Interregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 1 of 8 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

----------------------------------------------------------------------- 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 b y establishing tolerances for re sidues of triflusulfuron methyl, 2 [[[[[4
- (dimethylamino)
- 6
- (2,2,2
- trifluoroeth oxy)
- 1,3,5
- triazin
- 2
- yl ]amino]carbony l]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 triflusulf uron methy l in sugarbeets was studied using triflusulfuron methy l labeled separatel y with carbon
- 14 in the triazine ring and in the ester c arbon yl group. Triflusulfuron methy l 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 methy l levels dropped rapidly from 3 ppm in the sample taken on the day of the treatment to < 0.01 ppm 14 day s after treatment. The initial step in the metabolic breakdown of triflusulfuron methy l involves cleavage of the sulfony lurea bridge, which is followed by further metabolism of the initial degradates. The levels of principal radiolabeled metabolites found in plant samples (N
- desmethy l triazine amine, N,N
- bis
- desmeth yl triazine amine, acid sulfonamide, and its glucose conjugate) dropped to < 0.01 ppm at maturity. No significant (> 0.01 ppm) residues of triflusulf uron methy l or its radiolabeled metabolites were detected in mature roots or foliage. 2. Analytical method
. A method for quantitation of Triflusulfuron meth yl in garden beets uses a high performance liquid chromatograph (HPL C) with eluent and column
- swi tchingInterregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 2 of 8 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 chromatograph y using eluent
- switching. Column
- switching provides t he resolution required for quantitation of triflusulfuron methyl. The calculated LOQ values were 0.0069 ppm for roots and 0.0044 ppm on tops (leaves) respectivel y . Triflusulfuron methy l is detected at levels as low as 0.005 ppm. Triflusulfuron methy l recov eries 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 adequatel y understood thr ough 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 tox icity Category I V for oral and inhalation routes of exposure, and for dermal irritation. Triflusulfuron methyl is in acute toxicity

Category I II for dermal toxicity

and for ey e irritation. Acute oral toxicity in rats LD 50 5,000 mg/kg; acute dermal toxicit y in rabbits LD 50 2,000 mg/kg; and acute inhalation toxicity in rats L C 50 5.1 mg/L. Primary ey e irritation in rabbits , non irritant primary

dermal irritation in rabbits, non
- irritant dermal sensitization in guinea pigs, and non
- sensitizer acute neurotoxic ity 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 1,00 0μ mg/plate, the HDT; a Salmonella ty

phimurium plate incorporation assay which was negative at concentrations up to 3,000μ mg/plate, HDT; and a Chinese hamster ovary /hy poxanthine
- guanine (CHO/HPRT) assay

which was negative at concentrations up to 2,000 mg/kg/day , HDT. A chromosomal aberration/ human ly mphocy te assay was positive in the presence of metabolic activation at concentrations greater than or equal to 1,500 μ mg/mL . A second chromosomal aberration/human ly mphocy te 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 . I n three Salmonella t yphimurium plate incorporation assays , metabolites of triflusulfuron methy l were negative up to 5,000 μ mg/plate, HDT. 3. Reproductive and developmental toxicity
.Interregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 3 of 8 In a 2
- generation rat reproduction study , rats were fed dosages of 0, 0.58 8, 5.81, 44.0 and 89.5 mg/kg/day

(males) and 0, 0.764, 7.75, 58.0, and 115 mg/kg/ day s ( females) with a reproductive toxicity

NOAELequal to or greater than 89.5 and 115 mg/kg/day for males and females, respectivel y, based on the absence of reproductive eff ects in rats at the HDT. The NOAEL for systemic toxicity was 5.81 and 7.75 mg/kg/day for males and females, respectivel y based on decreased body weight/body

weight gain (b wt/bwt gain) and food efficiency

in males and females, and decreased weights of offsp ring from the F 0 generation on day s 14 and 21 post
- partum at 44.0 and 58.0 mg/kg/day in males and females, respectivel y. Technical triflusulfuron methyl was evaluated for developmental toxicity potential in rats and rabbits. Rats were fed dosages of 0, 3 0, 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 bod y 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 aborti ons, 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 i n 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 s ys temic toxicity NOAEL was equal to or greater than 1,000 mg/kg/day for males and fem ales. The dermal toxicit y 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 meth yl 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 stud y, 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 (fema les). Triflusulfuron methy l showed subchronic toxicity at dietary concentrations of 2,000 ppm (133 and 153 mg/kg/day for males andInterregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 4 of 8 females) or greater in the form of decreased bod y weight, decreased body weight gain, decreased food efficiency, and incr eased 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), res ulted in a NOAEL of 92.7 (males) and 7.1 mg/kg/ day (females). This was based on decreas ed 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 o f 3.87, 146.1, or 267.6 mg/kg/day

(males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methy l 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 enzy me levels and postm ortem evidence, including elevation in liver weights and microscopic evidence of bile stasis. Other microscopic findings considered to be treatment related were testicular atrophy and d ecreased testicular weights and hy

percellularity

of the sternal and fe moral bone marrow, with a corresponding increase in reticulocy te and leukocy

te 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 methy l was evaluated in dogs, mice, and rats. In a 1
- ye ar 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 hy pertrophy at the L OAEL of 111.6. For females, the NOAEL was 27.7 mg/kg/day ; this was based on incre ased liver weight and increased incidence of minimal centrilobular hepatocellular hy pertrophy 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 mic e had statistically

significant positive trends for hepatocellular adenomas and for combined adenoma/ carcinoma (driven entirel y b y adenomas) at 349 and 1,024 mg/kg/day. These increases were not significant in pair
- wise comparisons with control groups and were determined no t to be carcinogenic effects b y the Carcinogenicit y 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 / carcinogenicit y 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 s ignificant increasing trend and significant differences in pair
- wise c omparisons of the 30.6 and 64.5 mg/kg/day dose groups withInterregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 5 of 8 controls for interstitial cell adenomas. This effect was determined to be a carcinogenic effect b y 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 bod y weight and body weight gain, alternations in the hematology

paramete rs (males predominatel y) and an increased incidence of interstitial cell hy perplasia 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%), resultin g in NOAELs of 2.44 mg/kg/ day (males) and 3.28 mg/kg/day

(females). 6. Animal metabolism. For triflusulfuron meth yl , in both the rat and the goat, a majority of the administrated dose was excreted in feces and urine. The biotransformation pathway for triflusulfuron methy l in the rat and the goat was similar. The major pathway was demethy lation of the dimethylamino substituent on the triazine ring. The intermediate h ydrox yl ated metabolite was also present. The secondary biotransformation pathway was cle vage of the sulfony lurea bridge to form methy l saccharin, N
- desmeth yl triazine amine and N , N
bis
- desmethy l triazine amine. In the lactating goat, triflusulfuron methyl was not excreted to any appreciab le level in the milk. L evels of the ester carbonyl
- de rived residues were generall y below the limit of reliable measurement ( 0.0006μ mg equivalent triflusulfuron methy l/mL) and triazine
- derived residues reached a daily level of about 0.001 ppm. Therefore, the metabolic pathway s in rats and lactating goats wer e 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 methy l were to enter the livestock diet, triflusulfuron methyl and i ts 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
- desmethy l triazine amine, in male rats was 450 mg/k g/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 bod y weight and above. Clinical signs of toxicity were observed in lethall y and nonlethally dosed rats. In an in vitro gene mutation study , N,N,
- bis
- desmethy l triazine amine was not mutagenic in Salmonella ty phimurium 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 s ubstance 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 lethall y and nonlethally dosed animal s. In an in vitro gene mutation study , tria zine amine was not mutagenic in Salmonella ty phimurium up to a dose of 5,000μ mg/plate. 8. Endocrine disruption.Interregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 6 of 8 No special studies investigating potential estrogenic or other endocrine effects of methyl have been conducted. However, the standard batte ry 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. Bas ed on these studies there is no evidence to suggest that triflusulfuron methy l has an adverse effect on the endocrine sy stem. C. Aggregate Exposure 1. Dietary Exposure The chronic reference dose (cRfD) of 0.024 mg/k g/day is based on the NOELof 2.44 mg/kg/day

from a chronic rat feeding study and a 100X safet y factor. The residue of concern, as listed at 40 CFR 180.492, is parent triflusulfuron methy l onl y. 2. Food a. Chronic Dietary

Exposure Assessment Dietary exposure, resulting from the current and proposed uses of triflusulfuron methy l on sugar beets, chicory , and garden beets , is well within the acceptable limits for all sectors of the population, as predicted b y both the Chronic and Acute Modules of the Die tary Exposure Evaluation Model with Food Commodity I ntake Database (DEEM
FCID TM , 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 assume d for all crops that 100% was treated with triflu sulfuron methy l
. 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 y ears s ubgroup with an exposure of 0.000041 mg/kg bw/day . Based on a chronic NOE L of 2.44 mg/kg bw/day and a 100
- fold safet y factor, the cRfD would be 0.024 mg/kg bw/day . For both the U.S. population and the children 3
- 5 y ears subgroup, the predicted exposure i s 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 methy l. 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 WaterInterregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 7 of 8 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 y ears, was 0.00005 6 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 certaint y of no harm. 4. Non
- Dietary

Exposure Triflusulfuron me thyl is not registered for any use which could result in non
- occupational or non - dietary

exposure to the general population. D. Cumulative Effects Triflusulfuron meth yl belongs to the sulfony lurea class of crop protection chemicals. Other structurally

si milar compounds in this class are registered as herbicides. However, the herbicidal activity

of sulfony lureas is due to the inhibition of acetolactate sy nthase (AL S), an enz ym e found only in plants. This enzyme is part of the bios ynthesis pathway leading t o the formation of branched chain amino acids. Animals lack ALS and this biosy nthetic pathway . This lack of ALS contributes to the relativel y low toxicity of sulfony lurea herbicides in animals. There is no reliable information that would indicate or sugges t that triflusulfuron methyl has an y toxic effects on mammals that would be cumulative with those of any other chemical. E. Safet y Determination Based on data and information submitted by DuPont, EPA previously determined that the establishment of toler ances of triflusulfuron methy l 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 methy l on beet, garden, roots at 0 .01 ppm and beet, garden, tops at 0.02 ppm will also not adversel y 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 establis hed a cRfD of 0.024 mg/kg/day . This was based on the NOEL for the chronic rat stud y, 2.44 mg/kg/day , and a 100
- fold safet y factor. Ithas been concluded that the chronic dietary exposure was lessInterregional Research Number 4 (IR
- 4) Triflusulfuron Methyl

Page 8 of 8 than 1% of the cRfD. Generall y, 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 triflusul furon methy l residues. 2. Infants and Children In assessing the potential for additional sensitivity of infants and children to residues of triflusulfuron methy l, 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 methy l demonstrated no evidence of developmental toxicity at exposures below those causing maternal toxicity . This indicates that de veloping 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 meth yl 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 y ears, for whom exposure was less than 1% of the cRfD. Based on these conservative analy ses, there is reasonable certainty that no harm will result to infants and children from aggregate exposures to tr iflusulfuron methyl. F. International Tolerances There is neither a Codex proposal, nor a Canadian or Mexican tolerance for garden beets.