EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Bethany Benbow, 703

- 347

- 8072

FMC Corporation

PP# 1F7927

EPA has received a pesticide petition 1F7927 from FMC Corporation , 1735 Market street, Philadelphia, PA 19103 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. 551 by esta blishing a tolerance for residues of the herbicide, fluthiacet

- methyl, acetic acid [[2

- chloro

- 4

- fluoro

- 5

- [(tetrahydro

- 3

- oxo
- 1 H , 3 H

- [1,3,4]thiadiazolo[3,4

- ]pyridazin

- 1

- ylidene)amino]phenyl]thio]

- methyl ester, and its acid metabolite fluthiacet, [[2

- chloro

- 4

- fluoro

- 5

- [(tetrahydro

- 3

- oxo
- 1 H , 3 H

- [1,3,4]thiadiazolo[3,4

- ]pyridazin

- 1

- ylidene)amino]phenyl]thio] ] in or on the raw agricultural commodity , Crop Group 15, Cereal Grains (except rice) : Grain, cereal, group 15 (except rice grain) 0.01 ppm; Grain, cereal, forage, group 15 at 0.05 ppm; Grain, cereal, hay, group 15 at 0 .05 ppm; Grain, cereal, stover, group 15 at 0.0 5 ppm; Grain, cereal, straw, group 15 (except rice straw) at 0.05 ppm; , Pea and bean (except soybean) , dried shelled, crop subgroup 6C 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 the 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 fluthiacet

- m ethyl in plants is adequately understood. Corn, soybean and cotton metab olism studies with fluthiacet

- m ethyl have shown similar metabolic pathways. The residue of concern is primarily the parent fluthiacet

- m ethyl

.2. Analytical method. There is a practical analytical method for detec ting and

measuring levels of fluthiacet

- m ethyl in or on food with a limit of quantitation that allows monitoring of food with residues at or above the levels set or proposed in the tolerances. The analytical enforcem ent method for fluthiacet

- methyl was used with minor modification. The analytical method for all crop matrices consisted of solvent extraction using a high speed mixer, followed by centrifugation. An aliquot of the resulting supernatant was filtered and diluted as necessary for quantitation by high performance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS). The limit of quantitation (LOQ) for fluthiacet

- methyl was defined as 0.01 ppm with the limit of detection (LOD) set at 0 .002 ppm.

3. Magnitude of residues. The magnitude of the residue of fluthiacet

- m ethyl in/on raw agricultural commodities of wheat (forage, hay, grain and straw) , sorghum (forage, grain, and stover), and dry pea and bean treated with Cadet Herbicide at 1X, 1.5X and 5X rates were determined. Applicat ions to each treated plot in the s e studies were made using a spray solution of approximately 10 GPA. RAC for each crop was harvested at the appropriate time and subsequent analyses determined th at the residues of fluthiacet

- m ethyl would not exceed the proposed tolerances.

B. Toxicological Profile

1. Acute toxicity. Fluthiacet

- m ethyl acute toxicity studies’ results were as follows: oral LD 50 ( rat ) was greater than 5000 mg/kg, the acute dermal LD 50 ( rat ) was greater than 2 000 mg/kg and the acute inhalation LC 50 ( rat ) was greater than 5.05 mg/L, n on
- irritating to rabbit skin and minimally irritating to rabbit eyes. It did not cause skin sensitizatio n in guinea pi gs. An acute neurotoxicity testing in rat s up to 2000 mg/kg resulted in no neurotoxic effects.

2. Genotoxicty. Fluthiacet

- m ethyl showed negative results in the following in vitro gene mutation tests: Ames, Chinese hamster V79, rat hepato cyte DNA repair, and E. Coli lethal DNA damage. For t he in vitro chromosomal aberration tests: Chinese hamster ovary and lung tests and the human lymphocytes tests were positive at cytotoxic doses. For the i n vivo chromosome aberration tests: the m icronucleus assays in rat liver and the mouse bone marrow test s were negative.3. Reproductive and developmental toxicity. Fluthiacet

- m ethyl Teratology study in rats

had a maternal and developmental NOAEL equal to or greater than 1,000 milligram/kilogr am/day (mg/kg/day). Teratology study in rabbits with a maternal NOAEL greater than or equal to 1,000 mg/kg/day and a fetal NOAEL of 300 mg/kg based on a slight delay in fetal maturation. 2

- generation reproduction study in rats with a NOAEL of 36 mg/kg/day, based on liver lesions in parental animals and slightly reduced body weight development in parental animals and pups. The treatment had no effect on reproduction or fertility.

4. Subchronic toxicity. 90

- day subchronic neurotoxicity study in rats, the NOAEL was 0.5 mg/kg/day based on reduced body/weight/gain (bwt/gain). No clinical or morphological signs of neurotoxicity were detected at any dose level. The 28 day dermal toxicity study in rats had a NOAEL equal to or higher than the limit dose of 1,000 mg/kg. The 6 week dietary toxicity study in dogs had a NOAEL of 162 mg/kg/day in males and 50 mg/kg/day in females based on decreased body weight gain and modest hematological changes. The 90 day subchronic die tary tox icity study in rats had a NOAEL of 6.2 mg/kg/day based on liver changes and hematological effects.

5. Chronic toxicity. Fluthiacet

- m ethyl in a 24 month s combined chronic toxicity/ca rcinogenicity study in rats had a NOAEL of 2.1 mg/kg/day. Based on red uced bwt development and changes in bone marrow, liver, pancreas and uterus , the MTD was exceeded at 130 mg/kg/day. A positive trend of adenomas of the pancreas in male rats treated at 130 mg/kg/day and above may be attributable to the increased survival of the rats treated at high doses. The 18 month s oncogenicity study in mice had a NOAEL of 0. 14 mg/kg/day. Based on liver changes, the MTD was reached at 1.2 mg/kg/day. The incidence of hepatocellular tumors was increased in males treated at 12 and 37 mg/kg/day

6. Animal metabolism. The results from hen and goat metabolism studies, where fluthiacet

- methyl was fed at exaggerated rates, showed that the transfer of fluthiacet

- methyl residues from feed to tissues, milk and eggs is extremely low. No detectable residues of fluthiacet

- methy l (or metabolite fluthiacet) would be expected in meat, milk, poultry, or eggs after feeding the maximum allowable amount of treated
corn and soybeans. This conclusion is based on residue data from the corn and soybean metabolism and field residue chemist ry studies coupled with the residue transfer from feed to tissues, milk and eggs obtained in the goat and hen metabolism studies.7. Metabolite toxicology

. N / A

8. Endocrine disruption

. An evaluation of the potential effects on the endoc rine systems of mammals has not been determined; however, no evidence of such effects was reported in the chronic or reproductive toxicology studies described above. Considering further the low environmental concentrations and the lack of bioaccumulation, there is no risk of endocrine disruption in humans or wildlife. There is no evidence at this time that fluthiacet

- m ethyl causes endocrine effect.

C. Aggregate Exposure

1. Dietary exposure. Tolerances have been established for residues of fluthiacet

- methyl for corn, soybeans, and cotton (used as a defoliant). Tolerances for residues resulting from the direct application of fluthiacet

- methyl to peas and beans , wheat, and sorghum are proposed as part of this petition No FQPA safety factor is added for chronic exposures since there is no evidence of increased susceptibility of any subgroup, especially children and infants. Highly conservative chronic dietary exposure w as estimated using the Dietary Exposure Evaluation Mod el

- Food Consumption Intake Database (DEEM

- FCID TM , version 2.1 4 , Exponent, Inc). Both proposed and existing labeled crop tolerances were considered in DEEM

- FCID. Food consumption was based on data from the 1994

- 1996 USDA Continuing Surveys of Individual In takes (CSFII) and the 1998 Supplemental Children’s Survey. Residue model inputs of 0.02 ppm

were assumed, which is equivalent to two times the limit of quantitation (0.01 ppm)

- as no residues were detected

. For the proposed crops, market leader percent crop treated values were incorporated into the DEEM

- FCID model estimates

. For labeled crops, percent crop treated information from previous EPA risk assessments was used. Applying the assigned Q* value of 0.207 (mg/kg/day) - 1 to the highly conservative li fetime dietary fluthiacet

- methyl exposure (water and food) results in an acceptable cancer risk estimate of 8.28x10 - 7 (<1.0x10 - 6 ).

i. Food. The chronic reference dose ( c RfD) has been established at 0.0 01 mg/kg BW /day (cRfD=cPAD) . This c RfD is based on an 18

- month carcinogenicity in the mouse study with a LOAEL of 1.0 and 1.2 mg/kg/day for males and females respectively based on non

- neoplastic liver findings (increase in absolute and relative liver weights, fatty changes, chronic inflammation, karyomega ly, single cell necrosis, and ceroid/lipofuscin pigmentation. Estimated chronic exposure for general US population is 0.000005 mg/kg/day , which represents <1% of the total cPAD. C hronic exposure for non
- nursing infants (most sensitive subgroup) is estima ted to be 0.00 0015 mg/kg/day , which represents 1.5 % of the total c PAD . FMC concludes withreasonable certainty that no harm will result from the labeled and proposed uses of fluthiacet

methyl.

ii. Drinking water
. The chronic reference dose ( c RfD) has been established at 0.0 01 mg/kg BW /day (cRfD=cPAD) . This c RfD is based on an 18

- month carcinogenicity in the mouse study with a LOAEL of 1.0 and 1.2 mg/kg/day for males and females respectively based on non

neoplastic liver findings (increase in absolute and relative liver weights, fatty changes, chronic inflammation, karyomegaly, single cell necrosis, and ceroid/lipofuscin pigmentation. Estimated chronic exposure for general US population is 0.000005 mg/kg/day , which represents <1% of the total cPAD. C h ronic exposure for non
- nursing infants (most sensitive subgroup) is estimated to be 0.00 0015 mg/kg/day , which represents 1.5 % of the total c PAD . FMC concludes with reasonable certainty that no harm will result from the labeled and proposed uses of fluthia cet

methyl.

2. Non

- dietary exposure

. Non

- occupational exposures to carfentrazone

- ethyl are anticipated from the lawn, turf and aquatic applications. The resulting MOEs were calculated to be >500,000.

D. Cumulative Effects

Fluthiacet

- methyl provides its herbicide action by being a “protox inhibitor”. There is no’ reliable information (either from the toxicology studies conducted on fluthiacet

- methyl or by means of structure comparisons to other compounds) as to how to combine fluthiacet

- methy l with other protox inhibitors a cumulative risk assessment. Per EPA’s statement, “fluthiacet

methyl does not appear to produce a toxic metabolite produced by other substances” *66 FR Dec. 21, 2001 page 658461 ]

E. Safety Determination

1. U.S. popula tion. Using highly conservative exposure assessment analyses the estimated chronic exposure to the U.S. Population is 0.00 0005 mg/kg/day and utilizes <1 % of the cPAD. In addition, the highly conservative lifetime dietary fluthiacet

- methyl exposure (water and food) results in an acceptable cancer risk of 8.28x10 - 7 (<1.0x10 - 6 ). Based on this information, FMCconcludes that there is reasonable certainty that no harm will result from fluthiacet

- methyl

exposure associated with labeled and proposed uses.

2. Infants and children

. C hronic exposure for non
- nursing infants (most sensitive subgroup) is estimated to be 0.00 0015 mg/kg/day , which represents 1.5 % of the c PAD . FMC concludes with reasonable certainty that no harm will result from the labeled and propos ed uses of fluthiacet

- methyl on sensitive subgroups.

F. International Tolerances

No international tolerances have been established under CODEX for fluthiacet

- methyl.