Interregional Research Number 4 (IR-4) Triflusulfuron Methyl

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Notice of Filing of a Pesticide Petition for the Establishment of Tolerances for 

Residues of Triflusulfuron Methyl in or on Food Commodities

ENVIRONMENTAL PROTECTION AGENCY

EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4) 

Petition Number PP# 9E7669

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EPA has received a pesticide petition, PP# 9E7669, from IR-4, 500 College Road 

East, Suite 201W, Princeton, New Jersey, 08540, 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 tolerances for residues of triflusulfuron methyl, 2 [[[[[4-

(dimethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-

yl]amino]carbonyl]amino]sulfonyl]-3-methylbenzoate in or on the raw agricultural 

commodity beet, garden, roots at 0.01 ppm and beet, garden, tops at 0.02 ppm. EPA has 

determined that the petition contains data or information regarding the elements set forth 

in section 408(d)(2) of the FFDCA; 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. Metabolism of triflusulfuron methyl in sugarbeets was studied using 

triflusulfuron methyl labeled separately with carbon-14 in the triazine ring and in the 

ester carbonyl group. Triflusulfuron methyl was extensively metabolized by sugar beets 

treated at the 4-8-leaf growth stage with 100 grams active ingredient per half acre (g 

ai/ha). Triflusulfuron methyl levels dropped rapidly from 3 ppm in the sample taken on 

the day of the treatment to < 0.01 ppm 14 days after treatment. The initial step in the 

metabolic breakdown of triflusulfuron methyl involves cleavage of the sulfonylurea 

bridge, which is followed by further metabolism of the initial degradates. The levels of 

principal radiolabeled metabolites found in plant samples (N- desmethyl triazine amine, 

N,N-bis-desmethyl triazine amine, acid sulfonamide, and its glucose conjugate) dropped 

to < 0.01 ppm at maturity. No significant (> 0.01 ppm) residues of triflusulfuron methyl 

or its radiolabeled metabolites were detected in mature roots or foliage.

2. Analytical method. A method for quantitation of Triflusulfuron methyl in garden beets 

uses a high performance liquid chromatograph (HPLC) with eluent and column-switching 
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and ultra-violet (UV) detection at 232 nm for the determination of triflusulfuron methyl 

residues in garden beet foliage and roots. Sample clean-up is achieved through reversed 

phase chromatography using eluent-switching. Column-switching provides the resolution 

required for quantitation of triflusulfuron methyl. The calculated LOQ values were 

0.0069 ppm for roots and 0.0044 ppm on tops (leaves) respectively. Triflusulfuron 

methyl is detected at levels as low as 0.005 ppm. Triflusulfuron methyl recoveries 

averaged 99% for foliage and 110% for roots.

3. Magnitude of residues

Residue trials were conducted on garden beets at 8 locations across the U.S. and Canada. 

The nature of triflusulfuron methyl residue in garden beets is adequately understood 

through the sugar beet metabolism studies. These residue data were the basis for 

establishing tolerances for garden beet tops and roots.

B. Toxicological Profile

1. Acute toxicity. 

Based on EPA criteria, technical triflusulfuron methyl is in acute toxicity Category IV for 

oral and inhalation routes of exposure, and for dermal irritation. Triflusulfuron methyl is 

in acute toxicity Category III for dermal toxicity and for eye irritation. Acute oral 

toxicity in rats LD50 5,000 mg/kg; acute dermal toxicity in rabbits LD50 2,000 mg/kg; and 

acute inhalation toxicity in rats LC50 5.1 mg/L. Primary eye irritation in rabbits, nonirritant primary dermal irritation in rabbits, non- irritant dermal sensitization in guinea 

pigs, and non-sensitizer acute neurotoxicity no observed adverse effect level (NOAEL) =

2,000 mg/kg/day highest dose tested (HDT).

2. Genotoxicity. 

Mutagenicity data for technical triflusulfuron methyl include a reverse mutation assay

(Ames Test) which was negative at concentrations up to 1,000μ mg/plate, the HDT; a 

Salmonella typhimurium plate incorporation assay which was negative at concentrations

up to 3,000μ mg/plate, HDT; and a Chinese hamster ovary/hypoxanthine-guanine 

(CHO/HPRT) assay which was negative at concentrations up to 2,000 mg/kg/day, HDT. 

A chromosomal aberration/ human lymphocyte assay was positive in the presence of 

metabolic activation at concentrations greater than or equal to 1,500μ mg/mL. A second 

chromosomal aberration/human lymphocyte assay was positive in the presence of 

metabolic activation at concentrations of 2,000 μ mg/mL. Results in the absence of 

metabolic activation were inconclusive for both chromosomal aberration studies. The 

mouse bone marrow micronucleus test was negative at doses up to 5,000 mg/kg, HDT. In 

three Salmonella typhimurium plate incorporation assays, metabolites of triflusulfuron 

methyl were negative up to 5,000μ mg/plate, HDT.

3. Reproductive and developmental toxicity. 
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In a 2-generation rat reproduction study, rats were fed dosages of 0, 0.588, 5.81, 44.0 and 

89.5 mg/kg/day (males) and 0, 0.764, 7.75, 58.0, and 115 mg/kg/days (females) with a 

reproductive toxicity NOAEL equal to or greater than 89.5 and 115 mg/kg/day for males 

and females, respectively, based on the absence of reproductive effects in rats at the 

HDT. The NOAEL for systemic toxicity was 5.81 and 7.75 mg/kg/day for males and

females, respectively based on decreased body weight/body weight gain (bwt/bwt gain) 

and food efficiency in males and females, and decreased weights of offspring from the F0

generation on days 14 and 21 post-partum at 44.0 and 58.0 mg/kg/day in males and 

females, respectively. 

Technical triflusulfuron methyl was evaluated for developmental toxicity potential in rats 

and rabbits. Rats were fed dosages of 0, 30, 120, 350, and 1,000 mg/kg/day with a 

developmental NOAEL equal to or greater than 1,000 mg/kg/day (HDT) and a maternal 

toxicity NOAEL of 120 mg/kg/ day with a lowest observed adverse effect level (LOAEL) 

of 350 mg/kg/ day based on reduced body weight gain in the 350 and 1,000 mg/kg/day

animals, reduced food consumption in the 1,000 mg/kg/day animals and lower food 

efficiency in the 350 and 1,000 mg/kg/day. Rabbits were fed dosages of 0, 15, 90, 270, 

and 800 mg/kg/day with a NOAEL for developmental toxicity of 90 mg/kg/day with a 

LOAEL of 270 mg/kg/day based on the increase in abortions and a decrease in mean 

fetal body weight (bwt). The NOAEL for maternal toxicity is 90 mg/kg/day with a

LOAEL of 270 mg/kg/day based on the maternal death and abortions, and increase in 

clinical signs noted in the mid-high and high dose groups, decreased food efficiency and 

increased post mortem finding describing gastrointestinal effects.

4. Subchronic toxicity. 

The subchronic toxicity of technical triflusulfuron methyl was evaluated in rabbits, rats, 

and dogs. 

In a 21-day dermal toxicity study with rabbits fed dosages of 50, 300, or 1,000 

mg/kg/day, the systemic toxicity NOAEL was equal to or greater than 1,000 mg/kg/day

for males and females. The dermal toxicity NOAEL was equal to or greater than 1,000 

mg/kg/day for males and females. 

Two 90-day studies were conducted in the rat. In one study, rats were fed dosages of 6.2, 

127, 646, or 965 mg/kg/day (males) or 7.54, 150, 774, or 1,070 mg/kg/day (females). 

Triflusulfuron methyl exhibited subchronic toxicity at dietary concentrations of 2,000 

ppm (127 and 150 mg/kg/day for males and females) or greater in the form of decreased 

body weights, decreased body weight gains, decreased food efficiency, increased mean 

relative liver weights, and regenerative anemia. The NOAEL was 6.2 mg/kg/day (males) 

and 7.54 mg/kg/day (females). 

In another study, rats were fed dosages of 6.56, 133, 658, or 1,036 mg/kg/day (males) or 

7.71, 153, 783, or 1,124 mg/kg/day (females). Triflusulfuron methyl showed subchronic 

toxicity at dietary concentrations of 2,000 ppm (133 and 153 mg/kg/day for males and 
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females) or greater in the form of decreased body weight, decreased body weight gain, 

decreased food efficiency, and increased mean liver weights. The NOAEL was 6.56 

mg/kg/day (males) and 7.71 mg/kg/day (females).

A subchronic neurotoxicity study with rats fed dosages of 0, 6.1, 46.1, 92.7, or 186.2 

mg/kg/day (males) or 7.1, 51.6, 104.1, or 205.2 mg/kg/day (females), resulted in a 

NOAEL of 92.7 (males) and 7.1 mg/kg/ day (females). This was based on decreased 

body weight/body weight gain at the LOAEL of 186.2 mg/kg/day (males) and 51.6 

mg/kg/day (females). 

In another 90-day subchronic study, dogs were fed dosages of 3.87, 146.1, or 267.6 

mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methyl 

was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day males and 159.9 mg/kg/day

females), and greater elevated hepatic enzyme levels and postmortem evidence, including 

elevation in liver weights and microscopic evidence of bile stasis. Other microscopic 

findings considered to be treatment related were testicular atrophy and decreased 

testicular weights and hypercellularity of the sternal and femoral bone marrow, with a 

corresponding increase in reticulocyte and leukocyte counts seen in the high-dose males 

and females. Based on the microscopic findings in the liver and testes of the 4,000 ppm 

and greater treated animals, the NOAEL was 3.87 mg/kg/day (males) and 3.72 mg/kg/day

(females).

5. Chronic toxicity. 

The chronic toxicity of technical triflusulfuron methyl was evaluated in dogs, mice, and 

rats. In a 1- year oral toxicity study with dogs fed dosages of 1.0, 26.9, 111.6 mg/ kg/day

(males) and 1.2, 27.7, and 95.5 mg/kg/day (females), the NOAEL for males was 26.9 

mg/kg/day; this was based on increases in alkaline phosphatase, liver weight, and 

incidence of minimal centrilobular hypertrophy at the LOAEL of 111.6. For females, the 

NOAEL was 27.7 mg/kg/day; this was based on increased liver weight and increased 

incidence of minimal centrilobular hepatocellular hypertrophy at the LOAEL of 95.5 

mg/kg/day.

In an 18-month carcinogenicity study, mice were fed dosages of 1.37, 20.9, 349, and 

1,024 mg/kg/day (males) and 1.86, 27.7, 488, and 1,360 mg/kg/day (females). Male mice 

had statistically significant positive trends for hepatocellular adenomas and for combined 

adenoma/ carcinoma (driven entirely by adenomas) at 349 and 1,024 mg/kg/day. These 

increases were not significant in pair-wise comparisons with control groups and were 

determined not to be carcinogenic effects by the Carcinogenicity Peer Review Committee 

(CPRC). The NOAEL was based on body and organ weight effects and was 20.9 

mg/kg/day (males) and 27.7 mg/kg/day (females). 

In the combined chronic toxicity/ carcinogenicity study, rats were fed dosages of 0, 

0.406, 4.06, 30.6, and 64.5 mg/kg/day (males) and 0, 0.546, 5.47, 41.5, and 87.7 

mg/kg/day (females). Male rats have a significant increasing trend and significant 

differences in pair-wise comparisons of the 30.6 and 64.5 mg/kg/day dose groups with 
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controls for interstitial cell adenomas. This effect was determined to be a carcinogenic 

effect by the CPRC. No carcinogenic effects were noted in females up to and including 

87.7 mg/ kg/day HDT. The LOAEL for chronic toxicity is 30.6 mg/kg/day (males) and 

41.5 (females) based on decreased body weight and body weight gain, alternations in the 

hematology parameters (males predominately) and an increased incidence of interstitial 

cell hyperplasia in males. The NOAEL for chronic toxicity is 4.06 mg/kg/day (males) and 

5.47 mg/kg/day (females). This value is adjusted to the lowest concentration level of the 

chemical at this dosage (60%), resulting in NOAELs of 2.44 mg/kg/ day (males) and 3.28 

mg/kg/day (females).

6. Animal metabolism. 

For triflusulfuron methyl, in both the rat and the goat, a majority of the administrated 

dose was excreted in feces and urine. The biotransformation pathway for triflusulfuron 

methyl in the rat and the goat was similar. The major pathway was demethylation of the 

dimethylamino substituent on the triazine ring. The intermediate hydroxylated 

metabolite was also present. The secondary biotransformation pathway was clevage of 

the sulfonylurea bridge to form methyl saccharin, N-desmethyl triazine amine and N, Nbis-desmethyl triazine amine. In the lactating goat, triflusulfuron methyl was not excreted 

to any appreciable level in the milk. Levels of the ester carbonyl-derived residues were 

generally below the limit of reliable measurement (0.0006μ mg equivalent triflusulfuron 

methyl/mL) and triazine-derived residues reached a daily level of about 0.001 ppm. 

Therefore, the metabolic pathways in rats and lactating goats were very similar. There 

were no significant plant metabolites of triflusulfuron methyl that were not found in the 

rat or goat metabolism studies. In the unlikely event that triflusulfuron methyl were to 

enter the livestock diet, triflusulfuron methyl and its metabolites would be rapidly

excreted and would not accumulate in meat, meat by-products, or milk.

7. Metabolite toxicology. 

The approximate lethal dose (ALD) of the degradation product, N,N-bis-desmethyl 

triazine amine, in male rats was 450 mg/kg/day. Rats were fed dose rates of 200, 300, 

450, 670, 1,000, and 2,300 mg/kg of triflusulfuron methyl. Deaths occurred up to test day

7 in rats dosed at 450 mg/kg body weight and above. Clinical signs of toxicity were 

observed in lethally and nonlethally dosed rats. In an in vitro gene mutation study, N,N,-

bis-desmethyl triazine amine was not mutagenic in Salmonella typhimurium up to a dose 

of 5,000μ mg/ plate. For the degradation product, triazine amine, the ALD in male rats 

was 670 mg/kg/day. The test substance dose was 200, 300, 450, 670, 1,000, or 2,300 

mg/kg. Deaths occurred up to test day 4 in rats dosed at 670 mg/kg and above. Clinical 

signs of toxicity were observed in lethally and nonlethally dosed animals. In an in vitro 

gene mutation study, triazine amine was not mutagenic in Salmonella typhimurium up to 

a dose of 5,000μ mg/plate.

8. Endocrine disruption. 
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No special studies investigating potential estrogenic or other endocrine effects of methyl 

have been conducted. However, the standard battery of required toxicology studies has

been completed. These include an evaluation of the potential effects on reproduction and 

development, and an evaluation of the pathology of the endocrine organs following 

repeated or long-term exposure to doses that far exceed likely human exposures. Based 

on these studies there is no evidence to suggest that triflusulfuron methyl has an adverse 

effect on the endocrine system.

C. Aggregate Exposure

1. Dietary Exposure

The chronic reference dose (cRfD) of 0.024 mg/kg/day is based on the NOEL of 2.44 

mg/kg/day from a chronic rat feeding study and a 100X safety factor. 

The residue of concern, as listed at 40 CFR 180.492, is parent triflusulfuron methyl only.

2. Food

a. Chronic Dietary Exposure Assessment

Dietary exposure, resulting from the current and proposed uses of triflusulfuron methyl 

on sugar beets, chicory, and garden beets, is well within the acceptable limits for all 

sectors of the population, as predicted by both the Chronic and Acute Modules of the 

Dietary Exposure Evaluation Model with Food Commodity Intake Database (DEEMFCIDTM, Exponent, Inc., 2003 Version 2.14). The percentage or proportion of a crop that 

is treated can have a significant effect on the exposure profile. In this case, it was 

assumed for all crops that 100% was treated with triflusulfuron methyl. 

The predicted chronic exposure for the U.S. population was 0.000015 mg/kg bw/day. 

The population subgroup with the highest predicted level of chronic exposure was the 

children 3-5 years subgroup with an exposure of 0.000041 mg/kg bw/day. Based on a 

chronic NOEL of 2.44 mg/kg bw/day and a 100-fold safety factor, the cRfD would be 

0.024 mg/kg bw/day. For both the U.S. population and the children 3-5 years subgroup, 

the predicted exposure is equivalent to less than 1% of the cRfD. Since the predicted 

exposures, expressed as percentages of the cRfD, are well below 100%, there is 

reasonable certainty that no chronic effects would result from dietary exposure to 

triflusulfuron methyl.

b. Acute Dietary Exposure

There are no effects attributable to a single, oral dose of triflusulfuron methyl. Therefore, 

an acute dietary risk assessment was not conducted.

3. Drinking Water
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Based on the PRZM/EXAMS and SCI-GROW models the EECs of triflusulfuron methyl 

for chronic exposures are estimated to be 0.005 ppb for surface water and 0.5 ug/L 

(micrograms/Liter) for ground water. There was little change from the food-only dietary

risk assessments when the higher ground water concentration was included in the chronic 

dietary risk assessment; the predicted exposure for the general population was 0.000025

mg/kg/day, less than 1% of the cRfD, and the predicted exposure for the most sensitive 

subpopulation, children 3-5 years, was 0.000056 mg/kg/day, less than 1% of the cRfD. 

Thus, it can be concluded that the chronic dietary exposure of triflusulfuron methyl, 

including the contribution of drinking water, clearly meets the standard of reasonable 

certainty of no harm. 

4. Non-Dietary Exposure

Triflusulfuron methyl is not registered for any use which could result in non-occupational 

or non-dietary exposure to the general population.

D. Cumulative Effects

Triflusulfuron methyl belongs to the sulfonylurea class of crop protection chemicals. 

Other structurally similar compounds in this class are registered as herbicides. However, 

the herbicidal activity of sulfonylureas is due to the inhibition of acetolactate synthase 

(ALS), an enzyme found only in plants. This enzyme is part of the biosynthesis pathway 

leading to the formation of branched chain amino acids. Animals lack ALS and this 

biosynthetic pathway. This lack of ALS contributes to the relatively low toxicity of 

sulfonylurea herbicides in animals. There is no reliable information that would indicate or 

suggest that triflusulfuron methyl has any toxic effects on mammals that would be 

cumulative with those of any other chemical.

E. Safety Determination

Based on data and information submitted by DuPont, EPA previously determined that the 

establishment of tolerances of triflusulfuron methyl on the sugar beets and chicory raw 

agricultural commodities would protect the public health, including the health of infants 

and children.

Establishment of new tolerances for triflusulfuron methyl on beet, garden, roots at 0.01 

ppm and beet, garden, tops at 0.02 ppm will also not adversely impact public health.

1. U.S. Population

Based on the completeness and reliability of the toxicology database, and using the 

conservative assumptions presented earlier, EPA has established a cRfD of 0.024 

mg/kg/day. This was based on the NOEL for the chronic rat study, 2.44 mg/kg/day, and a 

100-fold safety factor. It has been concluded that the chronic dietary exposure was less 
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than 1% of the cRfD. Generally, exposure below 100% of the cRfD are of no concern 

because it represents the level at or below which daily dietary exposure over a lifetime 

will not pose appreciable risk to human health. Thus, there is reasonable certainty that no 

harm will result from chronic exposures to triflusulfuron methyl residues.

2. Infants and Children

In assessing the potential for additional sensitivity of infants and children to residues of 

triflusulfuron methyl, data from the previously discussed developmental and 

multigeneration reproductive toxicity studies were considered. 

Developmental studies are designed to evaluate adverse effects on the developing 

organism resulting from pesticide exposure during pre-natal development. Reproduction 

studies provide information relating to reproductive and other effects on adults and 

offspring from pre-natal and post-natal exposures to the pesticide. The studies with 

triflusulfuron methyl demonstrated no evidence of developmental toxicity at exposures 

below those causing maternal toxicity. This indicates that developing animals are not 

more sensitive to the effects of triflusulfuron methyl administration than adults. 

FFDCA section 408 provides that EPA may apply an additional uncertainty factor for 

infants and children in the case of threshold effects to account for pre- and post-natal 

toxicity and the completeness of the database. Based on current toxicological data 

requirements, the database for triflusulfuron methyl relative to pre- and post-natal effects 

for children is complete. The sub-population with the highest level of chronic exposure 

was Children 3-5 years, for whom exposure was less than 1% of the cRfD. Based on 

these conservative analyses, there is reasonable certainty that no harm will result to 

infants and children from aggregate exposures to triflusulfuron methyl. 

F. International Tolerances

There is neither a Codex proposal, nor a Canadian or Mexican tolerance for garden beets.