Page **1** of **10 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY** 

**WASHINGTON, D.C. 20460**

**OFFICE OF CHEMICAL SAFETY AND** 

**POLLUTION PREVENTION MEMORANDUM**  August 6 , 201 3 **SUBJECT: Sul**  **f**

**onylureas :**  Summary

of Hazard and Science Policy Council (HASPOC) Meeting on July

18, 2013 : Recommendations on Data R equirement for Immunotoxicity

Studies for Sulfonylurea P esticides . **PC Code s**  **:** See below **DP Barcode:** D412018 and D412408 **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 T **XR No.:** 0056723 **CAS No.:** See below **MRID No.:** N/A **40 CFR:** N/A **FROM:** Kristin Rury , MPH

Executive Secretary , HASPOC Health Effects Division (7509P) **THROUGH:** Jess Rowland, Co - Chair

Anna Lowit, Ph.D. , Co - Chair HASPOC Health Effects Division (7509P) **TO:** Jaime D’Agostino **,** Toxicologist

Risk Assessment Branch II Health Effects Division (7509P) MEETING ATTENDEES HASPOC Members: Anna Lo wit, Anwar Dunbar, Elizabeth Mendez, Jeff Evans, Jeff Dawson, John Kough, Jonathan Chen, Julie Van Alstine, Kristin Rury , Michael Metzger, PV Shah, Ray Kent Presenter: J a i me D’ Agostino Other Attendees: Abdallah Khasawinah, Christina Swartz Christopher Schlosser, Joey Bever, Monique Perron, Zaida FigueroaPage **2** of **10**

1. PURPOSE OF MEETING In accordance with the revised 2007 40 CFR Part 158 Toxicology Data Requirements, an immunotoxicity

study is required for food and non - food use pesticides. HED has received immunotoxicity

waiver requests from the registrants of bensulfuron methyl , orthosulfamuron and sulfosulfuron , however the HED Hazard and Science Policy Council (HASPOC) has decided to evaluate the sulfon ylurea (S U) pesticides as a class due to their structural and toxicological similarities. The HASPOC met on July 18 , 2013 to determine the need for the immunotoxicity study (870.7800) for the following sulfonylurea ( SU ) pesticides . **Chemical PC Code**  **CAS Number** Bensulfuron - methyl 128820 83055 - 99 - 6 Chlorsulfuron 118601 64902 - 72 - 3 Ethametsulfuron 129091 97780 - 06 - 8 Flazasulfuron 119011 104040 - 78 - 0 Foramsulfuron 122020 173159 - 57 - 4 Halosulfuron - methyl 128721 135397 - 30 - 7 Mesosulfuron - methyl 122009 400852 - 66 - 6 Metsulfuron - methyl 122010 868680 - 84 - 6 Orthosulf am uron 108209 213464 - 77 - 8 Primisulfuron - methyl 128973 113036 - 87 - 6 Prosulfuron 129031 94125 - 34 - 5 Sulfometuron - methyl 122001 74222 - 97 - 2 Sulfosulfuron 085601 141776 - 32 - 1 Triasulfuron 128969 82097 - 50 - 5 Tri flu sulfuron - methyl 129002 12 6535 - 15 - 7 II . SUMMARY OF USE PROFILE, EXPOSURE AND HAZARD CONSIDERATIONS **a. Use Profile**  : The use profile for the SU pesticides is presented in Appendix 1. **b. Toxicity**  **Profile:** The SUs have low toxicity following acute exposure via oral, inhalation , and dermal routes of exposure (Toxicity

Category I II - IV). Except for ethametsulfuron (Toxicity Category II) and metsulfuron methyl (Toxicity Category I ), there is no evidence of eye irritation. Except for tribenuron - methyl, the SUs are not dermal sensitizers. As a class, SU pesticides tend to target the liver or only cause general signs of toxicity , suc h as decreased body weight and body weight gain s . Other organs where toxicity was observed sporadicall y in the databases of indivi dual SUs include the kidney , hematopoietic sy stem, thy roid, bladder, testes, thy

mus , and spleen. Of the SUs that did cause toxicity in organs related to the immune sy stem (hematopoietic sy stem, thymus, and spleen), an immunotoxicity study was conducted (io dosulfuron, rimsulfuron, trifloxy sulfuron and chlorimuron ethyl) or the toxic effects were observed in the presence of toxicity to organs that were not related to the immunePage **3** of **10**

sy stem (primisulfuron and prosulfuron), such as the liver ; with the exception of s ulfometuron methyl, where the most sensitive toxic effect was hemoly tic anemia. For the SUs where dermal studies were performed, t oxicity was generally not seen f ol lowing dermal exposure except following dermal exposure to triasulfuron , halosulfuron methyl , metsulfuron methyl , and tribenuron meth yl . Developmental toxicity was obser

ved for the majorit y of the SU s; however, qualitative or quantitative susceptibility was not commonly

observed. When there was susceptibility in offspring , it was of low concern because there were clearly established no observed adverse effect levels (NOAELs ) and the endpoints chosen for risk assessment were protective of the developmental effects. Effects on reproduction were rare but were observed for so me SUs ( flazasulfuron, primisulfuron, prosulfuron, triasulfuron , and tribenuron methyl) . SUs did not show consistent evidence of neurotoxicity , except prosulfuron . None of the SUs were considered mutagenic and the majority of the SUs are classified as “ n ot likely to be carcinogenic ” or displayed no evidence of carcinogenicity . Triflusulfuron and tribenruon methyl were classified as possible human carcinogens, while orthosulfamuron was classified as having suggestive evidence of carcinogenicity. **c. Indicato**  **rs for Potential Immunotoxicity Param**  **eter Findings**  Hematology Indicators (WBC changes) Decreased white blood cells in dogs (halosulfuron methyl), mice (nicosulfuron), and rats (prosulfuron). Clinical Chemistry Indicators (A/G Ratio) Decreased A/G ratio in dogs (prosulfuron). Organ Weight Indicators (Spleen, Thymus) None. Histopathology Indicators (Spleen, Thymus, Lymph nodes) Histological changes in bone marrow in dogs (orthosulf

am uron). Toxicity Profile (Target Organs) None . The overall weight of evidence (WOE) suggests that these chemicals d o not target the immune sy stem. There were some effects on hematology , clinical chemistry , and histopathological alterations in immune - related tissues ; but these effects generall y were observed in the presenc e of toxicity

in other organs and were not considered major effect s . Furthermore , the majorit y of SUs did not show any

evidence of immunotoxicity . **d. Evidence for**  **Immunotoxicity from SAR Chemicals**  **– Retrospective Analysis**  . Acceptable guideline immunotoxicity studies have been submitted for seven SU pesticide chemicals. No immunotoxicity was seen following exposure to six of the seven chemicals. For one chemical ( i maz o sulfuron), evidence of immunosuppression ( i.e ., lower ant i - SRBC IgM concentration) was seen only at the highest dose tested (710 mg/kg/day) and in the presence of sy stemic toxicity . The NOA EL for immunotoxicity was 2 2 2 mg/kg/day

and the lowest observed adverse effect level ( LOAEL ) was 710 mg/kg/day . Sy stemic t oxicity , manifested as d ecreases inPage **4** of **10**

body weight/body

weight ga in, and food consumption were seen at 710 mg/kg/day (LOAEL); the NOAEL was 222 mg/kg/day . For i mazosulfuron , there was no impact of the immunotoxicity study to the points of departure (PODs) for risk assessment. The chronic r eference d ose (cRfD) is based on a POD of 75 mg/kg/day

which is approximately

3 - fold lower than the NOAEL for immunotoxicity , and th e POD used for assessing risks for s hort and i ntermediate - term i ncidental o ral exposure (235mg/kg/day) is numerically equivalent to the i mmunotoxicity NOAEL (222 mg/kg/day). **Chlorimuron ethyl** MRID No. 48691101 Immunotoxicity NOAEL 184 mg/kg/day (HDT) Immunotoxicity LOAEL Not Established Basis for LOAEL N one Systemic toxicity NOAEL 184 mg/kg/day Systemic Toxicity LOAEL Not Established Basis for the LOAEL None **Imaz o**  **sulfuron** MRID No. 48691004 Immunotoxicity NOAEL 22 2 mg/kg/day (HDT) Immunotoxicity LOAEL 710 Basis for LOAEL Decrease in anti - SRBC IgM Systemic toxicity NOAEL 222 mg/kg/day Systemic Toxicity LOAEL 710 mg/kg/day Basis for the LOAEL Decreases in body weight/body weight gain, and food consumption **Iodosulfuron methyl -**  **sodium** MRID No. 48592801 Immunotoxicity NOAEL 242 mg/kg/day (HDT) Immunotoxicity LOAEL Not Established Basis for LOAEL None Systemic toxicity NOAEL 73 mg/kg/day Systemic Toxicity LOAEL 242 mg/kg/day Basis for the LOAEL Decreases in body weight gain, and food consumption **Rimsulfuron** MRID No 48710305 Immunotoxicity NOAEL 1006 mg/kg/day (HDT) Immunotoxicity LOAEL Not Established Basis for LOAEL None Systemic toxicity NOAEL 1006 mg/kg/day Systemic Toxicity LOAEL Not Established Basis for the LOAEL NonePage **5** of **10 Thifensulfuron**  **- methyl**  MRID No. 48686101 Immunotoxicity NOAEL 529 mg/kg/day (HDT) Immunotoxicity LOAEL Not Established Basis for LOAEL None Systemic toxicity NOAEL 529 mg/kg/day Systemic Toxicity LOAEL Not Established Basis for the LOAEL None **Tribenuron -**  **methyl** MRID No. 48641101 Immunotoxicity NOAEL 44 mg/kg/day (HDT) Immunotoxicity LOAEL Not Established Basis for LOAEL None Systemic toxicity NOAEL 23 mg/kg/day Systemic Toxicity LOAEL 44 mg/kg/day Basis for the LOAEL Decreases in body weight/body weight gain, and food consumption **Trifloxysulfuron sodium** MRID No. 48857701 Immunotoxicity NOAEL 1066.6 mg/kg/day (HDT) Immunotoxicity LOAEL Not Established Basis for LOAEL None Systemic toxicity NOAEL 1066.6 mg/kg/day Systemic Toxicity LOAEL Not Established Basis for the LOAEL None **III . STUDY**  **WAIVER REQUESTS** A waiver is recommended for an immunotoxicity study for the SU pesticides based on the following considerations:

 There was minimal evidence of immunotoxicity in the available data base s for an y of the SU pesticides.  The liver, not the immune sy stem , is generall y the target organ for this chemical class, and h epatotoxicity or body weight changes are the primary toxicological endpoint s of concern .  PODs based on the most sensitive endpoints obtained via the appropriate routes of exposure in the most sensitive species are currently used for dietary and non - dietary risk assessments for most SUs .  There was no evidence of immunotoxicity with six other structurally - re lated sulfonylurea herbicides, namely

chlorimuron ethyl, iodosulfuron, rimsulfuron, thifensulfuron methyl , tribenuron meth yl , and trifloxy sulfuron sodium . While imazosulfuron did exhibitPage **6** of **10**

immunotoxicity , it was observed in the presence of sy stemic toxicity and at a relativel y high dose. All these factors indicate that an immunotoxicity study would most likely

not result in an adverse effect that could be used as an endpoint for SU risk assessment. **IV. HASPOC CONCLUSIONS** The HASPOC, based on a weight of evidence approach, concludes that immunotoxicity studies are not required as this time for bensulfuron - methyl, chlorsulfuron, ethametsulfuron, flazasulfuron, foramsulfuron, halosulfuron - methyl, mesosulfuron - methyl, metsulfuron - methyl, orthosulfamuron, primisulfuron - methyl, prosulfuron, sulfometuron - methyl, sulfosulfuron, triasulfuron, and triflusulfuron - methyl.Page **7** of **10**



### Appendix 1: **Use Profiles of Sulfonylurea Pesticides** 1. **Bensulfuron methyl (**  **128 820**  **):** C urrentl y registered for use on agricultural rice production (grain and straw) to control broadleaf weeds and sedges. Due to common crayfish aquaculture in flooded rice paddies, a tolerance for cray fish was established concomitant with the tolerance e stablishment for rice grain and rice straw. All registered formulations of bensulfuron methyl (dry flowable, granular, and emulsifiable concentrate) may

be applied to rice via ground or aerial equipment. 2. **Chlorimuron ethyl (**  **128901):** Currentl y registered for use on so ybeans, field corn, peanuts, low growing berries (subgroup 13 - 07H, except strawberry) and non - crop areas such as fence rows and roadsides. Soy bean is the predominant agricultural usage. Chlorimuron ethyl may

be applied to soy

beans at pre - plant, pre - emergence, post emergence, as a band treatment, broadcast, ground spray , low volume spray , or soil incorporation treatment. The use on corn is pre - plant, pre - and post emergence, applied as a band treatment, broadcast, and burndown treatment. Chlo rimuron ethyl may also be applied to non - crop land as a broadcast treatment. 3. **Chlorsulfuron (118601):** Currentl y registered for use on barley , oats, wheat, fallow fields, and ornamental turf to control grasses and broadleaf weeds. Based on the current use profile, exposures can be expected to occur via the dietary (food and drinking water), occupational (handler and post - application), and residential (handler and post application) routes for chlorsulfuron. 4. **Ethametsulfuron (129091):** C urrentl y registere d for a single, earl y postemergence application on canola, crambe, and rapeseed. These uses involve a broadcast foliar spray using ground equipment. The only relevant route of exposure is dietary , based on import tolerances. International registrations are limited to canola, rapeseed, crambe, must ard seed, and sunflower seeds. 5. **Flazasulfuron (119011):** C urrently registered for use on non - residential turf such as golf courses, sod farms, professionally managed athletic fields, commercial lawns , Christmas trees, and industrial vegetation management areas. Additionally , it is registered for agricultural use on citrus, grapes , and sugarcane. Flazasulfuron is a sulfonylurea herbicide used to control certain broad - leaf weeds and grasses . Although the dietary exposure from treated agricultural commodities is not affected b y the proposed turf grass use, flazasulfuron may

reach surface and/or groundwater and affect the drinking water component of the dietary exposure. Residential short - term (1 - 30 day s) dermal and inhalation exposures are expected from flazasulfuron handler activities associated with the proposed residential spot treatment use. 6. **Foramsulfuron (122020):** Currentl y registered for p ost - emergence use on field corn, sweet corn, popcorn, and also for use on golf course turf, sports fields, commercial lawns, cemeteries, parks, campsites, recreational areas, home lawns, roadsides, school grounds, and sod farms to control cool season grasses from tolerant grasses and broadleaf weeds . Foramsulfuron is labeled for ground and aerial application; it is not labeled forPage **8** of **10**

application via chemigation sy stems. Based on the existing use patterns, dietary exposure through food and water is possible following application to growing crops. In a ddition, dermal and inhalation exposures are possible for both residential and occupational handlers. Post - application exposure is possible for those who re - enter treated areas, including incidental oral (hand - to - mouth) and dermal post - application exposur es for toddlers playing on treated turf. 7. **Halosulfuron Methyl (128721):** Currentl y registered for used as a pre - and post emergent control of annual broadleaf weeds and nutsedges in several agricultural crops as well as residential turf grass and ornamenta ls. In addition to the agricultural food uses, halosulfuron - methyl is also registered for use on turfgrass, ornamentals, and a variety of non - crop areas including, but not limited to, airports, cemeteries, fallow non - crop areas, golf courses, landscaped areas, public recreation areas, residential property , roadsides, school grounds, sod or turf seed farms, sports fields, residential and commercial landscaped areas with established woody ornamentals, fairgrounds, race tracks, tennis courts, campgrounds, and rights - of - way . Halosulfuron - methyl is formulated as a water dispersible granule (WG) and applied as postemergence broadcast foliar spray s using ground or aerial equipment. Application through any t yp e of irrigation s ys tem is prohibited. 8. **Imazosulfuron ( 118602):**  Currentl y registered for use on tomatoes, peppers and rice in conjunction with turf grass (residential, commercial, golf courses and sod farms), ornamentals (field - grown conifers, deciduous trees, non - bearing fruit and nut trees and landscape plants) bare - ground non - crop areas. Soil - directed ground application is to be used for all tomatoes, peppers, and rice ; aerial application is permitted for rice onl y. Foliar application may

be allowed for tomato and rice. Applications to turf and ornamenta ls are made with ground equipment; applications to bare ground non - crop areas can be made with ground or aerial equipment. Potential exposure routes from the proposed non - crop, turf and ornamental uses are limited to drinking water and occupational and re sidential pathway s. 9. **Iodosulfuron Methyl (122021):** C urrentl y registered for foliar application to wheat, triticale, field corn , and turf (commercial/industrial, sod farms, ornamental, golf course, recreational, residential) and for preplant burndown application for cereal grains, soy bean, and cotton. All applications of this product are to be performed by professional (commercial) applicators only . HED assumes that the product is not available for direct residential use and HED did not conduct a res idential handler assessment. Occupational handlers may

experience short - /intermediate - term exposure to iodosulfuron - methyl sodium while mixing/loading and applying spray s . 10. **Mesosulfuron Methyl (122009):** Currentl y registered uses are wheat and triticale . Mesosulfuron - methyl is not intended for use in public or residential settings. Therefore, residential exposure is not expected. There is a potential for occupational exposure to mesosulfuron - methyl during mixing, loading, application, and post - applicat ion activities.Page **9** of **10**

11. **Metsulfuron Methyl (122010):** Metsulfuron - methyl is a herbicide used to control a variet y of annual grasses and broadleaf weeds. Metsulfuron - methyl is registered for use on a number of food and feed crops, on conifers and hardwoods, on industrial sites, and on turf. Based on the current use profile, exposures can be expected to occur via the dietary (food and drinking water), residential (handler and post - application), and occupational (handler and post - application) routes for metsulfuron - methyl. 12. **Nicosulfuron (129008):** Currently registered for use on fiel d corn, sweet corn, popcorn, and grasses (Bermuda grass, grass forage and grass hay). Nicosulfuron is also registered for use on sorghum plants in seed propagation fields. There are no residential uses of nicosulfuron. 13. **Orthosulfamuron (108209):** Currentl y registered for the control of annual and perennial broadleaf weeds, sedges, and barn yard grass. There are no registered residential uses for orthosulfamuron or uses that might result in residential exposure. 14. **Primisulfuron Methyl (128973):** Currentl y registered to control annual and perennial grass and broadleaf weeds. Based on the proposed use patterns, short - term dermal and inhalation exposures are expected. Intermediate - term dermal and inhalation exposures are possible for commercial or contract applicators. No residential handler or post application exposure risk has been calculated. 15. **Prosulfuron (129031):** Currently i s registered for use on field corn (grown for grain, silage, or seed), popcorn, grain sorghum (milo), wheat, barley , rye oats, triticale, proso millet, and following small grain harvest . Based on the current use profile, exposures can be expected to occur via the dietary (food and drinking water) and occupational (handler and post - application) routes for prosulfuron. 16. **Rim sulfuron (129009):**  Currently registered for use on non - residential turf such as golf courses, sod farms athletic fields, industrial and commercial lawns and similar nonresidential areas. Additionally , it is registered on agricultural food crops including bushberries, caneberries, soy beans, potatoes, field corn, tomatoes, grapes, various tree fruits, and tree nuts. There is currently a pending use on chicory . There are no proposed residential uses for rimsulfuron. 17. **Sulfometuron methyl (**  **12 2001**  **):** Currentl y registered 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). It is a non - foo d/non - feed use chemical with no current usage which could lead to exposures from consuming raw agricultural commodities (RACs) and/or processed foods. All sulfometuron methyl containing products are formulated as a water dispersible granule (WDG). Applic ations of sulfometuron methyl can be made aerially using fixed wing airplane and helicopter, and b y ground using groundboom, rights - ofway , and hand - held equipment. Sulfometuron methyl can also be used to impregnate or coat dry bulk fertilizer for application to forested areas. Sulfometuron methyl containingPage **10** of **10**

products are not labeled for use b y professionals in the residential marketplace (i.e., indoor or outdoor residential use sites). 18. **Sulfosulfuron (085601):** Currently registered as a selective pre - and post - emergent sulfonylurea herbicide for the control of various annual grasses and broadleaf weeds in winter and spring wheat, non - food crops and a variety of other non - crop sites including ornamentals, roadsides, airports, lumber yards, recreational area s, parks, golf courses, residential areas (lawns), industrial rights of way , etc. 19. **Thifensulfuron Methyl (128845):** Currently registered for use on cereal grains (barley , field corn, oats, rice, sorghum, wheat, and triticale), oilseed crops (canola, rape, and flax), soy beans, sugar beets and cotton. In addition to these crop uses, it is also registered for use on agricultural fallow, idle, and conservation reserve land. It is registered for use as preplant or preemergence applications for the selective c ontrol of broadleaf weeds, and it is applied using common agricultural equipment (i.e., aerial, ground, chemigation). There are no registered residential uses for thifensulfuron methyl. 20. **Triasulfuron (128969):** Currently registered for pre - emergence control of broadleaf and grass y weeds in wheat and post - emergence in wheat, barley , pastures, and rangeland. There are no residential uses for triasulfuron . O ccupational exposure occurs through simultaneous dermal and inhalation exposure. 21. **Tribenuron Methyl (128887):**  Currentl y registered for use on cereal grains (barley , field corn, oats, rice, sorghum, and wheat), oilseed crops (canola, flax, and sunflower), soy beans, and cotton. There is also a tolerance with regional registration for grass forage, fodder, and hay

(except Bermuda grass forage and hay). It is applied using common agricultural equipment (i.e., aerial, ground, chemigation). There are no registered residential uses for tribenuron methyl. 22. **Trifloxysulfuron Sodium (119009):** Currentl y registered for used for use on numerous agricultural food/feed crops, including almonds, citrus, cotton (picker variety only), sugarcane and tomatoes. Non - agricultural uses include sports fields and residential turf grass. 23. **Triflusulfuron Methyl (129002):** Currentl y registered for use on sugar beets, garden beets, and chicory

using broadcast (ground - or aerial - based) or band application methods at seasonal rates. There are no current or pending residential uses associated with triflusulfuron; therefore, a residential exposure assessment was not performed or required.