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

Interregional Research Project Number 4 (IR-4)

PP No. 1E7885

EPA has received a pesticide petition (PP No. 1E 7885) 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 sec tion 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] sulf onyl] -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 fo rth 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 thifen sulfuron 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-pressu re 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 samp les of chicory roots and chicory tops were <0.01 ppm for thifensulfuron-methyl after a tota l 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 c onsidered acute toxicity category IV for acute oral and inhalation toxicity and for eye irritati on and acute toxicity category III for acute dermal toxicity and for dermal irritation. Technical th ifensulfuron 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: mutage nicity in bacterial (Ames test) and mammalian (CHO/HGPRT assay) cells; in vitro cytoge netics (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 c onceptus (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 sm all renal papillae. In the rabbit developmental toxicity study, there was slight maternal toxic ity (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 effect s on fetal weights or the incidences of

malformations or variations were seen at a ny 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 exposur e 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 chemistr y 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 subc hronic (90-day dietary) exposure in dogs was 1500 and 7500 ppm in males and females (equiva lent 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 ta rget 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 approxi mately 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 ma les 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 ( 14 C-thiophene and 14 Ctriazine). In the thiophene study, the thifensu lfuron methyl was primarily excreted unchanged by rats following low dose (20 mg/kg), low dose following 21 days dietary preconditioning (100ppm), 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-aci d-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 CO 2 or volatile compounds occurred. These results are similar to those reported on the thiophene-labeled thifensulfur on 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 th an 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 radi oactive forms of thifensulfuron methyl ( 14 Ctriazine and 14 C-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 plan t metabolites of thifensu lfuron methyl found in food or feed products at crop maturity. Hence, t oxicity 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 estrogeni c or other endocrine effects of thifensulfuron methyl have been conducted. However, the sta ndard battery of required toxicology studies has been completed. These include an evaluati on 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 lik ely human exposures. Based on these studies there is no evidence to suggest that thifensulfur on 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/da y 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 (95 th 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 (95 th 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 95 th 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 assessmen t for thifensulfuron methyl, either dietary (food only) or aggregate (food and water), with an exposur e 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 thifensulfur on 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 95 th 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 95 th percentile of 0.001187 mg/kg/day, less than 1% of the aRfD. Therefore, one can conclude with reasonable certainty that residue s of thifensulfuron methyl in drinking water do not contribute significantly to the aggregate acute human health risk.

When the GENEEC 56-day estimated environm ental concentration of 0.65 ppb thifensulfuron methyl in surface water was included in the chr onic 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 estim ated 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 a ny uses that could result in non-occupational, nondietary exposure to the general population.

D. Cumulative Effects

Thifensulfuron methyl belongs to the sulfonylur ea 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 bi osynthesis pathway leading to the formation of

branched chain amino acids. Animals lack ALS a nd 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 sugge st 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 establis hed 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 beenconcluded that the chronic dietary exposure was le ss 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 fr om 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-na tal development. Reproduction studies provide information relating to reproductive and other eff ects on adults and offspr ing 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 acc ount for pre- and post-natal toxicity and the completeness of the database. Based on current toxi cological data requirements, the database for thifensulfuron methyl relative to pre- and post-na tal 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 r easonable 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 Ma ximum 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