Isoxaflutole

Isoxaflutole (IFT; 5-cyclopropyl-1,2-isoxazol-4-yl ααα-trifluoro-2-mesyl-p-tolyl ketone) is a 4-HPPD Inhibitor Herbicide. Pesticide Action Network lists it as a "Bad Actor" chemical and a carcinogen, with slight acute toxicity. As of 2012, isoxaflutole is only registered for use on corn. However, the EPA is reviewing whether to allow its use on soybeans. The manufacturer of Isoxaflutole, Bayer CropScience, has developed an Isoxaflutole-tolerant variety of soybean (FG72).

Between 2000 and 2008, an estimated average of 300,000 lbs of isoxaflutole was used in the U.S. each year. It was used on an estimated average of 5% of all U.S. corn.

History
Isoxaflutole was first synthesized in 1990 and its herbicidal properties were recognized in 1991. Credit for its discovery is given to "the herbicide discovery teams at the Ongar Research Station of Aventis CropScience." (The initial producer according to the EPA was Rhone-Poulenc Ag Company, which became Aventis CropScience and was then acquired by Bayer CropScience in 2001.)

Isoxaflutole was conditionally registered in the U.S. by the EPA in 1998. At that time, it was only registered for corn. The registration was a "conditional, time-limited, geographically-limited registrations of Technical Isoxaflutole and Balance Herbicide for use on field corn," expiring November 1, 2001. It was limited to the states of: Arkansas, Indiana, Illinois, Iowa, Kansas, Kentucky, Missouri, Montana, Nebraska, North Dakota, South Dakota, Tennessee, Ohio, Oklahoma, Texas (north of I-20), and Wyoming. Application rates were limited to "1 to 3 ounces of formulated product (0.046875 to 0.140625 pounds active ingredient) per acre" and only one application was allowed per season. At the time, the EPA wrote:


 * "Based upon a battery of acute toxicity studies, Balance Herbicide is classified as Toxicity Category III. Isoxaflutole demonstrates developmental toxicity and has been classified as a Group B2 carcinogen (probable human carcinogen). The data available at this time indicate that isoxaflutole is very phytotoxic. Isoxaflutole is persistent and mobile, and may leach and accumulate in groundwater and through surface water."

At the time of the conditional registration, the EPA noted several "data gaps," including "Developmental Neurotoxicity Study in Rats, Prospective Groundwater Studies, Surface Water Monitoring, Avian Reproduction Study with Major Metabolite, Acute Toxicity Study to Shrimp with Major Metabolite, Acute Toxicity Study to Estuarine Fish with Major Metabolite."

In 1998, the EPA set the tolerance limits for residues of isoxaflutole and its metabolites on various foods as follows:
 * "isoxaflutole tolerances were established for combined residues of isoxaflutole and its metabolites RPA 202248 and RPA 203328, calculated as the parent compound, in or on the following raw agricultural commodities: Corn, field, forage at 1.0 ppm; corn, field, grain at 0.20 ppm; and corn, field, stover at 0.50 ppm. Tolerances were established for the combined residues of isoxaflutole and its metabolite RPA 202248, calculated as the parent compound, in or on the following raw agricultural commodities: Cattle, fat at 0.20 ppm; cattle, liver at 0.50 ppm; cattle, meat at 0.20 ppm; cattle, meat byproducts, except liver at 0.10 ppm; egg at 0.01 ppm; goat, fat at 0.20 ppm; goat, liver at 0.50 ppm; goat, meat at 0.20 ppm; goat, meat byproducts, except liver at 0.10 ppm; hog, fat at 0.20 ppm; hog, liver at 0.50 ppm; hog, meat at 0.20 ppm; hog, meat byproducts, except liver at 0.10 ppm; horse, fat at 0.20 ppm; horse, liver at 0.50 ppm; horse, meat at 0.20 ppm; horse, meat byproducts, except liver at 0.10 ppm; milk at 0.02 ppm; poultry, fat at 0.20 ppm; poultry, liver at 0.30 ppm; poultry, meat at 0.20 ppm; sheep, fat at 0.20 ppm; sheep, liver at 0.50 ppm; sheep, meat at 0.20 ppm; and sheep, meat byproducts, except liver at 0.10 ppm."

In 2008, the EPA removed the benzoic acid metabolite RPA 203328 from its tolerance limits and increased the tolerance for residues of isoxaflutole and its metabolite RPA 202248 "in or on corn, field, forage from 0.02 ppm to 0.04 ppm." At the same time, the EPA removed the regulation that limited the residues of isoxaflutole and its metabolites in meat, milk, and eggs because it felt it was "unnecessary."

On April 27, 2010, the EPA granted an experimental use permit for isoxaflutole on isoxaflutole-tolerant soybeans.

In 2011, the EPA increased its tolerance for combined residues of isoxaflutole and its metabolites in "soybean, aspirated grain fractions" from 0.25 ppm [parts per million] to 0.30 ppm. The allowed tolerance for isoxaflutole in soybeans is 0.05 ppm.

Herbicidal Mode of Action

 * "Isoxaflutole is a pigment inhibitor. It works by preventing the biosynthesis of carotenoid pigments, which protect chlorophyll from decomposition by sunlight. Without carotenoid pigments, chlorophyll pigments are photo-oxidized and chloroplasts break down. Without the energy-collecting action of the chlorophyll, the whole plant eventually dies."

A more technical explanation reads:
 * "The biochemical target of [isoxaflutole] is 4-hydroxyphenylpyruvate dioxygenase (HPPD), inhibition of which leads to a characteristic bleaching of susceptible species. The inhibitor of HPPD is the diketonitrile derivative of [isoxaflutole] formed from opening of the isoxazole ring. The diketonitrile (DKN) is formed rapidly in plants following root and shoot uptake. The DKN is both xylem and phloem mobile leading to high systemicity."

Isoxaflutole, which has a halflife of 12 hours to 3 days, depending on soil type and other factors, also converts to diketonitrile in the soil. Isoxaflutole is retained at the soil surface, allowing it to be taken up by surface germinating weed seeds, whereas diketonitrile, which has a halflife of 20 to 30 days, penetrates the soil and is taken up by plant roots. In both plants and in the soil, diketonitrile is converted to the herbicidally inactive benzoic acid. "This degradation is more rapid in maize than in susceptible weed species and this contributes to the mechanism of selectivity, together with the greater sowing depth of the crop."

Isoxaflutole in the Environment
As noted above, isoxaflutole breaks down into diketonitrile, which further breaks down into benzoic acid. Under laboratory conditions, the halflife of the former is 12 hours to 3 days, and the halflife of the latter is 20 to 30 days.

In a study of 10 Iowa rivers in 2004, isoxaflutole was found in 4 of 75 water samples, but diketonitrile was found in 56 of the samples and benzoic acid was found in 43 of the samples. "The concentrations of DKN and BA were approximately 2 orders of magnitude less than those of the commonly detected triazine and acetamide herbicides and their degradation products." (However, isoxaflutole is only used on an estimated 5% of the U.S. corn crop (on average, between 2000 and 2008). ) Concentrations of isoxaflutole and its breakdown products were highest from May to July.

Groundwater Contamination
Upon granting conditional registration to isoxaflutole, the EPA required the the manufacturer to perform several small-scale Prospective Ground Water (PGW) studies to find out whether isoxaflutole would contaminate groundwater. An EPA memo in 2001 reviewed the initial studies and concluded:


 * "All three of these studies conñrm EFED's concern about the high mobility of isoxaflutole and its first degradate RPA-202248 (ìsoxañutole-DKN) and their potential to cause contamination of shallow ground water. DKN reached the three to six-foot depths within weeks or a few months at all three sites. EFED remains concerned about isoxañutole`s potential to contaminate shallow ground water (less than about 10 feet to the water table) in areas with soils that are not normally considered vulnerable. This is in addition to the soils that were labeled-off in the conditional registration... Further label restrictions regarding allowable soil types and water table depth may be necessary for this active ingredient."

Toxicity in Mammals
The EPA found:
 * "Isoxaflutole exhibited low acute toxicity via oral, dermal, and inhalation routes of exposure and it is not a dermal sensitizer. In long-term studies via the oral route, isoxaflutole caused ocular  toxicity in rats, hepatotoxicity (including liver tumor formation) and thyroid tumors in rats and mice, and hematotoxicity (toxicity to blood) in dogs and mice at high doses. The liver and ocular toxicities observed in rats were consistent with the mode of action of isoxaflutole in mammals (i.e., inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD)) that leads to a buildup of tyrosine in the blood and the eye.


 * "Developmental toxicity was observed in rats and rabbits primarily as growth retardations, including delays in skeletal ossification, effects that have been observed with other HPPD inhibitors (e.g., pyrasulfotole). There was no evidence of reproductive toxicity in the 2-generation reproductive toxicity study in rats; however, both adults and offspring exhibited ocular and liver toxicities as seen in long-term studies.


 * "In the acute and subchronic neurotoxicity studies in rats, mild changes in functional-observation battery (FOB) parameters (grip strength and/or landing foot splay) were observed in adult animals. However, similar effects were not observed either in pregnant animals or in offspring in a developmental neurotoxicity (DNT) study in rats. In both maternal animals and offspring, changes in body weight and/or food consumption were the primary effects seen in the DNT study and at the same dose tested. Decreased brain weights were observed in offspring on post-natal day (PND) 11 at the high dose only, but not at a later time point, an indicator of a developmental delay and/or a secondary effect of the decreased body weight. Although morphometric analyses were not performed in the study, there were no effects on pup swimming ability, learning, memory, motor activity, or auditory startle response at any dose, nor was there any evidence of neuropathology in the study at any dose. As a result, the missing morphometric measurements, while required, are unlikely to affect the tentative lowest-observed adverse-effect level (LOAEL) of the study (highest dose tested).


 * "Isoxaflutole was negative in a variety of genotoxicity screening assays. In carcinogenicity studies, isoxaflutole induced liver and thyroid tumors in rats and liver tumors in mice. Isoxaflutole was classified as "likely to be a human carcinogen." (emphasis added)

Brands and Manufacturers
The following Isoxaflutole herbicides are registered (legal) as "Restricted Use" in the United States:

Bayer CropScience: DuPont
 * Balance®
 * Balance® Flexx
 * Balance® Pro
 * Corvus®
 * Prequel®

Related SourceWatch Pages

 * Soybean Event FG72
 * Bayer
 * Herbicides
 * Herbicide Tolerant Crops

External Resources

 * Isoxaflutole, ToxNet.
 * 1/21/11- Isoxaflutole Reg Review Appendix A Registered Uses, EPA.
 * 6/22/11 - Isoxaflutole Registration Review Summary Document, EPA.
 * Michael Davy, "Review of Established Soybean Irrigation Studies for Isoxaflutole (Chemical 123000; DP Bar Code D257679)," EPA, July 16, 1999.
 * Michael Davy and James Breithaupt, "EFED Response to Rhone Poulenc Bebuttal to EFED’s Science Chapter for Isoxaflutole. DP Barcode D2365 64," July 13, 1999.
 * Michael Davy, "Isoxaflutole: Review of Rebuttal to Phytotoxicity Risk Assessment (Including Maps), DP Barcode D246665," EPA, August 25, 1998.
 * Barbara Madden, "Isoxaflutole - 123000: Health Effects Division Risk Characterization Document for the First Food Use of Isoxaflutole in/on Corn (6F4664)," EPA, February 5, 1998.
 * Elizabeth M. Leovey, "Isoxaflutole: Review of Eco~ToXicity Studies for New Chemical Registration, EPA, April 1, 1997.

External Articles

 * Michael T. Meyer, Elisabeth A. Scribner, and Stephen J. Kalkhoff, "Comparison of Fate and Transport of Isoxaflutole to Atrazine and Metolachlor in 10 Iowa Rivers," Environ. Sci. Technol., 2007, 41 (20), pp 6933–6939, DOI: 10.1021/es070903t.
 * Pamela J. Rice, William C. Koskinen, and Maria Jose Carrizosa, "Effect of Soil Properties on the Degradation of Isoxaflutole and the Sorption−Desorption of Isoxaflutole and Its Diketonitrile Degradate," J. Agric. Food Chem., 2004, 52 (25), pp 7621–7627, DOI: 10.1021/jf049914l.
 * Estelle Beltrán, Hélène Fenet, Jean-Françoise Cooper, and Camille-Michel Coste, "Fate of Isoxaflutole in Soil under Controlled Conditions," J. Agric. Food Chem., 2003, 51 (1), pp 146–151, DOI: 10.1021/jf0207878.
 * Pallett KE, Cramp SM, Little JP, Veerasekaran P, Crudace AJ, Slater AE, "Isoxaflutole: the background to its discovery and the basis of its herbicidal properties," Pest Manag Sci. 2001 Feb;57(2):133-42.