UNITED ST ATES ENVIRONMENTAL PROTECTION AGENCY 

:.:Q ~\ WASHINGTON, D.C. 20460 

~ \' ~ ll ~~~ ·•.ay ' ... f/ '<.:::.~ _c::.: '.~/ OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

August 6, 2013 

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. 

PC Codes: See below DP Barcode: D412018 and D412408 

Decision No.: NIA Registration No.: NIA 

Petition No.: NIA Regulatory Action: NIA 

Risk Assessment Type: NI A Case No.: NI A 

TXR No.: 0056723 CAS No.: See below 

MRID No.: NIA 40 CFR: NIA 

FROM: Kristin Rury, MPH ¥_(J----

Executi ve Secretary, HASioW 

Health Effects Division (7509P) 

THROUGH: Jess Rowl~nd, Co-Chair r ~) / 

Anna Low1t, Ph.D., Co-Chair ~ / / / P" 

HASPOC vtf_) D I 

Health Effects Division (7509P) · 

TO: Jaime D'Agostino, Toxicologist 

Risk Assessment Branch II 

Health Effects Division (7509P) 

MEETING ATTENDEES 

HASPOC Members: Anna Lowit, Anwar Dunbar, Elizabeth Mendez, Jeff Evans, Jeff Dawson, 

John Kough, Jonathan Chen, Julie Van Alstine, Kristin Rury, Michael Metzger, PV Shah, Ray 

Kent 

Presenter: Jaime D' Agostino 

Other Attendees: Abdallah Khasawinah, Christina Swartz Christopher Schlosser, Joey Bever, 

Monique Perron, Zaida Figueroa 

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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 sulfonylurea (SU) 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 

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, 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 III-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, 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 the SUs that did cause toxicity in organs related 

to the immune system (hematopoietic system, thymus, and spleen), an immunotoxicity study was 

conducted (iodosulfuron, rimsulfuron, trifloxysulfuron and chlorimuron ethyl) or the toxic 

effects were observed in the presence of toxicity to organs that were not related to the immune 
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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, toxicity was generally not seen following dermal exposure except 

following dermal exposure to triasulfuron, halosulfuron methyl, metsulfuron methyl, and 

tribenuron methyl. Developmental toxicity was observed for the majority of the SUs; 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 

some 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 “not 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. 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 chemicals do not target the immune 

system. There were some effects on hematology, clinical chemistry, and histopathological 

alterations in immune-related tissues; but these effects generally were 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 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 (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 immunotoxicity was 222 mg/kg/day and the lowest observed 

adverse effect level (LOAEL) was 710 mg/kg/day. Systemic toxicity, manifested as decreases in 
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body weight/body weight gain, and food consumption were seen at 710 mg/kg/day (LOAEL); 

the NOAEL was 222 mg/kg/day. 

For imazosulfuron, there was no impact of the immunotoxicity study to the points of departure 

(PODs) for risk assessment. The chronic reference dose (cRfD) is based on a POD of 75 

mg/kg/day which is approximately 3-fold lower than the NOAEL for immunotoxicity, and the 

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 None 
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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 currently used for dietary and non-dietary risk 

assessments for most SUs. 

 There was no evidence of immunotoxicity with six other structurally-related sulfonylurea 

herbicides, namely chlorimuron ethyl, iodosulfuron, rimsulfuron, thifensulfuron methyl, 

tribenuron methyl, and trifloxysulfuron sodium. While imazosulfuron did exhibit 
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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 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. 
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Appendix 1: Use Profiles of Sulfonylurea Pesticides 

1. Bensulfuron methyl (128820): Currently 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 crayfish was established 

concomitant with the tolerance establishment 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): 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 soybeans 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 treatment. 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 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 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 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 by 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 days) dermal and 

inhalation exposures are expected from flazasulfuron handler activities associated with 

the proposed residential spot treatment use. 

6. Foramsulfuron (122020): Currently registered for post-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 for 
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application via chemigation systems. Based on the existing use patterns, dietary exposure 

through food and water is possible following application to growing crops. In addition, 

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 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 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 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 ground application is to be 

used for all tomatoes, peppers, and rice; aerial 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. Potential 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/industrial, sod farms, ornamental, golf course, 

recreational, residential) and for preplant burndown application for cereal grains, 

soybean, 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 residential handler assessment. Occupational 

handlers may experience short-/intermediate-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 residential settings. Therefore, 

residential exposure is not expected. There is a potential for occupational exposure to 

mesosulfuron-methyl during mixing, loading, application, and post-application activities. 
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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 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 field 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): 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 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 postapplication exposure risk has been calculated. 

15. Prosulfuron (129031): Currently is 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. Rimsulfuron (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, 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 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-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 containing products are formulated as a water 

dispersible granule (WDG). Applications of sulfometuron methyl can be made aerially 

using fixed wing airplane and helicopter, and by 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 containing 
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products are not labeled for use by 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 areas, 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), 

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 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 

grassy weeds in wheat and post-emergence in wheat, barley, pastures, and rangeland. 

There are no residential uses for triasulfuron. 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.