EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITION 

EPA Registration Division Contact: Sidney Jackson (703) 305-7610

Docket ID Number: EPA-HQ-OPP-2012-0303

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number (PP#): 2E8007

EPA has received a pesticide petition (PP 2E8007) from Interregional Research 

Project Number 4 (IR-4), 500 College Road East, Suite 201W., Princeton, NJ 08540 

requesting, 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 by establishing a tolerance for 

residues of the herbicide ethalfluralin in or on the raw agricultural commodity rapeseed 

subgroup 20A and sunflower subgroup 20B at 0.05 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 support granting of the petition. 

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

A. Residue Chemistry

1. Plant metabolism. Nature of residue studies with 14C-ethalfluralin have 

demonstrated very low terminal residues and that ethalfluralin per se is the residue of 

concern in plants grown in soil treated with this compound and that there are no 

significant metabolic products. These studies indicate that it is appropriate to base a 

tolerance on residues of the parent compound, ethalfluralin.

2. Analytical method. Rapeseed/Canola - A residue method has been developed 

and validated at a limit of quantitation (LOQ) of 0.02 μg/g for the determination of 

ethalfluralin in rapeseed seed which utilizes capillary gas chromatography with mass 

selective detection (GC/MSD). Validation data were generated using this method during 

the analysis of the canola seed field samples from the magnitude of residue studies.

Safflower - Adequate residue analytical methods are available for purposes of registration 

based upon the analytical method for sunflower. A GC method, Method I, with electron 

capture detection is listed in the Pesticide Analytical Manual (PAM, Vol. II, Section 

180.416) for tolerance enforcement. Method I is applicable for analysis of ethalfluralin 

residues in/on sunflower seed. The LOQ is 0.01 ppm.
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3. Magnitude of residues. Canola - In the magnitude of residue field studies, 

herbicides containing the active ingredient ethalfluralin 

N-ethyl-N-(2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl) benzenamine were 

applied in 1996 at eight sites as a preplant incorporated application. Sonalan* 10G 

herbicide was applied directly to the soil surface and Sonalan* HFP herbicide was diluted 

in water and applied in a spray volume of 16 - 23 gal/A. The applications were made to 

field plots of canola at the rate of 1.25 lb a.i./A at all sites except Georgia and 

Washington, and at the rate of 0.75 lb a.i./A (Georgia and Washington). Three to five 

days after application, a second incorporation was done and canola seeds were planted. 

Samples of canola seed were collected at normal harvest, 87 - 216 days after the last 

application. Residues in canola seed collected at normal harvest were non detectable 

based on a method limit of detection of 0.006 ppm and limit of quantification of 0.02 

ppm. Residues in processed fractions after application of up to 3X maximum 

recommended rate showed non-detectable residues, and therefore there is no 

magnification of residues through processing.

Safflower - The magnitude of residue data from sunflower are surrogate data for 

safflower. The registered uses of ethalfluralin on sunflowers along with the established 

tolerances on these commodities are supported by acceptable field residue data from trials 

reflecting the maximum registered use patterns. In all cases, the residues were < LOQ = 

0.01ppm. The re-registration requirements for processing studies were fulfilled. 

Adequate processing studies have been conducted on sunflower seed. Field residue data 

resulting from up to 5X label rates showed non-detectable (<LOQ = 0.01ppm) residues of 

ethalfluralin in sunflower seed.

B. Toxicological Profile

1. Acute toxicity. Ethalfluralin is of relatively low toxicity. The rat oral LD50 is 

>5,000 mg/kg. The acute dermal lethal dose (LD)50 in rabbits is >5,000 mg/kg and the 

acute rat inhalation lethal concentration (LC)50 is >0.94 mg/l air. Ethalfluralin produced 

slight to moderate eye irritation and moderate to severe dermal irritation in rabbits. A 

guinea pig dermal sensitization study conducted by the modified Buehler method found 

no sensitization, whereas a study conducted by the Magnusson and Kligman 

maximization method showed a positive sensitization reaction. The signal word for the 

technical grade active ingredient is Caution.

2. Genotoxicty. Ethalfluralin was weakly mutagenic in activated strains TA1535 

and TA100 of Salmonella typhimurium, but not in strains TA1537, TA1538, and TA98 in 

an Ames assay. In a modified Ames assay with Salmonella typhimurium and Escherichia 

coli, ethalfluralin was weakly mutagenic in strains TA1535 and TA100, with and without 

activation, and in strain TA98 without activation, at the highest dose. No mutagenicity

was found in the mouse lymphoma assay for forward mutation. Ethalfluralin did not 
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induce unscheduled DNA synthesis in rat hepatocytes. In Chinese hamster ovary cells, 

ethalfluralin was negative without S9 activation, but it was clastogenic with activation.

3. Reproductive and developmental toxicity. The maternal NOAEL and LOAEL 

of ethalfluralin in rats was 50 mg/kg/day and 250 mg/kg/day, respectively, based on 

decreased body weight gain and dark urine. In this rat study, there was no observable 

developmental toxicity. The developmental NOAEL in rats was 1000 mg/kg/day, the 

highest dose tested. In rabbits the NOAELs for maternal and developmental toxicity

were 75 mg/kg/day. The maternal LOAEL of 150 mg/kg/day was based on abortions and 

decreased food consumption. These effects as well as decreased weight gain, enlarged 

liver, and orange urine were found at 300 mg/kg/day. In this study developmental 

toxicity was observed. The developmental LOAEL in rabbits was 150 mg/kg/day, based 

on slightly increased resorptions, abnormal cranial development, and increased sternal 

variants. In a three-generation rat reproduction study, the parental NOAEL was 12.5 

mg/kg/day. The parental LOAEL was 37.5 mg/kg/day, based on depressed mean body

weight gains in males in all generations. No treatment-related effects were noted on 

reproductive parameters and the NOAEL was 37.5 mg/kg/day or greater. A seven-month 

multigeneration bridging study was conducted with doses equivalent to 0, 8, 20, or 61 

mg/kg/day in the diet of Fischer 344 rats. The parental NOAEL was 20 mg/kg/day. The 

parental LOAEL was 61 mg/kg/day based on increased liver weights. No 

treatment-related effects were noted on reproductive parameters and the reproductive 

NOAEL was equal to or greater than 61 mg/kg/day.

4. Subchronic toxicity. Ethalfluralin was evaluated in five subchronic dietary

studies which showed NOAELs of 560 ppm in a three-month mouse study, 12 mg/kg/day

in a one-year mouse study, 29 mg/kg/day in a three-month rat study, 3.9 mg/kg/day in 

male rats and 4.9 mg/kg/day in female rats in a one-year study, and 27.5 mg/kg/day in a 

three-month dog study. A 21-day dermal study in rabbits showed no systemic toxicity, 

while slight to severe dermal irritation was observed.

5. Chronic toxicity. Ethalfluralin was administered to Fisher 344 rats in the diet 

for two years in combined chronic toxicity and carcinogenicity replicate studies. The 

doses were equivalent to 0, 4.2, 10.7, or 32.3 mg/kg/day. The NOAEL for systemic 

effects was 32.3 mg/kg/day. Mammary gland fibroadenomas were found in dosed female 

rats at statistically significant incidences in the mid and high doses. Ethalfluralin was 

administered to B6C3F1 mice in the diet for two years in combined chronic toxicity and 

carcinogenicity replicate studies. The doses were equivalent to 0, 10.3, 41.9, or 163.3 

mg/kg/day. No increased incidence of neoplasms was attributed to the treatment. The 

NOAEL was 10.3 mg/kg/day. The mid dose (LOAEL) and high dose showed focal 

hepatocellular hyperplasia in both sexes. There were increased relative liver, kidney, and 

heart weights in females. Some blood changes were found also, including decreased 

hematocrit, hemoglobin, and erythrocyte count accompanied by increased mean 
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corpuscular hemoglobin concentration in high dose females. Alkaline phosphatase 

values were increased at the high dose in both sexes. Body weight gain decreased at the 

high dose. 

Beagle dogs were given 0, 4, 20, or 80 mg/kg/day orally, by capsule, for one year. The 

NOAEL was 4 mg/kg/day. The LOAEL was 20 mg/kg/day, based on increased urinary

bilirubin, variations in erythrocyte morphology, increased thrombocyte count, and 

increased erythroid series of the bone marrow. Elevated alkaline phosphatase levels were 

found at the two higher doses and siderosis of the liver at the high dose.

The EPA Office of Pesticide Program's Carcinogenicity Peer Review Committee 

concluded that ethalfluralin should be classified as Group C, a possible human 

carcinogen, based on increased mammary gland fibroadenomas and 

adenomas/fibroadenomas combined in female rats. The tumor incidences were 

statistically significant at both the mid and high dose, and exceeded the upper range of 

historical controls. Based on a low dose extrapolation, the Q1* of 8.9 x 10-2 

(mg/kg/day)-1 has been calculated.

6. Animal metabolism. Fischer 344 rats were treated orally with a single low dose, 

a single high dose, or repeated low doses of radiolabeled ethalfluralin. Absorption of 

ethalfluralin was estimated at 79 - 87% of the dose for all dose levels. Ethalfluralin was 

rapidly and extensively metabolized, and 95% of the chemical was excreted in urine and 

feces by seven days. The major route of elimination for the radiolabel was in the feces, 

50.9 - 63.2%, and the levels remaining in the tissues after 72 hours were negligible. The 

major metabolites in urine and feces were identified.

7. Metabolite toxicology. The residue of concern is ethalfluralin per se, as 

specified in 40 CFR 180.416. Thus, there is no need to address metabolite toxicity.

8. Endocrine disruption. There is no evidence to suggest that ethalfluralin has an 

effect on any endocrine system.

C. Aggregate Exposure

1. Dietary exposure. Acute dietary risk assessments are performed for a food-use 

pesticide if a toxicological study has indicated the possibility of an acute effect of 

concern occurring as a result of a 1-day or single exposure. An acute dietary endpoint 

(i.e., single dose endpoint) for risk assessment was not identified in the toxicity database 

for the general US population. For females 13-49, the acute assessment was somewhat 

refined with the use of anticipated residues for existing commodities. However, the risk 

estimate is considered conservative because anticipated residues were only used for 

blended commodities, but tolerance-level and proposed tolerance-level residues were 

used for all others. In addition, an assumption of 100% crop treated (CT) was used. EPA 
5

has previously used a NOAEL of 75 mg/kg/day from a rabbit developmental toxicity

study as the toxicity endpoint for assessing acute dietary risk in females 13 - 49 years of 

age. An acute RfD of 0.75 mg/kg/day was calculated, based on a NOAEL of 75 

mg/kg/day and an uncertainty factor of 100 (10 for interspecies extrapolation and 10 for 

intraspecies variation). 

Chronic dietary exposure to ethalfluralin is possible due to the potential presence of 

ethalfluralin residue in certain foods. Chronic dietary risk was evaluated using a chronic 

RfD of 0.04 mg/kg/day, which is based on a NOAEL of 4 mg/kg/day from a chronic dog 

study along with an uncertainty factor of 100. EPA previously concluded that an FQPA 

Safety Factor of 1X is appropriate for assessing chronic dietary risk.

EPA has concluded that ethalfluralin should be classified as group C, a possible human 

carcinogen, based on increased mammary gland fibroadenomas and 

adenomas/fibroadenomas combined in female rats. Therefore, a cancer risk assessment 

was included. Based on a low dose extrapolation, the Q1* of 8.9 x 10-2(mg/kg/day)-1has 

been calculated and was used in this cancer risk assessment.

i. Food. The latest dietary exposure assessment was based on all commodities 

with tolerances for ethalfluralin established at 40 CFR 180.416 together with the 

tolerances of 0.05 ppm for rapeseed, and 0.05 ppm for canola and safflower. The Dietary

Exposure Evaluation Model (DEEM), which is produced by Exponent, Inc. and licensed 

to Dow AgroSciences, was used to estimate dietary exposure. This software used the 

food consumption data for the 1994-1996, 1998 USDA Continuing Surveys of Food 

Intake by Individuals (CSFII 1994-1996, 1998).

a. Acute: An acute dietary risk assessment was conducted with the conservative 

assumptions of 100% CT and tolerance level residues for all crops. These assumptions 

result in a very conservative estimate of human exposure and risk. Acute dietary risk for 

females 13-49 years old was assessed using an acute population adjusted (aPAD) of 0.75 

mg/kg/day. Even with conservative assumptions used in this analysis acute dietary

exposure was estimated to occupy only <1% of the aPAD for females 13-49 years old. 

Adverse effects are not expected for exposures occupying 100% or less of the aPAD. 

Therefore, acute exposure and risk from food is well within acceptable levels.

b. Chronic: Chronic dietary exposure and risk was estimated with the conservative 

assumptions of 100% crop treated and tolerance level residues for all crops. The estimate 

of potential chronic exposure and risk is very conservative and estimated risk would be 

substantially reduced with further refinement to the exposure estimate. Even with the 

conservative assumptions used in this analysis, chronic exposure is estimated to occupy 

only <1% of the RfD for the general U.S. population. Chronic dietary exposure is 

estimated to occupy 0.4% of the RfD for non-nursing infants, the population subgroup 
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estimated to have highest potential exposure. Therefore, chronic exposure and risk from 

food is well within acceptable levels.

c. Cancer: The cancer dietary analysis for ethalfluralin, although more refined than the 

chronic non-cancer assessment, is also conservative because 100% CT was assumed. 

The risk estimate for chronic cancer dietary exposure (0.000022 mg/kg/day) to 

ethalfluralin for the U.S. population yields a cancer risk estimate of 2 x 10-6. EPA 

generally considers cancer risks of 10-6or less to be below the level of concern. Based on 

registered product uses, exposure to ethalfluralin from food plus water is estimated to not 

exceed a lifetime cancer risk of 2 x 10-6. Additional refinement with %CT estimates 

would lead to a lower estimate of dietary cancer risk. EPA generally considers cancer 

risks of 10-6or less to be below the level of concern.

ii. Drinking water. There are no established Maximum Contaminant Levels 

(MCLs) for residues of ethalfluralin in drinking water and Health Advisory Levels 

(HALs) for ethalfluralin have not been established. EPA has previously used modeling 

for a screening level assessment of potential ethalfluralin exposure through drinking 

water. The Agency has used PRZM/EXAMS and SCI-GRO to provide a screening level 

assessment for surface water and groundwater, respectively. Modeled estimated drinking 

water concentrations (EDWCs) were higher for surface water sources of drinking water 

obtained from the PRZM-EXAMs model than ground water concentrations generated 

using the SciGrow model. Based on these models EPA has indicated the estimated 

environmental concentrations (EECs) for acute exposures are 11 parts per billion (ppb) 

for surface water and 0.02 ppb for groundwater. The maximum simulation, the 1-in-10 

year peak value, used for acute dietary exposure, was calculated for the use on canola 

using a maximum application rate of 1.15 lb ai/A. The estimated drinking water 

concentration (EDWC) from this simulation was 11 ppb. The maximum simulation for 

chronic exposures, or the 1-in-10 probability yearly, was calculated for the use on dill, 

with a maximum application rate of 1.5 lb ai/A. The EDWC from this simulation was 0.4 

ppb. For cancer risk assessment, the average of yearly means was estimated to be 0.2 

ppb. These estimated water values were entered directly in to the DEEM-FCID model (as 

0.011ppm acute, 0.0004 ppm chronic and 0.2 ppm cancer) for water, direct and indirect, 

all sources, for dietary exposure estimation. (US EPA OPPTS Ethalfluralin: Acute, 

Chronic Non-Cancer, and Chronic Cancer Dietary Risk Assessment. PC Code: 113101,

Decision Number: 336469, November 2, 2007)

a. Acute: In the dietary analyses, the peak value of 11 ppb was used for acute dietary

assessment . 

b. Chronic: for chronic dietary assessment, the 1-in 10-year average of 0.4 ppb was 

used. 
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c. Cancer: For cancer risk assessment, the average of yearly means was estimated to be 

0.2 ppb.

2. Non-dietary exposure. Ethalfluralin is not currently registered for use on any

residential non-food sites, and thus, it is not expected that non-occupational, non-dietary

exposures will occur.

D. Cumulative Effects. EPA at this time has not established methodologies to resolve the 

complex issues concerning common mechanism of toxicity in a meaningful way. 

Although ethalfluralin is a member of the dinitroaniline class of herbicides, there is no 

information available at this time to determine whether ethalfluralin has a common 

mechanism of toxicity with other substances or how to include this pesticide in a 

cumulative risk assessment. Based on the metabolic profile, ethalfluralin does not appear 

to produce a toxic metabolite produced by other substances. Therefore, only aggregate 

exposure and risk were considered.

E. Safety Determination

1. U.S. population. Using conservative exposure assumptions previously

described, chronic dietary exposure to residues of ethalfluralin from current uses 

including drinking water, was estimated to occupy only 0.2% of the chronic population 

adjusted dose (cPAD) for the general U.S. population. EPA generally has no concern for 

exposures below 100% of the cPAD since the cPAD represents the level at or below 

which daily exposure over a lifetime will not pose appreciable risks to human health. 

Cancer risk resulting from potential exposure to ethalfluralin through food and drinking 

water was estimated. Cancer risk from potential dietary and drinking water exposure for 

the general U.S. population was found to be within a range that EPA has generally 

considered negligible. Thus, based on the completeness and reliability of the toxicity

data and the conservative exposure assessment, it is concluded that there is a reasonable 

certainty that no harm will result to the general U.S. population from aggregate exposure 

to ethalfluralin residues from current and proposed uses.

2. Infants and children. Risk for developmental toxicity from acute exposure to 

ethalfluralin was evaluated only for females 13-49 years old. Risk from aggregate acute 

exposure to ethalfluralin through food and drinking water is well within acceptable 

levels. It can be concluded that there is a reasonable certainty that no harm will result for 

both females 13-49 years old and for the pre-natal development of infants from aggregate 

acute exposure to ethalfluralin.

Chronic aggregate exposure and risk was evaluated for children 1-2 years old, the 

population subgroup predicted to be most highly exposed, and was estimated to occupy 

only 0.3% of the cRfD for the general U.S. population . Risk from aggregate chronic 

exposure through food and drinking water is well within acceptable levels. Thus, based 
8

on the completeness and reliability of the toxicity data and the conservative exposure 

assessment, it can be concluded with reasonable certainty that no harm will result to 

infants and children from chronic aggregate exposure to ethalfluralin based on current 

and proposed uses.

F. International Tolerances There are no Codex, Canadian or Mexican Maximum 

Residue Limits established for ethalfluralin, therefore there are no international 

harmonization issues associated with this action.