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 establishing a 

tolerance for residues of the herbicide, fluthiacet-methyl, acetic acid [[2-chloro-4-fluoro-5-

[(tetrahydro-3-oxo-1H, 3H-[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-1H, 3H-

[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 0.05 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-methyl in plants is adequately 

understood. Corn, soybean and cotton metabolism studies with fluthiacet-methyl have shown 

similar metabolic pathways. The residue of concern is primarily the parent fluthiacet-methyl.
 2. Analytical method. There is a practical analytical method for detecting and 

measuring levels of fluthiacet-methyl 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 enforcement 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-methyl 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. Applications to each treated plot in these 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 that the residues of fluthiacet-methyl would not exceed the 

proposed tolerances.

B. Toxicological Profile

 1. Acute toxicity. Fluthiacet-methyl acute toxicity studies’ results were as follows: oral 

LD50 (rat) was greater than 5000 mg/kg, the acute dermal LD50 (rat) was greater than 2000 

mg/kg and the acute inhalation LC50 (rat) was greater than 5.05 mg/L, non-irritating to rabbit 

skin and minimally irritating to rabbit eyes. It did not cause skin sensitization in guinea pigs. An 

acute neurotoxicity testing in rats up to 2000 mg/kg resulted in no neurotoxic effects.

2. Genotoxicty. Fluthiacet-methyl showed negative results in the following in vitro 

gene mutation tests: Ames, Chinese hamster V79, rat hepatocyte DNA repair, and E. Coli lethal 

DNA damage. For the in vitro chromosomal aberration tests: Chinese hamster ovary and lung 

tests and the human lymphocytes tests were positive at cytotoxic doses. For the in vivo 

chromosome aberration tests: the micronucleus assays in rat liver and the mouse bone marrow 

tests were negative.
3. Reproductive and developmental toxicity. Fluthiacet-methyl Teratology study in rats 

had a maternal and developmental NOAEL equal to or greater than 1,000 

milligram/kilogram/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 dietary 

toxicity study in rats had a NOAEL of 6.2 mg/kg/day based on liver changes and hematological 

effects.

5. Chronic toxicity. Fluthiacet-methyl in a 24 months combined chronic 

toxicity/carcinogenicity study in rats had a NOAEL of 2.1 mg/kg/day. Based on reduced 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 months 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-methyl (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 chemistry 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 endocrine 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-methyl 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 was estimated using the Dietary Exposure Evaluation 

Model-Food Consumption Intake Database (DEEM-FCIDTM, version 2.14, 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 

Intakes (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)-1to the highly conservative lifetime 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 (cRfD) has been established at 0.001 mg/kg BW/day

(cRfD=cPAD). This cRfD 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. Chronic exposure for non-nursing infants (most sensitive subgroup) is estimated to 

be 0.000015 mg/kg/day, which represents 1.5% of the total cPAD. FMC concludes with 
reasonable certainty that no harm will result from the labeled and proposed uses of fluthiacetmethyl.

ii. Drinking water. The chronic reference dose (cRfD) has been established at 0.001

mg/kg BW/day (cRfD=cPAD). This cRfD 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 nonneoplastic 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. Chronic exposure for non-nursing infants (most sensitive subgroup) is estimated to 

be 0.000015 mg/kg/day, which represents 1.5% of the total cPAD. FMC concludes with 

reasonable certainty that no harm will result from the labeled and proposed uses of fluthiacetmethyl.

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-methyl 

with other protox inhibitors a cumulative risk assessment. Per EPA’s statement, “fluthiacetmethyl 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. population. Using highly conservative exposure assessment analyses the estimated 

chronic exposure to the U.S. Population is 0.000005 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, FMC 
concludes that there is reasonable certainty that no harm will result from fluthiacet-methyl 

exposure associated with labeled and proposed uses.

2. Infants and children. Chronic exposure for non-nursing infants (most sensitive 

subgroup) is estimated to be 0.000015 mg/kg/day, which represents 1.5% of the cPAD. FMC 

concludes with reasonable certainty that no harm will result from the labeled and proposed 

uses of fluthiacet-methyl on sensitive subgroups.

F. International Tolerances

No international tolerances have been established under CODEX for fluthiacet-methyl.