EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division cont act: 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 es tablishing a tolera nce for residues of the herbicide Flazasulfuron, N-[[(4,6-dimet hoxy-2-pyrimidinyl)amino]carbonyl]-3- (trifluoromethyl)-2-pyridinesulfonamide, in or on the followi ng 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 fort h 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 flazasulfuro n as well as the nature of the residues in plants is adequately understo od 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 mi nimal. 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-trifluoromethy l-2-pyridine sulfonamide (TPSA) and 2-amino-4,6-dimethoxypyridine (ADMP) or by rearrangement of the sulfonyl urea bridge to form (1-(4,6-di methoxypyridin-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 (D TPP) then oxidative demethylation to form 4-hydroxy-6-methoxy-2-(3 -trifluoromethyl-2-pyridyl amino)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-M S/MS is available for enforcement purposes. The limit of detection is 0.003 ppm.

3. Magnitude of residues. Eight sugarcane residue trials were conducted. In2

one additional trial, samples were treated at 10X the proposed use rate plus a shorter PHI and the sugarcane was proce ssed into molasses, refined sugar and baggase. No residues of flazasulfuron were detected in any sample of sugarcane or processed commodities. Twenty-two citrus tr ials (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, samp les were treated at 10X the proposed rate plus a shorter PHI and the grapes were processed into jui ce, pomace and raisins. No residues of flazasulfuron were found in either grapes or the processed fractions. No residues of DTPU were found in either gr apes or juice. DTPU wa s 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 LD 50 is greater than 5000 mg/kg and the acute inhalation LD 50 is greater than 4.0 mg/L. All study results are in Toxi city Category III or IV. Flazasulfuron is not irritating to the skin or eyes and is not a sensitizer. In an acute neurotoxicity study, Flazasul furon was administered by oral gavage to groups of Sprague-Dawley rats at do ses of 0, 50, 1000, or 2000 mg/kg/bwt. The animals were observed for 14 days. Mean mo tor activity measurements for mid and high dose males and females were statis tically significantly different from the respective control groups at 5 hours post-dos e. This possible effect was reversed by

the next scheduled observation. Neur ohistopathologic evaluation did not demonstrate any test material-related neur otoxic 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 us ed to assess reproductive capacity but kidney toxicity was observed in the paren tal animals. There was also a treatmentrelated effect on pup weight during la ctation. 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 hi ghest 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 lactationa l body weights of the F1 and F2 offspring at the next highest dose level.3

Two separate studies were conducted in two di fferent strains of rats to test for the potential for development effects of flazas ulfuron. In a study with Wistar-Imamichi rats, dose levels of 0, 100, 300 and 1000 mg /kg bwt/day were admi nistered 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 ef fects in the Wistar strain was 100 mg/kg bwt/day. The NOEL for maternal effect s in the Sprague-Dawley was 300 mg/kg bwt/day. The NOEL for developmental effect s in the Wistar st rain 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 ef fects, 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/d ay, a dosage that was maternally toxic. The NOEL for maternal and developm ental 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 1,0 00 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 base d 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 chan ges in the liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration , microgranulomas) at the ne xt 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 wa s 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 effe cts (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.4

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, respe ctively) 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 d ogs 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 change s 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 preval ent 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 am ounts (<5%) of other compounds.

The nature of the residue in ruminants is si milar to that in rats but more complex. In the liver and muscle tissues of goats, th e major extractable residue was HTPP. In kidney flazasulfuron, HTPP and DTPP were identified but the major compound

identified was DTPU. About 90% of the do se was eliminated in the urine and feces, mostly as glucuronide conju gates 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 me tabolites resulting from flazasulfuron are similar in plants and animals and, therefore, have already been evaluated toxicologically. The fact that no quantif iable residues were found in treated crops further indicates that exposures to and a ccumulation of metabolites are unlikely.

8. Endocrine disruption

. An evaluation of the po tential 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 fo r citrus, grapes, and sugarcane, using the5

Dietary Exposure Evaluation Model-Food Consumption Intake Database (DEEMFCID TM ) 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 chro nic population adjusted dose (cPAD) is also 0.013 mg/kg bwt/day since the FQPA safe ty 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 acut e neurotoxicity study adjusted by the uncertainty factor of 100. The acute populat ion 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 di et 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 commo dities, no adjustment for processing factors was necessary. Using all of the worst case exposure s cenarios 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 a ll 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 Rf D of 0.5 mg/kg/day wa s 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 whic h makes it protective for females. The acute dietary exposure es timate for females aged 13-49 is 0.004489 mg/kg bwt/day, well below HED’s level of co ncern 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 ground6

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 wat er concentrations based on the turf use. The highest estimated residues were obtain ed 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 wi th the treated turf may occur. In the 2005 EPA risk assessment, post-applicatio n dermal exposure was calculated for adults playing golf and adults playing sports on athletic fields. To calculate postapplication dermal exposure to a treated at hletic field, the agency applied the same calculation used to assess high contact a dult 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 re vised transfer coefficient results in a higher MOE (10,416) for adult post-applicat ion dermal exposure to treated turf compared to the MOE of 3,400 calcul ated in the 2005 risk assessment.

D. Cumulative Effects

EPA has not made a common mechanism of t oxicity 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 th is tolerance action, therefore, EPA has not assumed that flaz asulfuron has a common mechanism of toxicity with other substances.

E. Safety Determination

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

recreational contact with treated turf will be the major routes of exposure to the U.S. population. Ample margins of safe ty 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, wh ich 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 pro duct has been classified as “not likely to be carcinogenic to humans.”

An acute aggregate risk as sessment 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.7

Short-term aggregate risks include chroni c 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 wo uld result in intermediate-term exposure. As such, no intermediate-term aggr egate risk assessment is needed.

Based on the use pattern of flazasulfuron, no long-term residential exposures are expected. Therefore, the chronic aggregate ri sk assessment is based on exposure from food and drinking water only. Chro nic 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 ce rtainty that no harm will result from the aggregate exposure of residues of flazas ulfuron 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 th e offspring, they did not occur at doses below those that

elicited effects in the dams . An evaluation of these da ta indicates no increased susceptibility of the young to prenatal ex posure. It is concluded that the standard margin of safety will protect the safety of infants and children and that an additional FQPA safety fa ctor 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 di etary risk assessment, a complete commodity contribution analysis was conduct ed for children less than 1 year old. This analysis identified the indirect wa ter 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 pr oposed crops only added only 0.1% to the infants total exposure level.

It can be concluded that there is reaso nable 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 res idue levels (MRLs) established for residues of Flazasulfuron on any crop.