EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Hope Johnson, (703) 305-5410 

ISK Biosciences Corporation

9F7666

 EPA has received a pesticide petition (9F7666) from ISK Biosciences 

Corporation, 7470 Auburn Road, Suite A, Concord, Ohio, 44077, proposing, pursuant 

to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 

346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of the 

herbicide Flazasulfuron, N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-

(trifluoromethyl)-2-pyridinesulfonamide, in or on the following raw agricultural 

commodities: fruit, citrus, group 10 at 0.01 parts per million (ppm); grapes at 0.01

ppm; and sugarcane at 0.01 ppm. EPA has determined that the petition contains data or 

information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, 

EPA has not fully evaluated the sufficiency of the submitted data at this time or whether 

the data supports granting of the petition. Additional data may be needed before EPA 

rules on the petition.

A. Residue Chemistry

 1. Plant metabolism. The metabolism of flazasulfuron as well as the nature of 

the residues in plants is adequately understood for the purposes of these tolerances. 

Metabolism studies were conducted with three crops, grapes, sugarcane and 

tomatoes. Directed application to the soil results in rapid degradation of 

flazasulfuron. Uptake into plants is minimal. Plants show the same metabolic 

pathways as those found in soil and animals. Flazasulfuron is metabolized either by 

cleavage of the urea linkage to form 3-trifluoromethyl-2-pyridine sulfonamide 

(TPSA) and 2-amino-4,6-dimethoxypyridine (ADMP) or by rearrangement of the 

sulfonyl urea bridge to form (1-(4,6-dimethoxypyridin-2-yl)-1-(3-trifluoromethyl-2 

pyridyl)urea (DTPU) followed by cleavage of the amide to form 4,6-dimethoxy-2-(3-

trifluoromethyl-2 pyridylamino)pyridine (DTPP) then oxidative demethylation to 

form 4-hydroxy-6-methoxy-2-(3-trifluoromethyl-2-pyridylamino)pyridine (HTPP). 

The terminal metabolites TPSA, ADMP and HTPP form conjugates and ultimately 

bound residues. The only unconjugated metabolite found in the studies at levels 

above 10% of the TTR was DTPU in grapes.

 2. Analytical method. A practical analytical method for flazasulfuron and 

DTPU using Liquid Chromatography-MS/MS is available for enforcement 

purposes. The limit of detection is 0.003 ppm.

 3. Magnitude of residues. Eight sugarcane residue trials were conducted. In 
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one additional trial, samples were treated at 10X the proposed use rate plus a 

shorter PHI and the sugarcane was processed into molasses, refined sugar and 

baggase. No residues of flazasulfuron were detected in any sample of sugarcane or 

processed commodities. Twenty-two citrus trials (12 orange, 6 grapefruit, 4 lemon) 

were conducted. In one additional trial, samples were treated at 10X the proposed 

use rate and the oranges were processed into juice, dry pulp and orange oil. No 

residues of flazasulfuron or DTPU were detected in any sample of oranges, 

grapefruit, lemons or processed commodities. Twelve grape trials were conducted. 

In one additional trial, samples were treated at 10X the proposed rate plus a shorter 

PHI and the grapes were processed into juice, pomace and raisins. No residues of 

flazasulfuron were found in either grapes or the processed fractions. No residues of 

DTPU were found in either grapes or juice. DTPU was found just above the LOD 

(~0.004 ppm) in grape pomace. Raisins, with an additional factor of 10 

concentration due to the drying process, had DTPU residues at the LOQ (0.01 pp).

B. Toxicological Profile

1. Acute toxicity. Flazasulfuron exhibits low acute toxicity in rats and rabbits. 

The oral LD50 is greater than 5000 mg/kg and the acute inhalation LD50 is greater 

than 4.0 mg/L. All study results are in Toxicity Category III or IV. Flazasulfuron is 

not irritating to the skin or eyes and is not a sensitizer. 

In an acute neurotoxicity study, Flazasulfuron was administered by oral gavage to 

groups of Sprague-Dawley rats at doses of 0, 50, 1000, or 2000 mg/kg/bwt. The 

animals were observed for 14 days. Mean motor activity measurements for mid and 

high dose males and females were statistically significantly different from the 

respective control groups at 5 hours post-dose. This possible effect was reversed by 

the next scheduled observation. Neurohistopathologic evaluation did not 

demonstrate any test material-related neurotoxic lesions. Based on the transient loss 

of motor activity, the NOAEL was 50 mg/kg bwt. The LOAEL was 1000 mg/kg bwt. 

2. Genotoxicity. The genotoxic potential of flazasulfuron has been assessed as 

negative by several in vitro and in vivo mutagenicity studies. Flazasulfuron did not 

elicit a genotoxic response in any of the studies conducted. 

3. Reproductive and developmental toxicity. A two-generation study was conducted in 

Sprague-Dawley rats at dose levels in the diet of 0, 200, 2,000 and 10,000 ppm. There 

were no effects on any of the endpoints used to assess reproductive capacity but 

kidney toxicity was observed in the parental animals. There was also a treatmentrelated effect on pup weight during lactation. The NOEL for reproductive 

performance was considered to be 10,000 ppm (473 mg/kg bwt/day for males and 

613.7 mg/kg bwt/day for females), the highest dose tested. The NOEL for the 

offspring was 2000 ppm (87.5 mg/kg bwt/day for males and 124.5 mg/kg bwt/day for 

females) based on a reduction in lactational body weights of the F1 and F2 offspring 

at the next highest dose level. 
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Two separate studies were conducted in two different strains of rats to test for the 

potential for development effects of flazasulfuron. In a study with Wistar-Imamichi 

rats, dose levels of 0, 100, 300 and 1000 mg/kg bwt/day were administered from days 

6 to 15 of gestation. A second study was conducted with Sprague-Dawley rats at the 

same dose levels. The NOEL for maternal effects in the Wistar strain was 100 mg/kg 

bwt/day. The NOEL for maternal effects in the Sprague-Dawley was 300 mg/kg 

bwt/day. The NOEL for developmental effects in the Wistar strain was 100 mg/kg 

bwt/day based on increased incidence of visceral malformations (interventricular 

septal defect) observed at 300 mg/kg bwt/day. The NOEL for developmental effects 

in the Sprague-Dawley was 300 mg/kg bwt/day based on reduced fetal weights and 

retardation in ossification. These fetal effects, in both strains of rats, were all 

considered to be secondary to maternal toxicity. 

In a developmental toxicity study with New Zealand White rabbits, flazasulfuron 

was administered at dose levels of 0, 50, 150 and 450 mg/kg bwt/day from days 6 to 

18 of gestation. An increased incidence of abortion was observed but no evidence of 

developmental toxicity at 450 mg/kg bwt/day, a dosage that was maternally toxic. 

The NOEL for maternal and developmental effects was 150 mg/kg bwt/day.

4. Subchronic toxicity. A 90-day oral toxicity study was conducted in rats with 

dietary concentrations of 0, 40, 200 and 1,000 ppm technical flazasulfuron. The 

systemic NOEL was 200 ppm (11.66 mg/kg bwt/day) for males and 1000 ppm (61.5 

mg/kg bwt/day) for females based on based on depression of body weight gain 

(males and females) and slight anemia due to decrease in hemoglobin (females) at 

the next highest dose level. 

A 90-day oral toxicity study was conducted with dogs at dose levels of 0, 2, 10, 50, 

and 250 mg/kg bwt/day for males and 2, 10, 50, and 100 mg/kg bwt/day for females 

administered by capsule. The systemic NOEL was 2 mg/kg bwt/day for males and 

10 mg/kg bwt/day for females based on changes in the liver (increase in: deposition 

of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, 

inflammatory cell infiltration, microgranulomas) at the next highest dose level (10 

mg/kg bwt/day for males and 50 mg/kg bwt/day for females). 

 

Dermal application of flazasulfuron for 21 to 22 consecutive days at dose levels of 0, 

250, 500, and 1000 mg/kg bwt/day to the dorsal skin of New Zealand White rabbits 

resulted in no treatment-related findings. The systemic NOEL was considered to be 

1000 mg/kg bwt/day (highest dose tested). No dermal effects were observed. 

5. Chronic toxicity. An 18-month oncogenicity study was conducted in mice 

with dietary concentrations of 0, 500, 3,500 and 7,000 ppm technical flazasulfuron. 

The systemic NOEL was 500 ppm (77.3 and 93.7 mg/kg bwt/day for males and 

females, respectively) based on decreased body weights, body weight gains, food 

consumption and an increase in liver effects (liver weight and hepatocellular 

hypertrophy) at a dose of 3,500 ppm (552.7 and 659.8 mg/kg bwt/day for males and 

females, respectively). There was no evidence of carcinogenicity. 
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A 2-year chronic toxicity/carcinogenicity study was conducted in rats with dietary 

concentrations of 0, 40, 400 and 2,000 ppm technical Flazasulfuron for males and 0, 

40, 400, and 4,000 ppm for females. The systemic NOEL was 40 ppm (1.3 and 1.6 

mg/kg bwt/day for males and females, respectively) based on adverse changes in 

kidney function (chronic nephropathy) and kidney physiology (enlargement, dark 

color of kidney) at a dose of 400 ppm (13.3 and 16.4 mg/kg bwt/day for males and 

females, respectively). There was no evidence of carcinogenicity. 

A 52-week chronic toxicity study was conducted with beagle dogs at dose levels of 0, 

0.4 (males only), 2, 10 and 50 mg/kg bwt/day administered by capsule. The systemic 

NOEL was 2 mg/kg bwt/day based on changes in liver (increase in: inflammatory 

cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct 

proliferation) at 10 mg/kg bwt/day. 

6. Animal metabolism. The nature of residue in animals is adequately 

understood. Metabolism studies in the rat indicate that flazasulfuron is rapidly 

distributed and excreted in the urine and feces. Excretion in urine occurred more 

slowly in males (73%) than females (90%). Fecal elimination was greater in males 

(23%) than females (10%). The most prevalent metabolites (expressed as percent of 

administered dose) were HDTG+TPPG (~6.5-17.7% in urine, ~0.4-9.7% in feces, 

and ~6.5-14% in bile), with minor amounts (<5%) of other compounds. 

The nature of the residue in ruminants is similar to that in rats but more complex. 

In the liver and muscle tissues of goats, the major extractable residue was HTPP. In 

kidney flazasulfuron, HTPP and DTPP were identified but the major compound 

identified was DTPU. About 90% of the dose was eliminated in the urine and feces, 

mostly as glucuronide conjugates of the above compounds. Levels in milk and fat 

were too low for identification. 

7. Metabolite toxicology. Comparison of the metabolism of flazasulfuron by 

plants and in animals indicates that a number of the identified metabolites are 

common to both plants and animals. The data indicate that the final products of the 

metabolism of flazasulfuron in animals and plants represent differences in the 

extent of metabolism. Several of the metabolites resulting from flazasulfuron are 

similar in plants and animals and, therefore, have already been evaluated 

toxicologically. The fact that no quantifiable residues were found in treated crops 

further indicates that exposures to and accumulation of metabolites are unlikely. 

8. Endocrine disruption. An evaluation of the potential effects on the 

endocrine systems of mammals has not been determined. There is no evidence that 

flazasulfuron causes endocrine effects.

C. Aggregate Exposure

 1. Dietary exposure. Potential dietary exposures from food were estimated for 

all proposed and established tolerances for citrus, grapes, and sugarcane, using the 
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Dietary Exposure Evaluation Model-Food Consumption Intake Database (DEEMFCIDTM) version 2.16, and percent crop treated of 100%. 

For chronic dietary exposure, the chronic reference dose (RfD) of 0.013 mg/kg 

bwt/day was proposed by EPA for humans, based on the NOAEL from the rat 

combined chronic toxicity/carcinogenicity study (1.3 mg/kg bwt/day) and dividing 

by an uncertainty factor of 100. The chronic population adjusted dose (cPAD) is 

also 0.013 mg/kg bwt/day since the FQPA safety factor is anticipated to be 1 for 

flazasulfuron. 

For acute dietary exposure, the acute RfD of 0.5 mg/kg/day was based on the 

NOAEL of 50 mg/kg bwt/day from the acute neurotoxicity study adjusted by the 

uncertainty factor of 100. The acute population adjusted dose (aPAD) is also 0.5 

mg/kg bwt/day since the flazasulfuron FQPA safety factor is anticipated to be 1.

 i. Food. Tier 1 chronic and acute dietary exposure analyses were conducted 

for flazasulfuron in/on citrus, grapes, and sugarcane to determine the exposure 

contribution of these commodities to the diet and to ascertain the chronic and acute 

risk potential. The estimates were based on the proposed tolerance level residues, 

conservative market share assumptions of 100% crop treated, and consumption 

data from the USDA’s CSFII (1994 through 1996 and 1998) continuing survey of 

food intake. Since specific processing studies demonstrated that residues were 

unlikely to concentrate in processed commodities, no adjustment for processing 

factors was necessary. 

Using all of the worst case exposure scenarios listed above, the Tier 1 chronic 

dietary (food + drinking water) exposure estimates resulted in an estimated 

exposure for the general U.S. population of 0.001963 mg/kg bwt/day. This exposure 

corresponds to 15.1% of the cPAD of 0.013 mg/kg bwt/day. The highest exposure 

estimate calculated was for the subgroup all infants (< 1 year). This exposure was 

determined to be 0.006377 mg/kg bwt/day (49.1% of the cPAD); this compares to 

49% of the cPAD without the addition of the new proposed food uses (drinking 

water only). 

A Tier 1 acute dietary exposure assessment was performed for the subpopulation of 

females 13-49 years old only. The acute RfD of 0.5 mg/kg/day was derived from an 

acute neurotoxicity study with a NOAEL of 50 mg/kg/day. This endpoint is more 

conservative than that from the developmental study which makes it protective for 

females. The acute dietary exposure estimate for females aged 13-49 is 0.004489 

mg/kg bwt/day, well below HED’s level of concern at the 95th percentile. This is 

equivalent to 0.90% of the aPAD. 

It can be concluded that acute or long-term dietary exposure to flazasulfuron 

through residues on treated citrus, grapes, and sugarcane should not be of cause for 

concern. 

 ii. Drinking water. Since flazasulfuron is intended for application outdoors to 

field grown crops, the potential exists for parent and/or metabolites to reach ground 
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or surface water that may be used for drinking water. Screening level water 

exposure models used by EPA in 2005 to estimate residues in surface and ground 

water provided the estimated drinking water concentrations based on the turf use. 

The highest estimated residues were obtained from SCI-GROW which predicted the 

ground water concentration to be 92 ppb; this was used in both the acute and 

chronic DEEM dietary assessments. 

 2. Non-dietary exposure. Flazasulfuron is registered for use on golf courses 

and athletic fields. Applications are to be made by professional turf applicators 

only, thus there is no residential handler exposure. However, post-application 

dermal exposure from recreational contact with the treated turf may occur. In the 

2005 EPA risk assessment, post-application dermal exposure was calculated for 

adults playing golf and adults playing sports on athletic fields. To calculate postapplication dermal exposure to a treated athletic field, the agency applied the same 

calculation used to assess high contact adult re-entry to treated residential turf 

(Burke, 2005; US EPA, 2001). However, instead of utilizing the updated adult 

transfer coefficient (TC) of 14,500 cm2

/hour, the agency used the older TC of 43,000 

cm2

/hour (US EPA, 2001). The use of the revised transfer coefficient results in a 

higher MOE (10,416) for adult post-application dermal exposure to treated turf 

compared to the MOE of 3,400 calculated in the 2005 risk assessment. 

D. Cumulative Effects 

EPA has not made a common mechanism of toxicity finding as to flazasulfuron and 

any other substances, and flazasulfuron does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that flazasulfuron has a common mechanism of 

toxicity with other substances. 

E. Safety Determination

 1. U.S. population. Dietary and post-application dermal exposure from 

recreational contact with treated turf will be the major routes of exposure to the 

U.S. population. Ample margins of safety have been demonstrated for both 

situations. For the general U.S. population, the chronic dietary exposure to 

flazasulfuron is 0.001963 mg/kg bwt/day, which utilizes 15.1% of the RfD for the 

overall U.S. population, assuming 100% of the crops are treated. A cancer dietary 

assessment was not conducted because this product has been classified as “not likely 

to be carcinogenic to humans.” 

An acute aggregate risk assessment was conducted for the population subgroup of 

concern, females 13-49 years old. For this population, the acute dietary (food and 

drinking water) risk assessment represents acute aggregate risk since the dietary 

route alone is relevant for acute exposure and risk assessment. The acute dietary 

risk estimate associated with flazasulfuron is 0.90% of the aPAD, and therefore 

below the agency's level of concern.
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Short-term aggregate risks include chronic dietary and short-term residential 

sources of exposure. Potential inhalation exposure was not considered since it is 

negligible when assessing re-entry risks. The aggregate short-term MOE for the US 

general population is 7,539. 

There are no residential activities that would result in intermediate-term exposure. 

As such, no intermediate-term aggregate risk assessment is needed. 

Based on the use pattern of flazasulfuron, no long-term residential exposures are 

expected. Therefore, the chronic aggregate risk assessment is based on exposure 

from food and drinking water only. Chronic dietary risks are acceptable for all 

population groups. 

Based on the completeness and reliability of the toxicity data and the conservative 

exposure assessments, there is a reasonable certainty that no harm will result from 

the aggregate exposure of residues of flazasulfuron including all anticipated dietary 

exposure and all other non-occupational exposures. 

 2. Infants and children. Data from developmental toxicity studies in the rat 

and rabbit and a 2-generation reproduction study were considered. Although some 

effects were observed in the offspring, they did not occur at doses below those that 

elicited effects in the dams. An evaluation of these data indicates no increased 

susceptibility of the young to prenatal exposure. It is concluded that the standard 

margin of safety will protect the safety of infants and children and that an 

additional FQPA safety factor is not warranted. 

 The proposed tolerances plus drinking water input will utilize 49.1% of the cPAD 

for the “All Infants” subgroup, and 22.8% of the cPAD for the subgroup “Children 

(1-2 years)”. In order to determine which of the registered and proposed 

commodities were driving the revised dietary risk assessment, a complete 

commodity contribution analysis was conducted for children less than 1 year old. 

This analysis identified the indirect water contribution was the largest single 

contributor (42.4% of the 49% of the cPAD); the next highest contributor was 

direct water, at 6.5%. Residues from the proposed crops only added only 0.1% to 

the infants total exposure level. 

 It can be concluded that there is reasonable certainty that no harm will result to 

infants and children from acute or chronic exposure to Flazasulfuron.

F. International Tolerances

Presently, there are no Codex maximum residue levels (MRLs) established for 

residues of Flazasulfuron on any crop.