Sulfonylureas: Screening Analysis of 

Toxicological Profiles to Consider Whether a 

Candidate Common Mechanism Group Can Be 

Established.

Office of Pesticide Programs 

Office of Chemical Safety and Pollution Prevention 

U.S. Environmental Protection Agency 

Washington, DC 

 

September 9, 2015 

 

Page 3 of 13 

analysis.html). This document provides guidance on how to screen groups of pesticides for 

cumulative evaluation using a two-step approach beginning with the evaluation of available 

toxicological information and if necessary, followed by a risk-based screening approach. This 

framework supplements the existing guidance documents for establishing common mechanism 

groups (CMGs)1

 and conducting cumulative risk assessments (CRA)2. The Agency has utilized 

this framework for the sulfonylureas and determined that although the sulfonylureas share some 

chemical and toxicological characteristics, the toxicological database does not support a testable 

hypothesis for a common mechanism of action. No further mechanistic data are required and no 

further cumulative evaluation is necessary for the sulfonylureas.

Chemical PC Code CAS Number 

Bensulfuron-methyl 128820 83055-99-6 

Chlorimuron-ethyl 128901 90982-32-4 

Chlorsulfuron 118601 64902-72-3 

Ethametsulfuron 129091 97780-06-8 

Flazasulfuron 119011 104040-78-0 

Foramsulfuron 122020 173159-57-4 

Halosulfuron 128721 135397-30-7 

Imazosulfuron 118602 122548-33-8 

Iodosulfuron-methylsodium 122021 144550-36-7 

Mesosulfuron-methyl 122009 208465-21-8 

Metsulfuron 122010 868680-84-6 

Nicosulfuron 129008 111991-09-4 

Orthosulfamuron 108209 213464-77-8 

Primisulfuron-methyl 128973 86209-51-0 

Prosulfuron 129031 94125-34-5 

Rimsulfuron 129009 122931-48-0 

Sulfometuron-methyl 122001 74222-97-2 

Sulfosulfuron 085601 141776-32-1 

Thifensulfuron-methyl 128845 79277-27-3 

Triasulfuron 128969 82097-50-5 

Tribenuron-methyl 128887 101200-48-0 

Trifloxysulfuron-sodium 119009 199119-58-9 

Triflusulfuron-methyl 129002 126535-15-7 

 

 

1 Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity

(USEPA, 1999) 

2 Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity

(USEPA, 2002)
Page 4 of 13 

Sulfonylureas: Screening Analysis of Toxicological Profiles to Consider Whether a Candidate 

Common Mechanism Group Can Be Established. 

1.0 Introduction 

Sulfonylureas (SU) are a group of herbicides that control weeds through inhibition of the enzyme 

acetolactate synthase (ALS), which catalyzes the first step in the synthesis of branched-chain 

amino acids. They are used as pre- and post-emergent herbicides on a wide variety of crops, 

pasture land, rangeland, industrial sites, and turf grass. Currently, the SUs are undergoing 

registration review. 

EPA’s Office of Pesticide Programs has developed a draft guidance document entitled Pesticide 

Cumulative Risk Assessment: Framework for Screening Analysis

(http://www.epa.gov/oppfead1/cb/csb_page/updates/2015/framework-for-screeninganalysis.html). This document provides guidance on how to screen groups of pesticides for 

cumulative evaluation using a two-step approach beginning with the evaluation of available 

toxicological information and, if necessary, followed by a risk-based screening approach. This 

framework supplements the existing guidance documents for establishing common mechanism 

groups (CMGs)3 and conducting cumulative risk assessments (CRA)4. Consistent with the 

framework, the toxicological knowledgebase for the SUs was evaluated in terms of information 

on mode of action (MOA)/adverse outcome pathway (AOP), chemical structural similarity, and 

toxicological profile to determine if the available data supports establishing a candidate CMG for 

this class of pesticides. 

2.0 MOA/AOP 

The herbicidal MOA for SUs is inhibition of ALS, an enzyme that catalyzes the biosynthesis of 

three branched-chain amino acids (valine, leucine, and isoleucine), all of which are essential for 

plant growth. In contrast, no mammalian MOA data was available for the SUs. While humans do 

have an ALS enzyme, its function is unknown (Joutel et al., 1996), and therefore the human 

relevance of ALS inhibition is uncertain. Of note, valine, leucine, and isoleucine are essential 

amino acids, meaning they cannot be synthesized by mammals and must be ingested, indicating 

that the role of ALS in humans, if any, is likely different than in plants. Given that there is no 

mammalian MOA data for the SUs and that the function of ALS in humans is unknown, ALS 

does not provide a foundation for establishing a candidate common mechanism group. 

2.1 Chemical Structural Similarity 

All of the registered SUs contain a central sulfonylurea structure that terminates in different 

structures depending on the SU as depicted in Figure 2.1 and Appendix A. The SUs can be 

further subcategorized based on the substituent on the urea side of the molecule (R2). For the 

registered SUs this is either a substituted pyrimidine or triazine ring. 

 

3 Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity

(USEPA, 1999) 

4 Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity

(USEPA, 2002)
Page 5 of 13 

In contrast to the relative similarity of the substituents on the urea side, the substituents 

terminating the sulfonyl end of the molecule (R′) show a higher degree of structural variability. 

Due to this variability, the registered SUs could not be meaningfully subcategorized based on the 

substituents on the sulfonyl end of the molecule. 

In summary, although the degree of similarity varies depending on the substituents on either end 

of the chemical, the SUs can be considered to have a shared core chemical structure. 

Figure 2.1. Sulfonylurea chemical structure. 

2.2 Toxicological Profile 

The Pesticide Cumulative Risk Assessment: Framework for Screening Analysis document states 

that reviewers should conduct an initial review of the experimental toxicology data from the data 

submitted for pesticide registration for a group of pesticides to evaluate the extent to which 

common patterns of effects are observed among the members of the potential class. The 

document also emphasizes that effects at lower doses, particularly those used in deriving points 

of departure (PoDs) for single pesticide risk assessments, get more weight in the screening 

analysis. With these points in mind, the SUs were first screened to determine if there were 

common durations of exposure in which the effects observed for deriving the PoDs could be 

compared for common effects. Based on an initial screen, it was determined that only a small 

number of the SUs had an endpoint chosen for acute dietary risk assessment (8/23) and therefore, 

the studies chosen for acute dietary exposure would not be useful for comparing across the SUs 

as a class. In contrast, all of the SUs had chronic dietary endpoints, except for foramsulfuron 

where no toxicity was observed in any study and therefore only qualitative exposure assessments 

were performed. Since all of the quantitative assessments for the SUs had a chronic dietary 

endpoint and the chronic dietary endpoint would generally represent the most sensitive effects 

for each SU, the effects used for deriving the chronic dietary endpoints were focused on to 

determine if there were common patterns of toxicological effects across the SUs. 

For each SU, the chronic study used for the chronic dietary endpoint was evaluated to determine 

the toxicological effects at the LOAEL and the target organs or general effects (decreased body 

weight/body weight gain) were noted. The full toxicity profile of each SU was also evaluated to 

make sure the target organs identified and effects observed were consistent with the effects seen 

throughout the database of that chemical. Once the chronic endpoint for each SU was evaluated, 

the target organs were compared across the SUs as a class to see if there was a clear pattern 

indicating a common toxicological effect. Furthermore, since structurally the SUs could be subdivided based on the substituent on the urea portion of the molecule, as described in section 2.1, 

the target organs of each subclass were compared to see if there was a clear association between 

the identified target organs and the substituent on the urea side of the molecule. 
Page 6 of 13 

The chronic dietary endpoints and the target organs identified are summarized in Appendix B. 

The target organs/effects observed were as follows: 

 The hematopoietic system 

o Effects on the hematopoietic system were observed in 8/23 SUs (5/14, 

pyrimidine; 3/9, triazinine). 

o Effects were consistent across the SUs (signs of anemia and microscopic changes 

in the spleen and bone marrow). 

 The liver 

o Liver effects were observed in 7/23 SUs (5/14, pyrimidine; 2/9, triazinine). 

o The liver effects observed were non-specific (increased liver weights and elevated 

enzymes) and were not informative for determining if they were the result of a 

common mechanism of toxicity. 

 General body weight effects 

o Effects on body weight were observed in 6/23 SUs (5/14, pyrimidine; 7/9, 

triazinine). 

o Decreases in body weight are non-specific and not likely to be derived from a 

common toxicity pathway. 

 Other target organs 

o Kidney (3/23) 

o Thyroid (2/23) 

o Urinary tract (1/23) 

o Testes (1/23) 

o Thymus (1/23) 

It should be pointed out that the numbers above do not indicate that, for example, only 7 SUs 

showed evidence of liver effects. More SUs than outlined above had evidence of a particular 

effect; however, the effects were either seen inconsistently across the toxicity profile for the 

individual SU or were seen at higher doses and not considered a major target organ for that SU. 

Despite the fact that the most sensitive effects following chronic exposure were similar for some 

of the SUs, there was no consistent target organ/effect across the class that would be supportive 

of a common apical outcome. Further subdividing the SUs into subclasses based on the urea 

substituent did not result in a clear association between a target organ and either subclass. Taken 

together, the toxicological profiles of the SUs did not support a candidate CMG determination. 

3.0 Conclusions from CMG Screening Analysis and Options for Further CRA 

The SUs share a core chemical structure with varying degrees of structural similarity based on 

individual substituents on either side of the molecule. In addition, the SUs share a pesticidal 

MOA (inhibition of ALS), although the function of ALS in humans is unknown and the 

relevance of this MOA in humans in unclear. Based on toxicity studies, the SUs do not share a 

common toxicological profile; instead the target organs vary among the class and are often 

unspecific, such as changes in body weight or general effects on the liver. Further dividing the 

SUs into subclasses based on the urea substituent did not result in a clear association of a target 

organ with any particular substructure. 
Page 7 of 13 

Based on the weight of the evidence, considering the lack of common toxicological profile of the 

SUs, the uncertainty in the human relevance of ALS inhibition, and the lack of mammalian 

MOA data, a testable hypothesis for a common mechanism of action cannot be identified. 

Therefore, the Agency concludes that no common mechanism of toxicity exists among these 

pesticides and a CRA approach is not appropriate for this class of pesticides. 

4.0 References 

Joutel, A; Ducros, A; Alamowitch, S; et al. (1996). A human homolog of bacterial acetolactate 

synthase genes maps within the CADASIL critical region. Genomics 38(2):192-198. 

 
Page 8 of 13 

Appendix A. Sulfonylurea chemical structures and structural subcategory 

Chemical Name Structure Subcategory based 

on urea substituent 

Bensulfuron-methyl pyrimidine 

Chlorimuron-ethyl pyrimidine 

Chlorsulfuron triazine 

Ethametsulfuron triazine 

Flazasulfuron pyrimidine 

Foramsulfuron pyrimidine 

Halosulfuron pyrimidine 

Imazosulfuron pyrimidine 

Iodosulfuron-methyl-sodium triazine 

Mesosulfuron-methyl pyrimidine 

Metsulfuron triazine 
Page 9 of 13 

Chemical Name Structure Subcategory based 

on urea substituent 

Nicosulfuron pyrimidine 

Orthosulfamuron pyrimidine 

Primisulfuron-methyl pyrimidine 

Prosulfuron triazine 

Rimsulfuron pyrimidine 

Sulfometuron-methyl pyrimidine 

Sulfosulfuron pyrimidine 

Thifensulfuron-methyl triazine 

Triasulfuron triazine 
Page 10 of 13 

Chemical Name Structure Subcategory based 

on urea substituent 

Tribenuron-methyl triazine 

Trifloxysulfuron-sodium pyrimidine 

Triflusulfuron-methyl triazine 

 
Page 11 of 13 

Appendix B. Sulfonylurea Chronic Dietary Endpoints and Target Organs 

Chemical Name Chronic dietary endpoint1

 Target Organ Subcategory2

Bensulfuronmethyl Increased liver enzymes and 

liver weight (N= 21.4, L= 

237.3) 

Liver pyrimidine 

Chlorimuronethyl Hematological changes and 

atrophy of thymus (N=9, L= 

42.7) 

Hematopoietic, 

thymus 

pyrimidine 

Chlorsulfuron Decreased body weight (N=5, 

L=25) 

Body weight triazine 

Ethametsulfuron Decreased body weight and 

body weight gain (N=86.9, 

L=483) 

Body weight triazine 

Flazasulfuron Chronic nephropathy (N=1.3, 

L=13.3) 

Kidney, liver pyrimidine 

Foramsulfuron No toxicity observed in any 

study 

No endpoint pyrimidine 

Halosulfuron Decreased body weight gain, 

hematological changes, and 

clinical chemistry changes 

(N=10, L=40) 

Hematopoietic, body 

weight 

pyrimidine 

Imazosulfuron Thyroid hypertrophy (N=75, 

L=150) 

thyroid pyrimidine 

Iodosulfuronmethyl-sodium Hematopoietic histopathology 

(N=7.3, L=43.7) 

Hematopoietic triazine 

Mesosulfuronmethyl Increased mucous secretion 

(N=155, L=574) 

Other pyrimidine 

Metsulfuron Decreased body weight and 

body weight gain (N=25, 

L=250) 

Body weight triazine 

Nicosulfuron Decreased body weight gain 

and increased kidney/liver 

weight (N= 125, L= 500) 

Body weight pyrimidine 

Orthosulfamuron Decreased body weight gain 

and 

hepatotoxicity/nephrotoxicity 

(N=5, L=500) 

Kidney, liver, 

hematopoietic, body 

weight 

pyrimidine 

Primisulfuronmethyl Effects on blood cells, 

increased liver weight with 

histopathology, and thyroid 

hyperplasia (N=25, L= 125) 

Hematopoietic, liver, 

thyroid 

pyrimidine 

Prosulfuron Decreased body weight gain, 

hematological findings, and 

hepatotoxicity (N=5.3, L=54) 

Hematopoietic, liver, 

body weight 

triazine 

Rimsulfuron Decreased body weight gain 

and liver effects (N=11.8, 

L=121) 

Body weight, liver pyrimidine 
Page 12 of 13 

Chemical Name Chronic dietary endpoint1

 Target Organ Subcategory2

Sulfometuronmethyl Decreased body weight and 

hemolytic anemia (N=27.5. 

L=148.5) 

Hematopoietic, body 

weight 

pyrimidine 

Sulfosulfuron Urinary tract pathology 

(N=24, L=244.2) 

Urinary tract pyrimidine 

Thifensulfuronmethyl Decreased body weight and 

body weight gain (N=4.3, 

L=128) 

Body weight triazine 

Triasulfuron Centrilobular 

hepatocytomegaly (N=1.2, 

L=129) 

Liver triazine 

Tribenuronmethyl Decreased body weight gain, 

increased liver enzymes, and 

increased urinary volume 

(N=0.8, L=8.16) 

Body weight triazine 

Trifloxysulfuronsodium Tubular atrophy in kidney 

(N=23.7, L= 99.3) 

Kidney pyrimidine 

Triflusulfuronmethyl Decreased body weight/body 

weight gain, hematological 

changes, and interstitial cell 

hyperplasia (N=2.44, L=30.6) 

Body weight, 

hematopoietic, testes 

triazine 

1

N= NOAEL, L=LOAEL. All values presented in mg/kg/day. 

2

Subcatergory is based on the substituent on the urea side of the molecule. 

 
Page 13 of 13