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 sec tion 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 determin ed that the petition contains data or information regarding the elements set fort h 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 trif luralin 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 plan ts 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 tolera nces for residues of trifluralin per se in/on plant

commodities. The Pesticide Anal ytical 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 Pl easure (camelina), for preemergence control of annual grasses and broadleaf weeds. Produc tion 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 rapes eed/canola, sunflower, seed, an d cottonseed. Applications of

trifluralin in Gold of Pleas ure (camelina) and other members of the oilseed crop group 20 would be the similar to applications of trif luralin tested previous ly on representative crops: canola/rapeseed, sunflower, seed, and cottonseed

.

B. Toxicological Profile2

1. Acute toxicity. Acute toxicity studies are availa ble for technical trifluralin as well as manufactured products. T echnical trifluralin shows low acute toxicity via the oral, dermal and inhalation routes of exposur e (toxicity categories IV, III, and IV, respectively). Technical trifluralin showed so me irritation in the eye (toxicity category III), but not in the skin (toxici ty 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 pe rformed with negative results.

2. Genotoxicty. Extensive testing showed that trif luralin is neither mutagenic nor genotoxic. There was no evidence of mutageni city in rat dominant lethal, L5178Y mouse lymphoma, Salmonella typhimurium, Saccharomyces cerevisiae, and DNA repair assays, nor did it induce sist er chromatid exchange in Chinese hamster ovary cells.

These tests showed that triflu ralin does not inhibit the poly merization of microtubules in

mammalian cells.

3. Reproductive and developmental toxicity. Developmental toxicity of trifluralin in the rat and rabbit, as well as three 2-ge neration reproduction studies were evaluated. In all of these studies the NOAEL/LOAELs for pare ntal toxicity were th e 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 sp leen 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 a nd ribs were observed in both the rat and rabbit. In the reproduction studies kidney toxi city (acute renal failure, lesions of renal proximal tubule, increased relative liver we ight) and uterine atrophy in females were observed. Offspring toxicity consisted of decreased pup weight including an increase in the number of runts. Decreased fetal, ne onatal, and litter vi ability, and decreased

lactation index were also observed.

4. Subchronic toxicity. Trifluralin was evaluated in ra t and mouse oral studies, in rat and rabbit dermal studies, in a rat inha lation study, and in a 6-m onth 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 weight s in males and females were observed at the LOAEL of 391 mg/kg/day. In the mouse subchr onic oral toxicity study, no toxi city was observed at the highest dose tested of 375 mg/kg/day. In th e dog 6-month oral study, increased absolute and relative (to body) liver wei ghts, liver enlargement, disc olored kidneys, decreased red cell indices, increased platelets in male s; 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-epidermal3

inflamation and ulcerations at 200 mg/kg/da y. A rabbit 21-day dermal toxicity study with a formulation (35.8% trif luralin) also did not show a ny systemic toxicity at 1,000 mg/kg/day; dermal effects obs erved at the LOAEL (100 mg/k g/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 ra ts 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 expos ed to 169/219 mg/kg/day (males/females) included decreases in body we ight (NOAEL 40/53 mg/kg/day) . In a 2-year mouse study no systemic toxicity was observed at the hi ghest dose tested of 118 mg/kg/day. Two 12- month oral toxicity studies were performe d in the dog. In one study increased frequency of abnormal stool, decreased body weight s and body weight gains, decreased erythrocytes and hemoglobin, and increased th rombocytes 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 L OAEL 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 a ll 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, 14 C-trifluralin was administered by gavage at 300 mg/kg/day to 5 rats/sex on th ree 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 urin e, but no parent compound was detected. No single metabolite acc ounted for more than 8-10% of the total urinary radioactivity, and the majo rity of the metabolites were present at 1-2% of the total urinary radioactivity. Thus, almo st all of the metabolites we re minor (<5% of the total radioactive dose). Four metabolic pathways were identified as follows; (1) oxidative Ndealkylation of one or both propyl groups a nd 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) conjugati on 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 unde rgoing screening as part of Endocrine Disruptor Screening Program (EDSP).4

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 variet y of raw agricultural commodities. Dietary exposure estimates are also factored by the es timated 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 assessmen t was based on all commodities with

tolerances for trifluralin established at 40 CFR 180.207. The Dietary Exposure Evaluation Model (DEEM TM ) 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 th at 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

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

b. Chronic : Chronic dietary exposure to ethalflu ralin is possible due to the potential presence of ethalfluralin re sidue in certain foods. Chroni c 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 c oncluded 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 estimat es based on both food and drinking water sources. Estimates for dietary exposure ar e <1% cPAD for all population subgroups and therefore below the Agency’s level of concern.

Cancer. The estimated exposure of the genera l U.S. population (only) to trifluralin is 0.000028 mg/kg/day. Carcinogenic di etary risk is based on th e chronic exposure estimate for the general U.S. population derived from th e same residue, percent use, and averaged consumption data as used for the chronic exposure analysis. EPA has concluded that

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

cancer risk assessment was included. Ba sed on a low dose extrapolation, the Q 1 * of 5.8 x

10 -3 (mg/kg/day) -1 has been calculated and was used in the cancer risk assessment. Applying the Q 1 * 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.5

ii. Drinking water. The Agency lacks sufficient da ta to accurately determine dietary exposure from drinking water. Theref ore, contamination estimates for drinking water are refined by PRZMEXAMS modeling, in corporating percent cropped area (PCA) data. Since trifluralin is registered on several crops, Tier II modeling crop

scenarios were selected to re flect crops with the highest us es of triflura lin (soybeans and cotton), the maximum application rate (sugar cane), and availability of scenarios. The maximum daily peak concentr ation of triflura lin 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 surf ace water (1.9 ppb) is comparable to time weighted annual means (TWAM) concentra tions in USGS monitoring studies (0.618 ppb). . For further information on triflura lin modeling and monitoring, see docket ID

number OPP–2004–0142 at http:// www.epa.gov/edocket/ for the following documents: Trifluralin—Drinking Water A ssessment for Tolerance Reassessment Eligibility Decision and a memorandum entitled Clarification of the Trifluralin Drinking Water

assessment for the Health Effects Divisi on (HED) Tolerance Reassessment (PC Code: 036101) and characterization on relative di fferences of USGS NAWQA ground water monitoring data and its comparison to SCI-GRO W 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-di etary 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 residentia l 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 handl ers 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 associ ated 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 resi dential use patterns.6

The Agency has determined that there are potential exposures to residential handlers (i.e., mixer, loader, applicators) during the usua l use-patterns associated with trifluralin. Likewise, the Agency has determined that th ere are potential post-application exposures to adults and children in residential settings during the usual use-patterns associated with trifluralin. For non-cancer post-a pplication risks, since ther e is no short term dermal toxicological endpoint of concern for trif luralin and no interm ediate-term dermal exposure is anticipated, the only assessment is for incidental ingestion by toddlers. The Agency has also determined that there ar e potential post-application cancer risks for

adults in residential areas treated with trif luralin. The following scen arios 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 la wns. 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 cumula tive effects of a particular pesticide’s

residues and ‘‘other substances that ha ve a common mechanism of toxicity.’’ Unlike other pesticides for which EPA has fo llowed 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 substa nces 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 exposur e 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 fo r 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 resulti ng from potential exposure to ethalfluralin through food and drinking water wa s estimated. Cancer risk from potential dietary and drinking water e xposure for the general U.S. population was found to be within a range that EPA has generally consid ered negligible. The estimated exposure of the general U.S. population to triflura lin is 0.000028 mg/kg/day. Applying the Q 1 * 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 leve l 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 will7

result to the general U.S. population from a ggregate exposure to trif luralin residues from

current uses. .

1. Acute risk . A quantitative acute dietary assessment was not conducted for the general U.S. population or population subgroups othe r than females 13–49 because there was no appropriate single dose endpoint. Exposure to trifluralin is no t expected to pose an acute risk to these population groups. The uppe r-bound acute risk estimate for females 13–49 years of age is less than 1% of the aPAD at the 99.9 th exposure percentile.

2. Chronic risk . Dietary risk for trifluralin is assessed by comparing chronic dietary exposure estimates (in mg/kg/day) to the triflu ralin cPAD, with dietary risk expressed as a percent of the cPAD. The cPAD is the chr onic population adjusted dose; the chronic reference dose (0.024 mg/kg/day) modified by the FQPA safety fact or. 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 fr om current uses was estimated to occupy only <1% of the cPAD for the general U.S. populatio n .Exposure estimates that are less than

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

3. Short-term risk . Short-term aggregate exposure take s into account residential exposure plus chronic exposure to food and water (cons idered to be a background exposure level). Dietary exposure is assumed to be consta nt, 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 aggr egate risk does not exceed the Agency’s level

of concern.

The chronic dietary exposure and risk es timates for the general United States and population subgroups, are aggregate estimates based on both food and drinking water sources. The aggregate (3 specific exposure scen arios) 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 s hort-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 resi dential 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 asse ss a pesticide, the Agency considers all exposure to be additive to aggregate carcinogenic risk, re gardless of exposure route or exposure duration (per season). For trifluralin, this means th at the chronic exposure from8

foods (0.000022 mg/kg/day) is added to ch ronic 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 a pplicators vary significantly depending on the application method, even if othe r inputs (rate and ar ea treated) remain the same. Since the carcinogenic risk assessment attempts to refl ect long-term exposure, the most appropriate exposure estimate would be based on the most common application method; the pushtype spreader (for homeowners). The risk estim ate represents the probability of ‘‘excess’’

cancers attributable to triflu ralin. In general, the Agency considers carcinogenic risk estimates in the range of 10 -6 , or less, to be negligible. Applying the Q 1 * 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 resu lt to the general population, and to infants and children from aggregate expos ure 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 co mpleteness of the data base 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) f actors in calculating a dose level that poses no a ppreciable 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 a nd exposure data are complete or are estimated based on data th at 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 establ ished on several oilseed cr ops 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.