EPA Registration Division contact: Andrew Ertman: (703-308-9367) 

Interregional Research Project No. 4

PP No. 2E8011 

EPA has received a pesticide petition (2E8011) 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 trifluralin in or on the raw agricultural commodity oilseed crop group 20 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 supports granting of the petition. Additional data may be needed before EPA 

rules on the petition. 

A. Residue Chemistry 

 1. Plant metabolism. The qualitative nature of trifluralin residues in plants is 

adequately understood based on field corn and mustard green metabolism studies; 

supplemented with carrot, cotton, peanut, soybean, and sweet potato metabolism data. 

The residue of concern in plants is trifluralin per se and the current tolerance expression 

for plants is considered adequate.

 2. Analytical method. The reregistration requirements for residue analytical 

methods are fulfilled for plant commodities. Adequate methods are available for data 

collection and enforcement of tolerances for residues of trifluralin per se in/on plant 

commodities. The Pesticide Analytical Manual (PAM, Vol. II, Section 180.207) lists four 

GC methods (designated as Methods I, II, III, and A) with electron capture detection 

(ECD) and a detection limit of 0.005-0.01 ppm, as available for determination of 

trifluralin per se in/on plant commodities.

 3. Magnitude of residues. IR-4 received a request from Delaware and Montana for 

the use of trifluralin in or on Gold of Pleasure (camelina), for preemergence control of 

annual grasses and broadleaf weeds. Production practices, growth requirements and 

physical characteristics are very similar for Gold of Pleasure (camelina), canola/rapeseed, 

sunflower, seed and cottonseed. Trifluralin has tolerances for canola/rapeseed for seed, 

sunflower, seed, and cotton, undelinted seed (all 0.05 ppm) and based on the new Oilseed 

Crop Group 20, then all of the members in a petition can obtain a tolerance based on the 

representative crops of rapeseed/canola, sunflower, seed, and cottonseed. Applications of 

trifluralin in Gold of Pleasure (camelina) and other members of the oilseed crop group 20 

would be the similar to applications of trifluralin tested previously on representative 

crops: canola/rapeseed, sunflower, seed, and cottonseed.

B. Toxicological Profile
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 1. Acute toxicity. Acute toxicity studies are available for technical trifluralin as 

well as manufactured products. Technical trifluralin shows low acute toxicity via the oral, 

dermal and inhalation routes of exposure (toxicity categories IV, III, and IV, 

respectively). Technical trifluralin showed some irritation in the eye (toxicity category 

III), but not in the skin (toxicity category IV). In the dermal sensitization assay trifluralin 

was found to be a dermal sensitizer. Although not required, an acute delayed 

neurotoxicity study was also performed with negative results.

 2. Genotoxicty. Extensive testing showed that trifluralin is neither mutagenic nor 

genotoxic. There was no evidence of mutagenicity in rat dominant lethal, L5178Y mouse 

lymphoma, Salmonella typhimurium, Saccharomyces cerevisiae, and DNA repair 

assays, nor did it induce sister chromatid exchange in Chinese hamster ovary cells. 

These tests showed that trifluralin does not inhibit the polymerization of microtubules in 

mammalian cells.

 3. Reproductive and developmental toxicity. Developmental toxicity of trifluralin 

in the rat and rabbit, as well as three 2-generation reproduction studies were evaluated. In 

all of these studies the NOAEL/LOAELs for parental toxicity were the same as, or lower, 

than the NOAEL/LOAELs for reproductive and developmental toxicity. In the 

developmental toxicity studies, maternal toxicity consisted of decreased body weight gain 

and food consumption, increased liver and spleen weights, increased incidence of 

resorptions and litters (with total resorptions observed in the rat); and increased abortions, 

macroscopic changes in the liver and lungs, and decreased food consumption in the 

rabbit. Reduced ossification of vertebrae and ribs were observed in both the rat and 

rabbit. In the reproduction studies kidney toxicity (acute renal failure, lesions of renal 

proximal tubule, increased relative liver weight) and uterine atrophy in females were 

observed. Offspring toxicity consisted of decreased pup weight including an increase 

in the number of runts. Decreased fetal, neonatal, and litter viability, and decreased 

lactation index were also observed.

 4. Subchronic toxicity. Trifluralin was evaluated in rat and mouse oral studies, in 

rat and rabbit dermal studies, in a rat inhalation study, and in a 6-month oral study in the 

dog. In the rat subchronic oral toxicity study, minor decreases in overall body weight 

gains and food consumption in males and females, decreased hemoglobin, alkaline 

phosphatase, and alanine aminotransferase in the males, and increased absolute and 

relative (to body) liver weights in males and females were observed at the LOAEL of 391 

mg/kg/day. In the mouse subchronic oral toxicity study, no toxicity was observed at the 

highest dose tested of 375 mg/kg/day. In the dog 6-month oral study, increased absolute 

and relative (to body) liver weights, liver enlargement, discolored kidneys, decreased red 

cell indices, increased platelets in males; and increased alkaline phosphatase were 

observed at the LOAEL of 10 mg/kg/day. 

A 21-day dermal toxicity study in the rat showed no systemic toxicity at the limit 

dose of 1,000 mg/kg/day (only dose tested). A 31-day dermal toxicity study in the rat 

showed no systemic toxicity at 1,000 mg/kg/day; dermal effects included sub-epidermal 
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inflamation and ulcerations at 200 mg/kg/day. A rabbit 21-day dermal toxicity study 

with a formulation (35.8% trifluralin) also did not show any systemic toxicity at 1,000 

mg/kg/day; dermal effects observed at the LOAEL (100 mg/kg/day) included erythema, 

edema, and/or scaling and fissuring. The systemic NOAELs (1,000 mg/kg/day) 

observed in the dermal toxicity studies are consistent with the dermal absorption factor 

of 3%. A 30-day inhalation exposure to rats at 1,000 mg/m3 resulted in increased 

methemoglobin and bilirubin, as well as dyspnea and ruffled fur.

 5. Chronic toxicity. Chronic toxicity to trifluralin was evaluated in the rat, mouse, 

and dog. Systemic toxicity in rats exposed to 169/219 mg/kg/day (males/females) 

included decreases in body weight (NOAEL 40/53 mg/kg/day). In a 2-year mouse study 

no systemic toxicity was observed at the highest dose tested of 118 mg/kg/day. Two 12-

month oral toxicity studies were performed in the dog. In one study increased frequency 

of abnormal stool, decreased body weights and body weight gains, decreased 

erythrocytes and hemoglobin, and increased thrombocytes in males were observed at the 

LOAEL of 40 mg/kg/day. In the other study increased absolute liver weights in males 

were observed at the LOAEL of 3.8 mg/kg/day. 

The highest dose (325 mg/kg/day) resulted in significant increases of combined 

malignant and benign urinary bladder tumors in female Fischer rats. An increase in the 

incidence of carcinomas of the renal pelvis was seen in all dose groups of males. In 

addition, an increase in the incidence of thyroid gland follicular cell tumors (adenomas 

plus carcinomas combined) in males was found. The thyroid tumors were identified to 

form through a mechanism not relevant to humans.

 6. Animal metabolism. In a rat metabolism study, 14C-trifluralin was administered 

by gavage at 300 mg/kg/day to 5 rats/sex on three consecutive days. The objective of this 

study was to identify the urinary metabolites of trifluralin. There was no sex-dependent 

effect on metabolic profiles. A minimum of 20-30 non-conjugated metabolites and an 

additional 10-20 conjugated metabolites were present in the urine, but no parent 

compound was detected. No single metabolite accounted for more than 8-10% of the total 

urinary radioactivity, and the majority of the metabolites were present at 1-2% of the total 

urinary radioactivity. Thus, almost all of the metabolites were minor (<5% of the total 

radioactive dose). Four metabolic pathways were identified as follows; (1) oxidative Ndealkylation of one or both propyl groups and metabolites which were hydroxylated on 

the propyl side chain; (2) reduction of one or both nitro groups to the corresponding 

amine; (3) cyclization reactions to give a variety of substituted and unsubstituted 

benzimidazole metabolites; and (4) conjugation reactions, including acetylation of the 

reduced nitro groups, sulfate, and glucuronic acid conjugates.

 7. Metabolite toxicology. The residue of concern in plants is trifluralin per se and 

the current tolerance expression for plants is considered adequate.

 8. Endocrine disruption. Trifluralin is currently undergoing screening as part of 

Endocrine Disruptor Screening Program (EDSP). 
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9. Immunotoxicity. Based on the available toxicity studies trifluralin does not 

appear to be an immunotoxicant.

C. Aggregate Exposure

 1. Dietary exposure. Tolerances have been established (40 CFR 180.207) for the 

residues of trifluralin, in or on a variety of raw agricultural commodities. Dietary 

exposure estimates are also factored by the estimated weighted average usage, or percent 

crop treated (PCT) data. Risk assessments were conducted by EPA to assess dietary 

exposures from trifluralin in food as follows:

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

tolerances for trifluralin established at 40 CFR 180.207. The Dietary Exposure 

Evaluation Model (DEEMTM) analysis evaluated the individual food consumption as 

reported by respondents in the United States Department of Agriculture (USDA) 1994–

1996 and 1998 Nationwide Continuing Surveys of Food Intake by Individuals (CSFII) 

and accumulated exposure to the chemical for each commodity. 

a. Acute: An acute dietary assessment was not conducted for the general U.S. population 

or infants and children because there was no appropriate single dose endpoint selected.

Trifluralin is not acutely toxic and there is no expectation that single, or single-day highend exposure, including aggregate exposure, will have an adverse effect. The acute 

dietary risk estimates are below the Agency’s level of concern (<100% aPAD) at the 

99.9th exposure percentile for the females 13 - 49 years of age (<1% aPAD), the 

population subgroup of concern. 

b. Chronic: 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 0.024 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. Therefore the trifluralin cPAD is 0.024 

mg/kg/day. The chronic dietary exposure and risk estimates for the general United States 

and population subgroups, are aggregate estimates based on both food and drinking water 

sources. Estimates for dietary exposure are <1% cPAD for all population subgroups and 

therefore below the Agency’s level of concern. 

Cancer. The estimated exposure of the general U.S. population (only) to trifluralin is 

0.000028 mg/kg/day. Carcinogenic dietary risk is based on the chronic exposure estimate 

for the general U.S. population derived from the same residue, percent use, and averaged 

consumption data as used for the chronic exposure analysis. EPA has concluded that 

trifluralin should be classified as group C, a possible human carcinogen. Therefore, a 

cancer risk assessment was included. Based on a low dose extrapolation, the Q1* of 5.8 x 

10-3 (mg/kg/day)-1 has been calculated and was used in the cancer risk assessment. 

Applying the Q1* of 5.8 x 10-3 (mg/kg/day)-1 to the exposure value results in a cancer risk 

estimate of 1.64 x 10-7 (DEEM-FCID) which is also below the Agency’s level of concern. 
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 ii. Drinking water. The Agency lacks sufficient data to accurately determine 

dietary exposure from drinking water. Therefore, contamination estimates for drinking 

water are refined by PRZMEXAMS modeling, incorporating percent cropped area (PCA) 

data. Since trifluralin is registered on several crops, Tier II modeling crop 

scenarios were selected to reflect crops with the highest uses of trifluralin (soybeans and 

cotton), the maximum application rate (sugarcane), and availability of scenarios. The 

maximum daily peak concentration of trifluralin from PRZM/EXAMS simulation (38.1 

parts per billion (ppb)) is greater than the highest concentration in the United 

States Geological Survey (USGS) National Water Quality Assessment (NAWQA) 

monitoring database (1.74 ppb) for surface water. However, the maximum annual 

average trifluralin concentration in surface water (1.9 ppb) is comparable to time 

weighted annual means (TWAM) concentrations in USGS monitoring studies (0.618 

ppb). . For further information on trifluralin modeling and monitoring, see docket ID 

number OPP–2004–0142 at http:// www.epa.gov/edocket/ for the following documents: 

Trifluralin—Drinking Water Assessment for Tolerance Reassessment Eligibility 

Decision and a memorandum entitled Clarification of the Trifluralin Drinking Water 

assessment for the Health Effects Division (HED) Tolerance Reassessment (PC Code: 

036101) and characterization on relative differences of USGS NAWQA ground water 

monitoring data and its comparison to SCI-GROW model predictions as presented in the 

NRDC objection (see Imidacloprid in the Federal Register of May 26, 2004 (69 FR 

30042) (FRL–7355– 7)) and the trifluralin TRED. None of these models include 

consideration of the impact processing (mixing, dilution, or treatment) of raw water for 

distribution as drinking water would likely have on the removal of pesticides from the 

source water. The primary use of these models by the Agency at this stage is to provide a 

coarse screen for sorting out pesticides for which it is highly unlikely that drinking water 

concentrations would ever exceed human health levels of concern.

 2. Non-dietary exposure. The term ‘‘residential exposure’’ is used in this 

document to refer to non-occupational, non-dietary exposure (e.g., for lawn and garden 

pest control, indoor pest control, termiticides, and flea and tick control on pets). 

Trifluralin is currently registered for use on the following residential non-dietary sites: 

Home lawns, vegetable gardens, ornamental gardens (including planting beds, flowers, 

shrubs, and trees), including other residential sites such as golf courses, recreational 

parks, bike/golf cart paths, and cemeteries. The risk assessment was conducted using the 

following residential exposure assumptions: 

 For residential scenarios, homeowner handlers are expected to complete all tasks 

associated with the use of a pesticide product, including mixing/loading as well as 

application. 

 Residential handler exposure scenarios are only considered to be short-term in nature 

due to the episodic uses associated with homeowner products. 

 Label use rates and use information specific to residential products serve as the basis 

for the risk calculations. 

 Area/volumes of spray or chemical used in the risk assessment are based on Agency 

guidance specific to residential use patterns. 
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The Agency has determined that there are potential exposures to residential handlers (i.e., 

mixer, loader, applicators) during the usual use-patterns associated with trifluralin. 

Likewise, the Agency has determined that there are potential post-application exposures 

to adults and children in residential settings during the usual use-patterns associated with 

trifluralin. For non-cancer post-application risks, since there is no short term dermal 

toxicological endpoint of concern for trifluralin and no intermediate-term dermal 

exposure is anticipated, the only assessment is for incidental ingestion by toddlers. The 

Agency has also determined that there are potential post-application cancer risks for 

adults in residential areas treated with trifluralin. The following scenarios were assessed: 

 Dermal exposure to residue on lawns. 

 Dermal exposure to golf course turfgrass. 

 Dermal exposure to residue on home gardens. 

For the residential turfgrass scenario, the cancer risks were combined for residential 

handlers applying granular formulation to lawns with postapplication cancer risks to 

adults from exercising on just-treated lawns. This combined two screening-level 

calculations.

D. Cumulative Effects Section 408(b)(2)(D)(v) of FFDCA requires that, when 

considering whether to establish, modify, or revoke a tolerance, the Agency consider 

‘‘available information’’ concerning the cumulative effects of a particular pesticide’s 

residues and ‘‘other substances that have a common mechanism of toxicity.’’ 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on 

a common mechanism of toxicity, EPA has not made a common mechanism of toxicity 

finding as to trifluralin and any other substances and does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that has a common mechanism of toxicity with other 

substances.

E. Safety Determination

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

described, chronic dietary exposure to residues of trifluralin from current uses, including 

drinking water, was estimated to occupy only <1% of the 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. The estimated exposure of 

the general U.S. population to trifluralin is 0.000028 mg/kg/day. Applying the Q1* of 5.8 

x 10-3 (mg/kg/day)-1 to the exposure value results in a cancer risk estimate of 1.64 x 10-7

(DEEM-FCID). Therefore, estimated cancer risk is below HED’s level of concern. 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 
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result to the general U.S. population from aggregate exposure to trifluralin residues from 

current uses. . 

1. Acute risk. A quantitative acute dietary assessment was not conducted for the general 

U.S. population or population subgroups other than females 13–49 because there was no 

appropriate single dose endpoint. Exposure to trifluralin is not expected to pose an acute 

risk to these population groups. The upper-bound acute risk estimate for females 13–49 

years of age is less than 1% of the aPAD at the 99.9th exposure percentile. 

2. Chronic risk. Dietary risk for trifluralin is assessed by comparing chronic dietary 

exposure estimates (in mg/kg/day) to the trifluralin cPAD, with dietary risk expressed as 

a percent of the cPAD. The cPAD is the chronic population adjusted dose; the chronic 

reference dose (0.024 mg/kg/day) modified by the FQPA safety factor. The trifluralin 

cPAD is 0.024 mg/kg/day based on a RfD of 0.024 mg/kg/day, and incorporating the 

FQPA safety factor of 1X (no additional factor) for the overall U.S. population or any 

population subgroups. The cPAD method of risk assessment is applicable to the oral 

exposure route and is used to assess both food and drinking water exposure. Chronic 

dietary exposure to residues of trifluralin from current uses was estimated to occupy only 

<1% of the cPAD for the general U.S. population .Exposure estimates that are less than 

100% of the cPAD indicate a determination of safety can be concluded. 

3. Short-term risk. Short-term aggregate exposure takes into account residential exposure 

plus chronic exposure to food and water (considered to be a background exposure level). 

Dietary exposure is assumed to be constant, not seasonal and residential or other 

exposures are additive to this background. Homeowner use for trifluralin is highly 

seasonal and this exposure will likely be acute or short term. Thus, the route of exposure 

may be oral (children on turf), dermal, or inhalation where residential exposure could 

occur with the use of trifluralin. However, no toxicological effects have been identified 

for short-term toxicity. Therefore, the aggregate risk does not exceed the Agency’s level 

of concern. 

The chronic dietary exposure and risk estimates for the general United States and 

population subgroups, are aggregate estimates based on both food and drinking water 

sources. The aggregate (3 specific exposure scenarios) incidental oral exposure estimate 

for children on turf is 0.00009 mg/kg/day. When combined with the estimated chronic 

dietary exposure (0.000051 mg/kg/day) for children 1–2 years old, the sum is 0.00014 

mg/kg/day. Compared to the appropriate dose (10 mg/kg/day) for short-term incidentaloral risk assessment, this aggregate exposure estimate is much greater than the target 

MOE of 100, and a conclusion of safety can be made. 

4. Intermediate-term risk. Intermediate and long-term residential exposure is not expected 

for trifluralin and thus no such risk is expected from the use of trifluralin. 

5. Cancer risk. When using the Q1* approach to assess a pesticide, the Agency considers 

all exposure to be additive to aggregate carcinogenic risk, regardless of exposure route or 

exposure duration (per season). For trifluralin, this means that the chronic exposure from 
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foods (0.000022 mg/kg/day) is added to chronic exposure due to drinking water 

(0.000008 mg/kg/day) and this in turn is added to exposure estimated for residential use. 

Based on this assumption, carcinogenic risk estimates are made for those applying 

trifluralin themselves, each season, throughout adulthood (50 years). The exposure and 

carcinogenic risk estimates for residential applicators vary significantly depending on the 

application method, even if other inputs (rate and area treated) remain the same. Since the 

carcinogenic risk assessment attempts to reflect long-term exposure, the most appropriate 

exposure estimate would be based on the most common application method; the pushtype spreader (for homeowners). The risk estimate represents the probability of ‘‘excess’’ 

cancers attributable to trifluralin. In general, the Agency considers carcinogenic risk 

estimates in the range of 10-6, or less, to be negligible. Applying the Q1* of 5.8 x 10-3

(mg/kg/day)-1 to the exposure value, results in a cancer risk estimate of 1.64 x 10-7

(DEEM-FCID). Therefore, estimated cancer risk is below the Agency’s level of concern. 

6. Determination of safety. Based on these risk assessments, EPA concludes that there is 

a reasonable certainty that no harm will result to the general population, and to infants 

and children from aggregate exposure to trifluralin residues. 

 2. Infants and children. 

1. In general. Section 408 of FFDCA provides that EPA shall apply an additional tenfold 

margin of safety for infants and children in the case of threshold effects to account for 

prenatal and postnatal toxicity and the completeness of the database on toxicity and 

exposure unless EPA determines that a different margin of safety will be safe for infants 

and children. Margins of safety are incorporated into EPA risk assessments either directly 

through use of a MOE analysis or through using uncertainty (safety) factors in calculating 

a dose level that poses no appreciable risk to humans. 

2. Prenatal and postnatal sensitivity. There are no residual uncertainties for pre- and/or 

postnatal toxicity. 

3. Conclusion. There is a complete toxicity database for trifluralin and exposure data are 

complete or are estimated based on data that reasonably accounts for potential exposures. 

Based on this information and the lack of any residual concerns for pre- and/or postnatal 

toxicity, EPA concludes it has reliable data to remove the additional 10X FQPA safety 

factor.

F. International Tolerances

Trifluralin has MRL’s established on several oilseed crops by agencies as Codex, 

EU, Australia, Japan, Korea, Brazil, South-Africa, Taiwan. Some of these MRL’s are 

higher than the US-tolerances. Therefore, some compatibility questions exist with respect 

to U.S. tolerances.