EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: H eather Garvie, 703

- 308

- 0034

TEMPLATE:

ISK Biosciences Corporation

6 F8447

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 establishin g 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 co ntains 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 d a ta 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 res ults in rapid degradation of flazasulfuron. Uptake into plants is minimal. Plants show the same metabolic pathways as those found in soil and animals. Flaz asulfuron 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

- tri fluoromethyl

- 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 (HT PP). Th e 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

2. Analytical method. A practical analytical method for fl azasulfuron 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 olive s dur ing field trials. R esidues in/on olives and olive oil we re all below LOQ (Limit of Quantitation = 0.01 pm)

.

B. Toxicological Profile

1. Acute toxicity. Flazasulfuron exhibits low acut e toxicity in rats and rabbits. The oral LD 50 is greater than 5000 mg/kg and the acute inhalation LD 50 is gr eater than 4.0 m g/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 neu rotoxicity 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 h igh dose males and females were statistically significantly different from the respective control groups at 5 hours post

- dose. This po ssible effect was reversed by the next scheduled observation. Neurohistopathologic evaluation did not demonstrate any test mate rial

- related neurotoxic lesions. Based on the transient loss of motor activity , the NOAEL was 50 mg/kg bw t . The LOAEL was 1000 mg /kg bw t

.

2. Genotoxic i ty

. 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 obse rved 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 6 13.7 mg/kg bwt/day for females ), the highest dos e 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 cond ucted in two different strains of r ats 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 st udy 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 3 00 mg/kg bwt/day. The NOEL for developmental effects in t he Wistar strain was 100 mg/kg bwt/day based on increased incidence of visceral malformations ( interventricular3

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

- Dawley was 3 00 mg/kg bwt/day based on reduced f etal 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 develop mental 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 f la zasulfuron . The
sy stemic NOEL was 200 ppm (1 1.6 6 mg/kg bwt/day ) for male s 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 (i ncrease in: deposition of b rown pigments, glutamic pyruvic transaminase, creatine p hosphokinase, 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 applica tion 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 neurotoxi city was considered to be 10,000 ppm for males (649 mg/kg/day) a nd 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 we ight gains, and/or reduced f ood 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 oncoge nicity stu dy 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 decrease d body weight s , body weight gain s , food consumption and an increase in liver effects ( liver weight and hepatocellular4

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 toxici ty/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 femal es, respectively) based on a dverse change s in kidney function ( chronic nephropathy) and kidney physiology (enlargement, dark color of kidney) at a dose of 4 00 ppm (13.3 and 16.4 mg/kg bwt /day for males and females, respectively) . There was no evidence of c arcinogenicity.

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: inflam matory cell infiltration, hepatocellular necrosis, hepatocellular swellin g, 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 fla zasulfuron 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.

T he 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 con jugates 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 an imals . 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 a nd 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 eval uation of the potential effects on the endocrine systems of m ammals has not been determined. Th ere is no evidence that flazasulfuron causes endocrine effects.

C. Aggregate Exposure5

1. Dietary exposure. Potential dietary exposures from food were estimate d for all proposed and established tolerances for citrus, grapes, sugarcane, tree nuts , and olives using the Dietary Exposure E valuation Model

- Food Co mmodity Intake Database (DEEM

- FCID) /Calendex version 10 , and percent crop treated of 100%.

For chronic di etary 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 c hronic 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 o f 50 mg/kg bwt/day from the acute neurotoxicity study adjusted by the uncertainty factor of 100. The acute populatio n 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 anal yses 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 est ablished and proposed tolerance leve l residues , conservative market share assumptions of 100% crop treated, and cons umption data from the USDA’s con tinuing survey of food intake. U sing all of the worst case exposure scenarios listed above, the Tier 1 chro nic dietary (food + drinking water) exposure estimates resulted in an estimated exposure for the gen eral U.S. population of 0.002 082 mg/kg bwt/day. This exp osure corresponds to 16. 0 % of the cPAD of 0.013 mg/kg bwt/day. The highest e xposure estimate calculated was for the subgroup all infants (< 1 year). This exposure was determined to be 0.00 7724 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 popul ation 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 0.00 5465 mg/kg bwt/day , well below HED’s level of concern at th e 95th percenti le. This is e quivalent to 1. 09 % of the aPAD. The highest exposure estimate calculated was for the subgroup all infants . This expo sure was determined to be 0.0 18698 mg/kg bwt/day ( 3

. 74 % of the a PAD).

ii. Drinking water

. Since flazasulfuro n 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. E xposure models used by EPA in the 2012 tolerance assessment for grapes a nd citrus to estimate residues in surface and ground water provided the most conservative drinking water6

conc entrations . The highest estimated residues were obtained from PRZM

- EXAMS which predicted the ground water c oncentration to be 10 2 ppb; this was use d 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 ha ndler 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 athle tic fields. To calculate post

application 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 cm 2 /hour, the agency used the older TC of 43,000

cm 2 /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 trea ted 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 flaza sulfuron and
any other substances, and flaza sulfuron does not appear to produce a tox ic metabolite produced by other substances. For the purposes of this tolerance action, therefore , EPA has not assumed that flaza sulfuron has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. Dietary and p ost

- 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 dieta ry exposure to flazasulfuron is 0.002 082 mg/kg b wt /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. T he acute d ietary exposure to flazasulfuron is below the agency ’s level of concern for the general U.S. population and all pop ulation 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 ris ks include chronic dietary and short

- term residen tial sources of exposure. Potential inhalation exposure was not considered since it is7

negligible when assessing re

- entry risks. The aggregate short

- term MOE for adults and children 1

- 2 years old are 930 an d 550, respectively

.

T here 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 exp osures are expected. Therefore, the chronic aggregate risk assessment is based on exposure from food and drinking water only. C hronic dietary risks are acceptable for all population groups.

Based on the completeness and reliability of the toxicity data and the cons ervative 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

- genera tion 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 evalu ation 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 c PAD 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 har m will result to infants, children, or adults from dietary (food plus drinki ng water) exposure to flazasulfuron residues from proposed olive use , as well as all o ther existing flazasulfuron

- treated human dietary food sources.

F. International Tolerance s
Presently, t here are no Codex maximum residue levels (MRLs) established for residues of Flazasulfuron on any crop.