EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division Contact: Kable Bo Davis; 703-306-0415 

BASF Corporation

0E7794

 EPA has received a pesticide petition (0E7794) from BASF Corporation, 26 

Davis Drive, Research Triangle Park, NC 27709 proposing, pursuant to section 408(d) of 

the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 

CFR part 180.490 by establishing a tolerance for residues of imazapic (±)-2-[4,5-dihydro4-methyl-4-(1-methylethyl)-5-oxo-1-H-imidazol-2-yl]-5-methyl-3-pyridinecarboxylic 

acid in or on the raw agricultural commodity soybean at 0.5 parts per million (ppm). 

EPA has determined that the petition contains data or information regarding the elements 

set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the 

sufficiency of the submitted data at this time or whether the data supports granting of the 

petition. Additional data may be needed before EPA rules on the petition. 

A. Residue Chemistry

 1. Plant metabolism. The metabolic pathway of imazapic is understood and is 

similar in a range of different crops including Bermuda grass, sugarcane and peanuts (a 

legume), and is comparable to the metabolic pathway of a structural analogues, 

imazethapyr and imazamox, in soybean and wheat, respectively. The methyl group at 

position 5 of the pyridine ring, or in the case of imazethapyr the 5-ethyl group, is 

hydroxylated, and the hydroxyl group is conjugated to form a glucoside.

 2. Analytical method. The proposed analytical method for detecting residues of 

imazapic and the metabolites M715H001 (CL 263,284) and M715H002 (CL 189,215) in 

soybean seed and processed fractions is an LC-MS/MS method. This validated method 

has an LOQ of 0.01 mg/kg. 

Enforcement methods for analysis of residues of imazapic and metabolite M715H001 

(CL 263,284) in animal commodities have been previously submitted. The analytical 

method for analysis in meat and meat by-products is based on capillary electrophoreses 

with confirmation by LC/MS. The method LOQ is 0.05 mg/kg for meat and meat byproducts. The analytical method for analysis in milk and fat is based on determination by 

LC/MS with confirmation by LC/MS/MS. The method LOQ is 0.01 mg/kg for milk and 

0.05 mg/kg for fat. Both methods were successfully validated by an independent 

laboratory validation. 

 3. Magnitude of residues. i. Soybeans. Imazapic was applied at labeled rates in 8 

field trials. Residues of imazapic ranged from non-detect to 0.25 mg/kg in samples taken 

60 days after treatment. 
2

An additional residue decline trial was conducted using labeled rates. Samples were 

analyzed for imazapic and metabolites M175H001 (CL 263,284) and M715H002 (CL 

189,215). Residues of imazapic and the metabolite M715H001 (CL 263,284) were nondetect in all samples taken from 40 to 120 days after treatment and residues of the 

metabolite M715H002 (CL 189,215) were less than the LOQ (<0.01 mg/kg) in all 

samples taken from 40 to 120 days after treatment. 

A processing study was conducted using soybeans from two trials applied at two times 

and three times the proposed maximum seasonal application rate. The soybean samples 

were taken 60 days after treatment and processed into fractions (flake soybean, oil, meal, 

and toasted meal). The samples were analyzed for imazapic and metabolites M715H001 

(CL 263,284) and M715H002 (CL 189,215). Following treatment at three times the 

proposed maximum application rate, the residues of imazapic in soybean grain and all 

process fractions were <LOQ and residues of metabolites in soybean grain and all 

process fractions were < LOD. Therefore no processing factors could be determined 

from this site. Following treatment at two times the proposed maximum application rate, 

residues of the metabolite M715H001 (CL 263,284) were < LOQ in the grain and in all 

process fractions. Compared to the imazapic level in the grain, residues of the metabolite 

M715002 (CL 189,215) in the grain were much lower. The transfer factors show that 

imazapic residues do not concentrate in soybean process fractions. 

Soybean hulls and aspirated grain fractions were not analyzed in the processing study. 

However, soybean hulls and aspirated grain fractions are blended commodities and 

therefore any imazapic treated soybean hulls and aspirated grain fractions would be 

blended with untreated soybean hulls and aspirated grain fractions before being fed to 

cattle. Based on the limited import of imidazolinone-tolerant soybeans from Brazil and 

the blended nature of these commodities, any potential imazapic residues would be 

diluted and can be considered de minimus. 

ii. Ruminants. A cattle feeding study was conducted with four groups of cows, each 

group containing three animals, which were orally dosed with imazapic. Milk samples 

were collected twice daily during dosing and edible tissues, muscle, fat, liver and kidney 

were collected after sacrifice. 

All samples were analyzed for imazapic and the hydroxymethyl metabolite M715H001 

(CL 263,284). At the lowest feeding level of 67 mg/kg, imazapic residues in milk 

averaged 0.013 mg/kg and the residues of the metabolite averaged <0.010 mg/kg. 

Residues of both imazapic and the metabolite in muscle and fat were <0.05 mg/kg (LOQ) 

for all dosing levels. At 67 mg/kg imazapic residues in kidney and liver averaged 0.384 

mg/kg and <0.05 mg/kg, respectively, while metabolite M715H001 residues in liver and 

kidney were <0.05 mg/kg for all dosing levels. 

Based on the maximum reasonably balanced diet as defined by the EPA guidance 

document of 2009, the anticipated dietary burden for dairy cattle due to grass (tolerances 

for grass forage at 15 mg/kg; grass hay at 30 mg/kg) and peanut meal (tolerance of 0.1 

mg/kg) is 27.012 mg/kg. With the addition of soybean meal at 0.54 mg/kg (0.5 mg/kg x 
3

1.08), the estimated dietary burden for dairy cattle is 27.079 mg/kg, which is a negligible 

increase over the current dietary burden. Therefore, the existing tolerances for meat and 

milk commodities are sufficient to cover the proposed use on soybeans, and introducing 

the import tolerance for soybeans will not require any changes to the current meat and 

milk tolerances. 

iii. Poultry. Based on the maximum reasonably balance diet as defined by the EPA 

guidance document of 2009, the anticipated dietary burden for poultry was determined as 

0.135 mg/kg diet (without correction for dry matter). The only dietary input is from 

soybean meal with a proposed tolerance of 0.5 mg/kg and processing factor of 1.08. 

A metabolism study with 14C-imazapic was performed in laying hens at feeding levels of 

2.1 and 11.4 mg/kg feed. Based on a dietary burden of 0.135 mg/kg, the feeding levels in 

the metabolism study were 16 times (2.1/0.135) and 84.4 times (11.4/0.135) the expected 

dietary burden of imazapic. At the 11.4 mg/kg feeding level, 84.4 times the predicted 

feed burden, total 14C-residues found in eggs and all tissue, kidney, liver, muscle and skin 

with fat adhering were <LOQ of 0.01 mg/kg. Therefore, no residues would be expected 

in poultry commodities due to the import of Cultivance imidazolinone-tolerant soybean. 

B. Toxicological Profile

 1. Acute toxicity. Imazapic technical is considered to be nontoxic (toxicity 

category IV) to the rat by the oral route of exposure. In an acute oral toxicity study in 

rats, the LD50 value of imazapic technical was greater than 5,000 milligrams/kilograms 

body weight (mg/kg bw) for males and females. The results from an acute dermal toxicity 

study in rabbits indicate that imazapic is slightly toxic (toxicity category III) to rabbits by 

the dermal route of exposure. The dermal LD50 value of imazapic technical was greater 

than 2,000 mg/kg bw for both male and female rabbits. Imazapic technical is considered 

to be nontoxic (toxicity category IV) to the rat by the respiratory route of exposure. The 

4-hour LC50 value was greater than 5.52 mg/L (analytical) for both males and females. 

Imazapic technical was shown to be non-irritating to rabbit skin (toxicity category IV) 

and minimally irritating to the rabbit eye (toxicity category III). Based on the results of a 

dermal sensitization study, imazapic technical is not considered a sensitizer in guinea 

pigs. 

 2. Genotoxicity. Imazapic technical was tested in a battery of in vitro and in vivo 

genotoxicity assays measuring several different endpoints of potential genotoxicity. 

Collective results from these studies indicate that imazapic does not pose a mutagenic or 

genotoxic risk.

 3. Reproductive and developmental toxicity. i. The developmental toxicity study 

in Sprague Dawley rats conducted with imazapic technical showed no evidence of 

teratogenic effects in fetuses and no evidence of developmental toxicity. Thus, imazapic 

is neither a developmental toxicant nor a teratogen in the rat. In the rat developmental 

toxicity study with imazapic technical, the no observed adverse effect level (NOAEL) for 

maternal toxicity and developmental toxicity was 1,000 mg/kg bw/day, the highest dose 

tested. 
4

ii. Results from a developmental toxicity study in New Zealand White rabbits with 

imazapic technical also indicated no evidence of teratogenicity or developmental toxicity. 

Thus, imazapic technical is neither a developmental toxicant nor a teratogen in the rabbit. 

In the rabbit developmental toxicity study, the NOAEL for maternal toxicity was 350 

mg/kg bw/day, based on decreased food consumption and body weight gain at 500 mg/kg 

bw/day, the next highest dose tested. The NOAEL for developmental toxicity was 

determined by EPA to be 500 mg/kg bw/day; the excessive mortality in dams at 700 

mg/kg bw/day (the highest dose tested) resulted in too few fetuses that were available for 

evaluation. 

iii. The results from the two-generation reproduction toxicity study in rats with imazapic 

technical support a NOAEL for parental toxicity of 20,000 ppm (or approximately 1,205 

mg/kg bw/day in males and 1,484 mg/kg bw/day in females, calculated from food 

consumption data), the highest concentration tested. The NOAEL for growth and 

development of the offspring is also 20,000 ppm, or approximately 1,205 mg/kg bw/day 

in males and 1,484 mg/kg bw/day in females. Results from the reproduction study and the 

developmental toxicity studies conducted with imazapic technical show no increased 

sensitivity to developing offspring as compared to parental animals, because the 

NOAELs for growth and development of offspring were equal to or greater than the 

NOAELs for parental toxicity. 

 4. Subchronic toxicity. i. A short-term (21-day) dermal toxicity study in rabbits 

was conducted with imazapic technical. No dermal irritation or abnormal clinical signs 

were observed at dose levels up to and including 1,000 mg/kg bw/day (highest dose 

tested), supporting a NOAEL for dermal irritation and systemic toxicity of 1,000 mg/kg 

bw/day. 

ii. In a subchronic (13-week) dietary toxicity study in rats with imazapic technical, no 

signs of systemic toxicity were noted, supporting a NOAEL of 20,000 ppm (or 

approximately 1,552 mg/kg/day for males and 1,728 mg/kg/day for females, calculated 

from food consumption data), the highest concentration tested. The requirement for a 

subchronic dietary toxicity study in non-rodents is satisfied by the one-year dietary 

toxicity study in dogs. 

 5. Chronic toxicity. i. A one-year dietary toxicity study was conducted with 

imazapic technical in Beagle dogs at dietary concentrations of 0, 5,000, 20,000, and 

40,000 ppm. In this study, the NOAEL for systemic toxicity was less than 5,000 ppm or 

approximately 158 mg/kg bw/day (137 mg/kg bw/day for males and 180 mg/kg bw/day 

for females), calculated from food consumption data, based on a slight skeletal 

myopathy, characterized by degeneration/necrosis of single fibers (minimal severity) and 

lymphocyte/macrophage infiltration in skeletal muscle, in males and females, and slightly 

decreased serum creatinine in females at 5,000 ppm (lowest concentration tested). 

The skeletal myopathy observed at 5,000 ppm was considered of minimal toxicological 

significance because the limited presence and the minimal severity of skeletal myopathy 
5

was evident in only a few fibers out of hundreds evaluated per section per animal. 

Further, these focal myopathies of minimal severity were not consistently diagnosed in 

all skeletal muscles sites examined per dog (i.e., vastus and abdominal muscles, 

diaphragm and esophagus). Moreover, no clinical observations indicative of muscle 

dysfunction were noted in any animal in the study. Finally, although the skeletal 

myopathy noted at 40,000 ppm (highest concentration tested) was associated with 

increases in creatine kinase, aspartate aminotransferase and lactate dehydrogenase, no 

statistically or biologically significant increases in these serum enzymes were noted 

during the study period for animals in the 5,000 ppm group. As such, the minimal 

myopathy diagnosed microscopically at 5,000 ppm was not considered to impair or 

adversely affect the functional capacity of the affected skeletal muscles. 

ii. In a 2-year chronic dietary oncogenicity and toxicity study in rats conducted with 

imazapic technical, the NOAEL for oncogenicity and chronic systemic toxicity was 

20,000 ppm (approximately 1,029 mg/kg bw/day in males, 1,237 mg/kg bw/day in 

females, calculated from food consumption data), the highest concentration tested. 

iii. An 18-month chronic dietary oncogenicity and toxicity study in mice with imazapic 

technical supports a NOAEL for oncogenicity and for chronic systemic toxicity of 7,000 

ppm (or approximately 1,134 mg/kg bw/day in males, 1,422 mg/kg bw/day in females, 

calculated from food consumption data), the highest concentration tested. 

The EPA has classified imazapic as a group E carcinogen (evidence of 

noncarcinogenicity for humans) based on the absence of treatment-related tumors in 

acceptable carcinogenicity studies in both rats and mice. 

 6. Animal metabolism. The rat, goat and hen metabolism studies indicate that the 

qualitative nature of the residues of imazapic in animals is adequately understood. 

In the rat metabolism study conducted with radiolabeled imazapic (BAS 715 H, CL 

263,222), urinary excretion was the primary elimination route with 94% to 102% of the 

radioactivity excreted in the urine. The major component in the urine and feces was the 

unchanged parent compound. 

Lactating goats were orally treated using radiolabeled imazapic. Imazapic was mainly 

eliminated from the goat through urine and feces. HPLC of goat urine showed essentially 

unchanged imazapic, while residues in feces were comprised of imazapic and low levels 

of hydroxymethyl metabolites M715H001 (CL 263,284). There were no detectable 

radiolabeled imazapic-derived residues in milk during or after treatment, nor in tissues 

except kidney 20 hours after the last dose. The 14C-residue in the high-dose kidney (0.05 

mg/kg) was predominantly parent imazapic with low levels of metabolite M715H001 

(CL 263,284, 8% TRR, <0.01 mg/kg) and two unknowns, each ≤0.02 mg/kg. 

A ruminant metabolism study was also conducted with the radiolabeled imazapic 

hydroxymethyl metabolite M715H001 (CL 263,284). During treatment, TRR in the daily 

blood and milk samples were less than 0.01 mg/kg, regardless of the treatment dose 
6

levels. The TRR in liver, muscle, and omental fat were less than 0.01 mg/kg, regardless 

of the dose level. Analysis of the kidney extract showed that 9% (<0.01 mg/kg) of the 

extractable TRR was CL 263,284. 

A metabolism study was performed on hens using radiolabeled imazapic. Total recovery 

of radioactivity in urine and feces was 90.6% and 95.2% for the low and high doses, 

respectively. Residues in all tissues (liver, kidney, muscle, skin with adhering fat), blood 

and eggs were <0.01 mg/kg, the validated detection limit. 

A poultry metabolism study was also conducted with the radiolabeled imazapic 

hydroxymethyl metabolite M715H001 (CL 263,284). Total recovery of radioactivity in 

urine and feces was 85.3% and 88.6% for the low and high doses, respectively. Residues 

in all tissues, liver, kidney, muscle, skin with adhering fat, blood and eggs, were less than 

0.01 mg/kg, the validated detection limit. 

 7. Metabolite toxicology. Metabolism studies in grass, peanuts and sugar cane 

indicate that the only significant metabolites are the hydroxymethyl resulting from 

hydroxylation of the methyl group at the 5-position of the pyridine ring, (±)-2-[4,5-

dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-5-hydroxymethyl-3-

pyridinecaroxylic acid, and the conjugate resulting from glucosylation at the hydroxyl 

group. The hydroxymethyl metabolite was also identified in minor quantities in the rat 

metabolism study and in the goat metabolism study. No additional toxicologically 

significant metabolites were detected in the plant or animal metabolism studies. 

 8. Endocrine disruption. Collective organ weight data and histopathological 

findings from the two-generation rat reproductive study, as well as from the subchronic 

and chronic toxicity studies in three different animal species, demonstrate no apparent 

estrogenic effects or treatment-related effects of imazapic on the endocrine system. 

C. Aggregate Exposure

 1. Dietary exposure. 

 i. Food. 

a. Acute Dietary Exposure. An acute dietary assessment is not necessary because no 

acute dietary endpoint was selected based on the absence of an appropriate endpoint 

attributable to a single dose of imazapic. 

b. Chronic Dietary Exposure. A Tier 1 assessment of potential chronic dietary exposure 

was performed for the proposed import tolerance for use of imazapic on imidazolinonetolerant soybeans. The assessment was done using DEEMTM, incorporating the current 

tolerances as listed in 40 CFR 180.490 on peanut, tissues of cattle, sheep, goats, and 

horses, and milk and the proposed tolerance for imidazolinone-tolerant soybean. For this 

Tier 1 analysis, tolerance values were used for soybean at 0.5 mg/kg; peanut at 0.1 

mg/kg; fat of cattle, sheep, goats, and horses at 0.1 mg/kg; kidney of cattle, sheep, goats, 

and horses at 1.0 mg/kg; meat byproducts, except kidney of cattle, sheep, goats, and 
7

horses at 0.1 mg/kg; meat of cattle, sheep, goats, and horses at 0.1 mg/kg; and milk at 0.1 

mg/kg. Chronic dietary exposures for the overall U.S. population and population 

subgroups, including infants and children were compared to the chronic Reference Dose 

(RfD) of 0.46 mg/kg/day (based on a LOAEL of 137 mg/kg bw/day from the chronic dog 

toxicology study and a safety factor of 300). Results of the chronic dietary analyses for 

all population subgroups examined were at or below 1.0% of the chronic RfD. Exposure 

estimates for children 1-2 years old, the most highly exposed subpopulation, were only 

0.004470 mg/kg bw/day (or 1.0% of the RfD). Therefore, the results of the chronic 

dietary assessment demonstrate a reasonable certainty of no harm from the proposed and 

existing uses of imazapic. 

ii. Drinking water. Drinking water residues at an estimated drinking water 

concentration (EDWC) of 14 μg/L, i.e., the maximum level estimated by EPA, as 

reported in the 2001 Federal Register notice (66 FR 66325) were included in a dietary 

assessment using DEEMTM. A proposed tolerance for an imported commodity would 

have no impact on the exposure due to drinking water. The exposure estimates for all 

population subgroups when compared to the RfD of 0.46 mg/kg bw/day were at or below 

0.3% (non-nursing infants) of the chronic RfD. 

iii. Aggregate dietary. The aggregate exposure estimate due to food and water in 

the diet for children 1-2 years old, the most highly exposed subpopulation, was 0.004908 

mg/kg bw/day or less than 1.1% of the chronic RfD. 

 2. Non-dietary exposure. Residential aggregate exposure assessments are not 

required because the only source of potential imazapic exposure in the U.S. is via the diet 

and drinking water. 

D. Cumulative Effects. Imazapic belongs to the imidazolinone class of compounds a 

class comprised of a number of registered herbicides. The herbicidal activity of the 

imidazolinones is due to the inhibition of acetohydroxyacid synthase (AHAS), an enzyme 

only found in plants. AHAS is part of the biosynthetic pathway leading to the formation 

of branched chain amino acids. Animals lack AHAS and this biosynthetic pathway. This 

lack of AHAS contributes to the low toxicity of the imidazolinone compounds in animals. 

We are aware of no information to indicate or suggest that imazapic has any toxic effects 

on mammals that would be cumulative with those of any other chemical. 

E. Safety Determination

 1. U.S. population. Based on the chronic RfD of 0.46 mg/kg bw/day, the 

proposed soybean application, in addition to the existing uses, will utilize a maximum of 

approximately 1.1% of the RfD. Exposure estimates for the general U.S. population were 

only 0.001340 mg/kg/day or 0.29% of the RfD. Exposure estimates for children 1-2 

years old, the most highly exposed subpopulation, were only 0.004908 mg/kg/day or 

≤1.1% of the RfD. EPA generally has no concern for exposure below 100% of the RfD, 

which represents the level at or below which daily aggregate dietary exposure over a 

lifetime will pose no appreciable risks to human health. The complete and reliable 
8

toxicity data, indicating low potential mammalian toxicity, and the conservative chronic 

exposure assumptions support the conclusion that there is a “reasonable certainty of no 

harm” from aggregate exposure to imazapic residues. 

 2. Infants and children. The conservative dietary exposure estimates presented 

above will utilize 0.65% of the RfD for all infants and 1.1% of the RfD for children 1-2 

years old, the most highly exposed population subgroup. Results from the twogeneration reproduction study in rats and the developmental toxicity studies in rabbits 

and rats indicate no increased sensitivity to developing offspring when compared to 

parental toxicity. These results also indicate that imazapic is neither a developmental 

toxicant nor a teratogen in either the rat or rabbit. Therefore, an additional safety factor is 

not warranted, and the RfD of 0.46 mg/kg/day, which utilizes a 300-fold safety factor is 

appropriate to ensure a reasonable certainty of no harm to infants and children.

F. International Tolerances

 There are no Codex tolerances established for imazapic on soybeans.