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imazethapyr Herbicide Profile 3/89

<ENTR Accepted>
 
                          CHEMICAL FACT SHEET FOR
                                Imazethapyr                                 
FACT SHEET NUMBER: 196             
DATE ISSUED: MARCH 8, 1989                                                  
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1.  Description of Chemical                                                 
                                                                            
   - Common Name:  Imazethapyr                                              
   - Chemical Name:  (+)-2- 4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-
                     imidazol-2-y1|-5-ethyl-3-pyridinecarboxylic acid       
   - Trade Name:  Pursuit(R)                                                
   - OPP (Shaughnessy) NO.:  128982                                         
   - Chemical Abstracts Service (CAS) Number:                               
   - Empirical Formula:  C15H22N4O3                                         
   - Molecular Weight:  306.4                                               
   - Year of Initial Registration:  1989                                    
   - Pesticide Type:  Herbicide                                             
   - U.S. Producer:  American Cyanamid Company                              
 
2.  Use Patterns and Formulations                                           
                                                                            
   - Application Sites:  Terrestrial food crops                             
   - Major Crops Treated:  Soybeans                                         
   - Types and Methods of Application:  Foliar or soil, applied broadcast by
     ground equipment for control of broadleaf weeds and grasses.  Applied  
     early preplant, preplant incorporated, preemergence, or early          
     postemergence.                                                         
   - Application Rate:  0.0625 pounds active ingredient/acre (lb ai/A) or 4 
     ounces product/A.                                                      
   - Type of Formulations:  Emulsifiable concentrate.                       
   - Usual Carriers:  Water with crop oil or a nonionic surfactant.         
 
3.  Science Findings                                                        
                                                                            
   Chemical Characteristics                                                 
   - Technical:                                                             
     - Physical State:  Solid                                               
     - Color:  Off-white to tan                                             
     - Odor:  Pungent                                                       
     - Boiling Point:  N/A                                                  
     - Density:  0.396 g/mL untapped, 0.459 g/mL tapped                     
     - Solubility:                                                          
                                      Solubility at 25 C                    
       Solvent                        (g/100 mL Solvent)                    
       -------------------------------------------------                    
       Acetone                            4.82                              
       Dimethyl sulfoxide                42.25                              
       Heptane                            0.09                              
       Methanol                          10.50                              
       Methylene chloride                18.48                              
       2-Propanol                         1.73                              
       Toluene                            0.50                              
       Water (distilled)                  0.14                              
   - Vapor Pressure:  (pure form) < 1 x 10^-7 mm Hg at 60 C                 
   - Dissociation Constant:  pka = 3.9                                      
   - pH:  2.85 at 25 C                                                      
 
   Toxicological Characteristics                                            
   - Acute Toxicology - Technical:                                          
     - Acute Oral Toxicity - Rat:  > 5000 mg/kg/day (male and females)      
       Toxicity Category IV                                                 
     - Acute Dermal Toxicity - Rabbit:  > 5000 mg/kg/day (males and females)
       Toxicity Category III                                                
     - Primary Dermal Irritation - Rabbit:  Imazethapyr is minimally        
       irritating.  Toxicity Category IV                                    
     - Primary Eye Irritation:  Imazethapyr is practically nonirritating.   
       Toxicity Category III                                                
     - Dermal Sensitization - Guinea Pig:  Imazethapyr is not a dermal      
       sensitizer.                                                          
     - Acute Inhalation:  > 3.27 mg/L air (analytical) or 4.21 mg/L air     
       (gravimetric).  Toxicity Category III                                
   - Acute Toxicology - Pursuit Herbicide (22.6% Formulation)               
     - Acute Oral Toxicity - Rat:  > 5000 mg/kg (males and females)         
       Toxicity Category IV                                                 
     - Acute Dermal Toxicity - Rabbit:  > 5000 mg/kg (males and females)    
       Toxicity Category IV                                                 
     - Primary Eye Irritation - Rabbit:  Minimally irritating Toxicity      
       Category IV                                                          
     - Primary Dermal Irritation:  Minimally irritating Toxicity Category IV
   - Acute Toxicology - Pursuit Plus (2.39% Formulation)                    
     - Acute Oral Toxicity - Rat:  > 5000 mg/kg (males and females) Toxicity
       Category IV                                                          
     - Acute Dermal Toxicity - Rats:  > 2000 mg/kg (males and females)      
       Toxicity Category III                                                
     - Acute Inhalation Toxicity - LC50 (males and females) 1.29            
       mg/imazethapyr and 1.27 mg/pendimethalin.  Toxicity Category III     
     - Primary Eye Irritation - Rabbits:  Slight irritation at 24 hours     
       Toxicity Category III                                                
     - Primary Dermal Irritation - Rabbits:  No erythema or edema observed. 
       Toxicity Category IV                                                 
     - Dermal Sensitization - Guinea Pig:  Not a sensitizer.                
   - Subchronic Toxicity                                                    
     - Data are available to satisfy the requirements for sub chronic       
       feeding studies.  These data are discussed below:                    
       - A 90-day rat subchronic feeding study conducted at dose levels of  
         0, 1000, 5000, and 10,000 parts per million (ppm) (0, 50, 250, and 
         500 milligrams/kilogram  mg/kg|/day) resulted in a no-observable   
         effect level (NOEL) of 500 mg/kg/day (highest dose tested (HDT|).  
       - A 90-day dog subchronic feeding study conducted at dosages of 0,   
         1000, 5000, and 10,000 ppm (0, 25, 125, and 250 mg/kg/day) resulted
         in a NOEL of 250 mg/kg/day (HDT).                                  
       - A 21-day rabbit dermal study conducted at dosages of 0, 250, 500,  
         and 1000 mg/kg/day resulted in a NOEL of 1000 mg/kg/day (HDT).     
   - Chronic Feeding and Oncogenicity Studies                               
     - Data are available to satisfy the requirements for chronic feeding   
       studies and oncogenicity studies in two species.  These data are     
       discussed below:                                                     
       - A dog chronic feeding study conducted at dosages of 0, 1000, 5000, 
         and 10,000 ppm (0, 25, 125, and 250 mg/kg/day) resulted in a NOEL  
         of 250 mg/kg/day (HDT) in males and a NOEL for females of 25       
         mg/kg/day.  The lowest-observed-effect level (LOEL) of 125 mg/kg   
         for females was based on decreased packed cell volume hemoglobin   
         and erythrocytes at 250 mg/kg/day.                                 
       - A 2-year rat chronic feeding/oncogenicity study conducted at       
         dosages of 0, 1000, 5000, and 10,000 ppm (0, 50, 200, and 500      
         mg/kg) with no oncogenic effects observed up to 500 mg/kg/day      
         (HDT).  This study is acceptable as a chronic feeding study with a 
         NOEL of 500 mg/kg/day (HDT) but is classified as Supplemental for  
         an oncogenic study because the maximum tolerated dose (MTD) was not
         reached (no significant toxic effects at the HDT).  A repeat of    
         this study is not required at this time because 1) 500 mg/kg       
         (10,000 ppm) is within 50 percent of the limit dose for an         
         adequately conducted oncogenicity study on a chemical of low       
         toxicity; 2) this pesticide is closely related to two other        
         pesticides ("Scepter" and "Assert") which tested negatively in     
         oncogenicity testing; and 3) there were no positive mutagenicity   
         studies for any of the three pesticides except for "Pursuit," which
         had a positive result in the in vitro cytogenetics study, but only 
         at levels that were toxic to the cells.                            
       - A 78-week mouse oncogenicity feeding study conducted at dosages of 
         0, 1000, 5000, and 10,000 ppm (0, 50, 750, and 1500 mg/kg/day)     
         produced no oncogenic effects up to 1500 mg/kg/day (HDT).  The     
         systemic NOEL was 750 mg/kg/day based on decreased body weight     
         gains in both sexes.                                               
       - Justification that the highest dose level tested in the rat chronic
         feeding/oncogenicity study (1500 mg/kg) is sufficient or a new     
         study with an MTD will be required for before additional crop      
         tolerances or registrations can be issued.                         
   - Teratogenicity and Reproduction                                        
     - Data are available to satisfy the requirements for a 2-generation    
       reproduction study and teratology studies in two species.  These     
       studies are discussed below:                                         
       - A rat teratology study conducted at dosages of 0, 125, 375, or 1125
         mg/kg/day demonstrated an NOEL for developmental toxicity of 1125  
         mg/kg/day (HDT).  The NOEL for maternal toxicity was 375 mg/kg/day 
         and the LOEL was 1125 mg/kg/day (HDT).                             
       - A rabbit teratology study was calculated at dosages of 0, 100, 300,
         or 1000 mg/kg/day showed no teratogenic effects observed.  The NOEL
         for maternal toxicity was 300 mg/kg/day and the NOEL for           
         developmental (embryo/fetotoxicity was 1000 mg/kg/day (HDT)).      
       - A 2-generation rat reproduction study conducted at dosages of 0,   
         1000, 5000, and 10,000 ppm (0, 50, 200, and 500 mg/kg).  The       
         systemic and reproductive NOEL was 500 mg/kg/day.  The study is    
         classified as supplementary because the dose levels were not high  
         enough.  a repeat study is not required because it would not likely
         provide any useful information since the chronic dog study would   
         still be the preferred study.                                      
   - Mutagenicity                                                           
     - Acceptable data are available for imazethapyr to satisfy the         
       mutagenicity data requirements.  These data are discussed below:     
       - Data available to evaluate the potential of imazethapyr to induce  
         gene mutations include reverse mutation assays in S. typhimurium   
         and E. coli, both plate and disc tests.  Imazethapyr did not induce
         gene mutation in either system up to 5000 micrograms (ug)/plate or 
         1000 ug per disc.  Imazethapyr was also tested in a Chinese Hamster
         Ovary (CHO) cell gene mutation assay (HGPRT locus) up to the limit 
         of solubility with activation (3333 ug/mL) and beyond the limit of 
         solubility without activation (4000 ug/mL).  Imazethapyr did not   
         induce gene mutation in this system.                               
       - Imazethapyr did not result in a significant increase in chromosomal
         aberrations in rat bone marrow when tested in an acute in vivo     
         cytogenics assay at dose levels of 0.25, 0.8, and 2.5 grams (g)/kg 
         body weight.  When tested in an in vitro cytogenics assay in CHO   
         cells both with and without metabolic activation at dosage levels  
         of 1.14, 1.71, 1.82, 2.05, and 2.25 mg/mL imazethapyr increased    
         chromosomal aberrations without metabolic activation at dosage     
         levels toxic to cells and did not increase chromosomal aberrations 
         with metabolic activation.  Imazethapyr was also tested in a       
         dominant lethal rat study at dose levels of 0, 200, 1000, or 2000  
         mg active ingredient (ai) kg and did not induce dominant lethal    
         mutations.  This study is supplemental because it was questionable 
         whether or not dose levels were high enough for an adequate        
         negative study.  Another study is not required because the other   
         studies satisfy this requirement.                                  
       - Data available to evaluate the potential of imazethapyr to induce  
         DNA damage includes an in vitro unscheduled DNA synthesis study in 
         primary rat hepatocytes tested at dose levels ranging from 13 to   
         1333 ug/well.  Under the conditions of this test, imazethapyr did  
         not induce unscheduled DNA synthesis in rat hepatocytes.           
   - Metabolism                                                             
     - Two rat metabolism studies were conducted.  These studies do not     
       completely characterize the absorption, excretion, retention, and    
       metabolism of imazethapyr.  However, a repeat study is not necessary 
       for this use because currently available data give sufficient        
       evidence that most of the chemical will be eliminated via the urine  
       unchanged.                                                           
 
   Physiological and Biochemical Characteristics                            
   - Translocation and adsorption by plants:  Absorption through both roots 
     and foliage and translocated rapidly to growing points.                
   - Metabolism/persistence in animals:  Eliminated through the urine       
     unchanged.                                                             
 
   Environmental Characteristics                                            
   - Leaching and Adsorption/Desorption:  Laboratory studies show           
     imazethapyr to be very mobile in two sand loam and two silt loam soils.
     The percentage of organic matter and sand do not appear to have an     
     effect on the sorption of imazethapyr.                                 
   - Field dissipation tests were conducted using preplant incorporation,   
     pre- and postemergence applications.  Fields were planted to soybeans. 
     Irrigation was not used because irrigation is not a normal agricultural
     practice for soybeans.  In Kentucky silt loam imazethapyr was detected 
     at the 0- to 3-inch depth in all methods of application.  Half-lives of
     31 days for preplant incorporated, 20 days for preemergence, and 17    
     days for postemergence were calculated.  At one sampling for both      
     preemergence and preplant incorporated methods of application,         
     imazethapyr was detected at the 3- to 6-inch depth.  Imazethapyr was   
     not detected at other sampling intervals in 3- to 6-inch depths or at  
     6- to 9- and 9- to 12-inch sampling depths.  These plots did not       
     indicate leaching.                                                     
   - In an Illinois silt loam soil, residues of imazethapyr were detected in
     the 0- to 3-inch depth for all types of application.  Concentrations of
     imazethapyr detected between 30 and 60 days at the 3- to 6-inch depth  
     and persisted until the end of the study when imazethapyr was applied  
     preplant incorporated.  The half-life was calculated to be 287 days.   
     When applied pre- and postemergence, imazethapyr was not detected below
     the 0- to 3-inch depth.  The half-life was calculated to be 120 days.  
   - In coarse, sandy soils found in some soils in Georgia and Iowa,        
     movement to 12 inches was noted.  Further soil dissipation studies will
     be needed for future uses with agricultural practices different from   
     soybeans and in soil types similar to soils found in Georgia and Iowa. 
   - Microbial breakdown:  Imazethapyr degrades slowly under aerobic (half- 
     life of 33 to 37 months_ conditions and very slowly under anaerobic    
     conditions.                                                            
   - Loss from volatilization:  None expected because of low vapor pressure.
   - Degradation from photodecomposition and hydrolysis:  Imazethapyr is    
     stable to hydrolysis at pHs 5, 7, 9 in buffered or pond water.         
     Imazethapyr is resistant to degradation in soil when exposed to        
     artificially simulated sunlight.  Imazethapyr degrades when exposed to 
     artificially simulated sunlight with a half-life of 46 hours.          
   - Bioaccumulation fish:  Does not bioaccumulate in fish.                 
   - Potential to contaminate groundwater:  Imazethapyr is persistent and   
     mobile as indicated from laboratory studies.  In the field, imazethapyr
     consistently shows persistence, regardless of soil type, agricultural  
     practices, and climatic effects.  In the field, imazethapyr does not   
     leach to the same extent in all soil types and under all agricultural  
     practices.  Based on field dissipation studies performed on soils      
     planted to soybeans under normal agricultural practices (no irrigation)
     imazethapyr does not appear to leach.  Therefore, the potential to     
     contaminate groundwater from use on soybeans is low.                   
   - Exposure of humans to pesticides and reentry:  applicator exposure     
     assessment or reentry exposure are not required because lack of        
     significant chronic concerns and low acute toxicity (Category III and  
     IV) result in low exposure to humans from imazethapyr.                 
   - Based on available information, only the minimal reentry intervals     
     required by law should be imposed at this time.  Entry into treated    
     fields shall not be permitted without protective clothing until sprays 
     have dried and dusts have settled.                                     
 
   Ecological Characteristics                                               
   - Acceptable data are available to satisfy the requirements for an avian 
     single dose acute oral toxicity on one species; two subacute dietary   
     toxicity studies on one species of waterfowl and one species of upland 
     gamebird; two 96-hour fish acute toxicity studies on two species of    
     freshwater fish, preferably one coldwater species and one warmwater    
     species; a 48-hour acute toxicity study with freshwater invertebrates; 
     and an acute oral toxicity to honey bees.  Studies that satisfy these  
     requirements are listed below.                                         
     - Avian Acute Toxicity:  Bobwhite Quail LC50 > 2150 mg/kg and Mallard  
       Duck LC50 > 2150 mg/kg                                               
     - Avian Dietary Toxicity:  Mallard Duck LC50 > 5000 mg/kg and Bobwhite 
       Quail LC50 > 5000 mg/kg                                              
     - Freshwater Fish Acute Toxicity:  Channel Catfish LC50 240 mg/L,      
       Bluegill Sunfish LC50 420 mg/L, and Rainbow Trout LC50 340 mg/L      
     - Freshwater Invertebrate Toxicity:  Daphnia magna LC50 > 1000 mg/L    
     - Acute Contact Toxicity:  Honey Bee LC50 > 1000 ug/bee                
   - Based on the above data, imazethapyr is practically nontoxic to birds  
     on an acute and dietary basis, practically nontoxic to both warmwater  
     and coldwater fish, practically nontoxic to aquatic invertebrates, and 
     practically nontoxic to honey bees.                                    
 
   Tolerance Assessment                                                     
   - The nature of the residue in plants and animals has been adequately    
     defined for the use on soybeans and adequate analytical methods are    
     available for enforcement purposes.                                    
   - A tolerance is established for residues of the herbicide imazethapyr,  
     ammonium salt, (+)-2- 4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H- 
     imidazol-2-y1|-5-ethyl-3-pyridinecarboxylic acid) in or on the raw     
     agricultural commodity soybeans at 0.1 ppm.                            
   - The PADI was calculated to be 0.25 mg/kg/day.  This value was based on 
     a NOEL of 250 mg/kg/day from the 90-day dog feeding study.  An         
     uncertainty factor of 1000 was used because an MTD was not obtained in 
     the rat chronic/oncogenicity study.                                    
   - The theoretical maximum residue contribution (TMRC) from this tolerance
     is calculated to be 0.000034 mg/kg/body weight/day which occupies      
     approximately 0.014 percent of the PADI.  There are no other published 
     tolerances for this chemical.                                          
 
4.  Summary of Regulatory Position and Rationale                            
                                                                            
   - The available data submitted to the Agency provide sufficient          
     information to support registration of the use on soybeans.  Therefore,
     the Agency has accepted the use of imazethapyr on soybeans.            
 
5.  Summary of Major Data Gaps                                              
                                                                            
   - There are no data gaps for the use of imazethapyr on soybeans.         
 
6.  Contact Person at EPA                                                   
                                                                            
   - Robert J. Taylor                                                       
   - Product Manager 25                                                     
   - Fungicide-Herbicide Branch                                             
   - Registration Division (H7505C)                                         
   - Office of Pesticide Programs                                           
   - Environmental Protection Agency                                        
   - 401 M Street, SW                                                       
   - Washington DC 20460                                                    
     - Office Location and Telephone Number:                                
       - Room 243, Crystal Mall #2                                          
       - 1921 Jefferson Davis Highway                                       
       - Arlington, VA 22202                                                
       - (703) 557-1800                                                     
DISCLAIMER:
THE INFORMATION PRESENTED IN THIS CHEMICAL INFORMATION FACT SHEET
IS FOR INFORMATIONAL PURPOSES ONLY AND NOT TO BE USED TO FULFILL
DATA REQUIREMENTS FOR PESTICIDE REGISTRATION AND REREGISTRATION.
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