                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C. 20460

                                                 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.: 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
		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 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 

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 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 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
   
                             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 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. 

































	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, 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.  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 post-application) 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 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 post-emergent 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-methyl-sodium 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.

   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 post-application 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 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-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-of-way, 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 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.  




