimated that chronic dietary exposure to flumioxazin residues from all food commodities for which there are tolerances is 1.19 percent of the cpad of 0.02 mglkgiday for the most highly exposed sub-population (children one to two years old). Using the old cpad of 0.002 madday, dietary exposures would represent 11.9 percent of this value for the most highly exposed sub-population.
Ms. Melinda Bowman 4. The registrant also submitted a discussion on the mechanism of developmental toxicity reported in rats as determined by a series of studies (only the discussion paper was provided for the DOH's review). The registrant's conclusion from these studies is that the rat is a valid and conservative surrogate for evaluating flumioxazin's potential to cause developmental toxicity in humans. Basically, flumioxazin interferes with normal heme synthesis that results in anemia and porphyria in rats. The registrant postulates that h s anemia causes fetal hypoxia that Ieads to fetal growth retardation and death, enlargement of the heart and decreased fetal protein synthesis. The decreased fetal protein synthesis is believed to cause the edema and skeletal effects also noted in the developmental studies in rats. The enlargement of the heart is believed to be responsible for the failure of the interventricular foramen to close as observed in rat fetuses exposed to flurnioxazin during gestation. Sensitivity to flumioxazin's inhibition of a key enzyme in heme synthesis (protoporphyrinogen oxidase), postulated to be the root cause for the spectrum of effects observed in the rat development toxicity studies, was determined to be greater in rats than in humans or the other laboratory animals studied (dogs, mice and rabbits). In summary, the registrant provided information on the three options they were requested to address to mitigate the DOH'S remaining concerns regarding flumioxazin. The registrant's response, along with the DOH's own reading of the U.S. EPA documents, indicates that the removal of the 10-fold uncertainty factor in the case of flumioxazin resulted hm a philosophical change at the U.S. EPA in how they determine appropriate FQPA factors when assessing food tolerances. The registrant also provided a refmed analysis of dietary exposure to flumioxazin residues hrn food commodities, which indicates that such exposure would not exceed either the old or the new cpads. Based on this refined exposure analysis, dietary exposure to flumioxazin residues should not pose a significant risk for developmental effects on humans. The mechanistic data submitted by the registrant provides-supplementa1 support for this conclusion. In view of the above, the DOH does not object to registration of Chateau Herbicide products in New York State. ENVIRONMENTAL FATE RISK ASSESSMENT The Department's groundwater staff stated that he maximum application rate on pome and stone h it is 24 ounces of producb'acre/year or 0.765 lbs aildyr. This is the same maximum application rate as previously approved by the Department. The maximum application rate for strawberries is 3 oz of product/acre/year or 0.1 lb ai/alyr. The inerts do not appear to be solvent carriers. The following is the groundwater staffs review: Transformation products: APF THPA 482-HA SAT-482-HA-2 A-TPA 6-amiao-7-fluoro-4-(2-propynyl j- 1,4-benzoxazin-3 (2H)-one 3,4,5-6 tetrahydrophthalic acid 7-fluoro-5 [(2-carboxy-cyclohexenoy1)amino]-4-(2-propyny1)- l,4- benzoxazin-212h)-one Not defined 3,4,5-6 tekahydrophthalic acid anhydride Solubility: The solubility of flumioxazin is 1.79 m a. Hydrolysis: Flumioxazin hydrolyzes very rapidly and the rate increases as the ph of the solution increases. Two studies were submitted; the average half-lives fiom the two ring labeled studies were 4.2 days, 23 hours and 18.3 minutes for the ph 5,7, and 9 buffered solutions. Four
1 Ms. Melinda Bowman 5. I I I degradates were observed: 482-HA, APF, THPA and A-TPA. Dcg~ad;lle 482-WA was found at 93.7% of applied in the ph 9 and 9.3% in the ph 7 solutions. APF was 41.8% and 40% in the ph 5 and 7 solutions. THPA was 47.7 and 41.8% in the ph 5 and 7 solutions. A-TPA was a minor component in the ph 5 and 7 solutions. Aqueous Photolysis: Flumioxazin photodegrades very rapidly in water. The phenyl labeled ring degraded with a half-life of 20.9 hours in a ph 5 buffer solution. Two unidentified major degradates were.found, one at 74.6% and one at 16.8%. In a second study, the tetrahydrophthalimido labeled ring degraded with a half-life of 26.3 hours in a ph 5 buffer solution. THPA was found at 23.0%. Two more unidentified major degradates were found, one at 54.1%, and one at 35.1% Soil Pbotolysis: Flumioxazin photodegrades relatively slowly on the soil surface. In the phenyl labeled ring study, the half-life was 3.2 days in a sandy loam soil. In the tetrahydrophthalimido labeled ring study, the half-life was 8.4 days, with THPA reaching 12.9% ofapplied. Aerobic Soil Metabolism: In two ring labeled studies, flumioxazin had a half-life of 11.9 and 17.5 days in a sandy loam soil. In a nonradiolabeled study, flumioxazin had half-lives of 5.0 days in a sandy loam, 18.6 days in a clay loam, 18.9 days in a sand, and 15.6 days in a loam soil. ' Percent organic matter and phs were. not. provided in the Risk Assessment. Anaerobic Aquatic Metabolism: In two ring labeled studies, half-lives were 4.2 and 4.3 hours in a flooded sandy loam soil. In the water phase, 482-HA reached 45.5%. SAT-482-HA-2 reached 16.2%. Adsorption/Desorption: The -average&s of fl umioxazin in sand, sandy loam, silt loam and clay loam were 271, 112, 1190 and 656, respectively. AdsorptionlDesorption of Degradates: The &s for APF were 336 in a sandy loam, 391 in a loam, 502 in a sandy loam, 620 in a sandy loam, and 201 in a loam. The &s for THPA were 13. in a sandy loam, 248 in a loam, 66 in a sandy loam, 339 in a sandy loam, 75 in a lorn and 191 in a clay. Terrestrial Field Dissipation: MRXD44295045; The half-life was 10.3 days in a silt loam soil planted with soybeans. The registrant did not analyze for degradates. MRID44295047; The half-life was 14.8 days in a lorn soil planted with soybeans. No major degradates were found. MRID4.1295043; The half-life was 27 days in a bare ground sandy loam soil. The registrant did not analyze for degradates. MRID44295046; The half-life was 42 days in a silt loam soil planted with soybeans. The registrant did not analyze for degradates. MRID44295044; The half-life was 12.5 days on a no-till bare ground plot of silt loam soil. The registrant did not analyze for degradates.
Ms. Melinda Bowman 6. Modeling: In 2004, staff modeled flumioxazin on Riverhead soil using a K, of 105, a half-life of 18.9 days and the maximum application rate of 0.76 lb ailajyr. The model projected several peaks, all less than 0.1 1 ppb. Not enough information was presented in this application to model the degradates. Groundwater: According to the DOH letter dated September 19,2003, there are no chemical specific federal or State drinking watedgroundwater 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). Summary: No DERs were submitted, so staff used the January 5,2006 Risk Assessment for the technical review. Portions of the data appeared to conflict with the data submitted with the application in 2004. Also, it now appears that U.S. EPA has much greater concern regarding the leachability of the degradates than in the previous review. However, given that the uses in this major change in labeling are in line with those uses already registered and there is no increase in the application rate, staff do not object to the registration of this product as labeled. ECOLOGICAL RISK ASSESSMENT The Department's Division of Fish, Wildlife & Marine Resources' Bureau of Habitat (BOH) stated that the active ingredient, flumioxazin has been extensively reviewed several times by the BOH. Its ecotoxicity and environmental fate have been well documented. Previous risk assessments have found that flumioxazin presents little risk to birds and mammals. It is more toxic to aquatic organisms, and it is highly toxic, as would be expected, to algae and aquatic plants. However, flumioxazin is degraded in water by multiple pathways with half lives ranging fmm minutes to hours, depending on the ph and light intensity. Flumioxazin also dissipates fairly rapidly on soil with microbial degradation half lives between three and 12 days. Due to its rapid rate of degradation, flumioxazin will not be present long enough in the water column to harm aquatic plants or animals. Given the above, the BOH has no objections to registration. REGISTRATION SUMMARY The Department concludes that the use of Chateau Herbicide WDG and Chateau Herbicide SW should not have an adverse effect on the health of applicators or the general pubtic, the fish and wildlife resources, or the ground and surface water of New York State when used as labeled. Therefore. the De~artment herebv accedts for reeistration the new nesticide uroduct Chateau ~erbieide WDG (EPA Reg. NO. 59639-119) h d the supplemedtal labelkg for Chateau Herbicide SW (EPA Reg. No. 59639-99). A copy of the Certificate of Pesticide Registration and New York State stamped "ACCEPTED labeling for Chateau Herbicide WDG (EPA Reg. No. 59639-1 19) and Chateau Herbicide SW (EPA Reg. No. 59639-99) are enclosed for your records. Valent U.S.A Corporation is reminded that if New York State registration is requested for Chateau or for any other product which contains flumioxazin with an increased application rate, different application method and/or expanded use sites, the product will be considered a Major Change in Labeling and the Department will require an extensive review..
Ms. Melinda Bowman If you have any questions, please contact Mr. Samuel Jackling, Chief of our Pesticide Product Registration Section, at (518) 402-8768. Sincerely, Enclosures ecc: w/enc. - R. Mungari - NYS Dept. of Ag. & Markets A. Grey,%. Horn - NYS Dept. of Health W. Smith - Cornell University, PSUR Maureen P. SeraJini Director Bureau of Pesticides Management