EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Heather Garvie, 703-308-0034

TEMPLATE:

ISK Biosciences Corporation

6F8447

EPA has received a pesticide petition (6F8447) 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, 1-(4,6-dimethoxypyrimidin-2-yl)-3-(3-trifluoromethyl-2-

pyridylsulfonyl) urea, in or on the raw agricultural commodity Olive at 0.01 parts 

per million (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.
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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. Residue data was collected on olives during field 

trials. Residues in/on olives and olive oil were all below LOQ (Limit of Quantitation 

= 0.01 pm). 

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 treatment-related 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.

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 
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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.

In a subchronic neurotoxicity study in rats, there were no neurotoxic effects noted at 

any dietary exposure level. Based on these results, the no-observed-effect level 

(NOEL) for subchronic neurotoxicity was considered to be 10,000 ppm for males 

(649 mg/kg/day) and females (732 mg/kg/day) when flazasulfuron was offered on a 

continuous basis in the diet for approximately 90 days. Based on the lower mean 

body weights, body weight gains, and/or reduced food consumption in the 3000 ppm 

males and 10,000 ppm group males and females, the NOEL for systemic toxicity was 

considered to be 300 ppm for males (19 mg/kg/day) and 3000 ppm for females (229 

mg/kg/day).

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 
4

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.

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

all proposed and established tolerances for citrus, grapes, sugarcane, tree nuts, and 

olives using the Dietary Exposure Evaluation Model-Food Commodity Intake 

Database (DEEM-FCID)/Calendex version 10, 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, sugarcane, tree nuts, and olives 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 established and 

proposed tolerance level residues, conservative market share assumptions of 100% 

crop treated, and consumption data from the USDA’s continuing survey of food 

intake. 

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 0.002082 mg/kg bwt/day. This exposure 

corresponds to 16.0% 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 0.007724 mg/kg bwt/day (59.4% of the cPAD).

A Tier 1 acute dietary exposure assessment was performed for the general U.S.

population and all population subgroups. The acute RfD of 0.5 mg/kg/day was 

derived from an acute neurotoxicity study with a NOAEL of 50 mg/kg/day. The 

acute dietary exposure estimate for the total U.S. population is 0.005465 mg/kg 

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

to 1.09% of the aPAD. The highest exposure estimate calculated was for the

subgroup all infants. This exposure was determined to be 0.018698 mg/kg bwt/day 

(3.74% of the aPAD).

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 

or surface water that may be used for drinking water. Exposure models used by 

EPA in the 2012 tolerance assessment for grapes and citrus to estimate residues in 

surface and ground water provided the most conservative drinking water 
6

concentrations. The highest estimated residues were obtained from PRZM-EXAMS

which predicted the ground water concentration to be 102 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 0.002082 mg/kg bwt/day, which utilizes 16.0% 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.”

The acute aggregate risk is equal to the acute dietary (food and drinking water) 

exposure. The acute dietary exposure to flazasulfuron is below the agency’s level of 

concern for the general U.S. population and all population subgroups. The acute 

dietary exposure estimates at the 95th percentile are 1.09% of the aPAD for the 

general U.S. population and 3.74% of the aPAD for all infants (<1 year old), the 

most highly exposed population subgroup.

Short-term aggregate risks include chronic dietary and short-term residential 

sources of exposure. Potential inhalation exposure was not considered since it is 
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negligible when assessing re-entry risks. The aggregate short-term MOE for adults 

and children 1-2 years old are 930 and 550, respectively.

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 59.4% of the cPAD 

for the “All Infants” subgroup, and 22.4% of the cPAD for the subgroup “Children 

(1-2 years)”.

 

Based on the above information, there is reasonable certainty that no harm will 

result to infants, children, or adults from dietary (food plus drinking water) 

exposure to flazasulfuron residues from proposed olive use, as well as all other 

existing flazasulfuron-treated human dietary food sources.

F. International Tolerances

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

residues of Flazasulfuron on any crop.