### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES 

### Date: September 24, 2003

MEMORANDUM

Subject: Human Health Risk Assessment for th e Section 3 Registration of Trifloxysulfuronsodium on Almond, Citrus, Cotton, Sugarcane, Tomato, and Turf. PP# 1F06280.

DP Barcode: D284104 Submission: S618179 PC Code: 119009 Case: 294017 40 CFR 180: None (new a.i.) Class: Sulfonylurea Herbicide
From: Michael Doherty, Chemist Edwin Budd, Toxicologist Alan Levy, Toxicologist Shih-Chi Wang, Biologist Registration Action Branch 2 Health Effects Division (7509C)
Through: Gary Bangs, Industrial Hygenist Yan Donovan, Chemist Registration Action Branch 2 Health Effects Division (7509C)
Through: Richard Loranger, Branch Senior Scientist Registration Action Branch 2 Health Effects Division (7509C)
To: Jim Tompkins/Vickie Walters (25) Herbicide Branch Registration Division (7505C)

### i 1.0 EXECUTIVE SUMMARY

................................................... 1

2.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

................... 4

3.0 HAZARD CHARACTERIZATION

............................................ 5 3.1 Hazard Profile

....................................................... 5 3.2 FQPA Considerations

................................................ 10 3.3 Dose-Response Assessment

............................................ 11 3.4 Endocrine Disruption

................................................. 15

4.0 EXPOSURE ASSESSMENT

................................................ 15 4.1 Summary of Proposed Uses

............................................ 15 4.2 Dietary Exposure/Risk Pathway

........................................ 18 4.2.1 Residue Profile

.............................................. 18 4.2.2 Acute and Chronic Dietary Exposure and Risk

..................... 19 4.3 Water Exposure/Risk Pathway

......................................... 20 4.4 Residential Exposure/Risk Pathway

..................................... 21 4.4.1 Home Uses

................................................. 21 4.4.2 Recreational

................................................ 22 4.4.3 Other (Spray Drift, etc.)

....................................... 22

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

.......... 22 5.1 Acute Risk

......................................................... 23 5.2 Short-Term Ris k..................................................... 24 5.3 Intermediate-Term Risk

............................................... 25 5.4 Chronic Risk

....................................................... 25 5.5 Cancer Risk

........................................................ 26

6.0 CUMULATIVE RISK

...................................................... 26

7.0 OCCUPATIONAL EXPOSURE

.............................................. 27
8.0 DATA NEEDS AND LABEL REQUIREMENTS

................................ 30 8.1 Toxicology

........................................................ 30 8.2 Residue Chemistry

................................................... 30 8.3 Occupational and Residential Exposure

.................................. 31

### 1 of 32 1.0 EXECUTIVE SUMMARY
Note: Throughout this document, “trifloxys ulfuron-sodium” refers, specifically, to the sodium salt and “trifloxysulfuron” refers to the free acid form of the molecule.
Syngenta Crop Protection, Inc. has requested that the Agency grant a national registration for the use of the herbicide trifloxysulfuron-sodium on almonds, citrus, cotton, sugarcane, tomatoes, and turf, and establish tolerances for residues for trifloxysulfuron on almond, citrus, cotton, sugarcane, and tomato commodities. For cotton and sugarcane, trifloxysulfuron-sodium may be applied as a post-emergent over-the-top spray or as a directed spray at a total rate not to exceed 0.019 (cotton) or 0.07 (sugarcane) lb active ingredient (ai)/A per season. For established almond and citrus orchards, applications to the orchard floor may be made pre-emergent and/or post-emergent and may not exceed 0.056 lb ai/A/season. For tomatoes, post-emergent broadcast spray may be used prior to transplant and/or pos t-emergent directed spray following transplant. The total seasonal rate for tomatoes is not to exceed 0.014 lb ai/A. For turf, use is restricted to golf courses only and will not exceed 0.026 lb ai/Aper season. Trifloxysulfuron-sodium is not to be applied aerially or via any type of irrigation system (chemigation).
Trifloxysulfuron-sodium is a sulfonylurea herbicide that is intended to control or suppress a number of weeds including sedges, pigweed s, morning glory, and a variety of grasses. Like other sulfonylurea herbicides, trifloxysulfur on-sodium is highly toxic to susceptible plants and acts by inhibiting acetolactate synthase. This enzyme occurs only in plants. The leaves of susceptible plants typically turn yellow, red, or purple several days after application. Complete plant death occurs 1-3 weeks after application, depending on the species and environmental conditions.
Estimating risks from chemicals involves assessing both the hazard of the chemical by examining its toxicity, and exposure to the chemical by examining residues and various activities (eating, working, playing, etc.). The Health Effects Division (HED) has examined adequate toxicological and residue chemistry data submitte d to support the registration of trifloxysulfuronsodium. In mammals, trifloxysulfuron-sodium wa s shown to adversely affect the kidneys, the urinary bladder, the liver, heart development, body weight gain, motor activity, and lung tissue at relatively high dose levels. HED has used No Observed Adverse Effect Levels as the basis for the hazard component of this risk assessment. No Observed Adverse Effect Levels (NOAELs) are the highest dose levels in toxicological studies that did not cause adverse effects to the test animals. To ensure that risk estimates are protective of human health, HED has applied uncertainty factors to account for variability of toxi city within species and between species to the NOAELs. HED has considered the potential for enhanced sensitivity of infants and children to chemical effects. Developmental studies with rabbits show that infants and children may be more sensitive than adults to the effects of trifloxysulfuron-sodium, and this information has been incorporated into the risk assessment. Despite the noted effects and the potential sensitivity to infants and children, trifloxysulfuron-sodium exhibits relatively low toxicity in mammals. Trifloxysulfuron-sodium is classified as not likely to be carcinogenic to humans.

### 2 of 32 Residue chemistry data are sufficient to assess the potential exposure to trifloxysulfuron from food and drinking water. Because trifloxys ulfuron-sodium is highly toxic to plants, it is applied at very low rates, and high concentrations of this chemical are not expected in foods. The residue chemistry data show that trifloxys ulfuron was typically not detectable in studies designed to maximize the potential for residues of this compound in human foods and livestock feedstuffs. Because appropriate studies with clear NOAELs are used directly in this risk assessment to address the sensitivity of infants and children and the exposure data used in the assessment will not underestimate exposure, the special safety factor mandated by the Food Quality Protection Act of 1996 has been reduced from 10 to 1.
Trifloxysulfuron-sodium may be applied to golf-course turf as well as to agricultural crops; therefore, there is the potential for people to be exposed to this herbicide during golfing as well as through their diet. HED has performed an aggregate assessment that includes exposure from these two pathways. For the dietary exposure, the recreational exposure, and the aggregate exposure, HED is reasonably certain that no adverse human health effects will occur in the U.S. population or in any population subgroup, including those of infants and children, from the requested uses of trifloxysulfuron-sodium.
HED has also assessed the potential risks to workers involved in applying trifloxysulfuron-sodium or working in fields tr eated with the herbicide. Assuming that these workers are wearing minimal protection (e.g., shirt, pants, socks, shoes), the risks associated with exposure to trifloxysulfuron from these activities are minimal and are not cause for concern.
HED has a high degree of confidence in the data submitted to support the registration of trifloxysulfuron-sodium on the commodities addressed by Petition 1F06280. The risk estimates resulting from those data and presented in this assessment are, overall, highly conservative and likely overestimate the actual risks to the U.S. population, its various subgroups, and agricultural workers from the requested uses of this herbicide. Even with this overestimation, these risk estimates are all well below HED’s level of concern. HED recommends that the 75% ai WG formulation of trifloxysulfuron-sodium be gr anted a conditional registration for use on almond, citrus, cotton, sugarcane, and tomato; and that permanent tolerances be established for residues of trifloxysulfuron {N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-(2,2,2- trifluoroethoxy)-2-pyridinesulfonamide} as follows:

Almond . . . . . . . . . . . . . . . . . . . . 0.02 ppm Almond, hulls

................ 0.01 ppm Fruit, citrus, group 10

......... 0.03 ppm Cotton, undelinted seed

........ 0.05 ppm Cotton, gin byproducts . . . . . . . . . 1.0 ppm Sugarcane . . . . . . . . . . . . . . . . . . . 0.01 ppm Tomato . . . . . . . . . . . . . . . . . . . . . 0.01 ppm
Currently, the trifloxysulfuron-sodium database is lacking Agency validation of the analytical method and agreement between the proposed use on cotton and the design of the cotton field

### 3 of 32 trials. Additionally, revised Sections B and F of the petition are needed. A listing of the data gaps associated with Petition 1F06280 can be found in Section 8 of this document.

### 4 of 32 N O CF 3



### S N N H

N N OCH 3



### OCH 3 

### O O O Na + 

### 2.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

TABLE 2.1. Test Compound Nomenclature Compound
Trifloxysulfuron-sodium Chemical Structure

Common name Trifloxysulfuron-sodium Company experimental name CGA-362622 IUPAC name N-[(4,6-dimethoxy-2-pyrimidinyl)car bamoyl]-3-(2,2,2-trifluoroethoxy)-pyridin-2- sulfonamide sodium salt CAS name N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-(2,2,2-trifluoroethoxy)-2- pyridinesulfonamide sodium salt CAS Registry Number 199119-58-9 (sodium sa lt); 290332-10-4 (sodium salt monohydrate); 145099-21-4 (free sulfonylurea) End-use product/EP Trifloxysulfuron 75% a.i., wettable granule formulation Chemical Class Sulfonylurea Known Impurities of Concern None

TABLE 2.2. Physicochemical Properties
Parameter Value Reference Molecular Weight Monosodium salt: 459 Daltons Free acid: 437 Daltons –

Melting point/range 173-175 C MRIDs 45371904 and 45371910 pH 7.85 (saturated solution) MRID 45371905 Density 1.63 g/cm 3 at 21 C MRID 45371905 Water solubility (20 C) 63 mg/L at pH 5.06 5016 mg/L at pH 7.04 23.7 g/L at pH 7.71 38 g/L at pH 7.85 MRIDs 45371904 and 45371910

Solvent solubility (temperature not specified) methanol 39 g/L ethanol 5.6 g/L isopropanol 0.8 g/L acetonitrile 5 g/L acetone 12.4 g/L ethyl acetate 595 mg/L MRIDs 45371904 and 45371910

Vapor pressure (25 C) <1 x 10 -7 Pa MRIDs 45371904 and 45371910TABLE 2.2. Physicochemical Properties
Parameter Value Reference



### 5 of 32 Dissociation constant, pKa 4.76 (acidic) MRID 45371905 Octanol/water partition coefficient, logP OW (25 C) 1.4 at pH 5.0 -0.42 at pH 7.0 -1.6 at pH 9.1 MRIDs 45371904 and 45371910

UV/visible absorption spectrum not provided —


### Trifloxysulfuron-sodium is relatively soluble in water at neutral pH, but is significantly less soluble under acidic conditions, as would be expected given the compound’s pKa value of 4.76 (Table 2.2). Data were not provided regarding solubility in basic solutions; however, based on the properties summarized in Table 2.2, solubility under basic conditions is expected to be similar to that in neutral aqueous media. This herbicide has a low vapor pressure at 25 / 

### C and dissipation via volatilization is not expected under normal conditions.

3.0 HAZARD CHARACTERIZATION (HIARC Report, TXR No. 0052043, 7/22/03)



### 3.1 Hazard Profile
The toxicology data base is adequate to support the requested registrations and tolerancesfor trifloxysulfuron-sodium and there is high confidence in the hazard endpoints and doseresponse assessments conducted for this chemical. Technical grade trifloxysulfuron-sodium (CGA 362622) has minimal acute toxicity (Toxicity Category III or IV) and was a non-sensitizer in dermal sensitization studies.
In subchronic and chronic feeding studies in mice, rats, and dogs, trifloxysulfuronsodium generally caused decreased body weights and body weight gains, often accompanied by decreased food consumption. Decreased body weights, body weight gains and food consumption were observed in female mice at the highest dose tested in an 18-month carcinogenicity study. No other treatment-related effects were observed in male or female mice at the highest dose tested in this study or in a 3-month feeding study. In a 2-year combined chronic toxicity/carcinogenicity study in rats, the most sensitive treatment-related effect was tubular atrophy in the kidneys of females, which developed in the second year of the study. In the same study at higher doses, Leydig cell hyperplasia of the testes also developed in the second year in males. In 3-month and/or 28-day subc hronic oral studies in rats, the following effects were also noted: decreased thymus weight and slight hypertrophy of thyroid follicular epithelium in males and slight histopathology in the liver in females (single cell necrosis, focal necrosis, inflammation and hepatocellular hypertrophy). In a 28-day dermal study in rats, the only treatment-related effect was decreased body weight gain in females at the limit dose of 1000 mg/kg/day. No effects were observed in males and no dermal irritation was noted in males or females.
In a 1-year chronic toxicity study in dogs, the following treatment-related effects were observed at the highest dose tested: decreased body weight gain and histopathology in the lungs

### 6 of 32 of males (gray-white foci and fibrous thickening of the pleura) and increased incidence and severity of chronic inflammation in the urinary bladder of females. In 3-month and/or 28-day subchronic oral studies in dogs, the following e ffects were generally noted in both males and females: increased mortality (at high doses), clinical signs of toxicity (in moribund dogs), clinical chemistry changes (suggesting liver toxic ity), liver toxicity (histopathological findings, increased glycogen, increased liver weights), signs of anemia (slight hematological changes with secondary effects in liver, spleen and bone marrow), and histopathological findings in lungs, kidney, thyroid, spleen, thymus and testes.
In the developmental toxicity study in rats at the limit dose, there was a decrease inmaternal food consumption during treatment and a decrease in body weight gain during posttreatment . At the same dose, the offspring had a slight decrease in fetal body weights, an increase in minimal skeletal findings and an increase in poor/absent skeletal ossification. In the developmental toxicity study in rabbits, the NOAEL for maternal toxicity was 100 mg/kg/day. At a the same dose of 100 mg/kg/day, one fetus had an abnormally shaped heart and at 250 mg/kg/day, three fetuses from two litters had this finding. Historical control data from the registrant did not describe any fetuses with this observation. In the 2-generation reproduction study in rats, decreases in body weights, body wei ght gains and food consumption were observed in the parental animals. At the same dose, the offspring showed decreases in body weight and body weight gain, decreases in spleen and thymus weights and an increase in vaginal patency. There was no effect on reproduction. There was no evidence of increased quantitative or qualitative susceptibility in the developmental toxicity study in rats or in the 2-generation reproduction study in rats. In the developmental toxicity study in rabbits, there was an increase in quantitative susceptibility based upon the presence of abnormally shaped heart in one fetus at 100 mg/kg/day. Three additional fetuses from two litters at 250 mg/kg/day also had abnormally shaped hearts. The degree of concern for this finding was low beause there was a clear NOAEL for this effect, only 1 fetus had the effect at the LOAEL, and the effect was used as a toxicological endpoint in appropriate risk asse ssments. There are no residual uncertainties for pre-natal and/or post-natal toxicity.
In two acute neurotoxicity studies in rats, decreased motor activity was observed at the limit dose of 2000 mg/kg (only dose tested) in males and females on day 1 in the first study and only in females in the second study. A NOAEL of 600 mg/kg was established for this effect in females. Microscopic examination revealed lesions in the nervous system of 2 males and 1 female at the dose of 2000 mg/kg in the first study. Microscopic examination of nervous system tissues was not performed in the second study. In a subchronic neurotoxicity study in rats, no neurologic effects were observed in either the ma les or females. In a 90-day feeding study and in a 28-day feeding study in dogs, clinical signs of toxicity (including neurotoxic signs) were observed at high doses, but only in moribund dogs th at subsequently died or were sacrificed in extremis . In none of the other toxicity studies on trifloxysulfuron-sodium was there any evidence of treatment-related neurotoxicity. Overall, there is not a concern for neurotoxicity resulting from exposure to trifloxysulfuron-sodi um and a developmental neurotoxicity study in rats is not required.

### 7 of 32 In carcinogenicity studies in male and female rats and in male and female mice, trifloxysulfuron-sodium did not demonstrat e any biologically significant evidence of carcinogenic potential. Trifloxysulfuron-sodium is classified as “not likely to be carcinogenic to humans” according to the July 2, 1999 EPA Draft Proposed Guidelines for Carcinogen Risk Assessment

. Technical grade trifloxysulfuron-sodium di d not demonstrate any mutagenic potential in a battery of 5 mutagenicity studies. There is not a concern for mutagenicity resulting from exposure to trifloxysulfuron-sodium. Results were negative without and with rat S-9 activation in a reverse gene mutation study using Salmonella typhimurium/Escherichia coliand in a forward gene mutation study using CHO cells at the HGPRT locus. In an in vitro chromosomal aberration study in CHO cells, trifloxysulfuron-s odium was negative when tested without and with rat S-9 activation. In an in vivo micronucleus study in mice using bone marrow cells, the results were negative and in an in vitro unscheduled DNA synthesis assay in primary rat hepatocyte cultures, results also were negative.
In metabolism studies in rats, trifloxysulfuron-sodium was rapidly and nearly completely absorbed and excreted within 48 hours. Urinary excretion was the primary route of elimination. Females excreted more of the administered dose (AD) in the urine than did males. There was no evidence for an enterohepatic circulation. Less than 0.30% of the AD remained in the tissues after 168 hours. Unchanged parent was eliminated almost entirely in the urine. Females excreted more unchanged parent in the urine than did males. With the exception of unchanged parent, the metabolite profile was similar between urine and feces. The primary metabolites in both urine and feces in all treated groups were Metabolites J (desmethyl parent) and K (5'- hydroxypyrimidine of parent). Other major metabolites included Metabolites F (formed from hydroxylation of the parent at the 5' position), X and N (glucuronide conjugates of F), A and D (additional desmethyl moieties). Several minor metabolites were also identified.

Table 3.1. Acute Toxicity Profile - Trifloxysulfuron-sodium

Test Material GDLN Study Type MRID Results Tox Category

Technical 870.1100 Acute Oral - rat 45371922 LD 50> 5000 mg/kg IV
Technical 870.1100 Acute Oral - mouse 45371923 LD 50> 5000 mg/kg IV
Technical 870.1200 Acute Dermal - rat 45371925 LD 50> 2000 mg/kg III
Technical 870.1300 Acute Inhalation 45371927 LC 50(M & F): > 5.03 mg/L IV Technical 870.2400 Primary Eye Irritation 45371929 Moderate irritation to the eye III Technical 870.2500 Primary Dermal Irritation 45371931 Mild irritation to the skin IV

Technical 870.2600 Dermal Sensitization (Buehler) 45371933 Negative N/A

Technical 870.2600 Dermal Sensitization (Maximization) 45371934 Negative N/A

### 8 of 32 Table 3.2. Toxicity Profile of Trifloxysulfu ron-sodium Technical Grade Active Ingredient.
Guideline No. Study Type Results

870.3100 90-Day oral toxicity rodents (rats) NOAEL : 507/549 mg/kg/day (M/F) LOAEL : 1052/1128 mg/kg/day (M/F): M = decreased body weight, decreased body weight gain, equivocal increased testicular atrophy at end of recovery phase; F = decreased body weight, decreased body weight gain, equivocal slightly increased histopathology in liver (single cell necrosis, focal necrosis, inflammation, hepatocellular hypertrophy). 870.3100 90-Day oral toxicity rodents (mice) NOAEL : 1023/1507 mg/kg/day (M/F) LOAEL : >1023/>1507 mg/kg/day (M/F): M = not attained; F = not attained 870.3150 90-Day oral toxicity in nonrodents (dogs) NOAEL :19.8/19.6 mg/kg/day (M/F) LOAEL : 164.2/167.3 mg/kg/day (M/F): M = decreased body weight gain (20%), slight hematological e ffects, clinical chemistry changes suggesting hepatotoxicity, decreased thymus weight, thymic atrophy, increased glycogen in liver, hemorrhage in mesenteric lymph nodes; F = decreased body weight gain (44%), anemia with extramedullary hematopoiesis in liver/spleen and myeloid hyperplasia in bone marrow, clinical chemistry changes suggesting hepatotoxicity, decrease thymus weight, thymic atrophy and hyaline tubular change in kidney. 870.3200 21/28-Day dermal toxicity (rats) NOAEL : 1000/100 mg/kg/day (M/F) LOAEL : >1000/1000 mg/kg/day(M/F): M = not attained; F = decreased body weight gain. No dermal irritation M/F. 870.3700 Prenatal developmental in rodents (rats) Maternal NOAEL : 300 mg/kg/day Maternal LOAEL : 1000 mg/kg/day based on decreased foodconsumption during treatment, decreased body weight gain during posttreatment. Developmental NOAEL : 300 mg/kg/day Developmental LOAEL : 1000 mg/kg/day based on slight decrease in fetal weight, increased skeletal anomalies, increased poor/absent skeletal ossification. 870.3700 Prenatal developmental in nonrodents (rabbit) Maternal NOAEL : 100 mg/kg/day Maternal LOAEL : 250 mg/kg/day based on increased mortality, increased vaginal/anal bleeding. Developmental NOAEL : 50 mg/kg/day Developmental LOAEL : 100 mg/kg/day based on abnormally shaped heart (one fetus at 100 mg/kg/day and 3 fetuses from 2 litters at 250 mg/kg/day). 870.3800 Reproduction and fertility effects (rat) Parental systemic NOAEL :78.8/83.5 mg/kg/day (M/F) Parental systemic LOAEL :631/676 mg/kg/day (M/F) based on decreased body weight and gain as well as decreased food consumption. Offspring systemic NOAEL :78.8/83.5 mg/kg/day (M/F) Offspring systemic LOAEL : 631/676 mg/kg/day (M/F):decreased pup weight and weight gain, decreased spleen weight, thymus weight and increased vaginal patency. Reproductive NOAEL :968/1030 mg/kg/day (M/F) Reproductive LOAEL :>968/1030 (M/F) 870.4100a Chronic toxicity rodents (rat) See 870.4300
870.4100 Chronic toxicity dogs NOAEL : 51.1/45.3 mg/kg/day (M/F) LOAEL : 123/121 mg/kg/day (M/F): M = gray-white foci in lungs,Table 3.2. Toxicity Profile of Trifloxysulfu ron-sodium Technical Grade Active Ingredient.
Guideline No. Study Type Results



### 9 of 32 fibrous thickening of lung pleura, equivocal decreased body weight gain; F = equivocal increased incidence and severity of chronic urinary bladder inflammation. 870.4200 Carcinogenicity rats See 870.4300 870.4200 Carcinogenicity mice NOAEL :854/112 mg/kg/day (M/F) LOAEL :>854/818 mg/kg/day (M/F): M = not determined; F = decreased body weight, body weight gain and food consumption. Negative for carcinogenicity in M and F. 870.4300 Chronic feeding/Carcinogenicity rats NOAEL : 82.6/23.7 mg/kg/day (M/F) LOAEL : 429/99.3 mg/kg/day (M/F): M = decreased body weight and gains, decreased food consumption and increased Leydig cell hyperplasia in testes; F = increased tubular atrophy in kidneys. At 500 mg/kg/day decreased body weight, body weight gain, food consumption and increased tubular atrophy in kidneys. Negative for carcinogenicity in M and F. 870.5100 Gene Mutation bacterial reverse mutation assay (S. typhimurium/E. coli) Negative without and with S-9 activation.

870.5300 In vitro mammalian cell forward gene mutation assay (CHO cells/HGPRT locus) Negative without and with S-9 activation.

870.5375 In vitro mammalian cytogenetics assay in CHO cells Negative without and with S-9 activation.

870.5395 Cytogenetics - mammalian erythrocyte micronucleus test in the

mouse Negative at single oral doses up to 5000 mg/kg.

870.5500 In vitro unscheduled DNA synthesis (primary rat hepatocytes) Negative response up to 250 μg/mL. Cytotoxicity at $ 15.63 μg/mL.

870.6200 Acute neurotoxicity screening battery (rat) NOAEL :<2000 mg/kg/day (M/F) LOAEL : 2000 mg/kg/day (M/F): M&F = decreased motor activity on day 1, histopathological lesions in nervous system tissues. 870.6200 Acute neurotoxicity screening battery (rat) NOAEL : 2000/600 mg/kg/day (M/F) LOAEL : > 2000/2000 mg/kg/day (M/F): M = not attained; F = decreased motor activity on day 1 870.6200 Subchronic neurotoxicity screening battery (rat) NOAEL :112/553 mg/kg/day (M/F) LOAEL :472/1128 mg/kg/day (M/F): M = decreased body weight, body weight gain and food consumption.; F = decreased body weight. 870.6300 Developmental neurotoxicity (rat) No study performed.

870.7485 Metabolism and pharmacokinetics (rat) Rapidly absorbed and exceted. Most (>87%) of the administered dose (AD) was excreted within 24 hours. After 7 days, very little ( # 0.3% of AD) remained in the tissues. Urine was the primary route of excretion in males (50-61% of AD) and in females (70-80% of AD). Unchanged parent in males (11-20% of AD) a nd in females (37-47% of AD) was excreted almost entirely in the urine and only trace amounts were found in the feces. With the exception of the parent, the metabolite profile was similar between the urine and feces. The 2 primary metabolites in bothTable 3.2. Toxicity Profile of Trifloxysulfu ron-sodium Technical Grade Active Ingredient.
Guideline No. Study Type Results



### 10 of 32 urine and feces were Metabolite J (desmethyl parent, up to 26% of AD) and Metabolite K (5'hydroxy-pyrimidine of parent, up to 19% of AD). Other metabolites were Metabolites X, N, F, A and D, each up to 8.2% of the AD in males and up to 4.7% of the AD in females. Several minor metabolites were also identified as Metabolite Q, Metabolite P, guanidine, CGA-382997 and CGA-368732 (each # 4.4% of the AD). 870.7485 Biliary Metabolism (rat) In bile duct cannulated rats, absorption was 84-88% of the Administered Dose (AD) at 48 hours. Nearly all of the AD was excreted within 48 hours. Excretion in urine ranged from 58-76%, in bile from 5-27%, and in feces was about 6% of the AD. There was no evidence for an enterohepatic circulation. Biotransformation was similar to that in the conventional rat metabolism study. The metabolite profiles in urine, bile fluid and feces were all similar. 870.7600 Dermal Penetration (rat) No study performed.


### 3.2 FQPA Considerations
The HIARC met on July 1, 2003 to evaluate the potential for increased susceptibility of infants and children resulting from exposure to trifloxysulfuron-sodium according to the February 2002 OPP 10X Guidance Document. Th e HIARC concluded that the toxicological data base for trifloxysulfuron-sodium is complete for FQPA purposes. A complete complement of acceptable developmental, reproduction and mammalian neurotoxicity studies is available. Based on an evaluation of the hazard data, the HIARC indicated that the Special FQPA Safety Factor may be reduced to 1x. The Trifloxysulfuron-sodium Risk Assessment Team subsequentlyevaluated the quality and completeness of the exposure data, and, based on a weight-of-theevidence consideration of all the available data, recommended that the Special FQPA Safety Factor be reduced to 1x. This recommendation was based on the following:

C 

### The toxicological data base is complete for FQPA assessment.

C 

### There was no evidence of increased quantitative or qualitative susceptibility in the developmental toxicity study in rats. At the limit dose, maternal effects were decreased food consumption during treatment and decreased body weight gain during post-treatment. The only fetal findings noted at the limit dose were a slight decrease in fetal body weights, an increase in minimal skeletal findings and poor/absent skeletal ossification.

C 

### There was evidence of increased quantitative susceptibility in the developmental toxicity study in rabbits. The maternal NOAEL was 100 mg/kg/day based on increased mortality and increased vaginal/anal bleeding at the LOAEL of 250 mg/kg/day. The developmental NOAEL was 50 mg/kg/day based on an increased incidence of abnormally shaped hearts at the LOAEL of 100 mg/kg/day (one fetus at 100 mg/kg/day). Three additional fetuses from two litters at 250 mg/kg/day also had abnormally shaped hearts. In historical control data provided by the registrant, there were no reported instances of abnormally shaped hearts. The degree of concern is low for the quantitative evidence of susceptibility seen in the

### 11 of 32 rabbit developmental study because there was a clear NOAEL for this effect, only one fetus had the effect at the LOAEL, and the effect was used as a toxicological endpoint in appropriate risk assessments.

C 

### There was no evidence of increased quantitative or qualitative susceptibility in the 2-generation reproduction study in rats.

C 

### There are no residual uncertainties for pre-natal and/or post-natal toxicity.

C 

### A developmental neurotoxicity study in rats is not required.

C 

### The acute and chronic dietary food exposure assessments assumed tolerance level residue data and 100% crop treated. The acute and chronic risk assessments will not underestimate exposure or risk since the exposures are based on reliable data derived from studies designed to produce worst-case residues.

C 

### The dietary drinking water assessment used concentration values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high-end estimates of water concentrations which will not likely be exceeded. Furthermore, HED assumed that non-parent residues of concern occur at the highest levels observed in the environmental fate studies. This assumption results in overestimated levels of the total residues of concern since it assumes that all of the compounds occur simultaneously, ignoring the kinetics of their formation and dissipation.

C 

### The recreational exposure assessment will not underestimate postapplication exposure to golfers resulting from the use of trifloxysulfuron-sodium on golf course turf.
3.3 Dose-Response Assessment
For acute dietary exposure for females ( 13-49 years), the toxicology endpoint was selected from the developmental toxicity study in rabbits in which the developmental NOAEL was 50 mg/kg/day and the developmental LOAEL was 100 mg/kg/day based on an increased incidence of abnormally shaped hearts in fetuses. A conventional Uncertainty Factor (UF) of 100x (10x for interspecies extrapolation and 10x for intraspecies variation) was applied to the NOAEL to determine the aRfD of 0.5 mg/kg. Appli cation of the Special FQPA Safety Factor of 1 to the aRfD resulted in an aPAD of 0.5 mg/kg. The abnormally shaped hearts observed in this study are considered to possibly have been induced by a single dose of test material. Since these anomalies were observed in fetuses, this endpoint is applicable only to the population subgroup females (13-49 years).
For acute dietary exposure for the general population, the toxicology endpoint was selected from two acute neurotoxicity studies in rats in which the NOAEL was determined to be 600 mg/kg and the LOAEL to be 2000 mg/kg based on decreased motor activity on Day 1. This NOAEL of 600 mg/kg is considered to also be protective of the histopathological lesions described in nervous system tissues of males and females in one of these studies at the LOAEL of 2000 mg/kg. A conventional UF of 100x was applied to the NOAEL to determine the aRfD of 6.0 mg/kg. Application of the Special FQPA Sa fety Factor of 1 to the aRfD resulted in an aPAD of 6.0 mg/kg. The decreased motor activity and histopathological lesions observed in this study were induced by a single dose of test material.

### 12 of 32 For chronic dietary exposure for all population subgroups, the toxicology endpoint was selected from a combined chronic toxicity/ carcinogenicity study in rats in which the NOAEL was 23.7 mg/kg/day and the LOAEL was 99.3 mg/kg/day based on increased tubular atrophy in the kidneys of females. A conventional UF of 100x was applied to the NOAEL to determine the cRfD of 0.237 mg/kg/day. Application of the Sp ecial FQPA Safety Factor of 1 to the cRfD resulted in a cPAD of 0.237 mg/kg/day.
For short-term (1-30 days) incidental oral exposures, the toxicology endpoint was selected from the 2-generation reproduction study in rats in which the offspring NOAEL was 79 mg/kg/day and the offspring LOAEL was 631 mg/kg/day based on decreased body weights on day 21. For short-term incidental oral exposures, the Margin of Exposure (MOE) is 100. For intermediate-term (1-6 months) incidental oral exposures, the toxicology endpoint was selected from the 1-year chronic feeding study in dogs in which the NOAEL was 45 mg/kg/day and the LOAEL was 121 mg/kg/day based on decreased body weight gain and histopathology in the lungs of males and on chronic bladder inflammation in females. The NOAEL of 19.6 mg/kg/day from the subchronic 90-day feeding study in dogs was not used for intermediate-term oral, dermal, or inhalation exposures because it is approximately 8-fold lower than the LOAEL of 164 mg/kg/day in this study and is considered to be unrealistically low since a NOAEL of 45 mg/kg/day was determined in the longer-term 1-year chronic feeding study in dogs. For intermediate-term incidental oral exposures, the Margin of Exposure (MOE) is 100.
For short-term (1-30 days) dermal exposures, the toxicology endpoint was selected from a 28-day dermal toxicity study in rats in which the systemic NOAEL was 100 mg/kg/day and the systemic LOAEL was 1000 mg/kg/day based on decreased body weight gain in females. For short-term inhalation exposures, the toxicology endpoint was selected from the developmental toxicity study in rabbits in which the developmental NOAEL was 50 mg/kg/day and the developmental LOAEL was 100 mg/kg/day based on an increased incidence of abnormally shaped hearts in fetuses. For short-term dermal and inhalation exposures, the target MOE is the conventional 100. For intermediate-term (1-6 months) dermal and inhalation exposures, the toxicology endpoint was selected from the 1-y ear chronic feeding study in dogs in which the NOAEL was 45 mg/kg/day and the LOAEL was 121 mg/kg/day based on decreased body weight gain and histopathology in the lungs of males and on chronic bladder inflammation in females. For intermediate-term dermal and inhalation exposures, the target MOE is 100. For long-term (>6 months) dermal and inhalation exposures, th e toxicology endpoint was selected from the combined chronic toxicity/carcinogenicity study in rats in which the NOAEL was 23.7 mg/kg/day and the LOAEL was 99.3 mg/kg/day based on increased tubular atrophy in the kidneys of females. For long-term dermal and inhalation exposures, the target MOE is 100. For the intermediate- and long-term dermal exposures, a 30% dermal absorption factor was used since the toxicology endpoints for both exposures we re selected from oral studies. The dermal absorption factor of 30% was determined based on the high molecular weight of trifloxysulfuron-sodium, its ionic properties,its solubility characteristics in water and other solvents, and on the dermal absorption factors of other, closely related sulfonylurea herbicides [triflusulfuron-methyl, 27% (HIARC Report, 12/5/2001, TXR No. 0050332); and primisulfuronmethyl, 30% (HIARC Report, 4/26/2002, TXR No. 0050694)]. For intermediate-term dermal exposures, application of the 30% dermal absorption factor to the oral dose of 45 mg/kg/day

### 13 of 32 from the 1-year chronic feeding study in dogs results in an equivalent dermal dose of 150 mg/kg/day, which is higher than the dermal dose of 100 mg/kg/day used for the short-term dermal exposure. This difference, however, wa s determined to be of no practical significance when performing risk assessments for either exposure scenario, and the discrepancy will not be resolved at this time. For all the inhalation exposures, a 100% inhalation absorption factor (default value) was used since the toxicology endpoints for all exposures were selected from oral studies.
Trifloxysulfuron-sodium is classified as “not likely to be carcinogenic to humans” according to the July 2, 1999 EPA Draft Proposed Guidelines for Carcinogen Risk Assessment

. The HIARC recommended that when calculating aggregate exposures and risks, the oral and dermal routes could be combined since the toxicological effects are the same.

Table 3.3. Summary of Toxicological Doses and Endpoints for Trifloxysulfuron-sodium for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for

Risk Assessment Study and Toxicological Effects

Acute Dietary (females 13-49) Developmental NOAEL = 50 mg/kg/day UF = 100

Acute RfD =0.5 mg/kg FQPA SF = 1 aPAD = acute RfD FQPA SF
= 0.5 mg/kg Developmental Toxicity Study in Rabbits. Developmental LOAEL = 100 mg/kg/day based on increased incidence of abnormal shaped hearts in fetuses.

Acute Dietary (general population) NOAEL = 600 mg/kg UF = 100

Acute RfD =6.0 mg/kg FQPA SF = 1 aPAD = acute RfD FQPA SF
= 6.0 mg/kg Acute Neurotoxicity Studies in Rats. LOAEL = 2000 mg/kg based on decreased motor activity on day 1 and histopathological lesions in nervous system tissues of males and females.

Chronic Dietary (all populations) NOAEL= 23.7 mg/kg/day UF = 100

Chronic RfD = 0.237 mg/kg/day FQPA SF = 1 cPAD = chronic RfD FQPA SF
= 0.237 mg/kg/day Combined Chronic Toxicity/ Carcinogenicity Study in Rats. LOAEL = 99.3 mg/kg/day based on increased tubular atrophy in the kidneys of females (developing after 12 months).
Incidental Oral Short-Term (1 - 30 days) Offspring NOAEL = 78.8/83.5 (M/F) mg/kg/day ResidentialLOC for MOE = 100
Occupational= NA 2-Generation Reproduction Study in Rats. Offspring LOAEL = 631/676 (M/F) mg/kg/day based on decreased pup body weights on day 21.
Incidental Oral Intermediate-Term (1 - 6 months) NOAEL = 51.1/45.3 (M/F) mg/kg/day ResidentialLOC for MOE = 100
Occupational= NA 1-Year Chronic Feeding Study in Dogs. LOAEL = 123/121 (M/F) mg/kg/day based on decreased body weight gain and histopathology in lungs in males and chronic urinary bladder inflammation in females.Table 3.3. Summary of Toxicological Doses and Endpoints for Trifloxysulfuron-sodium for Use in Human Risk Assessments Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for

Risk Assessment Study and Toxicological Effects



### 14 of 32 Dermal Short-Term (1 - 30 days) Dermal study Systemic NOAEL= 100 mg/kg/day ResidentialLOC for MOE = 100
Occupational LOC for MOE = 100 28-Day Dermal Toxicity Study in Rats. Systemic LOAEL = 1000 mg/kg/day based on decreased body weight gain in females. We note that the short-term dermal NOAEL is lower than the “equivalent” NOAEL chosen for intermediate-term dermal assessments; however, the endpoint will not be revised at this time.
Dermal Intermediate-Term (1 - 6 months) Oral study NOAEL= 51.1/45.3 (M/F) mg/kg/day (dermal absorption factor = 30%) ResidentialLOC for MOE = 100
Occupational LOC for MOE = 100 1 Year Chronic Feeding Study in Dogs. LOAEL = 123/121 (M/F) mg/kg/day based on decreased body weight gain and histopathology in lungs in males and chronic urinary bladder inflammation in females.
Dermal Long-Term (> 6 months) Oral study NOAEL= 23.7 mg/kg/day (dermal absorption factor = 30%) ResidentialLOC for MOE = 100
Occupational LOC for MOE = 100 Combined Chronic Toxicity/ Carcinogenicity Study in Rats. LOAEL = 99.3 mg/kg/day based on increased tubular atrophy in the kidneys of females (developing after 12 months).
Inhalation Short-Term (1 - 30 days) Oral study NOAEL= 50 mg/kg/day (inhalation absorption factor = 100%) ResidentialLOC for MOE = 100
Occupational LOC for MOE = 100 Developmental Toxicity Study in Rabbits. LOAEL = 100 mg/kg/day based on increased incidence of abnormal shaped hearts in fetuses.

Inhalation Intermediate-Term (1 - 6 months) Oral study NOAEL= 51.1/45.3 (M/F) mg/kg/day (inhalation absorption factor = 100%) ResidentialLOC for MOE = 100
Occupational LOC for MOE = 100 1-Year Chronic Feeding Study in Dogs. LOAEL = 123/121 (M/F) mg/kg/day based on decreased body weight gain and histopathology in lungs in males and chronic urinary bladder inflammation in females.
Inhalation Long-Term (> 6 months) Oral study NOAEL= 23.7 mg/kg/day (inhalation absorption factor = 100%) ResidentialLOC for MOE = 100
Occupational LOC for MOE = 100 Combined Chronic Toxicity/ Carcinogenicity Study in Rats. LOAEL = 99.3 mg/kg/day based on increased tubular atrophy in the kidneys of females (developing after 12 months). Cancer (oral, dermal, inhalation) Classification: Not Likely to be carcinogenic to humans

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable


### 3.4 Endocrine Disruption

### 15 of 32 EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). In the available t oxicity studies on trifloxysulfuron-sodium, there was no toxicologically significant evidence of e ndocrine disruptor effects. When additional appropriate screening and/or testing protocol s being considered under the Agency’s EDSP have been developed, trifloxysulfuron-sodium may be s ubjected to further screening and/or testing to better characterize effects related to endocrine disruption.

4.0 EXPOSURE ASSESSMENT
4.1 Summary of Proposed Uses
Trifloxysulfuron-sodium is a low-application-rate herbicide belonging to the sulfonylurea class of chemicals. Like other herbicides in th is class, trifloxysulfuron-sodium acts by inhibiting the plant enzyme acetolactate synthase, resulting in reduced production of branched-chain amino acids. The leaves of susceptible plants typically turn yellow, red, or purple several days after application. Complete plant death occurs 1-3 weeks after application, depending on the species and environmental conditions. Trifloxysulfuron- sodium is being proposed for use on almonds, citrus, cotton, sugarcane, tomatoes, and turf. In conjunction with the subject tolerance petition, Syngenta has submitted an application for Section 3 registration of a 75% water-dispersible granule (WG) formulation (Trifloxysulfuron- Sodium 75WG Herbicide; EPA File Symbol 100-RRGE) for postemergence use, by ground equipment only, on almonds, citrus, cotton (picker varieties only), sugarcane, and tomatoes (transplanted tomatoes in FL only). The 75% WG formulation is to be applied at maximum seasonal rates ranging from 0.014 lb ai/A for tomatoes to 0.080 lb ai/A for turf. Pre-harvest intervals on the proposed labels range from 3 days for almond to 100 days for sugarcane. Rotational crop restrictions range from 2 months to 12 months, depending on the target crop and the rotational crop. These restrictions appear to be based on phytotoxicity, rather than residue chemistry, concerns. More details regarding the proposed uses are presented in Table 4.1.

### 16 of 32 Table 4.1. Summary of Directions for Use of Trifloxysulfuron-Sodium (75% WG formulation, EPA File Symbol 100-RRGE)

. Applic. Timing, Type, and Equip. Applic. Rate (lb ai/A) Max. No. Applic. per

Season Max. Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and Limitations

Almond Postemergence Directed to soil Ground Equip. 0.019 3 0.056 3 For use as a tank mix with glyphosate formulations registered for use on almonds. The minimum retreatment interval is 30 days. Application to newly established groves (<2 years old) is prohibited. Citrus Postemergence Directed to soil Ground Equip. 0.019 3 0.056 14 For use as a tank mix with glyphosate formulations registered for use on citrus. The minimum retreatment interval is 30 days. Application to newly established groves (<2 years old) is prohibited. Cotton (picker varieties only) Early postemergence Over-the-top (minimum of 5 true leaves) Ground Equip. 0.005- 0.007 Not specified

(NS) 0.019 60 Use limited to AL, AR, FL, GA, LA, MS, NC, SC, TN, VA, the boot heel area of MO and portions of OK and TX, excluding the high plains region of West TX and OK. Tank mixing with any other herbicides or additives (other than surfactant) or with insecticides containing malathion, profenofos, or emamectin benzoate is prohibited. Postemergence ( $ 8 inches in height to layby) Directed spray Ground Equip. 0.007- 0.012 NS 0.019 60 Use limited to AL, AR, AZ, CA, FL, GA, LA, MS, NC, SC, TN, VA, the boot heel area of MO and portions of OK and TX, excluding the high plains region of West TX and OK. The minimum retreatment interval is 14 days. Applications are to be directed to minimize contact with cotton leaves. Applications may be made alone or as a tank mix with glyphosate (to Roundup Ready® cotton varieties only), Caparol® (prometryn), Dual Magnum® (metolachlor), MSMA, Staple® (pyrithiobac-sodium), Cotoran® (fluometuron), or Buctril® (bromoxynil, BXN cotton varieties only). Tank mixing with insecticides containing malathion, profenofos, or emamectin benzoate is prohibited. Sugarcane Early postemergence (up to 24" tall) Over-the-top Ground Equip. 0.014 3 0.070 100 Use limited to FL, LA, and TX on ratoon sugarcane only. The minimum retreatment interval is 14 days. Applications may be made alone or as a tank mix with atrazine or asulam.Table 4.1. Summary of Directions for Use of Trifloxysulfuron-Sodium (75% WG formulation, EPA File Symbol 100-RRGE)

. Applic. Timing, Type, and Equip. Applic. Rate (lb ai/A) Max. No. Applic. per

Season Max. Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and Limitations



### 17 of 32 Postemergence (18" tall up to layby) Directed spray Ground Equip. 0.014- 0.028 3 0.070 100 Use limited to FL, LA, and TX on plant or ratoon sugarcane. The minimum retreatment interval is 14 days. Applications may be made alone or as a tank mix with atrazine or asulam. Tomato (transplanted tomatoes in FL only)Preemergence (pretransplant) Ground 0.007 1(+ 1 postemergence) 0.014 45 Use limited to FL. Mechanical incorporation of product into the soil is to be avoided. Postemergence Over-the-top or directed Ground Equip. 0.007- 0.014 1(+1 preemergence) 0.014 45 Use limited to FL. Application is to be made prior to fruit set.

Turf Postemergence Broadcast Ground Equip. 0.005 - 0.026 Not specified; 3

implied 0.080 N/A 12-month rotational restriction to anything other than turf grasses. Via communication with the petitioner, turf uses are to be restricted to golf courses only.



### 4.2 Dietary Exposure/Risk Pathway

4.2.1 Residue Profile (M. Doherty, D284480, 8/25/03; MARC Report, TXR No. 0052100, 8/25/03)


### The nature of the residues in plants and animals is adequately understood; the terminal residue of concern in plants and animals is trifloxysulfuron. In water, residues of concerninclude trifloxysulfuron as well as the metabolites CGA-053052, CGA-382997, and CGA368732 (see Section 4.3 for more details). Trifloxysulfuron-sodium was found to be extensively metabolized in plants. The leaves/foliage of pl ants were found to have the highest residues, with very low residues in the edible portions of th e crops. Trifloxysulfuron-sodium was found to be less extensively metabolized in livestock, although similar metabolites were found.
The available analytical methodology is tentatively considered to be adequate for tolerance enforcement, pending completion of a successful tolerance method validation (TMV). The limit of quantitation (LOQ) is 0.01 ppm for each plant substrate. Multiresidue methods currently in use by the FDA are not successful at extracting or quantitating residues of trifloxysulfuron-sodium.
Adequate field trial data are available for sugarcane, citrus, almond, and tomato. In samples from all of these trials, residues of trifloxysulfuron were < 0.01 ppm. HED notes that

### 18 of 32 the sugarcane residue data are not supported by adequate storage stability data ( # 

### 21-month storage of field trial sample vs. 9-month storage stability data). However, in the sugarcane metabolism study, which was conducted at 10 times the maximum proposed application rate, total radioactive residues (TRR) were <0.001 ppm in mature sugarcane. Therefore, further storage stability data for sugarcane will not be required. Apparent residues of trifloxysulfuron were found in some control samples of almond, citrus, and sugarcane at levels in excess of 20% of the LOQ. Therefore, HED is recommending that the proposed tolerances be raised to levels above the LOQ for those commodities (see below). Cotton field trial data were submitted from studies conducted at three times the maximum proposed use rate on cotton. Under those conditions, quantifiable residues were found in 2 out of 38 samples of cottonseed (0.039 ppm max.) and in 7 out of 12 samples of cotton gin byproducts (0.090 ppm max.). These data are acceptable for a conditional registration.
Processing studies were submitted for cotton, orange, and sugarcane and showed no concentration of trifloxysulfuron in any processed commodities derived from these raw agricultural commodities (RACs). A tomato processing study is not required for this herbicide based on field trials conducted at a 5X exaggerated rate that showed nonquantifiable residues of trifloxysulfuron in tomato.
Based on the results of the livestock metabolism studies and on the anticipated dietary burdens to livestock, there is no expectation of finite residues of trifloxysulfuron in livestock matrices [i.e., 40 CFR 180.6(a)(3)]. Livestock feeding studies have not been submitted for trifloxysulfuron and none are required at this time.
Confined rotational crop and field rotational crop studies showed residues of trifloxysulfuron to be < 0.01 ppm in all matrices. There is a storage stability data gap associated with the field rotational crop data; however, since the confined rotational crop study does not indicate the need for a field study, supporting stor age stability data are not required. The label lists a number of rotational crop restrictions which are, presumably, in place due to phytotoxicity

concerns. At present, there are no Canadian, Mexical, or Codex maximum residue limits (MRLs) and international harmonization is not an issue with the proposed uses.
Based on the available data, HED is recommending that the following permanent tolerances be established for residues of trifloxysulfuron in/on:

Almond . . . . . . . . . . . . . . . . . . . . 0.02 ppm Almond, hulls

................ 0.01 ppm Fruit, citrus, group 10

......... 0.03 ppm Cotton, undelinted seed

........ 0.05 ppm Cotton, gin by-products . . . . . . . . 1.0 ppm Sugarcane . . . . . . . . . . . . . . . . . . . 0.01 ppm Tomato . . . . . . . . . . . . . . . . . . . . . 0.01 ppm

### 19 of 32 4.2.2 Acute and Chronic Dietary Exposure and Risk (M. Doherty, D293086, 8/25/03)


### Acute and chronic dietary risk assessments were conducted in order to support the fooduse Section 3 registration requests for the new herbicide trifloxysulfuron-sodium on almonds, citrus, cotton, sugarcane, and tomatoes. Exposure estimates were obtained from the Dietary Exposure Evaluation Model (DEEM-FCID, Version 1.30), which uses food consumption data from the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. The analyses include the highly conservative assumptions that all crops from the requested uses are treated with trifloxysulfuron-sodium and that residues of the herbicide are at tolerance levels. Based on these assumptions, acute and chronic risk estimates for all of the examined population subgroups (including women of childbearing age, infants, and children) are less than 1% of the population-adjusted doses (Table 4.2) and are below HED’s level of concern (100% of the population-adjusted doses).

### 20 of 32 Table 4.2. Summary of Dietary Exposu re and Risk for Trifloxysulfuron-sodium

.

Population Subgroup a Acute Dietary (95th Percentile) Chronic Dietary Cancer

aPAD, mg/kg Exposure, mg/kg/dayb % aPAD cPAD, mg/kg/day Exposure, mg/kg/dayb % cPAD Dietary Exposure, mg/kg/day Risk

General U.S. Population 6.0 0.00024 < 1 0.237 0.000057 < 1 Not Applicable
All Infants (< 1 year old) 6.0 0.00010 < 1 0.237 0.000028 < 1

N/A N/A Children 1-2 years old 6.0 0.00074 < 1 0.237 0.000170 < 1

Children 3-5 years old 6.0 0.00055 < 1 0.237 0.000142 < 1

Children 6-12 years old 6.0 0.00036 < 1 0.237 0.000090 < 1

Youth 13-19 years old 6.0 0.00026 < 1 0.237 0.000058 < 1

Adults 20-49 years old 6.0 0.00018 < 1 0.237 0.000042 < 1

Adults 50+ years old 6.0 0.00015 < 1 0.237 0.000042 < 1

Females 13-49 years old 0.5 0.00020 < 1 0.237 0.000044 < 1

a The values for the population with the highest ri sk for each type of risk assessment are bolded.
b Reported to 2 significant figures.


### 4.3 Water Exposure/Risk Pathway (S. Termes, D276988, 8/20/03)


### Trifloxysulfuron-sodium is a new chemicalfor which no drinking water monitoring data are available. Therefore, the water resource assessments are based solely on model-estimated exposure concentrations. Estimates were only performed for parent trifloxysulfuron-sodium. Exposure concentrations for the water resources assessments were estimated for uses on almonds, citrus, cotton, sugar cane, tomato, and turf. The application rates, frequency and number of applications vary between crops and were taken from the proposed labels for products containing trifloxysulfuron as the active ingredient. There are no aerial applications permitted for this chemical.
In estimating residues of trifloxysulfuron-sodi um in water, the highest application rates, frequency, number and shortest application interval were selected to represent the use pattern that would represent the high-end of possible exposure. The turf use has the highest seasonal application rate (0.080 lb ai/A) and sugarcane has the highest per application rate (0.028 lb ai/A). Tomato use has the lowest seasonal application rate (0.014 lb ai/A) and fewest applications (2). Trifloxysulfuron-sodium can be applied up to three times for the other uses. It was assumed that all applications were made by ground spray to soil, except for turf, where a ground spray to

### 21 of 32 foliage was considered. The sugarcane use pattern was used to model residues in water.
The residues of concern in drinking water are parent trifloxysulfuron, CGA-053052, CGA-382997, and CGA-368732. In order to account for the potential residues of these breakdown products in water, HED has assumed that these metabolites occur at the maximum percent of the applied parent compound observed in 14 

### C-environmental fate studies. Those values are 61% of the a.i. for CGA-053052 (hydrolysis at pH 5 after 30 days), 54% of the a.i. for CGA-382997 (aerobic soil metabolism after 365 days), and 53% of the a.i. for CGA-368732 (hydrolysis at pH 7 after 30 days). The conve rsion factor to go from parent compound to all residues of concern is, therefore, 2.68. This assumption results in overestimated levels of the total residues of concern since it assumes that all of the compounds occur simultaneously, ignoring the kinetics of their formation and dissipation. These total-residue estimated environmental concentrations (EECs) are compared to aggregated exposure estimates (Section 5) to characterize the likelihood of aggregate risk exceeding HED’s levels of concern. Given that the EECs for surface water are greater than those for ground water, the surface water values are used in the aggregate assessment.

Table 4.3. Summary of Estimated Surface and Gro und Water Concentrations for Trifloxysulfuron-sodium and Associated Residues of Concern. Exposure Duration Trifloxysulfuron-sodium Trifloxysulfuron-sodium + CGA-053052 + CGA-382997 + CGA-368732 a
Surface Water

Conc., ppb b Ground Water Conc., ppb c Surface Water Conc., ppb Ground Water Conc., ppb
Acute 3.83 0.032 10.26 0.086 Chronic (non-cancer) 0.31 0.032 0.83 0.086

a Assumes worst-case factors, relative to trifloxysul furon-sodium, of 0.61 for CGA-053052, 0.54 for CGA382997, and 0.53 for CGA-368732; as provided in the MARC Repor t (TXR No. 0052100, 8/25/03). The conversion factor for trifloxysulfuron-sodium to all residues of concern is 2.68.
b From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on sugarcane grown in Florida.

c From the SCI-GROW model assuming a maximum seasonal use rate of 0.0788 lb ai/A, a K ocof 29, and a half-live of 29.84 days.


### 4.4 Residential Exposure/Risk Pathway (S. Wang, D284482, 9/20/03)



### 4.4.1 Home Uses
It is HED’s understanding, from communications with the petitioner, that the proposed turf use for trifloxysulfuron-sodium will be limited to golf courses only (See Section 4.4.2, below). Therefore, there are no home uses for trifloxysulfuron-sodium being proposed at this time and a residential exposure/risk assessment is not required. HED recommends that “for use on golf courses only” be included in the turf label.

4.4.2 Recreational

### 22 of 32 HED has examined the potential postapplication exposure to individuals over 12 years of age from the proposed use of trifloxysulfur on-sodium on golf courses. Duration of such exposure is anticipated to be short-term. The short-term dermal post-application exposure for golfing was estimated to be 0.005 mg/kg/day. The estimate assumes that 18 holes of golf are played in 4 hours, that there are 0.015 : 

### g ai/cm2

### of turf, that the transfer coefficient for turf is 500 cm2

### /hour, and that the average golfer weighs 60 kg (standard risk assessment weight for women and youth). The frequency and duration for the golfer exposure were based on information published in the 1992 Golf Course Operations: Cost of Doing Business/Profitability (The Center for Golf Course Management . Library of Congress GV975.G56 1992.). Transfer coefficients are based on surrogate data, from chlorothalonil and chlorpyrifos, describing actual, median-value exposures to golfers. Applying the short-term dermal NOAEL of 100 mg/kg/day results in a MOE for golfing of 200,000. This is well above the above the target Margin of exposure (MOE) of 100 and therefore considered to be safe.
The vapor pressure of trifloxysulfuron-sodium is very low (<1×10 -7 

### Pa, see Table 2.2) and, therefore, inhalation exposure to trifloxysulfuron-sodium vapor is not expected to occur. HED has not assessed inhalation exposure to tr ifloxysulfuron-sodium due to recreational activities.
4.4.3 Other (Spray Drift, etc.)
Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for trifloxysulfuron-sodium. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pe sticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risks associated with aerial as well as other application types where appropriate.

5.0 AGGREGATE RISK ASSESSMEN TS AND RISK CHARACTERIZATION
In assessing aggregate risks, HED has cons idered exposures from dietary (food and drinking water) and non-dietary (dermal and inha lation) pathways. For the dietary pathway, food exposure estimates come from the dietary exposure analysis discussed above (Section 4.2.2). Sufficient monitoring data for trifloxysulfuron are not available to include drinking water as a quantifiable pathway of exposure. Therefore, HED has calculated drinking water levels of comparison (DWLOCs) as a means of assessing whether or not aggregate exposures to trifloxysulfuron are likely to exceed our levels of concern. The DWLOCs represent the concentrations of a pesticide in surface or ground water below which there is reasonable

### 23 of 32 Risk Quotient RQ Estimated Exposure Target MOE NOAEL ( ) = × 

### (1)



# ( ) Max Allowable Drinking Water Exposure MADWE ARQ NOAEL Target MOE Oral Dietary or Non dietary 

### . ()
( ) 

### =− ×      

− 

### 1 

### (3)

DWLOC MADWE 1000 g mg Body Weight Water Consumption = × μ × 

### (4) certainty that no adverse health effects will occur, in light of other, non-drinking-water pathways of exposure. The DWLOCs are compared to the EECs (See Section 4.3) to determine if aggregate risks are likely to exceed our level of concern. For non-dietary pathways relevant to trifloxysulfruon-sodium, the only source of non-diet ary exposure is from golf course turf. For that scenario, which is short-term in duration, we have included the turf exposure for populations greater than 12 years of age only.
Drinking Water Levels of Comparison . The various single-pathway exposure estimates, target MOEs and NOAELs were used to calculate risk quotients (Eqn. 1) which were then combined to give aggregate risk quotients (Eqn. 2). The aggregate risk quotients, the oral NOAELs, and target MOEs were then used to calculate the maximum allowable drinking water exposures and the DWLOCs for each population subgroup (Equations 3 & 4). Based on standard expressions of NOAELs in terms of mg/kg/day, body weight in kg, and water consumption in L/day, the resulting DWLOCs are in terms of : 

### g/L (ppb).

Aggregate Risk Quotient (ARQ) = RQ Dietary+ RQ Non-dietary Oral + RQ Dermal + RQ Inhalation

### (2)

5.1 Acute Risk
Acute aggregate risk estimates include only dietary pathways of exposure and drinking water is addressed via DWLOCs. Non-dietary oral, dermal, and inhalation are not applicable routes for assessing acute exposure and their contribution, as a risk quotient, is zero. The dietary risk quotients are all well below the target risk quotient of one, indicating that there are not pathway-specific risks of concern. As shown in Table 5.1.2, the acute DWLOCs are at least 4 orders of magnitude greater than the EECs for all of the population subgroups. Therefore, acute aggregate risks are not likely to exceed HED’s level of concern.

### 24 of 32 Table 5.1.1. Acute Risk Quotie nts for Trifloxysulfuron-sodium. Population Subgroup NOAEL (mg/kg) Exposur e (mg/kg) Target MOE Risk Quotient Dietary General U.S. Popul ation 600 0.00020 100 0.00003 All Infants < 1 year 600 0.00010 100 0.00002 Children 1-2 years 600 0.00074 100 0.00012 Females 13-49 years 50 0.00020 100 0.00040

Table 5.1.2. Acute Drinking Water Levels of Comparison for Tr ifloxysulfuron-sodium. Pop. Subgroup Body Weight,

kg Water Consump.,

L/Day Risk Quotient Aggregate

Food NonDietary

Oral Dermal Inhalation Aggregate MADWE, mg/kg b DWLOC, : g/L c EEC, : g/L d

General U.S. Pop. 70 2 0.00003 0 0 0 0.00003 5.9998 210000 10.26

All Infants < 1 year 10 1 0.00002 0 0 0 0.00002 5.9999 60000 10.26

Children 1-2 years 10 1 0.00012 0 0 0 0.00012 5.9993 60000 10.26

Females 13-49 years 60 2 0.00040 0 0 0 0.00040 0.4998 15000 10.26

a WC = Water Consumption
b MADWE = Max. Allowable Drinking Water Exposure = Dietary NOAEL ÷ Target MOE × {1-Aggregate Risk Quotient}

c DWLOC = MADWE × 1000 : g/mg × Body Weight ÷ Water Consumption. Values are rounded to 2 significant figures.
D Surface water estimated environmental con centration. The ground water EEC is 0.054 : g/L. NA = Not Applicable



### 5.2 Short-Term Risk
Short-term aggregate risk includes the chronic estimated dietary exposure plus estimated dermal exposure resulting from the proposed use of trifloxysulfuron-sodium on turf. Note that exposure from this use is only applied to populations older than 12 years. In aggregating the short-term risk HED has used the NOAEL of 79 m/kg/day from the 2-generation reporduction study in rats (appropriate for short-term, incidental, oral exposure) to evaluate the dietary pathway, and the NOAEL of 100 mg/kg/day from the 28-day dermal toxicity study in rats (appropriate for short-term, dermal exposure) to evaluate the non-dietary pathway. For both pathways, the target MOE is 100. The resulting risk quotients for the dietary and dermal pathways are all well below the target risk quotient of one (Table 5.2.1), indicating that there are not pathway-specific risks of concern. As s hown in Table 5.2.2, the short-term DWLOCs are at least 3 orders of magnitude greater than the EECs for all of the population subgroups. Therefore, short-term aggregate risks are not likely to exceed HED’s level of concern.

### 25 of 32 Table 5.2.1. Short-term Risk Quotients for Trifloxysulfuron-sodium. Population Subgroup NOAEL (mg/kg) Exposur e (mg/kg) Target MOE Risk Quotient Dietary General U.S. Popul ation 79 0.000057 100 0.00007 Youth 13-19 years 79 0.000058 100 0.00007 Females 13-49 years 79 0.000044 100 0.00006
Dermal General U.S. Popul ation 100 0.0005 100 0.00050 Youth 13-19 years 100 0.0005 100 0.00050 Females 13-49 years 100 0.0005 100 0.00050

Table 5.2.2. Short-term Drinking Water Levelsof Comparison for Tr ifloxysulfuron-sodium. Pop. Subgroup Body Weight,

kg Water Consump.,

L/Day Risk Quotient Aggregate

Food NonDietary

Oral Dermal Inhalation Aggregate MADWE, mg/kg b DWLOC, : g/L c EEC, : g/L d

General U.S. Pop. 70 2 0.00007 0 0.00050 0 0.00057 0.7895 28000 0.83

Youth 13- 19 years 60 2 0.00007 0 0.00050 0 0.00057 0.7895 24000 0.83

Females 13-49 years 60 2 0.00006 0 0.00050 0 0.00056 0.7896 24000 0.83

a WC = Water Consumption
b MADWE = Max. Allowable Drinking Water Exposure = Dietary NOAEL ÷ Target MOE × {1-Aggregate Risk Quotient}

c DWLOC = MADWE × 1000 : g/mg × Body Weight ÷ Water Consumption. Values are rounded to 2 significant figures.
D Surface water estimated environmental con centration. The ground water EEC is 0.054 : g/L. NA = Not Applicable



### 5.3 Intermediate-Term Risk
There are no requested uses for trifloxysulfuron-sodium that require an assessment of intermediate-term aggregate risk.

5.4 Chronic Risk
Based on the proposed uses of trifloxysulfur on-sodium, chronic aggregate risk estimates need to include only dietary pathways of expos ure with the drinking water component addressed via DWLOCs. In the present situation non-dietary oral, dermal, and inhalation are not applicable routes for assessing chronic exposure and their c ontribution, as a risk quotient, is zero. The dietary risk quotients are all well below the targetrisk quotient of one, indicating that there are not pathway-specific risks of concern. As shown in Table 5.4.2, the chronic DWLOCs are at least 3 orders of magnitude greater than the EECs for all of the population subgroups. Therefore, chronic aggregate risks are not likely to exceed HED’s level of concern.

### 26 of 32 Table 5.4.1. Chronic Risk Quotients for Trifloxysulfuron-sodium. Population Subgroup NOAEL (mg/kg) Exposur e (mg/kg) Target MOE Risk Quotient Dietary General U.S. Population 23.7 0.000057 100 0.00024 All Infants < 1 year 23.7 0.000028 100 0.00012 Children 1-2 years 23.7 0.000170 100 0.00072 Females 13-49 years 23.7 0.000044 100 0.00019

Table 5.4.2. Chronic Drinking Water Levels of Comparison for Tr ifloxysulfuron-sodium. Pop. Subgroup Body Weight,

kg Water Consump.,

L/Day Risk Quotient Aggregate

Food NonDietary

Oral Dermal Inhalation Aggregate MADWE, mg/kg b DWLOC, : g/L c EEC, : g/L d

General U.S. Pop. 70 2 0.00007 0 0 0 0.00007 0.2370 8300 0.83

All Infants < 1 year 10 1 0.00007 0 0 0 0.00007 0.2370 2400 0.83

Children 1- 2 years 10 1 0.00006 0 0 0 0.00006 0.2370 2400 0.83

Females 13-49 years 60 2 0.00000 0 0 0 0.00000 0.2370 7100 0.83

a WC = Water Consumption
b MADWE = Max. Allowable Drinking Water Exposure = Dietary NOAEL ÷ Target MOE × {1-Aggregate Risk Quotient}

c DWLOC = MADWE × 1000 : g/mg × Body Weight ÷ Water Consumption. Values are rounded to 2 significant figures.
D Surface water estimated environmental con centration. The ground water EEC is 0.054 : g/L. NA = Not Applicable



### 5.5 Cancer Risk
Trifloxysulfuron-sodium has been classifi ed as “Not likely to be carcinogenic to humans.” Therefore, an assessment of aggregate cancer risk is not required.

6.0 CUMULATIVE RISK
The Food Quality Protection Act (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non-occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low-level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe.
HED did not perform a cumulative risk assessment as part of this risk assessment for

### 27 of 32 trifloxysulfuron-sodium because HED has not yet initiated a review to determine if there are any other chemical substances that have a mechanism of toxicity in humans in common with it. For purposes of this petition, EPA has assumed that trifloxysulfuron does not have a commonmechanism of toxicity with other substances. We note, however, that the metabolite CGA053052 which was identified as a residue of concern in water is a metabolite of other sulfonylurea herbicides.
On this basis, the petitioner must submit, upon EPA's request and according to a schedule determined by the Agency, such information as the Agency directs to be submitted in order to evaluate issues related to whether trifloxysulfuron shares a common mechanism of toxicity with any other substance and, if so, whether any tolerances for trifloxysulfuron need to be modified or revoked. If HED identifies other substances th at share a common mechanism of toxicity with trifloxysulfuron, HED will perform aggregate exposure assessments on each chemical, and will begin to conduct a cumulative risk assessment.
HED has recently finalized its guidance for conducting cumulative risk assessments on substances that have a common mechanism of toxicity. This guidance is available from the OPP Website (http://www.epa.gov/pesticides). In the guidance, it is stated that a cumulative risk assessment of substances that cause a common toxic effect by a common mechanism will not be conducted until an aggregate exposure assessment of each substance has been completed.
Before undertaking a cumulative risk assessment, HED will follow procedures for identifying chemicals that have a common mechanism of toxicity as set forth in the "Guidance for Identifying Pesticide Chemicals and Other Substances that Have a Common Mechanism of Toxicity" (64 FR 5795-5796, February 5, 1999).

7.0 OCCUPATIONAL EXPOSURE (S. Wang, D284482, 9/20/03)


### HED has assessed occupational exposures for application as well as postapplication activities on the following crops: cotton, sugarcane, citrus, almonds, tomatoes, and turfgrass. Based on the frequency of applications and app lication intervals provided in the proposed label, EPA assumes that both on-farm application handlers and post-application workers would be exposed for less than 30 days per year (short-term exposure) and that commercial pesticide handlers could be exposed for more than 30 days but less than 6 months (intermediate-term exposure). The NOAEL of 45 mg/kg/day assigned to be used in intermediate-term dermal assessments is from an oral study. Due to the use of a 30% dermal absorption factor, the “equivalent” dermal NOAEL is 150 mg/kg/day. Since this value is greater than the NOAEL of 100 mg/kg/day assigned for short-term dermal assessments, the short-term assessment is protective of intermediate-term exposures; therefore, an intermediate term assessment has not been conducted. Long-term exposure is not expected.
Margins of exposure for all of the application (Table 6.1) and postapplication (Table 6.2) activities are much greater than the target MOE of 100.

### 28 of 32 No chemical-specific data for assessing human exposures during pesticide handling activities were submitted to the Agency in support of the registration of trifloxysulfuron-sodium. Therefore, HED used surrogate data from th e Pesticide Handlers Exposure Database (PHED) Version 1.1. (8/98). Defaults established by the HED Science Advisory Council for Exposure (Exposure SAC) were used for acres treated pe r day and body weight. MOEs for the handlers performing agricultural crop uses ranged from 22,000 to 5,400,000 at the baseline level of personal protective equipment (PPE). MOEs for the handlers performing turfgrass uses ranged from 75,000 to 3,800,000 at the baseline level of PPE. The PPE on the proposed label specifies that applicators and other handlers wear long-sleev ed shirt, long pants, waterproof gloves, and shoes plus socks. Based on the chemical properties of trifloxysulfuron-sodium (Table 2.2), there is low probability for inhalation exposure to this chemical. Therefore, inhalation exposures were not aggregated with dermal exposures for the occupational assessment.
The occupational post-application exposure/risk were calculated using activity specifictransfer coefficient (Tc) values from the HED Exposure SAC Policy Number 3.1. Postapplication MOEs from this screening-level assessment ranged from 2,000 to 290,000. The assessment assumed exposure of 8 hours per day for 30 days per year. The default body weight for female workers (60 kg) was used since the regulatory endpoint was noted in females and use of this body weight produces an exposure estimate which is protective of both male and female workers.

Table 6.1. Short-term Occupational Exposure a nd Risk Estimates for Trifloxysulfuron-sodium. All estimates are at baseline mitigation (long-sleeve shirt, long pants, shoes, and socks and no respirator). The dermal NOAEL is 100 mg/kg/day; the inhalation NOAEL is 50 mg/kg/day. Exposure Scenario (Scenario #) Crop Daily Dermal Dose, mg/kg/day Daily Inhalation Dose, mg/kg/day Dermal MOE Inhalation MOE

Mixer/LoaderDry Flowables for Groundboom application (1) Cotton 0.00260 0.000030 38,000 1,700,000 Sugarcane 0.00248 0.000029 40,000 1,700,000

Tomato 0.00084 0.0000097 120,000 5,200,000 Turfgrass 0.00115 0.000013 87,000 3,800,000 Dry Flowables for Air Blast application (2) Citrus and Almonds 0.00083 0.0000096 120,000 5,200,000

Applicator Sprays with Ground-boom (3) Cotton 0.00055 0.000029 180,000 1,700,000 Sugarcane 0.00053 0.000028 190,000 1,800,000

Tomato 0.00018 0.0000093 560,000 5,400,000 Turfgrass 0.00025 0.000013 400,000 3,800,000 Sprays with Air Blast (4) Citrus and Almonds 0.0045 0.000056 22,000 890,000Table 6.1. Short-term Occupational Exposure a nd Risk Estimates for Trifloxysulfuron-sodium. All estimates are at baseline mitigation (long-sleeve shirt, long pants, shoes, and socks and no respirator). The dermal NOAEL is 100 mg/kg/day; the inhalation NOAEL is 50 mg/kg/day. Exposure Scenario (Scenario #) Crop Daily Dermal Dose, mg/kg/day Daily Inhalation Dose, mg/kg/day Dermal MOE Inhalation MOE



### 29 of 32 Mixer/Loader/Applicator Sprays with Back Pack Sprayer (5) Turfgrass 0.00133 0.000016 75,000 3,100,000

Table 6.2. Post-application Occupational Exposu re and Risk Estimates for Trifloxysulfuron-sodium . All estimates are for zero days after the final application.
Crop Work Activity Daily Dose (mg/kg/day) MOE

Cotton Irrigation, scouting, thinning, weeding immature/low foliage plants 0.00035 290,000 Irrigation, scouting, weeding mature/high foliage plants 0.0053 19,000 Hand harvesting 0.0088 11,000

Sugarcane Scouting immature plants 0.0084 12,000 Scouting mature plants 0.0169 6,000

Citrus Propping 0.0006 180,000 Irrigation, scouting, hand weeding 0.0060 18,000 Harvesting, pruning, training, tying, thinning 0.017 6,000 Harvesting, thinning, pollination, bagging, tying, misc. hand labor, staking topping, training 0.045 2,000

Almonds Irrigation, scouting, thinning, weeding 0.0030 36,000 Harvesting/poling, pruning, thinning 0.014 7,000

Tomatoes Irrigation, scouting, thinning, weeding immature plants 0.0014 70,000 Irrigation/scouting mature plants 0.0020 50,000 Hand harvesting, pruning, staking, tying 0.0028 35,000

Turfgrass Mowing 0.0010 100,000 Transplanting, hand weeding 0.032 3,100

### 30 of 32 8.0 DATA NEEDS AND LABEL REQUIREMENTS
8.1 Toxicology
No data gaps. Although HIARC recommended that a 90-day inhalation toxicity study in rats be required to be submitted to the Agency within a reasonable period of time (7/22/03, TXR No. 0052043), this requirement is waived for the registrations and tolerances addressed in this document. This waiver is in accordance with Criteria 4 in SOP 2002.01 - “HED Standard Operating Procedure: Guidance: Waiver Criteria for Multiple-Exposure Inhalation Toxicity Studies” (8/15/02), which states that “a waiver may be granted for an active ingredient that is Toxicity Category IV for inhalation provided an extrapolated inhalation MOE (based on an oral NOAEL) exceeds a target MOE of 1000 or greater”. Trifloxysulfuron-sodium is Toxicity Category IV for inhalation (Table 3.1) and the extrapolated inhalation MOEs for short-term occupational exposures range from 890,000 to 5,400,000 (Table 6.1). Inhalation exposures and risk assessments were not conducted for any of the other exposure scenarios described in this document because inhalation exposure is not expected to be significant based on low vapor pressure (<1 x 10 -7 

### Pa, Table 2.2) and dilution by outdoor air.
8.2 Residue Chemistry
860.1200 Directions for Use . The use directions for cotton should be modified to clarify the use patterns/situations when tank mixing with other herbicides is allowable.
860.1340 Residue Analytical Methods . The HPLC/UV method will be submitted to the ACL for Agency tolerance method validation (TMV). We note that the laboratory that conducted the ILV for the method recommended some changes/clarifications to the method procedures, including correction of a typographical error. Unless ACL concludes differently, the modifications recommended by the ILV laboratory will have to be made to the method prior to its acceptance as a tolerance enforcement method; any additional changes recommended by ACL will also have to be incorporated.
860.1500 Crop Field Trials . The submitted cotton field trial data cannot be used to support the proposed use on cotton because the field trial studies were conducted at application rates that were
- 

### 3x the proposed maximum seasonal rate. The petitioner should submit field trial data for cotton seed and gin byproducts reflecting application of trifloxysulfuron-sodium at 1x the maximum proposed application rate (0.019 lb ai/A) or submit a revised label reflecting the use pattern used to conduct the cotton field trials. Also, HED is requesting clarification that the cotton field trial samples were harvested by picker equipment since the requested use is for picker varieties of cotton only. The currently available data are sufficient for a conditional registration.
860.1550 Proposed Tolerances . The petitioner must revise the tolerance definition to remove the phrase “and metabolites converted to parent equivalents” and the reference to the sodium salt (i.e., the tolerance expression should be for trifloxysulfuron). Due to the level of apparent residues of trifloxysulfuron in c ontrol samples of almond nutmeat, and citrus

### 31 of 32 commodities, HED recommends that the proposed tolerances be increased in those commodities to ensure that tolerances are greater than 5 times the apparent residues. The recommended tolerance levels, as well as corrections to the commodity definitions, are presented in Table 8.1. A revised Section F is requested.
8.3 Occupational and Residential Exposure
According to the information provided by the registrant, there are no requested residential uses for trifloxysulfuron at this tim e. HED recommends that “for use on golf courses only” be explicitly included on the turf label.

Table 8.1. Tolerance Summary for Trifloxysulfuron-sodium Commodity Proposed Tolerance

(ppm) Recommended Tolerance

(ppm) Comments (correct commodity definition)

Almond Nutmeat 0.01 0.02 * Almond
Almond Hulls 0.01 0.01 —
Citrus 0.01 0.03 * Fruit, citrus, group 10
Cottonseed 0.05 0.05 Cotton trials conducted at 3X max. rate. As a condition of registration, the petitioner should submit data from trials conducted at the maximum recommended rate or revise the label to reflect the rate used in the field trials. Commodity Definition: cotton, undelinted seed Cotton By-products 1.0 1.0 Cotton trials conducted at 3X max. rate. As a condition of registration, the petitioner should submit data from trials conducted at the maximum recommended rate or revise the label to reflect the rate used in the field trials. Commodity Definition: cotton, gin by-products Sugarcane 0.01 0.01 —
Tomatoes 0.01 0.01 Tomato

* A higher tolerance is recommended due to apparent re sidues in control samples in excess of 20% of the proposed tolerance



### References:
1. Trifloxysulfuron-sodium - Report of the Hazard Identification Assessment Review Committee. E. R. Budd and A. C. Levy. 7/22/03. TXR No. 0052043.
2. Toxicology Disciplinary Chapter for the Registration Support Document. E. R. Budd and A. C. Levy. 8/21/03. TXR No. 0050906.
3. Trifloxysulfuron-sodium: Metabolism Assessment Review Committee Report. M. A. Doherty, E. R. Budd, A. C. Levy, S. C. Termes. 8/25/03. DP Barcode D293085. TXR No. 0052100.

### 32 of 32 4. Trifloxysulfuron-sodium. Section 3 Re gistration Request for Food Uses on Almond, Citrus (Group 10), Cotton, Sugarcane, and Tomato. Summary of Analytical Chemistry and Residue Data. Petition Number 1F06280. M. A. Doherty. 8/25/03. DP Barcode D284480.
5. Trifloxysulfuron-sodium: Acute and Chronic Dietary Exposure Assessments for the Section 3 Registration on Almonds, Citrus , Cotton, Sugarcane, and Tomato (PP# 1F06280). M. A. Doherty. 8/25/03. DP Barcode D293086.
6. Drinking water assessment for Trifloxysulfuron Sodium (“Trifloxysulfuron”) for use on cotton, sugarcane, almonds, citrus, tomatoes, and turf. J. K. Wolf and S. C. Termes. 8/20/03. DP Barcode D276988, D280727, D284104, D284108, D284113, D284117, D284478, D284116.
7. Occupational and Residential Exposure/Risk Assessment for a New Active Ingredient, Trifloxysulfuron, on Cotton, Sugarcane, Citrus , Almonds, Tomatoes, and Turfgrass. S. Wang. 9/20/03. DP Barcode D284482.
cc (without attachments): M. Doherty, E. Budd, A. Levy, S. Wang, RAB 2 Reading File