EPA Registration Division contact: Andrew Ertman, (703) 308-9367 

Interregional Research Project Number 4 (IR-4) 

 

PP No. 1E7885 

EPA has received a pesticide petition (PP No. 1E7885) from the Interregional Research Project 

No. 4 (IR-4), Rutgers, The State University of New Jersey, 500 College Road East, Suite 201W. 

Princeton, NJ 08540, proposing pursuant to section 408 (d) of the Federal Food, Drug, and 

Cosmetic Act, 21 U.S.C. 346a (d), to amend 40 CFR Part 180.478 by establishing a tolerance for 

residues of the herbicide thifensulfuron methyl {Methyl-3-[[[[(4-methoxy-6-methyl-1,3,5-

triazin-2-yl) amino] carbonyl] amino] sulfonyl] -2-thiophenecarboxylate}in or on the raw 

agricultural commodities chicory, roots at 0.01 ppm and chicory, tops at 0.01 ppm, for each 

analyte. 

This summary was prepared by the petitioner. 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 the petition. Additional data may be needed before EPA rules in the petition. 

A. Residue Chemistry 

1. Plant metabolism. 

The qualitative nature of the residues of thifensulfuron methyl in plants is adequately 

understood; therefore no additional metabolism data are required to support the proposed 

tolerances on chicory roots and chicory tops. 

2. Analytical method. 

Adequate analytical methodology, high-pressure liquid chromatography with ESI-MS/MS 

detection, is available for enforcement purposes. 

3. Magnitude of residues. 

a. Sulfonylurea tolerant chicory: 

The results from six trials show that all samples of chicory roots and chicory tops were <0.01 

ppm for thifensulfuron-methyl after a total application rate of approximately 0.005 

thifensulfuron-methyl a.i./A. 

B. Toxicological Profile 

1. Acute toxicity. 
Thifensulfuron methyl: 

Technical thifensulfuron methyl is considered acute toxicology category III based on overall 

results from several studies. This compound is considered acute toxicity category IV for acute 

oral and inhalation toxicity and for eye irritation and acute toxicity category III for acute dermal 

toxicity and for dermal irritation. Technical thifensulfuron methyl is not a dermal sensitizer. 

2. Genotoxicty. 

Technical thifensulfuron methyl was negative for genotoxicity in batteries of in vitro and in vivo

tests. These tests included the following: mutagenicity in bacterial (Ames test) and mammalian 

(CHO/HGPRT assay) cells; in vitro cytogenetics (chromosomal aberration in human 

lymphocytes); in vivo cytogenetics (bone marrow micronucleus assay in mice); and unscheduled 

DNA synthesis in rat primary hepatocytes. 

3. Reproductive and developmental toxicity. 

Thifensulfuron methyl: 

The results of a series of studies indicated that there were no reproductive, developmental or 

teratogenic hazards associated with the use of thifensulfuron methyl. In a 1-generation 

reproduction study in rats, the suggested NOEL was 7500 ppm (559 mg/kg/day males, 697 

mg/kg/day females). In a rat multigeneration reproduction study, the NOEL for reproductive 

effects of thifensulfuron methyl in adult rats and their offspring was 2500 ppm, the highest 

dietary level tested. This level was based on the absence of significant compound related effects 

observed in this study, and is equivalent to 175-180 mg/kg/day in adult male rats and 212-244 

mg/kg/day in adult female rats. There were no effects on fertility, lactation, litter size, or pup 

survival. Thifensulfuron methyl is not considered a reproductive toxin. 

In studies conducted to evaluate developmental toxicity potential, thifensulfuron methyl was 

neither teratogenic nor uniquely toxic to the conceptus (i.e., not considered a developmental 

toxin). In the rat study, there was no evidence of maternal toxicity at the highest dose tested (800 

mg/kg/day). Therefore, the maternal NOAEL is 725 mg/kg/day (analytically determined dose). 

The developmental NOAEL for rats was considered to be the 200 mg/kg/day dose level 

(analytically determined and set by EPA as 159 mg/kg/day) based on the decrease in mean fetal 

body weight and an increase in the incidence of small renal papillae. In the rabbit developmental 

toxicity study, there was slight maternal toxicity (decreased body weight gain) at a dose of 650 

mg/kg/day. No significant indications of maternal toxicity were evident at the mid-dose level 

(200 mg/kg/day). No compound-related effects on fetal weights or the incidences of 

malformations or variations were seen at any dose. The maternal NOEL was the 200 mg/kg/day 

dose (analytically determined and set by EPA at 158 mg/kg/day) and the developmental NOEL 

was the 650 mg/kg/day dose level (analytically determined and set by EPA at 511 mg/kg/day) 

for rabbits dosed with thifensulfuron methyl by gavage on gestation days 7-19. 

4. Subchronic toxicity. 
Thifensulfuron methyl: 

The most sensitive species to subchronic exposure of thifensulfuron methyl was the rat. The 

NOEL for thifensulfuron methyl was 100 ppm (7 and 9 mg/kg/day) for male and female rats, 

respectively, in the 90-day dietary study. This was based on the decreased body weight, food 

efficiency, and changes in clinical chemistry in the 2500 and 7500 ppm groups. For mice in both 

the 4-week range-finding and the 90-day studies, the NOEL for male and female mice under the 

conditions of this study was 7500 ppm. This was based on the lack of compound-related effects 

at the highest concentration, equivalent to 1427 mg/kg/day in male mice and 2287 mg/kg/day in 

female mice. EPA concluded the NOEL for subchronic (90-day dietary) exposure in dogs was 

1500 and 7500 ppm in males and females (equivalent to 37.5 mg/kg/day and 159.7 mg/kg/day) 

respectively. These levels were based on lower body weight and adrenal weight in males, and a 

lack of adverse effects in females at 7500 ppm, the highest concentration tested. No compoundrelated pathologic lesions were observed and no target organ was identified in all of the above 

tests. 

5. Chronic toxicity. 

Thifensulfuron methyl: 

The NOEL for chronic (2-year dietary) exposure in rats was 500 ppm (20 mg/kg/day for males 

and 26 mg/kg/day for females), based on body weight effects at 2500 ppm. Thifensulfuron 

methyl was not an oncogen in rats. 

In an 18-month study in mice, conducted at dietary levels of 0, 25, 750, and 7500 ppm, EPA 

concluded the NOEL was 25 ppm (4.3 mg/kg/day) based on decreased body weight gains in 

female mice at 750 ppm and above, and in male mice at 7500 ppm. No other effects were 

observed in the study. Thifensulfuron methyl was not an oncogen in mice. 

 

In a 1- year feeding study in dogs, the NOEL of thifensulfuron methyl was 750 ppm in male and 

female beagle dogs (equivalent to approximately 18.75 mg/kg/day), based on decreased body 

weights, body weight gains, and food efficiency in females and increased liver weights in males, 

all at 7500 ppm. The liver weight effects in males in the absence of other effects including 

histopathology may be adaptive rather than adverse. 

6. Animal metabolism. 

Thifensulfuron methyl: 

The metabolic pathway for thifensulfuron methyl in animals is understood. This metabolic 

pathway involves hydrolysis of the urea bridge, deesterification, and O-demethylation reactions. 

There was minimal potential for retention or accumulation of thifensulfuron methyl or its 

metabolites in animal tissues. Low levels of thifensulfuron methyl residues were found in goat 

tissues and insignificant tissue levels (i.e., less than 0.1% of the dose) were observed in the rat. 

Rats were dosed with two radioactive forms of thifensulfuron methyl (14C-thiophene and 14Ctriazine). In the thiophene study, the thifensulfuron methyl was primarily excreted unchanged by 

rats following low dose (20 mg/kg), low dose following 21 days dietary preconditioning (100 
ppm), and high dose (2,000 mg/kg) routines. Approximately 70% to 85% of the excreted 

radioactivity was thifensulfuron methyl. The urine was the primary excretion route and 

contained 71% to 92% of the original dose from the low and low-dose preconditioned groups. 

Combined urinary and fecal elimination was rapid, with over 90% of excretion completed by 48 

hours after dosing for both low-dose groups. The high-dose group peak elimination was delayed 

by approximately 24 hours compared to the other dose levels. Tissue radioactivity levels were 

low at sacrifice (96 hours after dosing) for all dosing groups, with no enhanced retention of 

radioactivity by any organ or tissue. Thifensulfuron methyl was the primary radiolabeled 

excretion product with thifensulfuron acid, 2-acid-3-sulfonamide, 2-ester-3-sulfonamide, and 

thiophene sulfonamide identified as minor metabolites. 

In the triazine study, thifensulfuron methyl was excreted primarily unchanged in urine and feces 

by male and female rats after administration of approximately 2000 mg/kg by oral gavage. Urine 

was the primary route of excretion, averaging 58.7% of the dose in males and 75.5% in females. 

Fecal excretion of the dose averaged 21.2% for the male rats and 15.8% for the females. Greater 

than 50% of the dose was excreted by 48 hours post-dosing. Essentially no elimination of the 

dose as radiolabeled CO2 or volatile compounds occurred. These results are similar to those 

reported on the thiophene-labeled thifensulfuron methyl. Intact thifensulfuron methyl was 

identified by mass spectrometry as the principal radioactive compound in urine (> 94%) and 

feces (> 77%). Three minor metabolites, each less than 3% of the dose, were identified in urine 

and feces by chromatographic retention comparison; they were thifensulfuron acid, O-demethyl 

thifensulfuron methyl, and triazine amine. 

Results from a metabolism study with two radioactive forms of thifensulfuron methyl (14Ctriazine and 14C-thiophene) in lactating goats show that most of the dosed radioactivity was 

rapidly excreted (primarily in the urine) and recovered as intact thifensulfuron methyl. 

Radioactivity in the milk (0.1 - 0.2 ppm) was comprised of mostly intact thifensulfuron methyl 

and a small amount of triazine amine and several very minor metabolites. Radioactivity did not 

accumulate in the tissues. After absorption, the major metabolic pathway involved cleavage of 

the carboxyl ester linkage, resulting in the formation of thifensulfuron acid. Oxidative 

O-demethylation occurred to a limited extent. 

There were no significant levels of unique plant metabolites of thifensulfuron methyl found in 

food or feed products at crop maturity. Hence, toxicity testing of other degradation products of 

thifensulfuron methyl is not needed. 

7. Metabolite toxicology. 

There is no evidence that the metabolites of thifensulfuron methyl, as identified in either the 

plant or animal metabolism studies, are of any toxicological significance. 

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

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 thifensulfuron methyl has an adverse effect on the endocrine 

system.

C. Aggregate Exposure 

1. Dietary exposure. 

Thifensulfuron methyl: 

The residue of concern, as listed at 40 CFR 180.439, is parent thifensulfuron methyl only. 

The acute reference dose (aRfD) of 1.59 mg/kg/day is based the NOEL of 159 mg/kg/day from a 

rat developmental study and a 100X safety factor. 

The chronic reference dose (cRfD) of 0.2 mg/kg/day is based on the NOEL of 20 mg/kg/day 

from a two-year rat feeding study and a 100X safety factor. 

a. Food. 

i. Acute 

Thifensulfuron methyl: 

The predicted acute exposure for the U.S. population subgroup was 0.000574 mg/kg bw/day 

(95th percentile). The population subgroup with the highest predicted level of acute exposure 

was the infants subgroup with an exposure of 0.001062 mg/kg bw/day (95th percentile). Based 

on an acute NOEL of 159 mg/kg bw/day and a 100-fold safety factor, the aRfD would be 1.59 

mg/kg bw/day. For both the U.S. population and the infants subgroup the predicted exposure (at 

the 95th percentile) is equivalent to less than 1% of the aRfD. Since the predicted exposures, 

expressed as percentages of the aRfD, are well below 100%, there is reasonable certainty that no 

acute effects would result from dietary exposure to thifensulfuron methyl. 

ii. Chronic 

Thifensulfuron methyl: 

There is no population in the chronic risk assessment for thifensulfuron methyl, either dietary (food 

only) or aggregate (food and water), with an exposure greater than 1% of the chronic reference dose. 

b. Drinking water. 
Thifensulfuron methyl: 

Surface water exposure was estimated using the Generic Expected Environmental Concentration 

(GENEEC) model, and groundwater exposures were estimated using SCI-GROW. There was 

little change from the food-only dietary risk assessments when the higher surface water 

concentrations were included in the acute and chronic dietary risk assessments. When the 

estimated maximum concentration of thifensulfuron methyl in surface water, 1.2 parts per billion 

(ppb), was included in the acute dietary assessment as a point estimate the predicted exposure at 

the 95th percentile for the general U.S. population was 0.000608 mg/kg/day which corresponds to 

less than 1% of the aRfD; the most sensitive subpopulation, infants, had an estimated exposure at 

the 95th percentile of 0.001187 mg/kg/day, less than 1% of the aRfD. Therefore, one can 

conclude with reasonable certainty that residues of thifensulfuron methyl in drinking water do 

not contribute significantly to the aggregate acute human health risk. 

When the GENEEC 56-day estimated environmental concentration of 0.65 ppb thifensulfuron 

methyl in surface water was included in the chronic dietary assessment, the predicted exposure 

for the general population was 0.000239 mg/kg/day, less than 1% of the cRfD; the most sensitive 

subpopulation, children 3-5 years, had an estimated exposure of 0.000536 mg/kg/day, less than 

1% of the cRfD. Thus, it can be concluded that the chronic dietary exposure of thifensulfuron 

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

certainty of no harm. 

2. Non-dietary exposure. 

Thifensulfuron methyl is not registered for any uses that could result in non-occupational, nondietary exposure to the general population. 

D. Cumulative Effects 

Thifensulfuron methyl belongs to the sulfonylurea class of crop protection chemicals. Other 

structurally similar compounds in this class are registered 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 thifensulfuron methyl has any toxic 

effects on mammals that would be cumulative with those of any other chemical. 

E. Safety Determination 

1. U.S. population. 

Thifensulfuron methyl: 

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

assumptions presented earlier, EPA has established a cRfD of 0.2 mg/kg/day. This was based on 

the NOEL for the chronic rat study, 20 mg/kg/day, and a 100-fold safety factor. It has been 
concluded that the chronic dietary exposure was less than 1% of the cRfD. Generally, exposures 

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 thifensulfuron methyl 

residues. 

 

2. Infants and children. 

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

thifensulfuron 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 thifensulfuron 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 thifensulfuron 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 

thifensulfuron methyl relative to pre- and post-natal effects for children is complete. In addition, 

the NOEL upon which the RfD is based is much lower than the NOELs defined in the 

reproduction and developmental toxicology studies. 

Conservative assumptions utilized to estimate aggregate dietary exposures of infants and 

children to thifensulfuron methyl demonstrated that less than 1% of the RfD would be utilized 

for the highest exposed group, Children 3-5 years old. 

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

infants and children from aggregate exposures to thifensulfuron methyl. 

F. International Tolerances 

A number of international tolerances (or Maximum Residue Levels, MRL's) have been 

established for thifensulfuron methyl including the following: 

Thifensulfuron methyl: 

Countries Crop Tolerance/MRL 

Canada Canola 0.1 ppm 

European Union (EU) Barley, Field Corn, Oats 

Soybeans, Wheat, Canola 

0.5 ppm 
(rapeseed), Cotton Seed, 

Flax (other oilseeds), Rice, 

Sunflowers, Sorghum