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

P P 4F83 08

EPA has received a pesticide petition ( PP 4F8308 ) from SePRO Corporation

, 11550 N orth Meridian Street, Suite 600, Carmel, IN 46032 request ing, 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

- pheny l

- 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 rega rding 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 t he 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 residue s 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 ch romatography with tandem mass spectroscopy (LC

MSMS)) 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
cotton seed 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.2

B. Toxicological Profile

1. Acute toxicity. Fluridone has low to moderate acute oral, inhalation and dermal toxicity. The acute oral LD 50 is > 10,000 mg/kg bw in rats. The acute dermal LD 50 of fluridone is >2000 mg/kg bw. The acute inhala tion L C 50 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 schedule d 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 65 0 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 treatment

rel ated 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 le vel 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 exc ept for t hree 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, flurido ne 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 tests3

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 bo ne 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 sy nthesis 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/d ay 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 toxici ty 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 establis hed, 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 imp lants 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 tre atment 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 r epeated dose, oral (dietary) toxicity studies4

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 subc hronic 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

correc ted 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

w eights, 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 sta bility 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/da y.
The dog subchronic 90

- day study was conducted at dose levels of 0, 50, 100, or 200 mg/kg/day. The LOAEL for fluridone i n 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 w ere not established.

A 28

- day d ietary 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

a ssay. 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 i n 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.5

Three concurrent studies were conducted in rats (one 1

- year study and two 2

- year studies) and reported as a combined c hronic 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 treat ment

- 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 pro vide 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 adm inistered 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 admi nistered dose in males and females, respectively. The majority of the radioactivity was eliminated via feces (approximately 70%). No tissue accumulation was observed. In a nother 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 d isruption

. The available fluridone data

- set, including reproductive toxicity

, did not reveal any potential for specific modulation of endocrine system s in the test species. There is no evidence to suggest that fluridone has an effect on the endocrine
sys tem

.

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 fluridone6

tolerances in 40 CFR 180.420. We assessed dietary e xposures 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 drin king 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 NO AEL 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 tre ated (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 ch ronic 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 1 998 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 child ren 1

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

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 (con sidered 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 a nd 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 a nd the intermediate

- term food, water, and residential exposures each result in aggregate MOEs of 2907

(liquids for pouring applications + swimming exposure) to 340 (liquids for garden hose end sprayer + swimming exposure). Because EPA's level of concern fo r 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 fl uridone.

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 billio n (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 w ere 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 non

occupational, non

- dietary exposure. We assessed residential exposure us ing the following assumptions: r esidents or consumers may experience short

- term (1

- 30 days) skin contact or inh alation 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 short

and inte rmediate

- term (1

- 6 months) in duration through dermal, ingestion, aural, buccal/sublingual, and nasal/orbital exposure. All residential handler and post

application 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 Effects8

Section 408(b)(2)(D)(v) of FFDCA requires that, when considerin g 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.”

F luridone does not s hare 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 c ommon 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 resul ting 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 tha n 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 chroni c 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 aggrega te 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 util ize 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.9

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 b ased 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 10 X, 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 regist ration review) and meets the new data requirements in 40 CFR P art 158 for conventional pesticide registration.

ii. The neurotoxicity data on fluridone indicate that it i s 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 developme ntal 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 ris k 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 b een established for this active ingredient

.10