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POLLUTION PREVENTION

MEMORANDUM

August 6, 2 0 13

SUBJECT: Sulfonylureas: Summary of Hazard and Science Policy Council (HASPOC) Meeting on July 18,2013 : Recommendations on Data Requirement for Immunotoxicity Studies for Sulfonylurea Pesticides

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PC Codes: 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

TXR No.: 0056723 CAS No.: See below

MRID No.: N/A 40 CFR: N / A

FROM: Kristin Rury, MPH 

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Executive Secretary,

# H~o**e::.:::J** Health Effects Division ( 7 509P)

Anna Lowit, Ph.D., Co

- Chair 

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### ~ THROUGH: Jess Rowland, Co

- Chair

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HASPOC 

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Health Effects Division ( 7 509P)

TO: Ja i me D' Agostino, Toxicologist

Risk Assessment Branch II
Health Effects Division ( 7 509P)

MEETING ATTENDEES

HASPOC Members: Anna Lowit, Anwar Dunbar

, Elizabeth Mendez

, Je f f Evans, Je f f Dawson,

John Kough

, Jonathan Ch e n , Juli e Van A lstine

, Kristin Rur y, Micha e l Metzger, PV Sh a h, Ray

Kent

Presenter : Jaime D' Agostino

Other A ttendees : Abdallah Khasawi n ah

, Christina Swart z Christopher Schlosser, Joey B ev er, Mo n iqu e P e rr o n, Zai d a Fig u e ro a

Page 1 of 10Page 2 of 10 1. PURPOSE OF MEETING

In accordance with the revised 2007 40 CFR Part 158 Toxicology Data Requirements, an immunotoxicity study is require d for food and non-food use pesticides. HED has received immunotoxicity waiver requests fr om the registrants of bensulfu ron methyl, orthosulfamuron and sulfosulfuron, however the HED Hazard and Sc ience Policy Council (HASPOC) has decided to evaluate the sulfonylurea (SU) pesticides as a class due to their struct ural 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

Orthosulfamuron 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 Triflusulfuron-methyl 129002 126535-15-7

II. SUMMARY OF USE PROFILE, EXPO SURE AND HAZARD CONSIDERATIONS

a. Use Profile :

The use profile for the SU pestic ides is presented in Appendix 1.

b. Toxicity Profile:

The SUs have low toxicity following acute exposu re via oral, inhalation, and dermal routes of exposure (Toxicity Category III-IV). Except fo r ethametsulfuron (Toxicity Category II) and metsulfuron methyl (Toxicity Category I), there is no evidence of eye irritation. Except for tribenuron-methyl, the SUs ar e not dermal sensitizers.

As a class, SU pesticides tend to target the liver or only cause general sign s of toxicity, such as decreased body weight and body weight gains. Other organs where toxicity was observed sporadically in the databases of individual SUs include the kidney, hematopoietic system, thyroid, bladder, testes, thymus, and spleen. Of th e SUs that did cause toxi city in organs related to the immune system (hematopoietic system, thymus, and spleen), an immunotoxicity study was conducted (iodosulfuron, rimsulfu ron, trifloxysulfuron and chlo rimuron ethyl) or the toxic effects were observed in the presen ce of toxicity to organs that were not related to the immunePage 3 of 10 system (primisulfuron and prosulfuron), such as the liver; with the exception of sulfometuron methyl, where the most sensitive toxic effect was hemolytic anemia. For the SUs where dermal studies were performed, toxic ity was generally not seen fo llowing dermal exposure except following dermal exposure to triasulfuron, ha losulfuron methyl, metsulfuron methyl, and tribenuron methyl. Developmenta l toxicity was observed for the majority of the SUs; however, qualitative or quantitative susceptibility wa s not commonly observe d. When there was susceptibility in offspring, it was of low con cern because there were clearly established no observed adverse effect levels (NOAELs) and th e endpoints chosen for risk assessment were protective of the developmental effects. Effect s on reproduction were rare but were observed for some SUs (flazasulfuron, primisulfuron, prosulfu ron, triasulfuron, and tribenuron methyl). SUs
did not show consistent evidence of neurotoxic ity, except prosulfuron. None of the SUs were considered mutagenic and the majority of th e SUs are classified as “not likely to be carcinogenic” or displayed no evidence of carcino genicity. Triflusulfur on and tribenruon methyl were classified as possible human carcinogens, wh ile orthosulfamuron was classified as having suggestive evidence of carcinogenicity.

c. Indicators for Potential Immunotoxicity

Parameter 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 (orthosulfamuron).

Toxicity Profile (Target Organs) None.

The overall weight of evidence (WOE) suggests that these chemi cals do not target the immune system. There were some effects on hematol ogy, clinical chemistry, and histopathological

alterations in immune-related tissu es; but these effects generally we re observed in the presence of toxicity in other organs and were not considered major effects. Furthermore, the majority of SUs did not show any evidence of immunotoxicity.

d. Evidence for Immunotoxicity from S AR Chemicals – Retrospective Analysis

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Acceptable guideline immunotoxicity studies ha ve been submitted for seven SU pesticide chemicals. No immunotoxicity was seen followi ng exposure to six of the seven chemicals. For one chemical (imazosulfuron), evidence of immunosuppression ( i.e ., lower anti-SRBC IgM concentration) was seen only at the highest dose tested (710 mg/kg/ day) and in the presence of systemic toxicity. The NOAEL for immunotoxic ity was 222 mg/kg/day and the lowest observed adverse effect level (LOAEL) was 710 mg/kg/day. Sy stemic toxicity, manifested as decreases inPage 4 of 10 body weight/body weight gain, and food consump tion were seen at 710 mg/kg/day (LOAEL); the NOAEL was 222 mg/kg/day.

For imazosulfuron, there was no impact of the im munotoxicity study to th e points of departure (PODs) for risk assessment. The chronic re ference dose (cRfD) is based on a POD of 75 mg/kg/day which is approximately 3-fold lo wer than the NOAEL for immunotoxicity, and th e POD used for assessing risks for short and intermediate-term incidental oral exposure (235mg/kg/day) is numerically equivalent to the immunotoxicity NOAEL (222 mg/kg/day).

Chlorimuron ethyl

MRID No. 48691101 Immunotoxicity NOAEL 184 mg/kg/day (HDT) Immunotoxicity LOAEL Not Established

Basis for LOAEL None Systemic toxicity NOAEL 184 mg/kg/day Systemic Toxicity LOAEL Not Established

Basis for the LOAEL None

Imazosulfuron

MRID No. 48691004 Immunotoxicity NOAEL 222 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 bases for any of the SU pesticides.

 The liver, not the immune system, is generally the target organ for this chemical class, and hepatotoxicity or body weight changes are the primary toxicological endpoints of

concern.

 PODs based on the most sensitive endpoints obtained via the appropriate routes of exposure in the most sensitive species are curre ntly used for dietary and non-dietary risk
assessments for most SUs.

 There was no evidence of immunotoxicity with six other structura lly-related sulfonylurea herbicides, namely chlorimuron ethyl, iodos ulfuron, rimsulfuron, thifensulfuron methyl, tribenuron methyl, and trif loxysulfuron sodium. While imazosulfuron did exhibitPage 6 of 10 immunotoxicity, it was observed in the presence of systemic toxicity and at a relatively 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 ap proach, concludes that immunotoxicity studies are not required as this time for bensulfu ron-methyl, chlorsulfuron, ethametsulfuron, flazasulfuron, foramsulfuron, halosulfuron-methyl , mesosulfuron-methyl, metsulfuron-methyl, orthosulfamuron, primisulfuron-methyl, pros ulfuron, sulfometuron-methyl, sulfosulfuron, triasulfuron, and triflusulfuron-methyl.Page 7 of 10 

### Appendix 1: Use Profiles of Sulfonylurea Pesticides

1. Bensulfuron methyl (128820): Currently registered for use on agricultural rice production (grain and straw) to control br oadleaf weeds and sedges. Due to common crayfish aquaculture in flooded rice paddies , a tolerance for crayfish was established
concomitant with the tolerance establishment fo r 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): Currently registered for use on soybeans, field corn, peanuts, low growing berries (subgroup 13- 07H, except strawberry) and non-crop areas such as fence rows and roadsides. Soybean is the predominant agricultural usage. Chlorimuron ethyl may be applied to soyb eans at pre-plant, pre-emergence, postemergence, 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 tr eatment. Chlorimuron ethyl may also be applied to non-crop land as a broadcast treatment.

3. Chlorsulfuron (118601): Currently registered for use on barley, oats, wheat, fallow fields, and ornamental turf to control grasse s and broadleaf weeds. Based on the current use profile, exposures can be expected to o ccur via the dietary (f ood and drinking water), occupational (handler and post-applicatio n), and residential (handler and postapplication) routes for chlorsulfuron.

4. Ethametsulfuron (129091): Currently registered for a single, early 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, mustard seed, and sunflower seeds.

5. Flazasulfuron (119011): Currently registered for use on non-residential turf such as golf courses, sod farms, professionally managed at hletic fields, commercial lawns, Christmas trees, and industrial vegetation management areas. Additionally, it is registered for agricultural use on citrus, grapes, and suga rcane. Flazasulfuron is a sulfonylurea

herbicide used to control certain broad-l eaf weeds and grasses. Although the dietary exposure from treated agricultural commodities is not affected by the proposed turf grass use, flazasulfuron may reach surface and/or groundwater and affect the drinking water component of the dietary exposure. Reside ntial short-term (1 - 30 days) dermal and inhalation exposures are expect ed from flazasulfuron handler activities associated with the proposed residential s pot treatment use.

6. Foramsulfuron (122020): Currently registered for post-emergence use on field corn, sweet corn, popcorn, and also for use on golf cour se turf, sports fields , commercial lawns, cemeteries, parks, campsites, recreational ar eas, 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 aeria l application; it is not labeled forPage 8 of 10 application via chemigation systems. Based on the existing use patterns, dietary exposure through food and water is possible following app lication to growing crops. In addition, dermal and inhalation exposures are possi ble for both residen tial and occupational handlers. Post-application exposure is possi ble for those who re-enter treated areas, including incidental oral (h and-to-mouth) and dermal pos t-application exposures for toddlers playing on treated turf.

7. Halosulfuron Methyl (128721): Currently registered for used as a pre- and postemergent control of annual broadleaf weeds and nutsedges in several agricultural crops as well as residential turf grass and ornamentals. In addition to the agricultural food uses, halosulfuron-methyl is also re gistered 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 recreati on areas, residential property, roadsides, school grounds, sod or turf seed farms, s ports fields, residential and commercial landscaped areas with established woody orna mentals, fairgrounds, race tracks, tennis courts, campgrounds, and rights-of-way. Halosu lfuron-methyl is formulated as a water dispersible granule (WG) and applied as postemergence broadcast foliar sprays using ground or aerial equipment. Application through any type of irrigation system is prohibited.

8. Imazosulfuron (118602): Currently 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 gr ound application is to be used for all tomatoes, peppers, and rice; aeri al application is permitted for rice only. Foliar application may be allowed for tomato and rice. Applications to turf and ornamentals are made with ground equipment; applications to bare ground non-crop areas can be made with ground or aerial equipment. Potentia l exposure routes from the proposed non-crop, turf and ornamental uses are limited to drinking water and occupational and residential pathways.

9. Iodosulfuron Methyl (122021): Currently registered for foliar application to wheat, triticale, field corn, and turf (commercial/i ndustrial, sod farms, ornamental, golf course, recreational, residential) a nd for preplant burndown a pplication for cereal grains, soybean, and cotton. All applications of this product are to be performed by professional (commercial) applicators only. HED assumes th at the product is not available for direct

residential use and HED did not conduct a re sidential handler assessment. Occupational handlers may experience short-/intermedia te-term exposure to iodosulfuron-methylsodium while mixing/loading and applying sprays.

10. Mesosulfuron Methyl (122009): Currently registered uses are wheat and triticale. Mesosulfuron-methyl is not intended for use in public or residentia l settings. Therefore, residential exposure is not expected. There is a potential for occupational exposure to mesosulfuron-methyl during mixing, loading, ap plication, and post-appl ication activities.Page 9 of 10 11. Metsulfuron Methyl (122010): Metsulfuron-methyl is a herbicide used to control a variety 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 indu strial sites, and on turf. Based on the current use profile, e xposures can be expect ed to occur via the dietary (food and drinking water), resident ial (handler and po st-application), and occupational (handler and post-applica tion) routes for metsulfuron-methyl.

12. Nicosulfuron (129008): Currently registered for use on field corn, sweet corn, popcorn, and grasses (Bermuda grass, grass forage and grass hay). Nicosulfur on is also registered for use on sorghum plants in seed propagation fields. There are no residential uses of

nicosulfuron.

13. Orthosulfamuron (108209): Currently registered for the control of annual and perennial broadleaf weeds, sedges, and barnyard grass. There are no registered residential uses for orthosulfamuron or uses that might result in residential exposure.

14. Primisulfuron Methyl (128973): Currently registered to control annual and perennial grass and broadleaf weeds. Based on the pr oposed use patterns, short-term dermal and inhalation exposures are expected. Intermed iate-term dermal and inhalation exposures are possible for commercial or contract app licators. No residential handler or postapplication exposure risk has been calculated.

15. Prosulfuron (129031): Currently is registered for us e on field corn (grown for grain, silage, or seed), popcorn, grain sorghum (milo ), wheat, barley, rye oa ts, 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. Rimsulfuron (129009): Currently registered for use on non-residential turf such as golf courses, sod farms athletic fields, industrial and co mmercial lawns and similar nonresidential areas. Additionally, it is re gistered on agricultural food crops including bushberries, caneberries, soybeans, 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 (122001): Currently registered for commercial pre- and postemergent applications to manage annual a nd perennial broadleaf weeds and grasses in non-agricultural sites (i.e., forestry, right s of way, non-crop industrial sites, and unimproved turf). It is a non-food/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 c ontaining products are fo rmulated as a water dispersible granule (WDG). Applications of sulfometuron methyl can be made aerially using fixed wing airplane and helicopter, and by gr ound using groundboom, rights-ofway, and hand-held equipment. Sulfometuron me thyl 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 by professiona ls in the residential marketplace (i.e.,

indoor or outdoor resi dential use sites).

18. Sulfosulfuron (085601): Currently registered as a se lective pre- and post-emergent sulfonylurea herbicide for the control of va rious annual grasses a nd broadleaf weeds in winter and spring wheat, non-food crops and a variety of other non- crop sites including ornamentals, roadsides, airports, lumber yard s, recreational areas, parks, golf courses, residential areas (lawns), i ndustrial rights of way, etc.

19. Thifensulfuron Methyl (128845): Currently registered for use on cereal grains (barley, field corn, oats, rice, sorghum, wheat, and trit icale), oilseed crops (canola, rape, and flax), soybeans, 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 control of br oadleaf weeds, and it is applied using common ag ricultural equipment (i.e., aer ial, ground, chemigation). There are no registered residentia l uses for thifensulfuron methyl.

20. Triasulfuron (128969): Currently registered for pre-em ergence control of broadleaf and grassy weeds in wheat and post-emergence in wheat, barley, pastures, and rangeland.

There are no residential uses for triasu lfuron. Occupational exposure occurs through simultaneous dermal and inhalation exposure.

21. Tribenuron Methyl (128887): Currently registered for use on cereal grains (barley, field corn, oats, rice, sorghum, and wheat), oilseed crops (canola, flax, and sunflower), soybeans, 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): Currently 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): Currently 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.