EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Kathryn Montague, 703-305-1243

EPA Company Number 67690

PP4F8308

EPA has received a pesticide petition (PP4F8308) from SePRO Corporation, 

11550 North Meridian Street, Suite 600, Carmel, IN 46032 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

1. by establishing a tolerance for residues of

1-methyl-3-phenyl-5-[3-(trifluoromethyl)phenyl]-4(1H)-pyridinone and its 

metabolites and degradates in or on the raw agricultural commodity cotton, undelinted 

seed at 0.1 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 nature of the residue is adequately understood and 

analytical methods are available for the determination of fluridone in cotton, undelinted 

seed. Nature of the residue studies have shown that fluridone residues are not present in 

treated cotton plants.

2. Analytical method. Adequate enforcement methodologies (enzyme-linked 

immunosorbant assay (ELISA), high performance liquid chromatography with ultraviolet 

detection (HLPC/UV), and liquid chromatography with tandem mass spectroscopy (LCMSMS)) are available to enforce the tolerance expression.

3. Magnitude of residues. Four studies consisting of 18 trials on cotton conducted 

in various representative geographical areas have been performed. In all trials the 

applications were made at exaggerated rates (1.3-6.7X) and support the main conclusion 

from the nature of residue studies that no residues of fluridone are present in treated 

cottonseed following application of fluridone. 

The residue data indicate that residues of fluridone (defined as the residue of concern for 

risk assessment and tolerance expression) are not present in cottonseed at levels 

significantly different from control samples, even at treatment rates up to 6.7X higher 

than intended.
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B. Toxicological Profile

1. Acute toxicity. Fluridone has low to moderate acute oral, inhalation and dermal 

toxicity. The acute oral LD50 is >10,000 mg/kg bw in rats. The acute dermal LD50 of 

fluridone is >2000 mg/kg bw. The acute inhalation LC50 in rats is >2.13 mg/L. 

Fluridone was shown to cause slight to moderate corneal dullness, iritis, and 

conjunctivitis and is a moderate irritant to the eyes. Fluridone is not irritating to skin, nor 

is it a skin sensitizer.

An acute neurotoxicity study was conducted in rats to evaluate the neurotoxic potential of 

fluridone. Fluridone was administered orally by gavage as a single dose to groups of 

Crl:CD(SD) rats at dose levels of 0, 125, 650, and 2000 mg/kg. All animals survived to 

the scheduled euthanasia (study day 15). There were no treatment-related clinical 

findings during daily observations. Mean body weights and body weight gains were 

unaffected by fluridone administration. Treatment-related FOB findings were noted at 

dose levels of 650 and 2000 mg/kg at the time of peak effect on study day 0. These 

findings included repetitive movement of the mouth and jaws, biting of the cage, and 

altered gait (hunched body), bizarre/stereotypic behavior, abnormal air righting reflex, 

and/or no hind limb extension, lack of response to stimuli (approach, touch, startle, and 

tail pinch), longer mean catalepsy times, and/or lower mean body temperatures for males 

and females. The functional domains, as defined by Moser (1991), affected by 

administration of fluridone included the CNS excitability, neuromuscular, sensorimotor, 

and physiological domains. No treatment-related FOB findings were observed at a dose 

level of 125 mg/kg, nor for all dose levels on study days 7 and 14. Treatment-related 

decreases in mean total and ambulatory locomotor activity were observed for males and 

females in the 650 and 2000 mg/kg dose groups during the first 30 minutes of testing, as 

well as when the overall ambulatory session was evaluated on study day 0. No treatmentrelated effects were noted in brain weights or brain dimensions for perfused animals. No 

treatment-related neuropathological lesions were observed during microscopic 

examination of central and peripheral nervous system tissues. 

Based on the results of the FOB evaluations at the time of peak effect on study day 0, 

CNS activity, neuromuscular, sensorimotor, and/or physiological functional domains 

described by Moser (1991) were affected at dose levels of 650 and 2000 mg/kg. 

Additionally, decreased total and ambulatory locomotor activity was noted for males and 

females in the 650 and 2000 mg/kg dose groups during the first 30 minutes of testing and 

at the time of peak effect on study day 0. No treatment-related effects were noted for 

either sex at the dose level of 125 mg/kg; therefore, the NOAEL for male and female 

neurotoxicity was determined to be 125 mg/kg.

2. Genotoxicty. Fluridone was negative for inducing mutations in all acceptable 

guideline studies of the standard battery of mutagenicity tests except for three assay 

systems. In a microbial mutagenicity assay using five Salmonella typhimurium strains 

fluridone was negative for the induction of gene mutations. In two in vitro unscheduled 

DNA synthesis (UDS) assays in primary rat hepatocyte, fluridone produced cytotoxicity 

at the highest concentration tested (1000 nmoles/ml) in the first study and at the two 

highest concentrations tested (500 and 1000 nmoles/ml) in the second study. The tests 
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were negative with fluridone at any concentration from 0.5 to 100 nmoles/ml. In an in 

vivo Chinese hamster bone marrow sister chromatid exchange (SCE) assay, cytotoxicity 

was produced at the two highest concentrations tested (250 and 500 mg/kg). Fluridone 

did not induce sister chromatid exchanges in hamster bone marrow cells compared to the 

solvent controls. Based on the database, fluridone was not mutagenic in a microbial 

mutagenicity assay (Ames assay) and in sister chromatid exchange assay in Chinese 

hamsters, and fluridone did not induce unscheduled DNA synthesis in primary rat 

hepatocytes.

3. Reproductive and developmental toxicity. A 3-generation reproduction study in 

rats was conducted at dose levels of 0, 200, 650, or 2000 ppm (equivalent to intakes of 0, 

10.6-11.1, 35.5-36.6, or 111.9-112.3 mg/kg/day in males and 0, 12.4-13.2, 40.4-44, or 

128-131.4 mg/kg/day in females). No maternal toxicity was seen at any of the dose 

levels and treatment with fluridone did not significantly affect any of the reproductive 

parameters. The NOAEL for maternal toxicity and reproductive toxicity was ≥ 2000 ppm 

(≥ 112 mg/kg/day, HDT). For offspring, there was decreased pup weight on lactation day 

21 at 112 mg/kg/day. Therefore, the NOAEL for offspring toxicity is 650 ppm (36 

mg/kg/day) and the LOAEL is 2000 ppm (112 mg/kg/day, HDT). Considering the 

overall toxicity profile and the doses and endpoints selected for risk assessment for 

fluridone, the degree of concern for the effects observed in this study was considered as 

low, noting that the study was well-conducted, clear NOAELs/LOAELs were established, 

and the dose response for the observed effects are well characterized.

The developmental toxicity studies in rats and rabbits showed no evidence of additional 

sensitivity to young rats or rabbits following pre- or postnatal exposure to fluridone and 

comparable NOAELs were established for adults and offspring.

A prenatal developmental toxicity study in rats included dose groups of 0, 100, 300, or 

1000 mg/kg/day on gestation days (GD) 6-15, inclusive. The LOAEL for maternal 

toxicity was 300 mg/kg/day, based on reduced body weight gains and food consumption, 

and the NOAEL for maternal toxicity was 100 mg/kg/day. There were no differences 

between the control group and all of the treated groups for number of females pregnant, 

corpora lutea, number of implants per pregnancy, percentage of live fetuses, or 

percentage of resorptions. No dead fetuses were observed in any groups. The LOAEL 

for developmental toxicity was 1000 mg/kg/day, based on decreased fetal weight, 

increased incidence of rudimentary ribs, and delayed ossification in sternebrae and pelvic 

girdle, and the NOAEL for developmental toxicity was 3000 mg/kg/day. 

A prenatal developmental study in rabbits included dose groups of 0, 125, 300, or 750 

mg/kg/day. The LOAEL for maternal toxicity was 300 mg/kg/day, based on increased 

incidence of abortions and slight decreases in body weight and food consumption, and the 

NOAEL for maternal toxicity was 125 mg/kg/day. No dead fetuses were observed in any 

group and the mean fetal body weights of all treatment groups were comparable to the 

control group. The LOAEL for developmental toxicity was 300 mg/kg/day, based on 

increased incidence of abortions, and the NOAEL was 125 mg/kg/day.

4. Subchronic toxicity. The following repeated dose, oral (dietary) toxicity studies 
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with fluridone are available: a 90-day oral toxicity in rats, a 90-day oral toxicity study in 

mice, a 90-day oral toxicity study in dogs, a 21-day dermal toxicity study in rabbits and a 

28-day immunotoxicity study in mice. 

The rat subchronic 90-day study was conducted at concentrations in the diet of 0, 330, 

560, 1000, 1400, or 2000 ppm (equivalent to 0, 30, 54, 106, 139, or 178.4 mg/kg/day for 

males and 0, 34, 53, 94, 126, or 202 mg/kg/day for females). The dosages were further 

corrected for stability of fluridone in diets. The corrected dosages administered to males 

were 0, 25, 44, 87, 114, or 146 mg/kg/day. The LOAEL for fluridone in rats was 44 

mg/kg/day, based on increased absolute and relative liver weights and relative kidney 

weights, and the NOAEL was 25 mg/kg/day. 

The mouse subchronic 90-day study was conducted at concentrations in the diet of 0, 62, 

110, 200, 330, or 560 ppm (equivalent to 0, 9.3, 16.5, 30, 49.5, or 84 mg/kg/day). The 

dosages were further corrected for stability of fluridone in diets. The corrected dosages 

administered were 0, 4.6, 8.3, 15, 25, or 42 mg/kg/day. The LOAEL for fluridone in 

mice was 25 mg/kg/day, based on increased incidence of hepatic centrilobular 

hypertrophy, and the NOAEL was 15 mg/kg/day. 

The dog subchronic 90-day study was conducted at dose levels of 0, 50, 100, or 200 

mg/kg/day. The LOAEL for fluridone in dogs was not established and the NOAEL was 

determined to be ≥ 200 mg/kg/day (HDT). 

The 21-day dermal toxicity study in rabbits was conducted at dose levels of 0, 192, 384, 

or 768 mg/kg/day. The LOAEL for systemic toxicity was 768 mg/kg/day, based on 

decreased relative kidney weights, and the NOAEL was 384 mg/kg/day. Based on 

dermal findings of slight erythema in 9 of 10 animals and slight desquamation at 192 

mg/kg/day (LDT), the LOAEL and NOAEL for dermal toxicity were not established.

A 28-day dietary study was conducted in female CD-1 mice to evaluate the potential 

immunotoxicity of fluridone. The dietary concentrations of 0, 200, 400, or 1000 ppm 

(equivalent to mean consumption of 0, 43.5, 89.1, or 205.4 mg/kg/day) were tested. 

There were no treatment-related effects on survival, clinical observations, body weight, 

food consumption, macroscopic findings, or liver weights in any of the treatment groups. 

There were no treatment-related effects on spleen or thymus weights, spleen cellularity, 

or in specific activity and total spleen activity, as measured by AFC assay. Treatment of 

female mice with 200, 400, and 1000 ppm of fluridone in the diet for 28-days did not 

suppress the humoral component of the immune system when evaluated using the AFC 

assay. Based on the weight of evidence in this study, the NOAEL for suppression of the 

humoral immune response was 1000 ppm, equivalent to 205.4 mg/kg/day (HDT).

5. Chronic toxicity. In a 1-year oral toxicity study in dogs, fluridone was 

administered in gelatin capsules at dose levels of 0, 75, 150, or 400 mg/kg/day. The 

LOAEL was 400 mg/kg/day, based on significant increases in absolute liver weights and 

increases in alkaline phosphatase activity in female dogs. The NOAEL was 150 

mg/kg/day, based on the slight weight loss in males and the trend towards increased 

alkaline phosphatase activity (120-170% of control values) in females. 
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Three concurrent studies were conducted in rats (one 1-year study and two 2-year 

studies) and reported as a combined chronic dietary toxicity and carcinogenicity study. 

Fluridone was administered to rats at dose levels of 0, 200, 650, or 2000 ppm (equivalent 

to 0, 7.65, 25.15, or 80.80 mg/kg/day in males and 0, 9.17, 30.11, or 97.00 mg/kg/day in 

females). The LOAEL for systemic toxicity was 650 ppm (80.8 mg/kg/day in males and 

97 mg/kg/day in females), based on decreased body weights, decreased eosinophil 

counts, and decreased absolute and relative liver and kidney weights, and the NOAEL for 

systemic toxicity was 200 ppm (7.65 mg/kg/day in males and 9.17 mg/kg/day in 

females).

Three concurrent carcinogenicity studies were conducted in mice (one 1-year study and 

two 2-year studies). Fluridone was administered at dose levels of 0, 33, 100, or 330 ppm 

(equivalent to 0, 5, 15, or 50 mg/kg/day). The LOAEL for systemic toxicity was 330 

ppm (50 mg/kg/day), based on an increase in alkaline phosphatase activity and increased 

incidence of hepatocellular hyperplasia, and the NOAEL was 100 ppm (15 mg/kg/day). 

There was not a treatment-related increase in tumor incidence in any treated groups when 

compared to controls. The tumor issue of this study was peer reviewed by the HED 

Cancer Assessment Review Committee (CARC, TXR 007726), which concluded that the 

available data did not provide enough evidence for the carcinogenicity of fluridone in 

mice. 

The HED CARC concluded that fluridone is classified as “not likely” to be a human 

carcinogen. Quantitative cancer risk assessment is not required.

6. Animal metabolism. Fluridone administered orally to rats is rapidly and almost 

completely absorbed into the systemic circulation and eliminated in both the male and 

female rats within 3 days. The total radioactivity recovered within 3 days after dosing 

were 78-90% and 87-97% of the administered dose in males and females, respectively. 

The majority of the radioactivity was eliminated via feces (approximately 70%). No 

tissue accumulation was observed. In another metabolism study in rats, the major 

components in the feces were identified as fluridone and fluridone metabolites produced.

7. Metabolite toxicology. Available data indicate that fluridone is the predominant 

residue in all crops studied and no individual metabolites or degradates of significance 

are formed.

8. Endocrine disruption. The available fluridone data-set, including reproductive 

toxicity, did not reveal any potential for specific modulation of endocrine systems in the 

test species. There is no evidence to suggest that fluridone has an effect on the endocrine 

system.

C. Aggregate Exposure

1. Dietary exposure. In evaluating dietary exposure to fluridone, we considered 

exposure via the proposed tolerance listed in this action as well as all existing fluridone 
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tolerances in 40 CFR 180.420. We assessed dietary exposures from fluridone in food as 

follows:

i. Food. The process of dietary risk assessment of pesticides considers acute 

and chronic exposures to the U.S. population and sensitive population 

subgroups. Additional exposures from potential residues in drinking water 

were also combined with acute and chronic food exposure estimations.

The EPA has established an acute reference dose (aRfD) for the purpose 

of the acute dietary assessment of 1.25 mg/kg/day for females 13-49 years 

old. This was based on the NOAEL of 125 mg/kg/day from a 

developmental toxicity study in rabbits and an uncertainty factor of 10X. 

In estimating acute dietary exposure for the subpopulation, females 13-49 

years, we used food consumption information from the United States 

Department of Agriculture (USDA) 1994-1996 and 1998 Nationwide 

Continuing Surveys of Food Intake by Individuals (CSFII). As to residue 

levels in food, we used tolerance level residues, DEEM (Ver. 7.81) default 

processing factors (as necessary) and 100 percent crop treated (PCT) for 

all commodities. The aPAD is less than 1% for females 13-49 years. 

Therefore, fluridone is not expected to pose an acute risk.

The EPA has established a chronic reference dose (cRfD) of 0.15 

mg/kg/day. The cRfD is based upon the 2-year chronic toxicity study in 

mice with a NOAEL of 15 mg/kg/day and an uncertainty factor of 10X. 

No additional FQPA safety factory is required. In conducting the chronic 

dietary exposure assessment we used the food consumption data from the 

USDA 1994-1996 and 1998 CSFII. As to residue levels in food, we used 

tolerance level residues, DEEM (Ver. 7.81) default processing factors (as 

necessary) and 100 PCT for all commodities. Chronic exposure to 

fluridone from feed and water will utilize 4% of the cPAD for children 1-2 

years of age, the population group with the greatest exposure.

Short- and intermediate-term aggregate exposure takes into account shortterm residential exposure or intermediate-term residential exposure plus 

chronic exposure to food and water (considered to be a background 

exposure level).

Fluridone is currently registered for uses that could result in short- and 

intermediate-term residential exposure, and the Agency has determined 

that it is appropriate to aggregate chronic exposure through food and water 

with short- and intermediate-term residential exposures to fluridone.

Using the exposure assumptions described above for short-term and 

intermediate-term exposures, we have concluded the combined short-term 

food, water, and residential exposures and the intermediate-term food, 

water, and residential exposures each result in aggregate MOEs of 290 
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(liquids for pouring applications + swimming exposure) to 340 (liquids for 

garden hose end sprayer + swimming exposure). Because EPA's level of 

concern for fluridone is a MOE of 100 or below, these MOEs are not of 

concern.

We did not use anticipated residue or PCT information in the dietary 

assessment for fluridone. Tolerance level residues and 100 PCT were 

assumed for all food commodities.

ii. Drinking water. We used screening level water exposure models in the 

dietary exposure analysis and risk assessment for fluridone in drinking 

water. These simulation models take into account data on the physical, 

chemical, and fate/transport characteristics of fluridone. 

Based on the FQPA Index Reservoir Screening Tool (FIRST) and 

Screening Concentration in Ground Water (SCI-GROW) models, the 

estimated drinking water concentrations (EDWCs) of fluridone for acute 

exposures are estimated to be 9.6 parts per billion (ppb) for surface water 

and 0.67 ppb for ground water. EDWCs of fluridone for chronic 

exposures for non-cancer assessments are estimated to be 2.5 ppb for 

surface water and 0.67 ppb for ground water.

Modeled estimates of drinking water concentrations were directly entered 

into the dietary exposure model. For acute dietary risk assessment, the 

water concentration value of 9.6 ppb was used to assess the contribution to 

drinking water. For chronic dietary risk assessment, the water 

concentration of value 2.5 ppb was used to assess the contribution to 

drinking water.

2. Non-dietary exposure. Fluridone is currently registered for one use that could 

result in residential handler and residential post-application exposures: Consumer use to 

control aquatic weeds in ponds. The term “residential exposure” is used to refer to nonoccupational, non-dietary exposure. We assessed residential exposure using the 

following assumptions: residents or consumers may experience short-term (1-30 days) 

skin contact or inhalation exposures. These exposures are assessed through residential 

handler scenarios. Post-application exposures of children and adults through contact with 

treated swimming ponds are also anticipated. These exposures are expected to be shortand intermediate-term (1-6 months) in duration through dermal, ingestion, aural, 

buccal/sublingual, and nasal/orbital exposure. All residential handler and postapplication scenarios from the uses of fluridone have been assessed and no risks of 

concern have been identified. The scenarios for residential handler and post-application 

exposure (combined dermal and inhalation) resulted in MOEs of 1,800 and 23,000, 

respectively.

D. Cumulative Effects
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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.”

Fluridone does not share a common mechanism of toxicity with any other substances, and 

fluridone does not appear to produce a toxic metabolite produced by other substances. 

For the purposes of this tolerance action, therefore, we have assumed that fluridone does 

not have a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. An acute aggregate risk assessment takes into account acute 

exposure estimates from dietary consumption of food and drinking water. An adverse 

effect resulting from a single oral exposure was identified for only the subpopulation 

females 13-49 years. Using the exposure assumptions described above for acute 

exposure, we have concluded that acute exposure to fluridone from food and water will 

utilize less than 1% of the aPAD for females 13-49 years. Therefore, fluridone is not 

expected to pose an acute risk.

Short- and intermediate-term aggregate exposure takes into account short-term residential 

exposure or intermediate-term residential exposure plus chronic exposure to food and 

water (considered to be a background exposure level).

Fluridone is currently registered for uses that could result in short- and intermediate-term 

residential exposure, and the Agency has determined that it is appropriate to aggregate 

chronic exposure through food and water with short- and intermediate-term residential 

exposures to fluridone.

Using the exposure assumptions described above for short-term and intermediate-term 

exposures, we have concluded the combined short-term food, water, and residential 

exposures and the intermediate-term food, water, and residential exposures each result in 

aggregate MOEs of 290 (liquids for pouring applications + swimming exposure) to 340 

(liquids for garden hose end sprayer + swimming exposure). Because EPA's level of 

concern for fluridone is a MOE of 100 or below, these MOEs are not of concern.

Using the exposure assumptions described above for chronic exposure, we have

concluded that chronic exposure to fluridone from food and water will utilize 4% of the 

cPAD for children 1-2 years, the population group receiving the greatest exposure. Based 

on the explanation above regarding residential use patterns, chronic residential exposure 

to residues of fluridone is not expected.

Based on these risk assessments, we conclude that there is a reasonable certainty that no 

harm will result to the general population, or to infants and children, from aggregate 

exposure to fluridone residues.
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2. Infants and children. Section 408(b)(2)(C) of FFDCA provides that EPA shall 

apply an additional tenfold (10X) 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 based on reliable data that a 

different margin of safety will be safe for infants and children. This additional margin of 

safety is commonly referred to as the FQPA Safety Factor (SF). In applying this 

provision, EPA either retains the default value of 10X, or uses a different additional SF 

when reliable data available to EPA support the choice of a different factor.

Prenatal and postnatal sensitivity. Based on the results in the developmental toxicity 

studies in rats and rabbits and in a three-generation reproduction study, no increased 

sensitivity of fetuses or pups (as compared to adults) was demonstrated for fluridone. 

There are no concerns or residual uncertainties for prenatal/postnatal toxicity following 

exposure to fluridone.

We have determined that reliable data show that the safety of infants and children would 

be adequately protected if the FQPA SF were reduced to 1X. That decision is based on 

the following findings:

i. The toxicity database for fluridone is complete (recently updated under registration 

review) and meets the new data requirements in 40 CFR Part 158 for conventional 

pesticide registration. 

ii. The neurotoxicity data on fluridone indicate that it is not neurotoxic and there is no 

need for a developmental neurotoxicity study or additional UFs to account for 

neurotoxicity.

iii. There is no evidence that fluridone results in increased susceptibility in in utero rats or 

rabbits in the prenatal developmental studies or in young rats in the 3-generation 

reproduction study.

iv. There are no residual uncertainties identified in the exposure databases. The dietary 

food exposure assessment utilized 100 PCT and tolerance-level residues (established or 

recommended). We made conservative (protective) assumptions in the ground and 

surface water modeling used to assess exposure to fluridone in drinking water. We used 

similarly conservative assumptions to assess post-application exposure of children as well 

as incidental oral exposure of toddlers. These assessments will not underestimate the 

potential exposure and risks posed by fluridone.

Based on these risk assessments, we conclude that there is a reasonable certainty that no 

harm will result to the general population, or to infants and children, from aggregate 

exposure to fluridone residues.

F. International Tolerances

No maximum residue levels have been established for this active ingredient.
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