UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: August 2, 2012 

TXR #: 0056431 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Sulfometuron Methyl: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of August 2, 2012: Recommendations on the Requirement 

of a 28-Day Inhalation Study, and Acute and Subchronic Neurotoxicity studies. 

PC Code: DP Barcode: N/ A 

Decision No.: N/A Registration No.: N/A 

Petition No.: N/A Regulatory Action: N/A 

Risk Assessment Type: N/A Case No.: N/A 

TXR No.: 0056431 CAS No.: 74222-97-2 

MRlD No.: N/A 40 CFR: §180.490 

FROM: Kristin Rury, MPH \C. £:6" 

Executive Secretary, HASPOC 

Health Effects Division (7509P) 

~~ · THROUGH: Jess Rowland, Co-Chair ~...._..::;;g,!.rl~""" ~~,) 

HASPOC 

Anna Lowit, Ph.D, Co-Chair ~ ~ 

Health Effects Division (7509P) 

TO: Jolm Liccione, Ph.D., Toxicologist 

Wade Britton, MPH, Risk Assessor 

Pete Savoia, Chemist 

Michael Metzger, Acting Branch Chief 

Risk Assessment Branch V 

Health Effects Division (7509P) 

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MEETING ATTENDEES 

HASPOC Members: 

Presenters: 

Other Attendees: 

Anna Lowit, Elissa Reaves, Elizabeth Mendez, Jeff Evans, Jess Rowland, 

P.V. Shah, Ray Kent 

John Liccione, Wade Britton 

Julie Van Alstine, Kristin Rury, Pete Savoia 

I. PURPOSE OF MEETING 

Risk Assessment Branch (RAB) V is preparing a Registration Review scoping document for the 

herbicide sulfometuron methyl. Under the current 40 CFR Part 158 data requirements, acute and 

subchronic neurotoxicity studies are required. A 28-day inhalation toxicity study in rats is also 

required due to the potential for repeated inhalation exposure to sulfometuron methyl. The 

Hazard and Science Policy Council (HASPOC) met on August 2, 2012 to discuss the need for 

acute and subchronic neurotoxicity studies, and a 28-day inhalation toxicity study to support the 

registered uses of sulfometuron methyl. 

II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT 

Sulfometuron methyl is a nonselective, sulfonyl urea herbicide and acts by inhibiting acetolactate 

synthase (ALS), an enzyme that catalyzes the biosynthesis of three branched-chain amino acids 

(valine, leucine, and isoleucine), all of which are essential for plant growth. His labeled for 

commercial pre- and post-emergent applications to manage annual and perennial broadleaf 

weeds and grasses in non-agricultural sites (i.e., forestry, rights of way, non-crop industrial sites, 

and unimproved turf). 

Sulfometuron methyl is a non-food/non-feed use chemical with no current or proposed uses 

which could lead to exposures from consuming raw agricultural commodities and/or processed 

foods. As a result, no tolerance levels have been established for this chemical and the 

requirements ofthe Food Quality Protection Act (FQPA) do not apply. 

Sulfometuron methyl is formulated as water dispersable granules (WDGs), ranging from 18 to 

75% ai and may be applied using ground or aerial equipment. Control is generally for a full 

season or longer with only one application required per year; however, in some situations (i.e., 

weed escapes) a second application may be made. While labeled use sites of sulfometuron 

methyl include turf (unimproved) and non-crop industrial, label language prohibits application to 

these sites in residential and recreational areas. 

In the most recent risk assessment (W. Britton, D385620, 08/ 11/2008), an oral Point of 

Departure (POD) was used for assessing risk via dietary (drinking water) and inhalation 

exposure from occupational uses. The POD was based on hemolytic anemia in both sexes and 

decreased body-weight gain in males begi1ming on the fourth week of exposure (and persisting 

throughout the entire study) seen at the lowest observed adverse effect level (LOAEL) of 148.5 

mg/kg/day in the chronic 1-year dog study (no observed adverse effect level; NOAEL = 27.5 

mg/kg/day). 

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Occupational inhalation MOEs for all registered uses of sulfometuron methyl range from 5,600 

to 680,000. Mixing/loading ofWDG formulations for aerial application to forestry and noncrop areas results in the highest inhalation exposure to sulfometuron methyl with an MOE of 

5,600. 

III. STUDY WAIVER REQUEST 

a. Inhalation Study 

Previously, the Office of Pesticide Programs (OPP) used a set of criteria to determine whether or 

not an inhalation study could be waived. These criteria considered the scientific information 

available for the chemical, including its: (1) degree of irritation and corrosivity; 2) volatility; 3) 

aerosol particle size; and 4) Acute Toxicity Category and extrapolated MOEs (e.g., MOEs 10 

times higher than the target). In 2009, OPP developed an issue paper on risk assessment 

approaches for semi-volatile pesticides. As part of that issue paper, an analytical comparison 

was conducted of oral and inhalation experimental toxicology studies. In general, this analysis 

showed that the degree to which oral PODs were protective of potential inhalation toxicity 

varied. In many cases the oral POD was protective, but in some cases the inhalation PODs were 

significantly more protective. Currently, OPP uses a weight of the evidence (WOE) approach 

that builds upon OPP's experience using the criteria listed above and conclusions from the 2009 

SAP. As approaches for route-to-route extrapolation continue to evolve and improve, OPP may 

incorporate additional considerations into the WOE analysis. 

Inhalation exposure can be to vapors, droplets, and/or particles/dusts. The form of inhalation 

exposure is determined by a number of factors including physical-chemical properties, use 

pattern, and exposure scenarios. OPP's interim WOE approach considers: 

1. Physical-Chemical Properties: Consideration of vapor pressure and the Henry's law 

constant are essential in assessing volatilization after sprays have settled. The vapor pressure 

of sulfometuron methyl is 5.4x 10-16 Torr at 20 °C. The Henry's law constant is l.lxl o-18 

atm-m3/mol at 20 °C. However, low vapor pressure and/or Henry's law constant does not 

preclude exposure to aerosolized droplets or particles/dusts. 

2. Use Pattern and Exposure Scenarios: Any application scenario that leads to inhalation 

exposure to droplets needs to be considered in the WOE analysis for an inhalation toxicology 

study waiver request. Airblast and aerial applications are more likely to lead to higher 

occupational handler inhalation exposure, particularly to droplets, and may also contribute to 

spray drift. In the case of sulfometuron methyl, mixing/loading WDG formulations for aerial 

application to forestry and non-crop areas results in the highest inhalation exposure. 

3. Margins of Exposure (MOEs): MOE estimates for inhalation scenarios were calculated using 

an oral toxicity study and should be considered in the WOE analysis for an inhalation 

toxicology study waiver request. In the past, OPP has used MOEs of approximately 10 times 

higher than the level of concern as a benchmark for granting waiver requests. The 2009 

analysis suggests this approach is appropriate for most pesticides but not all. Using this 

interim WOE approach, MOEs from 10-100 times greater than the level of concern (LOC) 

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will be considered in combination with other factors discussed here. In the case of 

sulfometuron methyl, the inhalation MOEs for occupational handlers range from 5,600 to 

680,000 and meet the waiver criterion of MOEs ranging from 10-100 times the LOC. 

4. Toxicological Effects: Sulfometuron methyl has relatively low acute toxicity via oral 

(Toxicity Category IV), inhalation (Toxicity Category IV), and dermal (Toxicity Category 

III) routes of exposure in the rat. It is a minimal eye irritant (Toxicity Category III), and is 

not irritating to the skin (Toxicity Category IV), or a dermal sensitizer. The primary toxic 

effect of sulfometuron methyl is hemolytic anemia, which represents the most sensitive toxic 

endpoint for risk assessment. A toxicity endpoint has been selected to assess potential risks 

resulting from drinking water and occupational exposure to sulfometuron methyl and 

provides a very conservative POD for risk assessment. In the absence of fully acceptable 

guideline studies which might yield a different acute dietary/drinking water endpoint (e.g., 

acceptable developmental toxicity studies), and considering the limited findings in the 

available developmental studies, use of the chronic dog endpoint has been considered to be 

protective of acute dietary exposure. In the rabbit pre-natal developmental toxicity study, a 

slight increase in the incidence of abortions was observed from doses close to or at the limit 

dose (750 and 1000 mg/kg/day). No maternal or developmental toxicity was observed in the 

prenatal developmental toxicity study in rats. There was no evidence of reproductive toxicity 

in any of the available studies. Carcinogenicity studies on sulfometuron methyl were not 

required since it is a non-food/non-feed pesticide and chronic exposure to this pesticide is not 

expected based on the use pattern. It was negative in the mutagenicity/genetic toxicity 

studies. 

For considering a waiver request for an inhalation toxicity study, the Agency will evaluate 

other pesticides which share the same mode of action (MOA) and/or are in the same class. 

These pesticides can provide important information with respect to potential inhalation 

toxicity. Specifically, if other similar pesticides show inhalation toxicity studies to be more 

sensitive, an inhalation toxicity study may be required regardless of MOE, depending on the 

exposure profile. Sulfometuron methyl is a member of the pyrimidinyl sulfonylurea class of 

herbicides that contains a number of other pesticides. Of this class, body weight changes, 

hematological changes, and liver effects were the most consistent toxicity findings, not 

inhalation toxicity. HASPOC has waived the required inhalation toxicity studies for many 

sulfonylurea herbicides, including halosulfuron-methyl, metsulfuron-methyl, nicosulfuron, 

orthosulfamuron, primisulfuron-methyl, thifensulfuron, and trisulfuron. 

Based on a weight of evidence (WOE) approach, the risk assessment team concludes that a 

28-day inhalation toxicity study is not required for sulfometuron at this time. This approach 

considered all of the available hazard and exposure information for sulfometuron methyl, 

including: (1) the physical/chemical properties and low volatility (5.4x10- 16 Torr at 20 °C) of 

sulfometuron methyl; (2) the low acute inhalation toxicity of sulfometuron methyl; (3) hemolytic 

anemia is the primary toxicological effect of concern following repeated sulfometuron methyl 

exposure; (4) on the use of an oral POD that results in occupational inhalation MOEs greater 

than 5,600; and (5) the low concern for inhalation toxicity in other members of this class of 

chemicals (i.e., sulfonylureas). 

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b. Neurotoxicity Screening Battery 

Acute and subchronic neurotoxicity studies are required in the 2007 revised 40 CFR Part 158 

Toxicology Data Requirements because they provide important scientific information on 

potential nervous system effects from pesticide exposure. These studies can provide data on a 

wide range of functional tests for evaluating neurotoxicity including sensory effects, 

neuromuscular effects, learning and memory and histopathology of the nervous system. The 

HASPOC used a WOE when considering the need for acute and subchronic neurotoxicity studies 

to support the registered uses of sulfometuron methyl. 

• Evidence for neurotoxicity in the sulfometuron database of toxicology studies: There 

are no clear signs of neurotoxicity following subchronic or chronic dosing in multiple 

species in the sulfometuron methyl database. Subchronic and chronic dietary 

administration of doses exceeding the limit dose did not produce adverse effects in rats or 

mice throughout the sulfometuron toxicity database. There was no indication of 

neurotoxicity in clinical observations of repeat-dose studies. 

• Evidence for neurotoxicity in the database of toxicology studies for other 

pyrimidinylsulfonylurea pesticides: Sulfometuron methyl is a member of the 

pyrimidinylsulfonylurea class of herbicides. Neurotoxicity studies are available for 

flazasulfuron, halosulfuron, imazosulfuron, prosulfuron, orthosulfamuron, and 

trifloxysulfuron. Evidence for neurotoxicity among this group occurred at high doses or 

near the limit dose (1,000 mg!kg/day). Clinical signs of neurotoxicity were seen at or 

above the limit doses for flazasulfuron (1 ,000 mg/kg/day), imazosulfuron (2,000 

mg/kg/day), and trifloxysulfuron (2,000 mg/kg/day). Neurotoxicity was seen as 

decreased motor activity at the limit dose in the prosulfuron acute neurotoxicity study; 

however, neither decreased motor activity nor other evidence of neurotoxicity was seen 

in the subchronic study. For orthosulfamuron, reduced motor activity was reported in 

the Fl males at 346 mg/kg/day in the multigeneration reproduction study. However, the 

decrease in motor activity was considered an isolated finding since similar decreases 

were not seen in females or F2 animals. 

Neurotoxicity studies are not available for bensulfuron, chlorimuron-ethyl, mesosulfruon, 

nicosulfuron, metsulfuron-methyl, primisulfuron-methyl, rimsulfuron, sulfometuron and 

sulfosulfuron. However, there is no evidence of neurotoxicity in the available toxicity 

studies for these chemicals. Further, a search of the open literature did not provide data 

on neurotoxicity for these chemicals. 

The HASPOC concluded, based on a weight of evidence (WOE) approach, that acute and 

sub-chronic neurotoxicity studies are not required at this time. This approach included the 

following considerations: 1) the lack of neurotoxicity in the available toxicology studies for 

sulfometuron methyl; 2) hemolytic anemia is the primary toxic effect seen in the sulfometuron 

methyl database and provides the most sensitive POD for irks assessment; and 3) the low 

concern for neurotoxicity in other members of this class of chemicals (i.e., sulfonylureas) for 

which evidence for neurotoxicity among this group occurred at high doses or near the limit dose 

(1,000 mg/kg/day. 

Page 5 of6 
IV. HASPOC RECOMMENDATIONS 

Based on a WOE approach and considering all of the available sulfometuron methyl hazard and 

exposure information, the HASPOC concludes that a 28-day inhalation toxicity, acute 

neurotoxicity, and subchronic neurotoxicity studies are not required for sulfometuron methyl at 

this time. 

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