UN ITED STATES ENVIRONMENTAL PROTECTION AGENCY WASH I NGTON, D.C. 20460



### MEMORANDUM DATE: August 2, 20 1 2
TXR # : 0056431 O FFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Sulf ometuron Methyl: Summary of Hazard and Scienc e Policy Council (HASPOC) Meeting of August 2, 2012 : Recommendations on the Requiremen t of a 28-Day Inhalation Study, and Acu te and Subchronic Neurotoxicity studies.
PC Code: DP Barcode: N / A Decision No

. : N/ A Registration No.: N /A Petition No.: N / A Regu latory Action: N /A Risk Assessment Type: N/ A Case No.: N/A T XR No.: 0056431 CAS No. : 74222-97

-2 M R lD No.: N/ A 40 CFR: § 1 80.490 

### F ROM: Kri s tin Rury, MPH 

# \C.

# £:6"
Executive Secretary, HASPOC Health E ffects Division (7509P)

### ~~**·** THROUGH: Jess Rowland, Co-Chair

### ~...._..::;;g,!.rl~"""**~~ ,)**  Anna Lowit, Ph .D , Co-Chair

### ~**~** HASPOC Health E ffects Division (7509P) TO : Jolm Liccione , Ph.D. , T oxico logist Wade Britton , MPH, Risk Assessor Pete Savoia, Chemist Michael Metzger, Acting Branch Chief Risk Asses s ment Branch V Health Effects Division (7509P)

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### of6MEETING 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 O F MEETING Risk Assessment Branch (RAB) V i s preparing a Registration Review scoping document for the herbicide su lfometuron 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 Counci l (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 i s a nonselective, sulfonyl urea herbicide and acts by inhibiting aceto l actate synthase (ALS), an enzyme that cata lyzes the biosynthesis of three branched-chain amino acids (vali ne, leucine , and isoleucine), all of which are essential for p lant growth. His labeled for commercial pre- and post-emergent applications to manage annual and perennial broadleaf weeds and grasses in non-agricultura l sites (i.e., forestry, rights of way, non-crop industrial sites, and unimproved turf)

. Sulfometuron methyl is a non-food/non-feed use chemical w ith no current or proposed uses which could lead to exposures f rom consum ing 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 d i sper sab le 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 app li cation required per year; however, in some situations (i.e

. , weed escapes) a second app li cati on may be made. While labe led use s ites of sulfometuron methyl include turf (unimproved) and non - crop indust ri al, labe l l anguage prohib its app li cation 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 begi 1 ming on the fourth week of exposure (and persisting throughout the entire study) seen at the lowest observed adverse effect level (LOAEL) of 14 8.5 mg/kg/day in the chronic 1- year dog study (no observed adver se effect level; NOAEL 

### = 27

. 5 mg/kg/day).
Page 2 of6Occupational 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 resu lts in the highest inhalation exposure to s ulfometuron 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 informa tion 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, thi s analysis showed that the degree to which oral PODs were protective of potential inhal ation 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 t he 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. Inh al ation 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.l xl 

# 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 expos ure to drop lets 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. I n the case of sulfometuron methyl, mixing/loading WDG formu l ations for aerial application to forestry and non-crop areas results in the highest inhalation exposure.
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. Margins of Exposure (MOEs): MOE estimates fo r inhalation scenarios were calculated using an oral toxicity study and should be considered in the WOE analysis for an inhalation toxicology study waiver re quest. In th e past, OPP has used MOEs of approximate ly 10 ti mes 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) Page 

### 3 of6will be considered in combination with other factors discussed here. In the case of sulfometuro n methyl, the inhalation MOEs for occupational handler s ran ge from 5,600 to 680,000 and meet the waiver cr i terion of MOEs ranging from 1 0

- 100 times the LOC

. 4. Toxicological Effects: Sulfometuron methyl has relatively low acute toxicity via oral (Toxicity Category IV), inhalat ion (Tox i c ity Category IV), and dermal (Toxicity Category III) routes of exposure in the rat. It i s a minimal eye irritant (Toxicity Category III ), and i s not irritating to the skin (T oxicity Category IV), or a de rm al sensitizer. The primary toxic effect of sulfometuron methyl is hemolyti c anemia, which represents the most sens iti ve toxic endpo int for risk assessment. A toxicity endpoint has been selected to assess potential risks resulting from drinking water and occupatio n al exposure to sulfometuron methy l and provides a very conservative POD for risk assessment. In the absence of fully acceptable gu ide line studies which might yield a different acu te dietary/ drinking water endpo int (e.g., acceptable developmental toxicity studies), and considering the limited findings in the avail able developmental studies, use of the chronic dog endpoint has been considered to be protective of acute dietary exposure. In the rabbit pre-natal developmental toxic ity study, a sligh t increase in th e in cidence of aborti on s was observed from doses close to or at the limi t dose (750 and 1000 mg/kg/day). No maternal or developmental toxicity was observed in the prenata l developme ntal t oxicity study in rats. T h ere was no evidence of r eproductive toxicity in any of the avai lable studies. Carc inogenicity studies on sulfometuron met hyl were not required since it is a non-food/non-feed pesti cide and chronic exposure to this pesticide is not expected based on the use pattern. It was negative in the mutagenicity/genetic toxicity studies. F or consideri n g a waiver request fo r an inhalation toxicity study, th e Agency will evaluate other pesticides w h ich share the same mode of acti on (MOA) and/or are in the same class. These pesticides can provide important informat ion with respect to pot ential inhalat i on tox i c ity. Specifically, if other s imilar pesticides show inhalation toxicity studies to be more sensitive, an inhalation toxicity study may be required regardless of MOE, depending on the exposure profile

. Sulfome tu ron methyl is a member of th e pyrimidinyl su lfonylurea class of he rbicides that contains a number of other pesticides. Of this class , body weight changes, hematolog ical changes, and liver effects were the mos t consis tent toxicity fi ndings, not inhalation toxicity. HASPOC has waived the required inhalation toxic ity studies for many sulfony lurea h erbicides, including halosulfuron-methyl, metsulfuron-methyl, nicosulfuron, orthosulfamuro n , primisulfuron-methyl, thife n sulfuron, 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 avai l able hazard and exposure information for sulfometuron meth yl, including: (1) the p h ysical / chemical properties and l ow volatili ty (5.4x10- 16 Torr at 20 °C) of sulfome t uron methyl; (2) th e low acute inhala t ion toxicity of sulfometuron methyl; (3) hemolytic anemia is the pr imary toxico l og i cal effect of concern following repeated sulfometuron me thyl 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 toxici t y in other members of this class of chemicals (i

. e., sulfony lureas).
Page 4 of6b. Neurotoxicity Screening Battery Ac ute and subchronic neuro toxicity studies are required in th e 2007 revised 40 CFR Part 158 Toxicology Data Requirements because they provide important scientific information on potentia l nervous system effects from pesticide exposure. These studies can provide data on a wide range of functional tests for evalua ting neuro tox icity including sensory effects, neuromu scular effects, learning and memory and histopathology of the nervous system. The HA SPOC used a WOE when considering the need for acute and subchronic neurotoxicity studies to support the registered uses of su lfometuron 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 su lfometuron methyl database. Subchronic and chronic dietary administration of doses exceeding the limit dose did not produce adverse effec ts in rats or mice throughout th e 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. Neuro toxicity studies are available for flazasulfuron, halosulfuron, imazosulfuron, prosulfuron, orthosulfamuron, and trifloxysulfuron. Evidence for neurotoxicity among this group occurred at high doses o r near the limit dose (1,000 mg!kg/day). Clinical signs of neuro toxicity 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). Neuro to xicity 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 activ ity was reported in the F l males at 346 mg/kg/day in the multigeneration reproduction study. However, the decrease in motor activity was considered an iso l ated 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, rim su lfuron, sulfometuron and sulfosulfuron. However, there is no evidence of neurotoxicity in the available toxicity st

ud ies 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 approac h 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 th e most sensitive POD for irks assessment; and 3) the low concern for neurotoxicity in other members of this class of chemicals (i.e., s u lfony lureas) for which evidence for neurotoxicity among this gro up occurred at high doses or near the limit dose (1,000 mg/kg/day.

Page 5 of6IV. HASPOC RECOMMENDATIONS Based on a WOE approach and considering all of the avail ab le su lfometuron 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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