Fluridone Human Health Risk Assessment DP No. 423464 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: January 20, 20 16 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Fluridonc. Human Health Risk Assessment for Registration Review and to 

Support the Registration of the Use on Cotton. 

PC Code: I 12900 DP Barcode: 423464 

Decision No.: 494948 Registration No.: 67690-NEW 

Petition No.: 4F8308 Regulatory Action: Registration Review 

Ris k Assessment Type: Single Chemical Aggregate Case No.: 7200 

TXR No.: NA CAS No.: 59756-60-4 

MRID No.: NA 40 CFR: 180.420 

FROM: 

Alexa

Ronni ndra .Beve GaverJr. lek, PhD Biologist DAB~ 1 h._ .i'; 

M\ ~~-~A 

Uma 

Kelly 

Habiba

M. Lowe

, Che

, Environmental 

mist 

Scientist ~ 

~ 

Risk Assessment Branch V N II 

Health Effects Division (7509P) ~ 

Ri

Austin 

sk Assessment 

Wray, Toxico

Bran

logist 

ch IV 

~ /1.J' ~ 1 )----

Health Effects Division (7509P) ~/ j J) (/\ 

THROUGH: Michael Metzger, Branch Chief, Risk Assessment Branch YNII ~ {t /) JJ1"}i , . 

Donna Davis, Risk Assessment Review Committee Designated eviewer U~ 

Anna Lowit, Risk Assessment Review Committee Designated Reviewer(} /!._ ) / 

Health Effects Division (7509P) '-'(D ~ 

TO: Sarah Meadows, Risk Manager Reviewer 

Kathryn Montague, Risk Manager 

Registration Division 

Leigh Rimmer, Chemical Review Manager 

Tom Myers, Team Leader 

Kevin Costello, Branch Chief 

Pesticide Re-Evaluation Division 

Page I of 83 
Fluridone Human Health Risk Assessment DP No. 423464

Page 2 of 83

1.0 Executive Summary........................................................................................................... 4

2.0 HED Recommendations.................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 7

2.2 Tolerance Considerations.............................................................................................. 7

2.2.1 Enforcement Analytical Method ............................................................................ 7

2.2.2 Recommended Tolerances....................................................................................... 7

2.2.3 Revisions to Petitioned-For Tolerances ................................................................. 9

2.2.4 International Harmonization................................................................................ 10

2.3 Label Recommendations.............................................................................................. 10

2.3.1 Recommendations from Residue Reviews........................................................... 10

2.3.2 Recommendations from Occupational Assessment............................................ 10

2.3.3 Recommendations from Residential Assessment................................................ 11

3.0 Introduction...................................................................................................................... 11

3.1 Chemical Identity ......................................................................................................... 11

3.2 Physical/Chemical Characteristics ............................................................................. 11

3.3 Pesticide Use Pattern.................................................................................................... 11

3.4 Anticipated Exposure Pathways................................................................................. 13

3.5 Consideration of Environmental Justice.................................................................... 14

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 14

4.1 Toxicology Studies Available for Analysis................................................................. 14

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 15

4.2.1 Dermal Absorption................................................................................................... 15

4.3 Toxicological Effects .................................................................................................... 16

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 17

4.4.1 Completeness of the Toxicology Database.............................................................. 17

4.4.2 Evidence of Neurotoxicity........................................................................................ 18

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 18

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 18

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 18

4.5.1 Dose-Response Assessment...................................................................................... 18

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment..... 20

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 20

4.6 Endocrine Disruption................................................................................................... 22

5.0 Dietary Exposure and Risk Assessment......................................................................... 23

5.1 Metabolite/Degradate Residue Profile ....................................................................... 23

5.1.1 Summary of Plant and Animal Metabolism Studies .......................................... 23

5.1.2 Summary of Environmental Degradation ........................................................... 23

5.1.3 Comparison of Metabolic Pathways..................................................................... 24

5.1.4 Residues of Concern Summary and Rationale.................................................... 24

5.2 Food Residue Profile .................................................................................................... 25

5.3 Water Residue Profile.................................................................................................. 26

5.4 Dietary Risk Assessment.............................................................................................. 27
Fluridone Human Health Risk Assessment DP No. 423464

Page 3 of 83

5.4.1 Description of Residue Data Used in Dietary Assessment ................................. 27

5.4.2 Percent Crop Treated Used in Dietary Assessment............................................ 27

5.4.3 Acute Dietary Risk Assessment ............................................................................ 27

5.4.4 Chronic Dietary Risk Assessment ........................................................................ 27

5.4.5 Cancer Dietary Risk Assessment.......................................................................... 28

5.4.6 Summary Table...................................................................................................... 28

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 28

6.1 Residential Handler Exposure .................................................................................... 28

6.2 Residential Post-Application Exposure...................................................................... 31

6.3 Residential Risk Estimates for Use in Aggregate Assessment.................................. 32

6.4 Residential Bystander Post-Application Inhalation Exposure ................................ 32

6.5 Spray Drift.................................................................................................................... 32

7.0 Aggregate Exposure/Risk Characterization.................................................................. 35

7.1 Acute Aggregate Risk................................................................................................... 35

7.2 Short-Term Aggregate Risk........................................................................................ 35

7.3 Intermediate-Term Aggregate Risk ........................................................................... 35

7.4 Chronic Aggregate Risk .............................................................................................. 36

7.5 Cancer Aggregate Risk ................................................................................................ 36

8.0 Cumulative Exposure/Risk Characterization ............................................................... 36

9.0 Occupational Exposure/Risk Characterization ............................................................ 36

9.1 Short-/Intermediate-Term Handler Risk................................................................... 36

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 43

9.2.1 Dermal Post-application Risk............................................................................... 43

9.2.2 Inhalation Post-application Risk .......................................................................... 43

Appendix A. Toxicology Profile and Executive Summaries .................................................. 46

A.1 Toxicology Data Requirements................................................................................... 46

A.2 Toxicity Profiles............................................................................................................ 47

A.3 Hazard Identification and Endpoint Selection.......................................................... 52

A.4 Executive Summaries................................................................................................... 54

Appendix B. Physical/Chemical Properties............................................................................. 71

Appendix C. Review of Human Research................................................................................ 72

Appendix D. International Tolerances and MRLs.................................................................. 73

Appendix E. NMF Exposure and Risk Assessment................................................................ 75
Fluridone Human Health Risk Assessment DP No. 423464

Page 4 of 83

1.0 Executive Summary

The Registration Division (RD) has requested an assessment of human health risk to support the 

proposed new use of fluridone on pre-emergent cotton and the Pesticide Re-evaluation Division 

(PRD) has requested a draft assessment of human health risk to support the registered uses of 

fluridone (1-methyl-3-phenyl-5-[3-trifluoromethyl)phenyl]-4(1 H)-5-[3-

(trifluoromethyl)phenyl]-4(1 H )-pyridinone) as part of Registration Review. 

Fluridone is a systemic herbicide used on ponds (including a homeowner use), lakes, reservoirs, 

irrigation canals, drainage canals, and rivers. It inhibits carotene synthesis, which causes the loss 

of chlorophyll. Current labels permit single treatments of up to a concentration of 90 ppb for 

whole lake treatments and 150 ppb for partial lake treatments, with a maximum cumulative 

application concentration of 150 ppb per lake weed growth cycle. Water from areas treated with 

fluridone can be used for the irrigation of crops and pastures or used as drinking water for 

livestock. Tolerances are currently established for inadvertent residues of fluridone in numerous 

crops, livestock commodities, fish and crayfish as a result of the aquatic uses. There is also a 

proposed new use of fluridone as a pre-emergent (direct soil) treatment to cotton. HED has 

determined that the current tolerance of 0.1 ppm for inadvertent residues of fluridone in cotton is 

adequate to cover any residues that may occur in cotton commodities as a result of the proposed 

direct soil use for cotton.

Humans may be exposed to fluridone in food and drinking water. In a residential setting, 

applicators may be exposed while applying the pesticide to residential ponds. There is also 

potential for residential post-application exposure to fluridone while swimming in treated water. 

In an occupational setting, applicators may be exposed while handling the pesticide prior to 

application, as well as during application. There is negligible post-application exposure for 

workers based on the registered and proposed use. 

The toxicology database is adequate to assess current and proposed uses for fluridone; the 

subchronic neurotoxicity and inhalation studies were waived by the Hazard and Science Policy 

Council (HASPOC). The liver and kidneys were identified as the primary target organs based on 

a multitude of organ specific effects noted across the toxicity database. All species exhibited 

indications of liver toxicity that were often accompanied by body weight effects. Mice were the 

most sensitive species examined, and dogs were the most tolerant. Rat sensitivity was 

comparable (chronic exposure) to or slightly less (subchronic exposure) than mice; however, rats 

were the only species to exhibit minor kidney effects in addition to liver and body weight 

toxicity. Progression of toxicity from subchronic to chronic exposures was not observed in mice 

and was limited (2-fold difference) in rats. No evidence of fetal sensitivity was observed in rats 

or rabbits. Body weight effects in the F2 rat offspring during the lactation period were suggestive 

of susceptibility in the young. However, the effects were isolated to the F2 offspring; body weight 

of the F2 offspring returned to control levels after the lactation period; and no subsequent 

evidence of susceptibility was observed in progeny of the F2 generation. Furthermore, the 

offspring effects occurred at doses 2 to 4.5 times higher than the target organ and body weight 

toxicity noted in adult rodents in other studies. Behavioral anomalies, physiological effects, and 

locomotor impairment consistent with neurotoxicity were only observed following acute gavage 

exposure to doses that likely exceeded linear pharmacokinetics and were at least 13 to 26 times 
Fluridone Human Health Risk Assessment DP No. 423464

Page 5 of 83

higher than the lowest doses causing liver and kidney effects in rodents. No signs of 

neurotoxicity were identified in the rest of the toxicity database. Toxicity from repeated dose 

dermal exposures was limited to irritation effects on the skin (erythema, desquamation, 

epidermal fissures). No evidence of immunotoxicity, mutagenicity, or carcinogenicity were 

noted in the toxicity database. 

An acute population adjusted dose (PAD) for all populations was selected from an acute 

neurotoxicity study in rats based on decreased ambulatory counts and the prevalence of 

functional observational battery (FOB) anomalies in males and females. No acute effect specific 

to child bearing females was observed in the submitted studies; therefore, no acute endpoint was 

selected for the female 13-49 subpopulation. A chronic PAD was selected from a 2 year mouse 

cancer study based on increased alkaline phosphatase activity and increased incidence of 

hepatocellular hyperplasia. A slightly lower NOAEL was noted in the rat combined chronic 

toxicity/carcinogenicity study; however, this fact was considered to be due to dose-selection. 

Considering the mouse and rat exhibited comparable sensitivity to chronic exposure, the mouse 

point of departure (POD) was protective of the chronic effects in the rat. The same endpoints 

from the 2 year mouse study were selected for short-and intermediate-term incidental oral, 

dermal and inhalation exposures, because mice were the most sensitive species and there was no 

progression of toxicity from subchronic to chronic exposures in mice. An upper bound dermal 

absorption factor of 39% was used in the dermal assessment to account for route to route 

extrapolation. In the inhalation assessment, absorption was assumed to be 100% using the oral 

endpoint. An uncertainty factor of 100x was applied to endpoints selected for all exposure routes 

(10x for interspecies extrapolation, 10x for intraspecies variation). The Food Quality Protection 

Act safety factor (FQPA SF) was reduced to 1X for fluridone because the developmental and 

offspring effects are well defined and have clear no observed adverse effect levels (NOAEL) and 

lowest observed adverse effect levels (LOAEL), PODs selected for risk assessment are 

protective of the developmental and offspring effects, and there are no residual uncertainties in 

the fluridone exposure or toxicity database.

Acute and chronic unrefined dietary assessments were conducted for fluridone that incorporated 

tolerance-level residues, 100% crop treated, and default processing factors. Modeled estimated 

drinking water concentrations (EDWCs) were directly incorporated into the assessment as point 

estimates. Acute and chronic dietary (food and drinking water) exposure and risk estimates were 

not of concern to HED for the general US population and all population subgroups (i.e., all risk 

estimates were <100% of the population-adjusted dose).

The residues of concern for tolerances and risk assessment purposes for both food and livestock 

is the parent fluridone. The appropriate tolerance level would be 0.1 ppm for all crops for which 

there were no direct uses, except for animal feed non-grass group 18 and grass forage; a 

tolerance of 0.15 ppm would be appropriate for those livestock feed items. No residue data were 

submitted with the Section 3 request for use on cotton. Given the absence of fluridone residues 

in cottonseed and whole cotton plants from geographically appropriate field trials, it can be 

concluded that residues of fluridone from the proposed Section 3 use would not exceed the 

current tolerance level of 0.1 ppm for cottonseed, undelinted. HED has recommended that a 

tolerance for fluridone on cotton gin byproducts also be established at 0.1 ppm.
Fluridone Human Health Risk Assessment DP No. 423464

Page 6 of 83

The proposed new use on cotton is not anticipated to result in residential exposures; however, the 

existing aquatic uses of fluridone were assessed as part of Registration Review. The residential 

handler assessment assessed dermal and inhalation exposure of homeowners applying fluridone 

to ponds; there were no risks of concern for residential handlers (i.e., all combined margins of 

exposure (MOEs) ≥ 100). The residential post-application exposure assessment assessed adults 

and children (3 to < 6 years old) who may be exposed to fluridone while swimming in treated 

water (dermal, inhalation and incidental ingestion exposure routes). There were no risks of 

concern for swimmers for the individual routes (i.e., all fluridone MOEs ≥ 100). Since all the 

routes of exposure are based on the same effect, the exposures can be combined across routes. 

The combined MOEs for adults and children (3 to < 6 years old) are also not of concern (i.e., all 

fluridone combined MOEs ≥ 100).

The acute aggregate risk is equivalent to the acute dietary risk estimates. The acute dietary 

exposure estimates for fluridone (food and drinking water) are not of concern to HED (<100% 

aPAD) for the general U.S. population and all population subgroups. For the short-term 

aggregate risk assessment, potential residential exposures (dermal, inhalation and incidental 

ingestion from swimming in treated waters) were combined with chronic dietary exposures. The 

short-term aggregate MOEs for fluridone for adults and children are greater than the level of 

concern (LOC) and are, therefore, not of concern. Intermediate-term residential exposures are 

not likely because of the intermittent residential exposure to fluridone; therefore, an 

intermediate-term aggregate risk assessment is not required. There are no chronic residential 

exposure scenarios; therefore, the chronic aggregate risk is equivalent to the chronic dietary risk 

estimate. The chronic dietary (food and drinking water) exposure estimates for fluridone are not 

of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups. 

Occupational exposure is anticipated from both the proposed cotton use, as well as the existing 

aquatic uses. Occupational handlers may be exposed via dermal and inhalation routes, while 

mixing/loading and applying the products to aquatic areas or to cotton. There were no risks of 

concern for occupational handlers making applications to cotton via groundboom equipment 

with the proposed label-required clothing. There are risk estimates of concern for some of the 

registered aquatic use scenarios. Occupational handler combined dermal and inhalation MOEs 

range from 6.1 to 18,000 with baseline clothing (single layer clothing, shoes plus socks, no 

gloves, and no respirator for all scenarios, except aerial applicator where engineering controls 

were used). The scenario of mixing/loading/applying with a handwand sprayer to aquatic sites 

was not of concern with the addition of gloves. The scenario of mixing/loading/applying product 

with backpack sprayer to aquatic sites was not of concern with the addition of double layer 

clothing and gloves. For aquatic use applications, the current product labels do not require PPE. 

Because of the risk concerns identified in the occupational handler assessment for the aquatic 

uses, it is recommended that the product labeling for aquatic uses direct applicators to wear longsleeved shirt, long pants, shoes plus socks, as well as additional PPE, such as gloves and a 

coverall (i.e., double layer of clothing) for applications with handheld equipment. 

There is potential non-occupational exposure via spray drift from the proposed agricultural use 

on cotton. The spray drift assessment assessed adults and children (1 to <2 years old) who may 

be exposed to residues of fluridone on a lawn next to a field that was previously treated with 
Fluridone Human Health Risk Assessment DP No. 423464

Page 7 of 83

fluridone. There were no risks of concern for exposures from spray drift at the field edge

(dermal and incidental oral MOEs ≥ 100 at the edge of the field).

As the proposed use is on pre-plant or pre-emergent cotton, occupational post-application dermal 

exposure to residues on foliage is expected to be negligible. The restricted entry interval (REI) of 

24 hours on the proposed label for the cotton use is adequate and meets the minimum WPS 

requirements. Since the currently registered uses of fluridone are in aquatic environments, there 

are no occupational post-application activities which would result in occupational exposures 

from treated bodies of water. As application to aquatic/de-watered areas do not fall under the 

purview of WPS, and worker re-entry exposure is considered to be negligible, an REI is not 

applicable for these uses.

Based on the Agency’s current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for fluridone at this time. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational

post-application inhalation exposure assessment for fluridone.

2.0 HED Recommendations

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available in the Pesticide Analytical Manual (PAM) Volume II for the 

enforcement of tolerances for residues of fluridone in plant commodities, including cotton. The 

plant method is an HPLC method (originally submitted as method AM-AA-CA-RO52-AA-755). 

The limit of quantitation is 0.05 ppm. There are also PAM Vol II methods for fluridone in 

livestock commodities (LOQ = 0.05 ppm) and for residues of fluridone and the metabolite,

4-hydroxy-fluridone, in fish (LOQ = 0.10 ppm and 0.05 ppm, respectively).

2.2.2 Recommended Tolerances

HED has reviewed the petition request to determine the appropriate tolerances which are to be 

established for the residues of fluridone. The recommended tolerance expression is as follows; 

(a)General. (1) Tolerances are established for residues of the herbicide fluridone, 

including its metabolites and degradates, in or on the commodities in the table in this 

paragraph. Compliance with the tolerance levels specified in this paragraph is to be 

determined by measuring only the only fluridone, 1-methyl-3-phenyl-5-(3-

(trifluoromethyl)phenyl)-4(1H)-pyridinone, in or on the commodity.
Fluridone Human Health Risk Assessment DP No. 423464

Page 8 of 83

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Crayfish 0.50

Fish 0.50

(2) Tolerances are established for residues of the herbicide fluridone, including its 

metabolites and degradates, in or on the commodities in the table in this paragraph. 

Compliance with the tolerance levels specified in this paragraph is to be determined by 

measuring only fluridone, 1-methyl-3-phenyl-5-(3-(trifluoromethyl)phenyl)-4(1H)-

pyridinone, in or on the commodity.

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Cotton, undelinted seed 0.10 0.1

Cotton, gin byproducts None 0.1

Cattle, fat 0.05

Cattle, kidney 0.10

Cattle, liver 0.10

Cattle, meat 0.05

Cattle, meat byproducts 0.05

Egg 0.05

Goat, fat 0.05

Goat, kidney 0.10

Goat, liver 0.10

Goat, meat 0.05

Goat, meat byproducts 0.05

Hog, fat 0.05

Hog, kidney 0.10

Hog, liver 0.10

Hog, meat 0.05

Hog, meat byproducts 0.05

Horse, fat 0.05

Horse, kidney 0.10

Horse, liver 0.10

Horse, meat 0.05

Horse, meat byproducts 0.05

Milk 0.05

Poultry, fat 0.05

Poultry, kidney 0.01

Poultry, liver 0.01

Poultry, meat 0.05

Poultry, meat byproducts 0.05

Sheep, fat 0.05

Sheep, kidney 0.10

Sheep, liver 0.10

Sheep, meat 0.05

Sheep, meat byproducts 0.05

(d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent 

residues of the herbicide fluridone, including its metabolites and degradates, in or on the 
Fluridone Human Health Risk Assessment DP No. 423464

Page 9 of 83

irrigated crop commodities and crop groupings in the table in this paragraph, resulting 

from use of irrigation water containing residues of 0.15 parts per million following 

applications of fluridone on or around aquatic sites. Where tolerances are established at 

higher levels from other uses of fluridone on the crops in the table in this paragraph, the 

higher tolerance also applies to residues in or on the irrigated commodity. Compliance 

with the tolerance levels specified in this paragraph is to be determined by measuring 

only fluridone, 1-methyl-3-phenyl-5-(3-(trifluoromethyl)phenyl)-4(1H)-pyridinone, in or 

on the commodity.

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity 

Definition

Animal feed, non-grass, group 18 0.15

Avocado 0.10

Berry, group 13 0.10

Cotton, undelinted seed 0.10

Cranberry 0.10

Fruit, citrus, group 10 0.10

Fruit, pome, group 11 0.10

Fruit, stone, group 12 0.10

Grain, cereal, forage, fodder and straw, 

group 16

0.10

Grain, cereal, group 15 0.10

Grape 0.10

Grass, forage 0.15

Hop, dried cones 0.10

Nut, tree, group 14 0.10

Okra 0.10

Strawberry 0.10

Vegetable, brassica, leafy, group 5 0.10

Vegetable, cucurbit, group 9 0.10

Vegetable, fruiting, group 8 0.10

Vegetable, leafy, except brassica, group 4 0.10

Vegetable, leaves of root and tuber, group 2 0.10

Vegetable, legume, group 6 0.10

Vegetable, root and tuber, group 1 0.10

Upon establishment of the tolerances listed above, tolerance listings for cotton undelinted seed in 

180.420(b) and 180.420(d) should be revoked since it is included in the new listing.

2.2.3 Revisions to Petitioned-For Tolerances

HED agrees with the petitioner that the proposed tolerance for fluridone on cotton, undelinted 

seed should remain at the current 0.1 ppm level; that level is adequate to cover any residues that 

may result from the proposed direct application to cotton.

The cotton, undelinted seed tolerance of 0.1 ppm should be added to 40 CFR 180.420 (a) general

section. The tolerance of 0.1 ppm for cotton, undelinted seed listed in 40 CFR 180.420 (d) for 

inadvertent residues (from treated irrigation water) should be removed. The cotton, undelinted 
Fluridone Human Health Risk Assessment DP No. 423464

Page 10 of 83

seed tolerance of 0.1 ppm in the 40 CFR 180.420 section (b) Section 18 emergency exemptions

should also be removed.

The petitioner did not propose a tolerance for residues of fluridone on cotton gin byproducts. 

HED has recommended that a tolerance for fluridone on cotton gin byproducts be established at 

0.1 ppm. A cotton gin byproduct tolerance is needed to cover this cotton raw agricultural 

commodities (RAC). There are no other differences between the requested and recommended 

tolerances. 

The petitioner did not propose tolerances for fluridone on cotton processed commodities. HED 

agrees that separate tolerances for cotton processed commodities are not required based on 

nondetectable residues in cotton RACs in exaggerated rate studies. The residue definition under 

40 CFR 180.420 (a) needs slight modification to be consistent with the guidance on tolerance 

expressions (S. Knizner, 5/27/09). The appropriate language is described below.

(2) Tolerances are established for residues of the herbicide fluridone, including its 

metabolites and degradates, in or on the commodities in the table in this paragraph. 

Compliance with the tolerance levels specified in this paragraph is to be determined by 

measuring only fluridone, 1-methyl-3-phenyl-5-(3-(trifluoromethyl)phenyl)-4(1H)-

pyridinone, in or on the commodity.

2.2.4 International Harmonization

There are no Codex, Mexican, and/or Canadian maximum residue limits (MRLs) established for 

the residues of fluridone. Therefore, international harmonization is not an issue for 

consideration. Refer to Appendix D for a summary of international tolerances and MRLs.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None.

2.3.2 Recommendations from Occupational Assessment

Proposed Cotton Use: No label recommendations.

Registered Aquatic Use: Although aquatic applications do not fall under the purview of the 

Worker Protection Standard (WPS), HED recommends that product labeling direct applicators to 

wear long-sleeved shirt and long pants and shoes plus socks. Because of the risk concerns 

identified in the occupational handler assessment, it is recommended that the product labeling for 

aquatic uses require handlers to wear additional PPE. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 11 of 83

2.3.3 Recommendations from Residential Assessment

None.

3.0 Introduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature.

Chemical Structure

Empirical Formula C19H14F3NO

Common Name Fluridone

Company experimental name

IUPAC name 1-methyl-3-phenyl-5-(α,α,α-trifluoro-m-tolyl)-4-pyridone

CAS Name 1-methyl-3-phenyl-5-[3-(trifluoromethyl)phenyl]-4(1H)-pyridinone

CAS Registry Number 59756-60-4

End-use product/EP EL171, SP1621

Chemical Class Pyridazone Herbicide

Known Impurities of Concern N/A

3.2 Physical/Chemical Characteristics

Fluridone is an off-white crystalline solid with a melting point of 154-155o

C and a bulk density 

of 1.4 g/cm3 (pyconometer method). It has a log octanol/water partition coefficient of 2.54 and 

a vapor pressure of <9.77 × 10-8 torr at 25oC. Fluridone in the environment is not persistent or 

mobile (Kd range from 5.56 to 70.3 ml/gram). Fluridone is minimally soluble in water (8.3 mg/L) 

and soluble in organic solvents (0.5 to >10 mg/ml). See Table B1 in Appendix B for the physicochemical properties of fluridone.

3.3 Pesticide Use Pattern

Proposed Use on Cotton

Table 3.3.1 provides a summary of the proposed cotton use. The proposed use is for a liquid 

formulation to be applied via groundboom equipment at a maximum rate of 0.3 lb ai/A. The 

proposed product label for the pre-emergent cotton use directs applicators and other handlers to 

wear long sleeved shirt, long pants, chemical-resistant gloves, shoes plus socks and protective 

eyewear. The restricted entry interval (REI) on the proposed label for cotton is 24 hours. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 12 of 83

Registered Aquatic Uses

Table 3.3.2 provides a summary of the registered aquatic uses of fluridone. The end-use 

products registered for use in aquatic settings are formulated as liquids, granulars, and water 

dispersible granulars (WDGs). In aquatic settings, fluridone can be applied: (1) via aerial, boom 

or handheld applications to ponds/lakes at a maximum application rate of 0.4 lb ai/A-ft; (2) via 

direct metering to moving water at a maximum rate of 0.11 lb ai/A-ft; (3) via handheld 

equipment to static canals at a maximum rate of 2 lb ai/A; and (4) via open pour to residential 

ponds at a maximum rate of 0.12 lb ai/A-ft. The registered product labels for the aquatic uses do 

not require specific clothing or any personal protective equipment (PPE). The aquatic labels do 

not include a REI statement. 

Table 3.3.1. Summary of Directions for Proposed Uses of Fluridone.

Applic. Timing, 

Type, and Equip.

Formulation 

[EPA Reg. No.]

Applic. Rate (lb 

ai/A)

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate (lb 

ai/A)

PHI 

(days) Use Directions and Limitations

Cotton

Pre-plant/preemergent

Foliar Broadcast 

Groundboom

Soluble 

Concentrate 

[67690-NEW]

0.3 (pre-plant, fine 

to medium texture 

soil)

1 0.3 N/A Do not apply by air or irrigation system. 

Apply prior to planting or prior to emergence 

of cotton. At least 0.5 inches of rain or 

irrigation must occur prior to planting to 

activate a.i. in soil. Use an alternative 

herbicide after two years of application. Avoid 

drift to all other crops and non-target areas. 

Apply when the potential for drift to adjacent 

sensitive areas is minimal.

Table 3.3.2. Summary of Directions for Existing Aquatic Uses of Fluridone.

Applic. Timing, 

Type, and Equip.

Formulation 

[EPA Reg. No.]

Applic. Rate (lb 

ai/A)

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate (lb 

ai/A)

PHI 

(days) Use Directions and Limitations

Aquatic Sites 

Broadcast, 

Metering

Granular

[8959-58]

[67690-3]

[67690-12]

[67690-21]

[67690-32]

[67690-45]

[61842-29]

[81927-50]

90 ppb: 7.7 fl oz / 

acre-foot = 0.24 lb 

ai/acre-foot

150 ppb: 13 fl oz / 

acre-foot = 0.4 lb 

ai/acre-foot; 

2 qts/acre = 2 lb 

ai/acre; 

Moving water: 

maintain 

concentration of 

up to 40 ppb

N/A 90 ppb in ponds, 

150 ppb in lakes 

and reservoirs;

Static/dry canals: 

2 qts/acre;

Moving water: 

maintain 

concentration of 

up to 40 ppb

N/A Do not apply to waters less than 2 ft deep. 

Do not apply to water used for hydroponic 

farming. 

Do not use water treated with this product for 

irrigation in greenhouses/nursery plants.

Direct Application Ready-to-use

[8959-59]

[67690-48]

[61842-28]

[81927-51]

Aquatic weed: 1 

qt/acre-foot = 0.08 

lb ai/acre-foot

Watermeal: 1.5 

qt/acre-foot

= 0.12 lb ai/acrefoot

N/A Aquatic weeds in 

Ponds: 1 qt/acrefoot

Watermeal in 

ponds: 1.5 

qts/acre-foot

N/A Do not apply through irrigation system.

Do not use water treated with product to 

irrigate crops, turf, and plants for 30 days. 

Do not use water treated with this product to 

irrigate seedlings/new plantings for 60 days. 

Must stay in contact with aquatic weeds for at 

least 45 days. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 13 of 83

Table 3.3.2. Summary of Directions for Existing Aquatic Uses of Fluridone.

Applic. Timing, 

Type, and Equip.

Formulation 

[EPA Reg. No.]

Applic. Rate (lb 

ai/A)

Max. No. 

Applic. 

per 

Season

Max. Seasonal 

Applic. Rate (lb 

ai/A)

PHI 

(days) Use Directions and Limitations

3 qts/acrefoot/seasonNo swimming, water consumption 

restrictions. 

Broadcast, 

metering

[42750-280]

Liquid

90 ppb: 7.7 fl oz / 

acre-foot = 0.24 lb 

ai/acre-foot

150 ppb: 13 fl oz / 

acre-foot = 0.4 lb 

ai/acre-foot

N/A 90 ppb in ponds

150 ppb in 

lakes/reservoirs

20 ppb near 

potable water 

intakes

N/A Do not apply through irrigation system. 

Do not used treated water for hydroponic 

farming. 

Do not use to irrigate greenhouse/nursery.

If 150 ppb or less, water may be used for 

drinking, watering livestock/pets, fishing, and 

swimming. 

Broadcast, 

metering

Liquid 

Concentrate

[67690-4]

[67690-30]

[61842-11]

[81927-45]

90 ppb: 7.7 fl oz / 

acre-foot = 0.24 lb 

ai/acre-foot

150 ppb: 13 fl oz / 

acre-foot = 0.4 lb 

ai/acre-foot

N/A 90 ppb in ponds

150 ppb in 

lakes/reservoirs

20 ppb near 

potable water 

intakes

N/A Do not apply through irrigation system. 

Do not used treated water for hydroponic 

farming. 

Do not use to irrigate greenhouse/nursery.

If 150 ppb or less, water may be used for 

drinking, watering livestock/pets, fishing, and 

swimming. 

Broadcast, 

metering

Liquid 

Concentrate

[67690-54]

90 ppb: 0.48 gal/ 

acre-foot = 0.24 lb 

ai/acre-foot

150 ppb: 0.81 gal/ 

acre-foot = 0.4 lb 

ai/ acre-foot

N/A 90 ppb in ponds, 

150 ppb in lakes 

and reservoirs

N/A Do not apply through irrigation system. 

Do not used treated water for hydroponic 

farming. 

Do not use to irrigate greenhouse/nursery.

If 150 ppb or less, water may be used for 

drinking, watering livestock/pets, fishing, and 

swimming.

Broadcast, 

metering

Solid

[67690-61]

90 ppb: 0.48 gal/ 

acre-foot = 0.24 lb 

ai/acre-foot

150 ppb: 0.81 gal/ 

acre-foot = 0.4 lb 

ai/ acre-foot

N/A 90 ppb in ponds, 

150 ppb in lakes 

and reservoirs

N/A Do not apply through irrigation system. 

Do not used treated water for hydroponic 

farming. 

Do not use to irrigate greenhouse/nursery.

If 150 ppb or less, water may be used for 

drinking, watering livestock/pets, fishing, and 

swimming.

3.4 Anticipated Exposure Pathways

The Registration Division (RD) has requested an assessment of human health risk to support the 

proposed new use of fluridone on pre-emergent cotton, and the Pesticide Re-evaluation Division 

(PRD) has requested an assessment of human health risk to support the registered uses of 

fluridone as part of Registration Review. Humans may be exposed to fluridone in food and 

drinking water. Fluridone is currently registered as an aquatic herbicide; therefore, residues of 

fluridone may get into food at low levels when treated water is used to irrigate crops. Also, 

fluridone is proposed for pre-emergent treatment of cotton, resulting in levels which do not 

exceed those currently established based on use of treated irrigation water in cotton. These 

treatments may result in fluridone reaching surface and ground water sources of drinking water. 

In a residential setting, applicators may be exposed to fluridone while applying the pesticide to 

residential ponds. There is also potential for residential post-application exposure to fluridone 

while swimming in treated water. In an occupational setting, applicators may be exposed to 

fluridone while handling the pesticide prior to application, as well as during application. There 

is negligible post-application exposure for workers based on the registered and proposed uses. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 14 of 83

Risk assessments have been previously prepared for the existing uses of fluridone (Dole, 2004,

D306456). This risk assessment considers all of the aforementioned exposure pathways and 

includes the newly proposed use of fluridone on cotton. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.archives.gov/federal-register/executive-orders/pdf/12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The fluridone toxicity database is adequate for risk assessment (Appendix A). The following 

studies were considered in designating the points of departure (PODs) for each exposure 

scenario:

• 90 day oral toxicity study – rat and mouse

• 21 day dermal toxicity study – rabbit 

• Prenatal developmental toxicity study – rat and rabbit

• Multi-generation reproduction and fertility toxicity study – rat

• 1 year chronic toxicity study – dog

• 2 year chronic toxicity/carcinogenicity study – rat and mouse

• Mutagenicity battery

• Acute neurotoxicity study (ACN) – rat 

• Metabolism pharmacokinetics study – rat 

• Immunotoxicity study
Fluridone Human Health Risk Assessment DP No. 423464

Page 15 of 83

HASPOC waived the subchronic neurotoxicity study (Rury, 2013, TXR 0056853) using a weight 

of evidence (WOE) approach that considered the low incidence of neurotoxic effects in the ACN 

study, the high doses required to elicit behavioral changes in the ACN study, and the protective 

nature of the previously selected PODs. HASPOC also waived the subchronic inhalation study 

(Leshin, 2015, TXR 0057221) using a WOE approach that considered the physical/chemical 

properties of fluridone including low vapor pressure, low acute inhalation toxicity (Category III),

and the large short- and intermediate-term inhalation MOEs calculated with previously selected 

PODs. No deficiencies exist in the database for the parent compound.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Three studies were submitted detailing the fluridone ADME profile. In each study male and 

female rats were administered a single or multiple fluridone doses via oral gavage at dose levels 

ranging from 10 -1000 mg/kg/day.

The ADME profile did not vary significantly between males and females. Ingested fluridone was 

rapidly and almost completely absorbed into the systemic circulation. Elimination was equally 

rapid and the rate was dose-dependent. In one study, fecal and urinary excretion following acute 

and repeated dose 10 mg/kg oral exposures were nearly identical (80-90% in 24 hours, 90-97% 

in 48 hours) and faster than elimination of a single 1000 mg/kg oral dose (~30% in 24 hours, 82-

88% in 48 hours). A similar trend was observed in another study: single low dose exposures 

ranging from 10-500 mg/kg were eliminated more quickly (67-89% in excreta after 24 hours; 86-

98% in 72 hours) than a single dose exposure to 1000 mg/kg (43-49% in excreta after 24 hours; 

78-87% in 72 hours). Fluridone was eliminated predominately in the feces (68-92%) and, to a 

lesser extent, the urine (4-19%). The release of fluridone in expired air was insignificant relative 

to the other elimination pathways (<0.01%). The major component in the excreta of rats exposed 

to 10 mg/kg were fluridone metabolites produced primarily by ring hydroxylation and Ndemethylation (single low dose = 3.9-5.1% parent, 59.4-66.5% metabolite; multiple low doses = 

3.9-7.3% parent, 54.7-57.1% metabolite). The opposite was true in rats exposed to 1000 mg/kg. 

At this high dose metabolic pathways became saturated and the parent compound was the 

dominant chemical species (52.9-60.3% parent, 30.3%-33.8 metabolite) in the excreta. Fourteen 

metabolites were identified in the feces and urine (detailed in section A.4.8). On average, 61-

66% of the total radioactivity was present in the bile 48 hours after administration of a 100 

mg/kg oral dose. The fluridone fraction in the bile consisted of unidentified highly polar 

metabolites (37% of administered dose [AD]), parent (8% of AD), and the 4-hydroxyphenyl 

fluridone (6% of AD).

The percentage of fluridone in the tissues (<1%) was minimal relative to the eliminated fraction. 

The highest tissue concentrations were observed in the liver and kidney (~0.3-0.7%) and the 

highest tissue to plasma ratios were found in the liver, kidney, ileum, and colon. The 

concentration accumulated in tissues was proportional to the dose. 

4.2.1 Dermal Absorption

No dermal absorption study was submitted by the registrant; therefore, a dermal absorption 

factor (DAF) of 39% was calculated using the ratio of the 21 day rabbit dermal toxicity study 

NOAEL (768 mg/kg/day) and the rabbit developmental toxicity study LOAEL (300 mg/kg/day).
Fluridone Human Health Risk Assessment DP No. 423464

Page 16 of 83

No systemic effects were observed at the highest dose tested (768 mg/kg/day) in the rabbit 

dermal study thus the estimated DAF represents the upper bound limit of dermal absorption for 

fluridone. The DAF of 39% will be applied to convert oral doses to dermal equivalent doses, 

since an oral toxicity study was selected to assess risks from dermal exposures (see Section 

4.5.1)

DDDDDD =

300 mmmm

kk /dddddd

768 mmmm

kk /dddddd

× 100 = 39%

4.3 Toxicological Effects

Fluridone is a systemic herbicide that inhibits phytoene desaturase, disrupting the conversion of 

phytoene into phytofluene in the carotenoid biosynthetic pathway causing the loss of chlorophyll 

(Kowalczyk-Schrder and Sandmann 1992). The mode of action in mammals is unknown; 

however, the majority of the effects occurred in the liver of all species tested and in the kidneys 

of rats, which is consistent with the distribution profile (i.e. higher tissue concentration and 

higher tissue to plasma ratio) of these two organs. Mice were the most sensitive species to 

repeated dose oral exposure and their response to exposure was irrespective of duration. At doses 

of 25 mg/kg/day and above mice exhibited hepatocellular hyperplasia and centrilobular 

hypertrophy, leading to increased liver weight and elevated alkaline phosphatase activity. At 

slightly higher doses, rats exhibited similar liver weight and liver histopathological effects along 

with an increase in absolute and relative kidney weight. Although rats exhibited progression of 

toxicity from subchronic to chronic exposure, the magnitude of progression was low (2-fold 

difference). The lack of progression in the mouse and slight progression of toxicity with duration 

in the rat is supported by the similarities in clearance patterns following low single and multiple 

dose exposure regimens and minimal accumulation in tissues. No incidences of liver or kidney 

tumors were observed in either rodent species. Dogs were more tolerant of fluridone exposure; 

the onset of liver effects (increased absolute liver weight and alkaline phosphatase activity) 

occurred at a much higher dose level (400 mg/kg/day) than the other mammalian species tested. 

Other systemic effects were observed concurrently with the liver and kidney effects in both 

rodents and dogs, including decreases in body weight and body weight gain. In all species, the 

onset of target organ and body weight effects were at doses that within the linear 

pharmacokinetic range. 

In contrast, concurrence of behavioral anomalies (uncoordinated air righting reflex, muted 

response to touch, approach, startle and tail pinch) with impaired physiological (depressed 

catalepsy time) and locomotor (decreased average ambulatory counts) function were observed in 

rats only at acute gavage doses (650 mg/kg/day and above) that likely exceeded linear 

pharmacokinetics and were least 13-26 times above those eliciting the aforementioned kidney 

and liver effects in repeated dose exposures. No symptoms consistent with neurotoxicity were

observed during subchronic and chronic oral exposures to mice, rats, or dogs. 

Fluridone exposure was linked to increased incidences of abortions in pregnant rabbits during the 

last 5 days of gestation at 300 and 750 mg/kg/day and to lower fetal body weight and skeletal 
Fluridone Human Health Risk Assessment DP No. 423464

Page 17 of 83

malformations in developing rats at 1000 mg/kg/day. In both mammals, concurrent maternal 

body weight effects likely contributed to the developmental anomalies and abortions; therefore, 

neither were considered evidence of fetal sensitivity. Evidence suggestive of susceptibility was 

evident in the F2 offspring manifesting as reduced body weight gain during lactation period and 

body weight on lactation day 21 at 112 mg/kg/day. However, these effects were isolated to the F2 

offspring; body weight of the F2 offspring returned to control levels after the lactation period;

and no subsequent evidence of susceptibility was observed in progeny of the F2 generation. 

Furthermore, the offspring effects were only observed at doses 2 to 4.5 times above those 

eliciting target organ and body weight toxicity in rodents in other studies.

Fluridone was not mutagenic or carcinogenic. Acute dermal administration was minimally toxic 

and did not cause dermal irritation or sensitization. Likewise, systemic toxicity was not observed 

in repeated dermal doses up to 768 mg/kg/day; however, the longer duration dermal exposure did 

produce dermal irritation effects (erythema, desquamation, epidermal fissures) not observed in 

the acute exposure. Fluridone was also identified as an ocular irritant based on slight to moderate 

corneal dullness, iritis, and conjunctivitis following acute eye exposure.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The 10x FQPA Safety Factor (FQPA SF) was reduced to 1X based on the following 

considerations:

1. The toxicology and exposure databases for fluridone are complete and the toxicology 

studies are adequate for assessing increased susceptibility under FQPA.

2. There was no evidence of qualitative susceptibility in fetuses in the rat and rabbit 

developmental study. Suggestive evidence of susceptibility was observed in the 

young from the F2 population in the reproductive study during the lactation phase 

(based decreased body weight); however, body weight of the F2 offspring returned to 

control levels after the lactation period and no evidence of susceptibility was 

observed in the F3 offspring. 

3. The LOAELs and NOAELs for the rat and rabbit developmental, and rat reproduction 

studies are clearly defined.

4. The endpoints selected for the assessment are protective of the offspring effects.

5. There are no residual uncertainties in the toxicology database.

6. Exposure assessments are conservative and will not under-estimate exposure (see 

4.4.4 below).

4.4.1 Completeness of the Toxicology Database

The toxicity database is adequate to assess risk for infants and children. Two developmental 

studies and a three generation reproductive study are available for the parent compound. The 

registrant submitted an acute neurotoxicity and immunotoxicity test to fulfill guideline 

requirements. The subchronic neurotoxicity and inhalation studies were waived by HASPOC

(see 4.1). No deficiencies are present in the fluridone toxicity database that would hinder 

assessment of the currently registered uses and the new use on cotton. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 18 of 83

4.4.2 Evidence of Neurotoxicity

The combination of behavioral anomalies and impaired physiological and locomotor function in 

the ACN study were suggestive of neurotoxicity following high dose acute exposure. However, 

the concern for neurotoxicity arising from registered and proposed uses is low because: the 

adverse effects in the ACN study were only seen at relatively high gavage doses (650-2000 

mg/kg/day), which may exceed the linear range of excretion kinetics; there were no 

corresponding neurohistopathological findings; there were no indications of neurotoxicity in the 

rest of the toxicity database; and the endpoints selected for risk assessment are protective of 

these adverse effects. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Rat and rabbit fetuses did not demonstrate an increased sensitivity to in utero fluridone exposure. 

Developmental toxicity was either at doses concurrent with or higher than maternal toxicity. 

Suggestive evidence of susceptibility was observed in the young animals from the F2 generation 

(reduced body weight gain during lactation period and body weight on lactation day 21) in the 

reproductive study. However, body weight of the F2 offspring returned to control levels after the 

lactation period; and no evidence of susceptibility was observed in the F1 or F3 offspring. The 

POD selected to assess risk for chronic dietary and residential exposure is protective of the 

suggestive susceptibility in young animals.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary exposure estimates are 

unrefined and reflect primarily tolerance-level residue in food, 100% crop treated (CT), and 

upper-bound drinking water estimates based on modeling. These assumptions and refinements 

are detailed in the Section 5.4.1. Additionally, HED does not believe that non-occupational 

exposure estimates are underestimated. The assumptions are detailed in Section 6.0. 

4.5 Toxicity Endpoint and Point of Departure Selections

The full suite of submitted toxicity studies used to select endpoints and PODs for each exposure 

scenario are presented in Appendix A.2. An acute dietary POD was established for the general 

population and the previous acute dietary POD for the female 13-49 subpopulation was reevaluated; otherwise, no updates were made to endpoints from the most recent risk assessment 

(Drew, 2012, D399892).

4.5.1 Dose-Response Assessment

The acute reference dose (aRfD) for the general population was set at 1.25 mg/kg/day based on 

endpoints from the ACN. The NOAEL for the study was 125 mg/kg/day, based on decreased 

ambulatory counts and the prevalence of FOB anomalies at 650 mg/kg/day. Adverse effects 

following acute exposure were only seen at relatively high doses (>650 mg/kg/day) that are not 

anticipated based on current and proposed use patterns; however an endpoint was still selected to 
Fluridone Human Health Risk Assessment DP No. 423464

Page 19 of 83

be protective of the observed effects. Uncertainty factors for interspecies variation (10x) and 

intraspecies variation (10x) were applied to the NOAEL to calculate the aRfD. The acute 

population adjusted dose (aPAD) was identical to the aRfD, because the FQPA SF was reduced 

to 1x. In the previous risk assessment, abortions on gestation days 20-25 were selected as the 

endpoint for the female 13-49 acute dietary assessment. However, this endpoint was re-evaluated 

as part of registration review and determined to not be an acute effect, because the abortions 

occurred late in the gestation period and were likely the result of multiple doses over the course 

of the exposure period. None of the acute effects observed in the guideline studies were specific 

to child bearing females. Consequently, the female 13-49 subpopulation was assessed with the 

general population. 

The chronic reference dose (cRfD) was set at 0.15 mg/kg/day based on endpoints from the 2-year 

carcinogenicity study in mouse. The NOAEL for the study was 15 mg/kg/day based on increased 

alkaline phosphatase activity and increased incidence of hepatocellular hyperplasia at 50 

mg/kg/day. Uncertainty factors for interspecies variation (10x) and intraspecies variation (10x) 

were applied to the NOAEL to calculate the cRfD. The chronic population adjusted dose (cPAD) 

was identical to the cRfD, because the FQPA SF was reduced to 1x. A slightly lower NOAEL (8 

mg/kg/day) was noted in the rat combined chronic toxicity/carcinogenicity study; however, this 

fact was considered to be due to dose-selection (i.e. 15 mg/kg/day was not tested in this rat 

study); the LOAELs were similar. The NOAEL in the mouse study is protective of adverse 

findings noted in the rat combined chronic toxicity/carcinogenicity study, as well as the offspring 

effects in the rat 3-generation reproduction study. The selected NOAEL is also protective of 

effects noted in the chronic dog study.

The 2-year mouse study was used to set residential PODs for short- and intermediate-term 

incidental oral, dermal and inhalation exposure and occupational PODs for short- and 

intermediate-term dermal and inhalation exposure. The main effects in this study are detailed in 

the previous paragraph. 

The mouse chronic endpoint was appropriate for short-and intermediate-term fluridone 

exposures, because: (i) mice were the most sensitive species in subchronic exposures; (ii)

fluridone is rapidly metabolized and eliminated from the body at low doses (≤10 mg/kg) in acute 

and repeat dosing metabolism studies with a similar pattern of excretion (amount in feces and 

urine and rate of excretion); and (iii) no progression of toxicity was evident when comparing the 

mouse subchronic toxicity study to the chronic toxicity study. Progression of toxicity was 

observed in rats; however, rat sensitivity was either less than (subchronic exposure) or similar 

(chronic exposure) to mice. The POD from the 2-year mouse study was, therefore, both 

protective of the effects observed in rats and representative of short- and intermediate-term 

exposure durations. 

The guideline dermal study was not used to set endpoints for the dermal assessment, because the 

study did not address concerns for the possible sensitivity in the young observed in the 

3-generation reproduction study. The systemic NOAEL from the dermal study is 384 mg/kg/day, 

but offspring toxicity is apparent at 112 mg/kg/day. The NOAEL from the 2-year mouse cancer 

study is 38.5 mg/kg/day, after accounting for route-to-route extrapolation (DAF=39%), which is 

protective of the offspring effects. The mouse oral endpoints were used for the inhalation 
Fluridone Human Health Risk Assessment DP No. 423464

Page 20 of 83

assessment, because a route-specific inhalation study was not available. Inhalation exposure was 

assumed to be equivalent to oral exposure. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential residential exposures to the pesticide, aggregate risk assessment must 

consider exposures from three major sources: oral, dermal and inhalation exposures. Exposures 

via the oral, dermal and inhalation routes can be combined for short- and intermediate-term 

assessments because PODs for these routes were all based on liver effects observed in the 2 year 

mouse carcinogenicity study (increased alkaline phosphatase activity and incidence of 

hepatocellular hyperplasia). 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Fluridone did not demonstrate mutagenic behavior either in vitro or in vivo nor did exposure 

result in an increased incidence of tumors. The HED Cancer Peer Review Committee (TXR 

0007726, July 15 and October 7, 1985) concluded that fluridone should be classified as “not 

likely” to be a human carcinogen and a subsequent quantitative cancer risk assessment is not 

required. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Fluridone for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects

Acute Dietary

(General 

Population)

NOAEL = 

125 

mg/kg/day 

UFA=10x

UFH=10x

FQPA SF = 1X 

aRfD = 

aPAD = 1.25

mg/kg/day

Acute Neurotoxicity - Rat

LOAEL = 650 mg/kg/day based 

decreased ambulatory counts and the 

prevalence of FOB anomalies in males 

and females

Chronic 

Dietary (All 

Populations)

NOAEL= 

15 

mg/kg/day 

UFA=10x

UFH=10x

FQPA SF=1x

cRfD = 

cPAD = 0.15 

mg/kg/day

2-year cancer study – Mouse 

LOAEL = 50 mg/kg/day based on 

increased alkaline phosphatase activity 

and increased incidence of 

hepatocellular hyperplasia

Incidental 

Oral Shortand 

IntermediateTerm 

NOAEL = 

15 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF=1x

MOE = 100 2-year cancer study – Mouse 

(Same as above)
Fluridone Human Health Risk Assessment DP No. 423464

Page 21 of 83

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Fluridone for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/ 

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm 

NOAEL = 

15 

mg/kg/day

UFA=10x

UFH=10x

dermal absorption 

factor = 39%

MOE = 100 2-year cancer study – Mouse 

(Same as above)

Dermal LongTermThis endpoint is not applicable because use patterns preclude long term exposure

Inhalation 

Short- and 

Intermediateterm

NOAEL = 

15 

mg/kg/day

UFA=10x

UFH=10x

MOE = 100 2-year cancer study – Mouse 

(Same as above)

Inhalation 

Long-Term

This endpoint is not applicable because use patterns preclude long term exposure

Cancer (oral) Fluridone is classified as “not likely” to be a human carcinogen. Quantitative cancer risk 

assessment is not required (TXR 007726).

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluridone for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm 

NOAEL = 

15 

mg/kg/day

UFA=10x

UFH=10x

MOE = 100 2-year cancer study – Mouse 

(Same as above)

Dermal LongTermThis endpoint is not applicable because use patterns preclude long term exposure

Inhalation 

Short- and 

Intermediateterm

NOAEL = 

15 

mg/kg/day

UFA=10x

UFH=10x

MOE = 100 2-year cancer study – Mouse 

(Same as above)
Fluridone Human Health Risk Assessment DP No. 423464

Page 22 of 83

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluridone for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment Study and Toxicological Effects

Inhalation 

Long-Term

This endpoint is not applicable because use patterns preclude long term exposure

Cancer 

(dermal, 

inhalation)

Fluridone is classified as “not likely” to be a human carcinogen. Quantitative cancer risk 

assessment is not required (TXR 007726).

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental,

reproductive, and general or systemic toxicity. These studies include endpoints which may be

susceptible to endocrine influence, including effects on endocrine target organ histopathology,

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss,

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and

chronic studies that assess growth, developmental and reproductive effects in different

taxonomic groups. As part of its preliminary re-registration decision for fluridone, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), fluridone is 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2

testing is designed to identify any adverse endocrine-related effects caused by the substance, and

establish a dose-response relationship between the dose and the E, A, or T effect.
Fluridone Human Health Risk Assessment DP No. 423464

Page 23 of 83

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 20131 and includes some

pesticides scheduled for Registration Review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website2

.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Fluridone irrigated crop metabolism studies were conducted on grapefruit, corn, soybeans, 

lettuce, and alfalfa. In addition, soil applications were conducted with corn and alfalfa. Greater 

than 73% of the residue in all crops was identified as the parent compound, fluridone. The risk 

assessment team has reviewed the applicable studies and has determined that if finite residues are 

present, fluridone is the most likely species present.

Livestock metabolism studies have been conducted with cattle, swine, and chickens. All studies 

have shown considerable metabolism of the parent compound with subsequent incorporation into 

the livestock tissues. Fluridone and its 4-hydroxy metabolite were found in cattle and swine liver 

at levels less than 4% each of the total radioactive residue (TRR) for cattle and 0.5% each for 

swine. No attempt was made to identify the TRR in poultry, due to low levels. Given the 

relatively low dietary burden of fluridone, and the extensive metabolism of fluridone and the low 

residues expected in edible commodities, the risk assessment team has concluded that the residue 

of concern for risk assessment and tolerance-setting purposes is the parent, fluridone.

5.1.2 Summary of Environmental Degradation

Fluridone is relatively non-volatile, and moderately mobile in soil. The compound is relatively 

persistent in soil, with a 213-day half-life in moist soil and a 117-day half-life in flooded soil. 

Fluridone’s degradation under anaerobic conditions is uncertain due to lack of acceptable data. 

Fluridone did not photolyze in soil in one system and acceptable data are not available to 

describe photolysis in water.

 1 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals.

2 http://www.epa.gov/endo/
Fluridone Human Health Risk Assessment DP No. 423464

Page 24 of 83

Fluridone does not abiotically hydrolyze in water. It bioconcentrates in fish only to 44x, and its 

depuration rate is unknown. Acceptable aquatic metabolism data are not available.

Sorption of fluridone to soil correlates with soil organic carbon content (FAO soil mobility 

classification of moderately mobile; FAO, 2014). With moderate mobility in soil and little to no 

degradation in sub-surface soils, fluridone may pose a ground water concern.

Important means of transport off of agricultural fields following application will include spray 

drift, runoff of residues, and leaching. Fluridone dissipated in the field with half-lives in soil 

ranging from 38 days to >15 months, and half-lives in water bodies ranging from 5 to 60

days, all based on studies in review.

5.1.3 Comparison of Metabolic Pathways

In plant metabolism studies, greater than 73% of the residue in all crops was identified as the 

parent compound, fluridone. All livestock metabolism studies have shown considerable 

metabolism of the parent compound with subsequent incorporation into the livestock tissues. 

In a metabolism study in rats, fluridone was 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 in the urine and feces were 78-90% and 

87-97% of administered dose in males and females, respectively. The majority (approximately 

70%) of the radioactivity was eliminated via feces. No tissue accumulation was observed. The 

major components in the feces were fluridone and fluridone metabolites produced primarily by 

ring hydroxylation and N-demethylation.

5.1.4 Residues of Concern Summary and Rationale

A summary of the fluridone metabolites and degradates included in the risk assessment and 

tolerance expression is included in Table 5.1.4. No major plant metabolites were found in the 

irrigated crop study, so only the parent compound is included. Extensive metabolism of the low 

total residues were found in the ruminant, poultry, and swine metabolism studies, so no major 

degradates were identified. 4-hydroxyfluridone is the major degradate in fish and is assumed to 

have approximately equivalent toxicity to the parent, so both are included in the risk assessment 

and tolerance expression. Benzoic acid and its 3-trifluroromethyl benzoic acid are aqueous 

photolysis products found in laboratory studies conducted with lake water. Although these 

compounds would not have toxicity profiles similar to the parent considering their molecular 

structures, there is not a concern for adverse health effects at the levels found as a result of 

fluridone applications. 

Another aqueous photoproduct found in laboratory studies, N-methylformamide (NMF), is more 

toxic than the parent compound and requires a separate assessment (Dole, 2004, D306456). 

According to the Environmental Fate and Effects Division (EFED), NMF remains a residue of 

concern unless acceptable aqueous photolysis data are submitted (Orrick; 2015, D423846). An 

assessment for NMF is provided in Appendix E.
Fluridone Human Health Risk Assessment DP No. 423464

Page 25 of 83

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop Fluridone Fluridone

Rotational Crop Fluridone Fluridone

Livestock

Ruminant Fluridone Fluridone

Poultry Fluridone Fluridone

Fish

Fluridone

4-hydroxyfluridone

Fluridone

4-hydroxyfluridone

Drinking Water Fluridone, Nmethylformamide (NMF)a Not Applicable

a. An assessment for NMF is provided in Appendix E. 

5.2 Food Residue Profile

There is adequate residue data for risk assessment and tolerance assessment. An irrigated crop 

study was used to set the current inadvertent tolerances of fluridone, which are listed in the 

40CFR 180.420. Residue data on irrigated crops involved studies on two crops from each crop 

grouping. Residues were below the limit of detection (<0.05 ppm) for most crops. It was 

determined that the appropriate tolerance level would be 0.1 ppm for all crops for which there 

were no direct uses, except for animal feed non-grass group 18 and grass forage; a tolerance of 

0.15 ppm would be appropriate for those livestock feed items.

Adequate storage stability data was submitted. 

The residues found in the present metabolism and distribution on representative crops studies

represent the maximum levels that are likely to be encountered through direct irrigation from 

water treated with fluridone from the currently registered aquatic use, and also for crops that may 

be grown in rotation with treated cotton. The confined rotational crop studies indicate no uptake 

of fluridone from soil containing residues that would be expected within one month of 

application to bare soil in root and tuber vegetables and leafy vegetables (as levels were constant 

in the soil from the time of application to the end of the one year aging period), and in cereals 

after a five month aging period.

Wheat and soybean rotational crops (planted following harvest of cottonseed) showed no 

detectable residues after plantback intervals of 5 and 12 months, respectively. Total radioactive 

residues were very low, 0.003 and 0.002 ppm in beets and lettuce, respectively, grown in bare 

soil treated at 0.4 lb ai/A following a 10 month plantback interval. The proposed plant back 

interval on the label is adequate, which ranges from 8 to 18 months for various crops.

No detectable residues were found in meat, milk, poultry, and eggs (MMPE). The current 

tolerances for MMPE are adequate. Cotton gin byproducts do not have an impact on the 

livestock dietary burden. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 26 of 83

No residue data were submitted with the Section 3 request for use on cotton. Several literature 

and unpublished study citations were provided by the petitioner. The residues found in the cotton 

studies were non-detectable in all samples, including those treated at exaggerated rates. This 

issue was addressed in HED’s Chemistry Science Advisory Council (ChemSAC), and it was 

agreed upon that no additional field trials were needed. The limit of detection (LOD) was 

determined to be 0.01 ppm for cotton. The conclusions of select unpublished studies were briefly 

summarized and indicated that residues of fluridone on cotton would not be expected to exceed 

the tolerance of 0.1 ppm. 

Given the absence of fluridone residues in cottonseed and whole cotton plants from 

geographically appropriate field trials conducted at exaggerated rates (1.3X - 6.7X compared to 

the proposed rate of 0.3 lb ai/A), it can be concluded that residues of fluridone from the proposed 

S3 use would not exceed the current tolerance level of 0.1 ppm for cottonseed, undelinted. 

Based on nondetectable residues in the RAC in the exaggerated rate studies, residues would not 

be expected in cotton processed commodities and separate tolerances would not be needed.

In the absence of cotton gin byproducts magnitude of the residue data, the TRR data for whole 

plants provided in the metabolism study should be used to determine the tolerance for cotton gin 

byproducts. HED has recommended that a tolerance for fluridone on cotton gin byproducts also 

be established at 0.1 ppm.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED (Orrick, 

2015, D423846) and incorporated directly into this dietary assessment as point estimates. The 

maximum screening-level acute and chronic estimated drinking water concentrations (EDWCs:

34 and 32 μg/L, respectively) are based on the proposed use of fluridone on cotton at 0.3 lbs 

a.i./acre per year. Water residues in Table 5.3 were incorporated in the DEEM-FCID into the 

food categories “water, direct, all sources” and “water, indirect, all sources.” The most 

conservative values, based on ground water modeling (Tier I: PRZM-GW), were used in the 

acute (0.034 ppm) and the chronic (0.032 ppm) assessments.

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for Fluridone

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 24 34

Chronic (non-cancer) 21 32

a From the Tier I FIRST. b From the PRZM-GW model.

Fluridone: Drinking Water Exposure Assessment for Proposed New use on Cotton” (Orrick, 2015, D423846)
Fluridone Human Health Risk Assessment DP No. 423464

Page 27 of 83

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Fluridone is not applied directly to crops or livestock, but treated water may be used to irrigate 

food and feed crops or fed to livestock. Tolerances have been established in 40 CFR §180.420 

for crop groups. The proposed Section 3 use on cotton is a direct soil application; however, the 

tolerance is the same as for fluridone use on cotton as an irrigated crop. Tolerance values were 

used in the acute and chronic dietary exposure assessments with no refinements for percent crop 

treated. The default processing factors in DEEM-FCID, Version 3.16 were also used. The 

drinking water residues for fluridone used in the dietary risk assessment were provided by EFED

and incorporated directly into this dietary assessment as point estimates (see Section 5.3). 

5.4.2 Percent Crop Treated Used in Dietary Assessment

No refinements were done for crop treated; 100% crop treated was used for fluridone in the 

assessment.

5.4.3 Acute Dietary Risk Assessment

The acute dietary (food and drinking water) assessment was unrefined. 100% crop treated, 

established tolerance residues, and default processing factors were used for this assessment. For 

acute assessments, HED is concerned when dietary risk exceeds 100% of the PAD. The most 

highly exposed sub-population was children aged 1-2, with a risk estimate of 1.3% of the aPAD

(at the 95th percentile of exposure). These risk estimates are all well below 100% of the PAD and 

are not of concern. The DEEM-FCID analyses estimate the dietary exposure of the U.S. 

population and various population subgroups. The results are reported in Table 5.4.6 for 

fluridone for the general U.S. Population, all infants (<1 year old), children 1-2, children 3-5, 

children 6-12, youth 13-19, females 13-49, adults 20-49, and adults 50+ years. 

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) assessment was unrefined. 100% crop treated, 

established tolerance residues, and default processing factors were used for this assessment. For 

chronic assessments, HED is concerned when dietary risk exceeds 100% of the PAD. The most 

highly exposed sub-population was children aged 1-2, with a risk estimate of 5.5 % of the cPAD. 

These risk estimates are all well below 100% of the PAD and are not of concern. The DEEMFCID analyses estimate the dietary exposure of the U.S. population and various population 

subgroups. The results reported in Table 5.4.6 are for the general U.S. Population, all infants (<1 

year old), children 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, adults 20-49, 

and adults 50+ years. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 28 of 83

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not conducted, as fluridone is classified as “not likely to be 

carcinogenic”. 

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary Food and Drinking Water Exposure and Risk for Fluridone

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD* Dietary Exposure(mg/kg/day) % cPAD*

General U.S. Population 0.006443 <1 0.002583 1.7

All Infants (<1 year old) 0.011772 <1 0.004922 3.3

Children 1-2 years old 0.015597 1.3* 0.008312 5.5*

Children 3-5 years old 0.011639 <1 0.006077 4.1

Children 6-12 years old 0.007305 <1 0.003568 2.4

Youth 13-19 years old 0.004442 <1 0.002129 1.4

Adults 20-49 years old 0.004236 <1 0.002098 1.4

Adults 50+ years old 0.003918 <1 0.001975 1.3

Females 13-50 years old 0.004157 <1 0.002042 1.4

*The highest exposed population subgroup

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are existing residential uses 

that have been reassessed in this document for Registration Review. The registered aquatic uses 

have been assessed according to HED’s November 2015 Draft Aquatic Use SOP. Residential 

handler and post-application exposures are expected for fluridone. The revision of residential 

exposures will impact the human health aggregate risk assessment for fluridone.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED, as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

The ready-to-use (RTU) aquatic products registered for fluridone state that “unless the pond is 

privately owned by the applicator, prior to application, consult with appropriate state or local 

water authorities.” Therefore, it is assumed that this type of product can be applied by the 

homeowner to their privately owned pond. The quantitative exposure/risk assessment developed 

for residential handlers is based on the following scenario: 

• Ready-to-use (RTU) aquatic applications
Fluridone Human Health Risk Assessment DP No. 423464

Page 29 of 83

Residential Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

handler risk assessments. Each assumption and factor is detailed below.

Application Rate: The maximum rate for residential use from Table 4.1.2 was used; 0.12 lb 

ai/acre-foot = 0.00000275 lb ai/ft3.

Unit Exposures and Area Treated or Amount Handled:

Unit exposure values to represent a homeowner pouring a RTU formulation have been adjusted 

from the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table3”, which, 

along with additional information on HED policy on use of surrogate data, including descriptions 

of the various sources, can be found at the Agency website4. The occupational unit exposure 

(representing long-sleeved shirt, long pants, and no gloves) has been adjusted to represent a 

homeowner wearing a short-sleeved shirt and shorts. Estimates for area treated or amount 

handled were taken from HED’s Draft November 2015 Aquatic Use SOP. 

Exposure Duration: Residential handler exposure is expected to be short-term in duration. 

Intermediate-term exposures are not likely because of the intermittent nature of applications by 

homeowners.

Residential Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate exposure and dose for residential handlers can be found in 

Appendix A and/or the 2012 Residential SOPs5 and/or the draft November 2015 Aquatic Use 

SOP.

Combining Exposures/Risk Estimates:

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological 

effects for these exposure routes were the same. Dermal and inhalation risk estimates were 

combined using the following formula:

Total MOE = Point of Departure (mg/kg/day) ÷ Combined Dermal + Inhalation dose (mg/kg/day)

Summary of Residential Handler Non-Cancer Exposure and Risk Estimates

Residential handler combined dermal and inhalation MOEs range from 1,800 to 1,400,000. 

Since the MOEs are greater than the LOC of 100, there are no risk estimates of concern for 

residential handlers. 

 3 Available: http://www2.epa.gov/sites/production/files/2015-09/documents/handler-exposure-table-2015.pdf 4 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handlerexposure-data 5 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-proceduresresidential-pesticide
Fluridone Human Health Risk Assessment DP No. 423464

Page 30 of 83

Table 6.1.1. Residential Handler Non-Cancer Exposure and Risk Estimates for Fluridone.

Exposure Scenario Level of 

Concern

Dermal Unit 

Exposure 

(mg/lb ai)1

Inhalation 

Unit Exposure 

(mg/lb ai)1

Maximum 

Application 

Rate2

Area Treated or 

Amount Handled 

Daily3

Dermal Inhalation Combined

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE

(LOC = 100)8

Mixer/Loader/Applicator

Ready-to-use – Open Pour 

to Recreational Ponds 100 0.232 0.219 0.12 lb ai/acrefoot

2.5 acres, 7 foot 

depth 0.0024 6,300 0.0057 2,600 1,800

Ready-to-use – Open Pour 

to Ornamental Ponds 100 0.232 0.219 0.00000275 lb 

ai/ft3

500 ft2, 2 foot 

depth 0.0000031 4,800,000 0.0000075 2,000,000 1,400,000

1 Unit exposure values based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015) adjusted for difference in clothing (short-sleeved shirt and short 

pants vs long-sleeved shirt and long pants).

2. Based on registered labels.

3 Based on HED’s Draft November 2015 Aquatic SOP.

4 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre-ft or lb ai/ft3) × Area Treated or Amount Handled (A-ft/day or ft3/day) × Dermal Absorption Factor (39%) ÷ Body 

Weight (80 kg).

5 Dermal MOE = Dermal NOAEL (15 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre-ft or lb ai/ft3) × Area Treated or Amount Handled (A-ft/day or ft3/day) ÷ Body Weight (80 kg).

7 Inhalation MOE = Inhalation NOAEL (15 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (15 mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).
Fluridone Human Health Risk Assessment DP No. 423464

Page 31 of 83

6.2 Residential Post-Application Exposure

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with fluridone. The recreational swimmer has 

the potential for exposure to fluridone in treated water. The quantitative exposure/risk 

assessment for residential post-application exposures is based on the following scenarios: 

• Adults and children (3 to <6 years old) swimming in treated water (dermal, inhalation

and incidental ingestion)

Residential Post-Application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the Draft 2015 

Aquatic Use SOP.

Application Rate: As was done in the previous assessments, the maximum label rate of 150 ppb 

(0.15 mg/L) was used to assess aquatic exposure of fluridone. 

Exposure Duration: Residential exposure is expected to be short-term in duration. 

Residential Post-application Non-Cancer Exposure and Risk Equations

The algorithms used to estimate residential post-application exposure and dose can be found in 

Appendix A and/or the Draft November 2015 Aquatic Use SOP.

Combining Exposure and Risk Estimates

Since dermal, inhalation and incidental oral exposure routes share a common toxicological 

endpoint, exposure estimates have been combined for those routes. 

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

For fluridone, the combined MOE for adults swimmers is 52,000 and for child swimmers is 

12,000; therefore, there are no risk estimates of concern (LOC = 100). 

Table 6.2.1. Residential Post-application Non-cancer Exposure and Risk Estimates for Fluridone.

Lifestage

Post-application Exposure 

Scenario Application 

Rate1

Dose 

(mg/kg/day)2 MOEs3

Combined Routes

(X indicates 

Combined)

Combined MOEs

Use Site Route of 

Exposure

Adult

Aquatic

Dermal

150 ppb

0.00028 54,000 X

52,000 Inhalation 4.05E-8 370,000,000 X

Incidental 

Ingestion 9.4E-6 1,600,000 X

Child (3 to 

<6 years)

Dermal 0.00114 13,000 X

12,000 Inhalation 2.8E-7 54,000,000 X

Incidental 

Ingestion 9.87E-5 150,000 X

1 Based on registered labels.

2 Dose (mg/kg/day) equations:

• Inhalation Dose (mg/kg/day) = [Concentration in water (0.15 mg/L) * Dimensionless Henry’s law constant (3.38E-07) * CF (1000 

L/m3

) * IR (0.64 m3/hr for adults and 0.32 m3/hr for children) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW (80 kg 

for adults and 19 kg for children).

• Dermal dose (mg/kg/day) = [Concentration in water (0.15 mg/L) * Permeability constant (0.0763) * Surface area (19,500 cm2 for 
Fluridone Human Health Risk Assessment DP No. 423464

Page 32 of 83

adults and 7,600 cm2 for children) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW (80 kg for adults and 19 kg for 

children).

• Incidental ingestion dose (mg/kg/day) = [Concentration in water (0.15 mg/L) * Ingestion rate (0.05 L/hr) * Exposure time (0.1 hr for 

adults and 0.25 hr for children)] / BW (80 kg for adults and 19 kg for children).

3 MOE = POD (15 mg/kg/day) ÷ Dose (mg/kg/day).

4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for fluridone.

• The recommended residential exposure for use in the adult aggregate assessment reflects 

dermal and inhalation exposure from applications via pouring to recreational ponds.

• The recommended residential exposure for use in the child (3 to <6 years old) aggregate 

assessment reflects dermal, inhalation, and incidental oral exposures from postapplication exposure to aquatic applications.

Table 6.3.1. Recommendations for the Residential Exposures for the Fluridone Aggregate Assessment.

Lifestage Exposure 

Scenario

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Handler –

RTU 0.0024 0.0057 N/A 0.0081 6,300 2,600 N/A 1,800

Child (3 to < 

6 years old) Swimming 0.00114 2.8E-7 9.9E-5 0.0012 13,000 54,000,000 150,000 12,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral 

(where applicable).

2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental 

Oral MOE), where applicable.

6.4 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-

0037). The agency has evaluated the SAP report and has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

fluridone.

6.5 Spray Drift

Off-target movement of pesticides can occur via many types of pathways, and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up 

off-target and can lead to exposures to those people it may directly contact. They can also 
Fluridone Human Health Risk Assessment DP No. 423464

Page 33 of 83

deposit on surfaces where contact with residues can eventually lead to indirect exposures (e.g., 

children playing on lawns where residues have deposited next to treated fields). The potential 

risk estimates from these residues can be calculated using drift modeling onto 50-feet wide lawns 

coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 

prevent them.6

 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 to 2 years old) and adults who have contact with 

turf where residues are assumed to have deposited via spray drift, thus resulting in an indirect 

exposure, are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, a 

residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of fluridone. In the spray drift scenario, the 

deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the recently 

revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs). 

A screening approach was developed based on the use of the AgDrift model in situations where 

specific label guidance that defines application parameters is not available.7 AgDrift is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 

1 option) were incorporated into the model and represent each equipment type and use under 

varied conditions. The screening options specifically recommended in this methodology were 

selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

be evaluated, unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). Section 6.5.1 provides the screening level drift-related risk estimates. 

 6 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

7http://www.agdrift.com/ 
Fluridone Human Health Risk Assessment DP No. 423464

Page 34 of 83

6.5.1 Risk Estimates From Lawn Deposition Adjacent to Applications

Fluridone is a systemic herbicide, meaning its herbicidal mode of action requires it to be 

absorbed and translocated in the weeds. It is not a contact herbicide, and thus the application 

method is not as a broadcast application meant to cover the surface area of the weeds. For the 

aquatic uses, it is applied in a directed manner, usually using a hose, wand or meter, as a surface 

or subsurface application to water in order to maintain a specified herbicide concentration in the 

water body to control aquatic weeds systemically. The large/coarse droplet size and directed 

spray methods greatly reduce the spray drift potential for aquatic applications. As the 

application methods are not conducive to spray drift as described and assessed as part of the 

spray drift policy, a quantitative spray drift assessment is not required for the aquatic uses of the 

herbicide. 

The spray drift risk estimates for the proposed use on cotton are based on an estimated deposited 

residue concentration, as a result of the screening level agricultural application scenarios. 

Fluridone is proposed for use on pre-emergent cotton and can be applied via groundboom. 

Aerial application is prohibited. The spray drift assessment was completed assuming the highest 

proposed single application rate to cotton of 0.3 lb ai/A. The recommended drift scenario 

screening level options are: 

• Groundboom applications are based on the AgDrift option for high boom height and 

using very fine to fine spray type using the 90th percentile results. 

The applicable Level of Concern is 100, so MOEs < 100 would be of concern. Exposures were 

considered for 50 feet wide lawns where the nearest side of the property was directly adjoining 

the treated field (at field edge). Results are presented in Table 6.5.1; no risk estimates of concern 

were identified at field edge. 

Table 6.5.1 Adult and Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for 

Fluridone.

Population 

and 

Exposure 

Route

Application 

Method

Spray Type/ Nozzle 

Configuration

Appl. Rate 

(lb ai/A) TTR (μg/cm2)a MOE At Field Edge

Cotton 

Adults –

Dermal Groundboom High Boom Very fine to Fine

0.3 0.033

1,800

Children (1 to 

<2 years) –

Combined 

Dermal and 

Hand-tomouth

Groundboom High Boom Very fine to Fine 880

a. TTR = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.1 and D = 0.10 per day 
Fluridone Human Health Risk Assessment DP No. 423464

Page 35 of 83

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

7.1 Acute Aggregate Risk

The acute aggregate risk is equivalent to the acute dietary risk estimates. The acute dietary 

exposure estimates for fluridone (food and drinking water) are not of concern to HED (<100% 

aPAD) for the general U.S. population and all population subgroups.

7.2 Short-Term Aggregate Risk

Short-term aggregate risk assessments for fluridone are necessary since there is potential for 

residential exposure to fluridone from the aquatic uses. For the short-term aggregate risk 

assessment, potential residential exposures were combined with chronic dietary exposures. See 

Table 6.3.1 for more information on the residential risk estimates that are recommended for use 

in the aggregate assessment for fluridone. The short-term residential exposure estimates were 

aggregated with the chronic dietary exposure to provide a worst-case estimate of short-term 

aggregate risk for adults and children. The short-term aggregate MOEs for adults and children 

are greater than the LOC of 100 for fluridone and are therefore not of concern. 

Table 7.2.1 Short-Term Aggregate Risk Calculations for Fluridone

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day3

Residential 

Exposure 

mg/kg/day4

Total 

Exposure 

mg/kg/day5

Aggregate 

MOE (food, 

water, and 

residential)6

Adult 15 100 0.15 0.002098 0.0081 0.0102 1,500

Child 15 100 0.15 0.008312 0.0012 0.009512 1,600 1 LOC based on the standard inter- and intra- species uncertainty factors totaling 100. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Average food and water exposure from chronic dietary exposure for adults 20-49 yrs and children 1-2 yrs old (see Table 

5.4.6.1). 

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure], where applicable. 5 Total Exposure = Avg Food & Water Exposure + Residential Exposure 6 Aggregate MOE = [NOAEL (15 mg/kg/day)/ (Total Exposure, mg/kg/day)]

7.3 Intermediate-Term Aggregate Risk

Intermediate-term residential exposures are not likely because of the intermittent residential

exposure to fluridone; therefore, an intermediate-term aggregate risk assessment is not required.
Fluridone Human Health Risk Assessment DP No. 423464

Page 36 of 83

7.4 Chronic Aggregate Risk

There are no chronic residential exposure scenarios; therefore, the chronic aggregate risk is

equivalent to the chronic dietary risk estimate. The chronic dietary (food and drinking water) 

exposure estimates for fluridone are not of concern to HED (<100% cPAD) for the general U.S. 

population and all population subgroups.

7.5 Cancer Aggregate Risk

Fluridone is classified as “not likely” to be a human carcinogen. A quantitative cancer risk 

assessment is not required.

8.0 Cumulative Exposure/Risk Characterization

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 fluridone and 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, EPA has not 

assumed that fluridone has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism 

of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the registered and

proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is 

based on the following scenarios: 

Proposed use on cotton:

• Mix/load liquid for groundboom application to pre-emergent cotton

• Applying spray by groundboom application to pre-emergent cotton
Fluridone Human Health Risk Assessment DP No. 423464

Page 37 of 83

Registered aquatic uses:

• Mix/load liquid for aerial/boom application or direct metering to lakes/canals

• Mix/load WDG/granule for aerial/boom application to lakes/canals

• Applying spray by aerial/boom application to aquatic area

• Applying granule by aerial/boom application to aquatic area

• Mixing/loading/applying with handheld equipment to aquatic areas (lakes/canals)

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: Application rates are provided in Tables 3.3.1 and 3.3.2.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1, the AHETF database, or other registrant-submitted occupational exposure 

studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data 

protection provisions of FIFRA. The standard values recommended for use in predicting handler 

exposure that are used in this assessment, known as “unit exposures”, are outlined in the 

“Occupational Pesticide Handler Unit Exposure Surrogate Reference Table8

”, which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at the Agency website9

. 

Area Treated or Amount Handled: For proposed cotton use: 200 acres for groundboom 

application to high-acreage crop (based on ExpoSAC Policy 9.1).

For existing aquatic use: area treated assumption (30 acres) is based on information from the

Army Corp of Engineers [for more details, please see the occupational aquatic assessment in the 

endothall reregistration eligibility decision (Tadayon, 2005, D319373) and the 2,4-D RED (Dole,

2005, D316596). The depth of 7 feet is assumed to be consistent with the EFED farm pond 

model. For application to aquatic sites with handheld equipment, it is assume the area treated is 

5 acres of surface area and a depth of 1 foot. For static canals, the area treated is assumed to be a 

canal 1 mile long and 20 ft wide (2.5 acres). For assessing flowing water, it is assumed that the 

upper end of the flow rate is 200 cubic feet/second (endothall RED, Tadayon, 2005, D319373). 

This is equivalent to approximately 400 acre-feet treated.

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 30 

days to six months as intermediate-term. Exposure duration is determined by many things, 

including the exposed population, the use site, the pest pressure triggering the use of the 

pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is 

reasonable to believe that occupational handlers will not apply the same chemical every day for 

more than a one-month time frame; however, there may be a large agribusiness and/or 

 8 Available: http://www2.epa.gov/sites/production/files/2015-09/documents/handler-exposure-table-2015.pdf 9 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handlerexposure-data
Fluridone Human Health Risk Assessment DP No. 423464

Page 38 of 83

commercial applicators who may apply a product over a period of weeks (e.g., completing 

multiple applications for multiple clients within a region). For fluridone, based on the proposed 

use, short- and intermediate-term exposures are expected.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were 

calculated for various levels of personal protective equipment (PPE). Results are presented for 

“baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, 

shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels 

of PPE as necessary (e.g., gloves, respirator, etc). The proposed product label for the preemergent cotton use directs applicators and other handlers to wear long sleeved shirt, long pants, 

chemical-resistant gloves, shoes plus socks and protective eyewear. The registered product 

labels for the aquatic uses do not require any PPE.

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be 

found in Appendix A of the ORE memo (Gavelek, 2015, D431020).

Combining Exposures/Risk Estimates:

Dermal and inhalation exposure estimates were combined in this assessment, since the 

toxicological effects for these exposure routes were the same. Dermal and inhalation exposure 

estimates were combined using the following formula:

Total MOE = Point of Departure (mg/kg/day) ÷ Combined dermal + inhalation dose (mg/kg/day)

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

Proposed Cotton Use: There are no risk estimates of concern for the proposed cotton use (i.e., 

all MOEs ≥ LOC of 100; see Table 9.1.1). Occupational handler combined dermal and 

inhalation MOEs range from 230 to 640 with baseline clothing (long sleeved shirt, long pants, 

shoes plus socks, no gloves, and no respirator for all scenarios except aerial applicator where 

engineering controls were used). The proposed product label for the pre-emergent cotton use 

directs applicators and other handlers to wear long sleeved shirt, long pants, chemical-resistant 

gloves, shoes plus socks and protective eyewear. 

Registered Aquatic Uses: There are risk estimates of concern for some of the registered aquatic 

use scenarios (see Table 9.1.2). Occupational handler combined dermal and inhalation MOEs 

range from 6.1 to 18,000 with baseline clothing (single layer clothing, shoes plus socks, no 

gloves, and no respirator for all scenarios, except aerial applicator where engineering controls 

were used). The registered product labels for aquatic uses do not require any PPE. The scenario

of mixing/loading/applying product with handwand sprayer to aquatic sites was not of concern 

with the addition of gloves. The scenario of mixing/loading/applying product with backpack 

sprayer to aquatic sites was not of concern with the addition of double layer clothing and gloves.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 
Fluridone Human Health Risk Assessment DP No. 423464

Page 39 of 83

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.
Fluridone Human Health Risk Assessment DP No. 423464

Page 40 of 83

Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for the Proposed Uses of Fluridone on Cotton. 

Exposure Scenario Crop or 

Target

Level of 

Concern

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1 Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Combined

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE

(LOC = 100)8

Mixer/Loader

Mixing/loading liquid for 

Groundboom Application Cotton 100 SL/No G:

220

No R:

0.219

0.3 lb 

ai/acre 200 acres 0.0644 230 0.000164 91,000 230

Applicator

Applying Spray with 

Groundboom Application Cotton 100 SL/No G:

78.6

No R:

0.34 0.3 lb ai/acre 200 acres 0.023 650 0.000255 59,000 640

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: SL/ No G = Single layer, no gloves. 

2 Based on proposed label.

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL (15 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL (15 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (15 mg/kg/day) ÷ Dermal Dose + Inhalation Dose.

Table 9.1.2. Occupational Handler Non-Cancer Exposure and Risk Estimates for the Registered Aquatic Uses of Fluridone. 

Exposure Scenario Crop or 

Target

Level of 

Concern

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1 Maximum 

Application

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Combined

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE

(LOC = 100)8

Mixer/Loader

Mix/Load Liquid for 

Aerial/Boom Application 

or Direct Metering

Aquatic: 

Pond/Lake 100

SL/No G:

220

No R:

0.219

0.4 lb 

ai/acre-foot

30 acres / 7 

foot depth

0.0902 170 0.00023 65,000 170

Mix/Load Granular for 

Aerial/ Boom Application 

SL/No G:

8.4

No R:

1.7 0.00344 4,400 0.00179 8,400 2,900

Mix/load WDG for Aerial/ 

Boom application SL/ No G: 227 No R: 8.96 0.0931 160 0.00941 1,600 150
Fluridone Human Health Risk Assessment DP No. 423464

Page 41 of 83

Table 9.1.2. Occupational Handler Non-Cancer Exposure and Risk Estimates for the Registered Aquatic Uses of Fluridone. 

Exposure Scenario Crop or 

Target

Level of 

Concern

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1 Maximum 

Application

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Combined

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE

(LOC = 100)8

Mixing/loading liquid for 

direct metering 

Aquatic: 

Moving 

Water

100 SL/No G:

220

No R:

0.219

40 ppb; 0.11 

lb ai/acrefoot

200 CFS = 

400 acrefeet/day0.0472 320 0.000121 120,000 320

Applicator

Applying spray with Aerial 

Application

Aquatic: 

Pond/Lake 100

Eng. Control: 

2.08

Eng. Control: 

0.0049

0.4 lb 

ai/acre-foot

30 acres / 

7 foot 

depth

0.000853 18,000 0.0000052 2,900,000 18,000

Applying spray with Boat 

Boom Application

SL/No G:

78.6

No R:

0.34

0.032 470 0.000358 42,000 460

Applying granular with 

Aerial Application

Eng. Control:

1.7

Eng. Control:

1.3 0.000697 22,000 0.00136 11,000 7,300

Applying granular with 

boat spreader

SL/No G:

9.9

No R:

1.2 0.00406 3,700 0.00126 12,000 2,800

Mixer/loader/Applicator

Mixing/loading/applying 

liquid/WDG with backpack 

sprayer

Aquatic: 

Pond/Lake 100

SL/No G:

8260

No R:

2.58

0.4 lb 

ai/acre-foot 5 acre / 1 

foot depth

0.0804 190 0.0000645 230,000 190

Mixing/loading/applying 

liquid/WDG with 

handwand sprayer

SL/No G: 

100,000 No R:

30

0.975 15

0.00075 20,000

15

SL/G: 430 0.00419 3,600 3,100

Mixing/loading/applying 

liquid/WDG with handgun 

sprayer

SL/No G:

1300

No R: 

3.9 0.0127 1,200 0.0000975 150,000 1,200

Loading/applying granules 

with backpack SL/No G: 155 No R: 23.8 0.00151 9,900 0.000595 25,000 7,100

Mixing/loading/applying 

liquid/WDG with backpack 

sprayer Static Canal 100

SL/No G:

8260 No R:

2.58 2 lb ai/acre 2.5 acres

0.201 75

0.000161 93,000

75

SL/G: 8260 0.201 75 75

DL/G: 4120 0.1 150 150

Mixing/loading/applying SL/No G: No R: 2.44 6.1 0.00188 8,000 6.1
Fluridone Human Health Risk Assessment DP No. 423464

Page 42 of 83

Table 9.1.2. Occupational Handler Non-Cancer Exposure and Risk Estimates for the Registered Aquatic Uses of Fluridone. 

Exposure Scenario Crop or 

Target

Level of 

Concern

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1 Maximum 

Application

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Combined

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE

(LOC = 100)8

liquid/WDG with 

handwand sprayer

100,000 30

SL/G: 430 0.0105 1,400 1,200

Mixing/loading/applying 

liquid/WDG with handgun 

sprayer

SL/No G:

1300

No R: 

3.9

0.0317 470 0.000244 61,000 470

Loading/applying granules 

with backpack SL/No G: 155 No R: 23.8 0.00378 4,000 0.00149 10,000 2,900

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: SL/ No G = Single layer, no gloves. SL/G = Single layer, gloves. No R = 

no respirator. Eng. Control = Engineering controls. Unit exposure for groundboom application used as surrogate for boat boom sprayer/spreader.

2 Based on registered labels.

3 Exposure Science Advisory Council Policy #9.1 or as described in Section 6.1 above.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL (15 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL (15 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (15 mg/kg/day) ÷ Dermal Dose + Inhalation Dose.
Fluridone Human Health Risk Assessment DP No. 423464

Page 43 of 83

9.2 Short-/Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Dermal Post-application Risk

Proposed Cotton Use: As the proposed use is on pre-plant or pre-emergent cotton, no 

occupational post-application dermal exposure to residues on foliage is expected.

Registered Aquatic Use: Since the currently registered uses of fluridone are in aquatic 

environments, there are no occupational post-application activities which would result in 

occupational exposures from treated bodies of water. While scouting may include identifying 

aquatic weed re-growth, this activity is not conducted until a few weeks after application. 

Therefore, occupational post-application exposure of workers to previously treated water bodies/ 

dry canals is expected to be negligible.

Restricted Entry Interval

Proposed Cotton Use: The REI specified on the proposed label is based on the acute toxicity of 

fluridone. Fluridone is classified as Toxicity Category III via the dermal route and Toxicity 

Category IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 156.208 (c) 

(2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin 

irritation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection 

Statement interim REI of 12 hours is adequate to protect agricultural workers from postapplication exposures to fluridone. The REI of 24 hours on the proposed label for the cotton use

is adequate and meets the minimum WPS requirements. It should be noted that the proposed 

label is a multiple active ingredient product, and should be considered when setting the REI for 

the end-use product. 

Registered Aquatic Use: As application to aquatic areas do not fall under the purview of WPS 

and re-entry exposure is considered to be negligible, an REI is not applicable for these uses.

9.2.2 Inhalation Post-application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 
Fluridone Human Health Risk Assessment DP No. 423464

Page 44 of 83

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037). The agency 

has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for fluridone.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

10.0 Epidemiology

S. Recore and E. Evans, D426709, 6/2/15.

The current Incident Data System (IDS) analysis from January 1, 2010 through May 21, 2015

(Recore, 2015, D426709), shows one incident reported involving fluridone in Main IDS 

involving multiple chemicals and two incidents reported to Aggregate IDS. There were no 

single chemical incidents reported to IDS. In addition, a query of SENSOR-Pesticides 1998-2011 

identifies the three cases involving fluridone.

Based on the low frequency and low severity of incident cases reported for fluridone in both IDS 

and NIOSH SENSOR-Pesticides, there does not appear to be a concern at this time that would 

warrant further investigation. The Agency will continue to monitor the incident information and 

if a concern is triggered, additional analysis will be conducted.

11.0 References 

Dole, T. D306456. Human Health Risk Assessment for Fluridone TRED. 17-AUG-2015.

Gavelek, A. D431020. Fluridone. Occupational and Residential Exposure Assessment for 

Registration Review and to Support the Registration of Proposed Use on Cotton. 06-JAN-2016.

Habiba, U., D427717. Fluridone: Acute and Chronic Dietary Food and Drinking Water Exposure 

and Risk Assessments for the Section 3 Registration Action. 20-JAN-2016.

Recore, S. and Evans, E. D426709, Fluridone: Tier I Update Review of Human Incidental for 

Draft Risk Assessment. 02-JUN-2015.

Drew D., Lloyd M., and Irwin W. D399892, Fluridone: ID#12AR01 Section 18 Emergency 

Exemption for Use on Cotton in Arkansas, South Carolina, Tennessee, and Florida. 05-APR2012.

Tadayon, N. D319373. Revised Occupational and Residential Exposure Assessment and 

Recommendations for the Reregistration Eligibility Decision Document for Endothall. 12-AUG2005.
Fluridone Human Health Risk Assessment DP No. 423464

Page 45 of 83

Dole, T. D316596. 2,4-D: 3nd Revised Occupational and Residential Exposure and Risk 

Assessment and Response to Public Comments for the Registration Eligibility Decision (RED) 

Document. 04-MAY-2005.

Orrick, G. D423846. Fluridone: Drinking Water Exposure Assessment for Proposed New Use on 

Cotton. 07-MAY-2015.
Fluridone Human Health Risk Assessment DP No. 423464

Page 46 of 83

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food-use for fluridone are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation..............................................

870.2600 Dermal Sensitization .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 28-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

waived1

yes

yes

yes

-

-

870.3700 Developmental Toxicity (rodent)...................................

870.3700 Developmental Toxicity (nonrodent) .............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100 Chronic Toxicity (rodent)...............................................

870.4100 Chronic Toxicity (nonrodent).........................................

870.4200 Oncogenicity (rat) ..........................................................

870.4200 Oncogenicity (mouse) ....................................................

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial reverse mutation assay ....................

870.5300 Mutagenicity—gene mutation test-mammalian ......................

870.53xx Mutagenicity—chromosome aberration test ..........................

870.53xx Mutagenicity—other .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100 Acute Delayed Neurotoxicity (hen)................................

870.6100 90-Day Neurotoxicity (hen) ...........................................

870.6200 Acute Neurotoxicity Screening Battery (rat)..................

870.6200 90-Day Neurotoxicity Screening Battery (rat) ...............

870.6300 Developmental Neurotoxicity .......................................

no

no

yes

waived2

no

-

-

yes

-

no

870.7485 General Metabolism......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

no

yes

1

Waived by HASPOC (Leshin, 2015, TXR 0057221)

2

Waived by HASPOC (Rury, 2013, TXR 0056853)
Fluridone Human Health Risk Assessment DP No. 423464

Page 47 of 83

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance 

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 00135206 LD50 = 10 g/kg IV

870.1200 Acute dermal [rabbit] 00082347 LD50 > 2g/kg III

870.1300 Acute inhalation [rat] 00135206 LC50 > 2.13 mg/L IV

870.2400 Acute eye irritation [rabbit] 00135206 Slight to moderate 

corneal dullness, 

iritis, & 

conjunctivitis 

w/clearing by 4 

days

II

870.2500 Acute dermal irritation [rabbit] 41424102 Non- irritant IV

870.2600 Skin sensitization [guinea pig] 47425708 Not a sensitizer n/a
Fluridone Human Health Risk Assessment DP No. 423464

Page 48 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

MRID 00135209 (1978)

Acceptable/Guideline

0, 330, 560, 1000, 1400, 

or 2000 ppm (males: 0, 

30, 54, 106, 139, or 178.4; 

females: 0, 34, 53, 94, 

126, or 202 mg/kg/day 

based on initial food 

consumption) to Fischer 

344 rats via diet for 90 

days

NOTE: 81.9% of the 

theoretical concentration was 

present in the feed sample 

after 1 week storage. 

Therefore, corrected doses 

administered are 25, 44, 87, 

114, or 146 m/k/d for males.

NOAEL* = 25 mg/kg/day

LOAEL = 44 mg/kg/day based on ↑absolute 

and relative liver (112-113% of controls) and 

relative kidney weights (106% of controls) 

(males only)

In males at 2 highest doses (114 and 146 m/k/d)

↑ centrilobular hypertrophy of the liver

(1/15 of 114 m/k/d group)

(12/15 of 146 m/k/d group)

*see note under doses

870.3100 90-Day oral 

toxicity (mouse)

MRID 00082342 (1978)

Acceptable/Guideline

0, 62, 110, 200, 330, or 

560 ppm (equivalent to 0, 

9.3, 16.5, 30, 49.5 or 84 

mg/kg/day based on 1 

ppm = 0.15 mg/kg/day) to 

ICR/SPR mice via diet for 

90 days

NOTE: 50% of the 

theoretical concentration was 

present in the feed sample 

after 3 months storage. 

Therefore, corrected doses 

administered are 4.6, 8.3, 15, 

25, & 42 mg/kg/day.

NOAEL* = 15 mg/kg/day

LOAEL = 25 mg/kg/day based on ↑ 

centrilobular hypertrophy of the liver

(incidences of centrilobular hypertrophy of the 

liver were 0/30, 1/28, 2/29, 3/29, and 6/30 cases 

in control, low-, mid-, high- and highest-doses)

NOTE: The dose related findings of this lesion 

was also observed in other 90-day mouse study 

with fluridone (MRID No. 82341)

*see note under doses

870.3150 13-Week oral 

toxicity (dog)

MRID 00082344 (1978)

Unacceptable/Guideline

0, 50, 100, or 200 

mg/kg/day to beagles via 

oral capsules

NOAEL = 200 mg/kg/day (HDT)

LOAEL was not established

870.3200 21-Day dermal 

toxicity (rabbit)

MRID 00103299 (1981)

Acceptable/Guideline

0, 192, 384 or 768 

mg/kg/day to New 

Zealand white rabbits for 

21 days (6 hours/day and 

5 days/week).

Systemic: NOAEL = 768 mg/kg/day;

LOAEL was not established

Dermal: NOAEL < 192 (LDT) mg/kg/day; 

LOAEL = 192 mg/kg/day (LDT) based on 

transient, slight erythema in 9/10 animals 

accompanied by slight desquamation
Fluridone Human Health Risk Assessment DP No. 423464

Page 49 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3465 90-Day inhalation 

toxicity (rat) Waived by HASPOC (TXR 0057221)

870.3700 Prenatal 

developmental in 

(rat)

MRID 00159963 (1986)

Acceptable/Guideline

0, 100, 300, or 1000 

mg/kg/day to CD rats

via oral gavage on 

gestation days 6

through 15 inclusive

Maternal: NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on ↓ body 

weight gain and food consumption

Developmental: NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day based on ↓ fetal 

body weight, ↑ rudimentary ribs and ↑ delayed 

ossification in sternebrae and pelvic girdle 

870.3700 Prenatal 

developmental in 

(rabbit)

MRID 00103302 (1980)

Acceptable/Guideline

0, 125, 300, or 750 

mg/kg/day to

Dutch Belted rabbits 

(15/sex/dose) via oral 

gavage on days 6-18 of 

gestation 

Maternal: NOAEL = 125 mg/kg/day

LOAEL = 300 mg/kg/day based on ↓ body 

weight and food consumption and ↑ incidences 

of abortions (4/14 aborted between days 20 and 

25 of gestation)

Developmental: NOAEL = 125 mg/kg/day

LOAEL = 300 mg/kg/day based on ↑ 

incidences of abortions (as above)

At 750 mg/kg/day, 6/11 aborted between days 

20 and 25 of gestation

870.3800 Reproduction and 

fertility effects (rat)

3-generation

MRID 00103304 (1980)

Acceptable/Guideline

0, 200, 650, or 2000 ppm 

to Fischer 344 rats via diet 

Calculated intake of 

fluridone during the 

growth phases over the 3 

generations were 10.6-

11.1, 35.5-36.6, or 111.9-

112.3 mg/kg/day for 

males and 12.4-13.2, 

40.4-44, or 128-131.4 

mg/kg/day for females.

Parental and offspring: NOAEL > 112 

mg/kg/day (HDT)

LOAEL was not established

Reproductive: NOAEL > 112 mg/kg/day 

(HDT)

LOAEL was not established 

Developmental: NOAEL = 36 mg/kg/day

LOAEL = 112 mg/kg/day based on ↓pup 

weight (90.7% of controls; p<0.05; on lactation 

day 21 in F2 generation)

870.4100 Chronic toxicity

(rat)

See guideline 870.4300 

870.4100 Chronic Toxicity 

(Dog) – 1 Year

MRID 00103336 (1981)

Acceptable/Guideline

0, 75, 150, or 400 

mg/kg/day to beagles via 

gelatin capsules for 52 

weeks

NOAEL = 150 mg/kg/day

LOAEL = 400 mg/kg/day based on ↑ absolute 

liver weights and ↑alkaline phosphatase activity 

(in female dogs).
Fluridone Human Health Risk Assessment DP No. 423464

Page 50 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200 Carcinogenicity 

(mouse) -

2 year

MRID 

00103252/00103335 

(1981-1982)

Acceptable/Guideline

0, 33, 100, or 330 ppm for 

2 years (equivalent to 0, 5, 

15 or 50 mg/kg/day) to 

ICR mice via diet for 104 

weeks 

NOAEL = 15 mg/kg/day

LOAEL = 50 mg/kg/day based on ↑alkaline 

phosphatase activity (209% of controls) and ↑ 

incidence of hepatocellular hyperplasia

(2, 2, 4, and 6 cases in control, low-, mid-, & 

high-doses)

*No increase in tumor incidence was found.

870.4300 Combined Chronic 

Toxicity/

Carcinogenicity 

(rat) – 2 Years

MRID 

00103305/00103251 

(1980)

Acceptable/Guideline

0, 200, 650, 2000 ppm for 

2 years (0,7.65, 25.15, 

80.8 mg/kg/day in males 

and 9.17, 30.11, 97.00

mg/kg/day in females) to 

Fischer 344 rats via diet 

for 104 weeks

NOAEL = 7.65 mg/kg/day

LOAEL = 25.15 mg/kg/day based on ↓ body 

weights (92% of controls; p<0.05), ↓ eosinophil 

counts, ↑ absolute and relative liver and kidney 

weights

No increase in tumor incidence was found.

At 80.8 mg/kg/day (HDT)

↑ mortality (87% in ♂; 37% in ♀)

↑ chromorhinorrhea, anorexia, cloudy eyes, 

pale eyes

↓ body weight (59-66% in ♂; 81-89% in ♀)

↓ food consumption

↓ RBC counts, Hb, hematocrit, MCV, MCH

↓ lymphocyte and eosinophil counts

↑ nucleated erythrocytes, leukocyte & 

neutrophil counts

↑ total leukocyte count

↑ BUN, creatinine, bilirubin

↑ small testes, dose-related trends in number of 

enlarged, pale and/or granular kidneys; opaque, 

cloudy, pale, red, or ulcerated eyes; & skin

nodules or masses.

↑ absolute and relative liver & kidney weights

↑ atrophy of testes, ocular keratitis, epidermal 

inclusion cyst

870.5100 Gene Mutation 

(Ames Assay)

MRID 00255339 Not mutagenic

870.5375 In vivo mammalian 

cytogenics – sister 

chromatid 

exchange in CHO

MRID 00070942 Not mutagenic

870.5550 Unscheduled DNA 

damage/repair

MRID 00070942 Not mutagenic

870.5550 Unscheduled DNA 

damage/repair

MRID 00070942 Not mutagenic
Fluridone Human Health Risk Assessment DP No. 423464

Page 51 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200 Neurotoxicity 

screening battery –

Acute 

Neurotoxicity – Rat

Crl:CD(SD)

MRID 48939603 (2012)

0 (vehicle control), 125, 

650, or 2000 mg/kg bw &

observed for 14 days. 

Dose volume = 5 mL/kg

98.02% a.i.

NOAEL = 125 mg/kg bw/day

LOAEL = 650 mg/kg bw/day based anomalies 

in open field, and sensory parameters, and 

increased catalepsy time concurrent with 

decreased mean ambulatory counts.

870.6200 Neurotoxicity 

screening battery –

Subchronic 

Neurotoxicity (rat) Waived by HASPOC (TXR 0056853)

870.7485 Metabolism and 

pharmacokinetics

(rat)

MRID 

00103261/00103262

(1981)

Unacceptable/Nonguideline

14C-labeled Fluridone (14C 

labeled in the 4-position 

of the pyridinone ring)

10, 100, 250, 500 or 1000 

mg/kg to Fischer 344 rats 

via single oral gavage

-Readily absorbed and eliminated

-Total recovery of dosed radioactivity = 78-

90% (3 days); 4-19 % (urine); 68-85 % (feces); 

Negligible% (tissues and carcasses); 66% (bile)

Component in urine and feces–not identified

-Major component (37% of dose) in bile–not 

identified

-Minor component in bile: Fluridone (8% of 

dose) 4-hydroxyphenyl fluridone (6% of dose)

870.7485 Metabolism and 

pharmacokinetics

(rat)

MRID 44265101 (1997)

14C-labeled Fluridone

10 or 1000 mg/kg via 

single oral gavage

-Majority of administered dose (79-92%) was 

eliminated in the feces, higher dose led to 

higher fecal elimination. Lower levels detected 

in the urine (9-15%). Most elimination 

occurred within 24 hours at low dose, 72 hours 

for high dose. 

-Tissue residues were low (0.3-0.7%) but 

proportional to the dose, highest tissue residue 

levels in liver and kidney

-Eight (8) metabolites were identified from 

feces. Fluridone was extensively metabolized 

primarily through ring hydroxylation and N 

demethylation.

-Recovered >93% of administered dose in both 

genders

-minimal recovery from expired air

870.7600 Dermal absorption No study submitted

DAF = 39% - an upper bound estimate of dermal absorption calculated from 

the ratios the rabbit 21 day dermal toxicity study NOAEL & the rabbit

developmental toxicity study LOAEL. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 52 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fluridone

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7800 Immunotoxicity MRID 48939601 (2012)

Acceptable/Guideline 

Fluridone (98.02%,

a.i., Batch No. 

MAR11BE011) 

0, 200, 400, or 1000 ppm 

(equivalent to 0, 43.5, 

89.1, & 205.4 mg/kg 

bw/day, respectively) to 

CD-I female mice 

(10/group) in the diet for 

28 days.

Systemic: NOAEL = 205.4 mg/kg bw/day

(HDT)

LOAEL was not established.

Immunotoxicity: NOAEL = 205.4 mg/kg 

bw/day

LOAEL was not established.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Parent Compound Endpoint Selection

A.3.1.1 Acute Reference Dose (aRfD) – General Population

Study Selected: Acute Neurotoxicity - Rat

MRID No.: 48939603

Executive Summary: See Appendix A, Guideline [§ 870.6200] 

Dose and Endpoint for Risk Assessment: NOAEL = 125 mg/kg/day based on decreased 

ambulatory counts and the prevalence of FOB anomalies in males and females observed at LOAEL 

= 650 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation, 10x for intraspecies variation, and 1x 

FQPA SF 

Comments about Study/Endpoint: The adverse behavioral effects observed at 650 mg/kg/day 

in the ACN were in response to a single oral dose and thus were representative of an acute 

exposure.

A.3.1.2 Acute Reference Dose (aRfD) - Females age 13-49

No acute dietary endpoint was identified that is specific to the female 13-49 subpopulation. 

A.3.1.3 Chronic Reference Dose (cRfD)

Study Selected: 2 year carcinogenicity study - mouse

MRID No.: 00103252/00103335

Executive Summary: See Appendix A, Guideline [§ 870.4200] 

Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increased alkaline 

phosphatase activity and increased hepatocellular hyperplasia seen at LOAEL = 50 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation, 10x for intraspecies variation, and 1x 

FQPA SF 
Fluridone Human Health Risk Assessment DP No. 423464

Page 53 of 83

Comments about Study/Endpoint: The 2 year carcinogenicity study chronicles adverse 

responses to a chronic oral exposure, which is well suited for assessing the chronic dietary risks. 

A slightly lower NOAEL (8 mg/kg/day) was noted in the rat combined chronic 

toxicity/carcinogenicity study; however, this fact was considered to be due to dose-selection (i.e. 

15 mg/kg/day was not tested in this rat study). The NOAEL in the mouse study is protective of 

adverse findings noted in the rat combined chronic toxicity/carcinogenicity study, as well as the 

rat 3-generation reproduction study. The selected NOAEL is also protective of effects noted in 

the chronic dog study.

A.3.1.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: 2 year carcinogenicity study - mouse

MRID No.: 00103252/00103335

Executive Summary: See Appendix A, Guideline [§ 870.4200] 

Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increased alkaline 

phosphatase activity and increased hepatocellular hyperplasia seen at LOAEL = 50 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation

Comments about Study/Endpoint: The mouse chronic endpoint was appropriate for short-and 

intermediate-term fluridone exposures, because mice were the most sensitive species in subchronic 

exposures, fluridone is rapidly metabolized and eliminated from the body at low doses (≤10 

mg/kg), and no progression of toxicity was evident when comparing the mouse subchronic toxicity 

study to the chronic toxicity study. Progression of toxicity was observed in rats; however, rat 

sensitivity was either less than (subchronic exposure) or similar (chronic exposure) to mice. The 

POD from the 2 year mouse study was, therefore, both protective of the effects observed in rat and 

representative of short- and intermediate-term exposure durations.

A.3.1.5 Dermal Exposure (Short- and Intermediate-Term)

Study Selected: 2 year carcinogenicity study - mouse

MRID No.: 00103252/00103335

Executive Summary: See Appendix A, Guideline [§ 870.4200] 

Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increased alkaline 

phosphatase activity and increased hepatocellular hyperplasia seen at LOAEL = 50 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation

Comments about Study/Endpoint: The guideline dermal study was not used to set endpoints 

for the dermal assessment, because the study did not address concerns for sensitivity in the 

young described in the 3-generation reproduction study. The systemic NOAEL from the dermal 

study is 384 mg/kg/day, but offspring toxicity is apparent at 112 mg/kg/day. The NOAEL from 

the 2 year mouse cancer study is 38.5 mg/kg/day after accounting for route-to-route extrapolation 

(DAF=39%), which is protective of the offspring effects. The mouse chronic endpoint was 

appropriate for short-and intermediate-term fluridone exposures, because mice were the most 

sensitive species in subchronic exposures, fluridone is rapidly metabolized and eliminated from 

the body at low doses (≤10 mg/kg), and no progression of toxicity was evident when comparing 

the mouse subchronic toxicity study to the chronic toxicity study. Progression of toxicity was 

observed in rats; however, rat sensitivity was either less than (subchronic exposure) or similar 

(chronic exposure) to mice. The POD from the 2 year mouse study was, therefore, both 
Fluridone Human Health Risk Assessment DP No. 423464

Page 54 of 83

protective of the effects observed in rat and representative of short- and intermediate-term 

exposure durations. 

A.3.1.6 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: 2 year carcinogenicity study - mouse

MRID No.: 00103252/00103335

Executive Summary: See Appendix A, Guideline [§ 870.4200] 

Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day based on increased alkaline 

phosphatase activity and increased hepatocellular hyperplasia seen at LOAEL = 50 mg/kg/day.

Uncertainty Factors: 100 – 10x for interspecies variation and 10x for intraspecies variation

Comments about Study/Endpoint: A route specific study was not available for the inhalation 

assessment; however, HASPOC approved substitution with an oral study because the calculated 

risk estimates using an oral endpoint and assuming 100% absorption were not of concern. The 

mouse chronic endpoint was appropriate for short-and intermediate-term fluridone exposures, 

because mice were the most sensitive species in subchronic exposures, fluridone is rapidly 

metabolized and eliminated from the body at low doses (≤10 mg/kg), and no progression of toxicity 

was evident when comparing the mouse subchronic toxicity study to the chronic toxicity study. 

Progression of toxicity was observed in rats; however, rat sensitivity was either less than 

(subchronic exposure) or similar (chronic exposure) to mice. The POD from the 2 year mouse 

study was, therefore, both protective of the effects observed in rat and representative of short- and 

intermediate-term exposure durations. 

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat MRID 00135209

In a 90-day oral toxicity study (MRID 00135209), fluridone (98.6% a.i.; Lot # 367-Q52-59) was 

administered to 15 SPF-CD Fischer 344 rats/sex/dose in the diet at concentrations 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 based on initial food consumption).

There were no treatment-related effects on survival, clinical signs, body weights, food 

consumption, and hematology or clinical chemistry parameters. 

Treatment related effects were limited to statistically significant increases in absolute and 

relative liver and kidney weights in both the male and female animals (Table 1). In male rats 

receiving the 560 ppm diets, absolute and relative liver weights (112-113% of controls) and 

relative kidney weights (106% of controls) were significantly increased. 

In both males and females receiving the 1000 ppm diets and above, absolute and relative liver 

and kidney weights were significantly increased (105-124% of controls). Histological 

alterations were limited to liver centrilobular hypertrophy in male rats in the two highest doses 

groups (0/15 of control, 330, 560, and 1000 ppm groups, 1/15 of 1400 ppm and 12/15 of 2000 
Fluridone Human Health Risk Assessment DP No. 423464

Page 55 of 83

ppm groups). In this study, only tissues from liver and kidneys were examined microscopically 

because the high doses of fluridone (2000, 4000, and 8000 ppm diets) had been shown to 

produce alterations in only liver and kidney in the previous study (MRID No: 00135208). 

Stability study of fluridone in diets showed that only 81.9% of the theoretical concentration of 

fluridone in the 330 ppm (30 mg/kg/day) diet was present in the feed sample after 1week storage. 

The recovery of 81.9% of the test compound necessitated estimating a NOAEL for this study. 

The estimated NOAEL is 81.9% of 30 mg/kg/day or 25 mg/kg/day. Also, the estimated LOAEL 

is 81.9% of 54 mg/kg/day (560 ppm) or 44 mg/kg/day.

The LOAEL for fluridone in rats is 44 mg/kg/day based on increased absolute and relative 

liver weights and relative kidney weights. The NOAEL is 25 mg/kg/day. This 90-day oral 

toxicity study is classified Acceptable/Guideline and satisfies the guideline requirements for a 

90-day oral toxicity study in the rat (OCSPP 870.3100; OECD 408). 

870.3100 90-Day Oral Toxicity – Mouse MRID 00082342

In a 90-day oral toxicity study (MRID No. 00082342), fluridone (97.8% a.i.; Lot # D36-Y25-

091) was administered to 15 ICR/SPR mice/sex/dose in the diet at concentrations of 0, 62, 110, 

200, 330 or 560 ppm (equivalent to 0, 9.3, 16.5, 30, 49.5 or 84 mg/kg/day based on 1 ppm = 0.15 

mg/kg/day).

There were no treatment-related effects on appearance, behavior, body weights or liver weights. 

Four males (2, 1, and 1 death in the 110, 200, and 330 ppm groups, respectively) and one female 

(in the 62 ppm group) died during the study but none of the deaths were attributed to treatment. 

Treatment related effects were limited to increased incidence of hepatic centrilobular 

hypertrophy with increasing dose of fluridone in the male mice. The incidence of this lesion 

seen in the males was 1/28, 1/29, 3/29, or 6/30 in 110, 200, 330 or 560 ppm groups, respectively. 

The dose related findings of this lesion was also observed in other 90-day study with fluridone 

(MRID No. 00082341) with the incidence of 5/30, 8/30, or 26/30 in 330, 560, or 1400 ppm 

groups, respectively.

Stability study of fluridone in diets showed that approximately 50% of the theoretical 

concentration of fluridone was present in the feed samples after 3 months storage. Therefore, the 

recovery of 50% of the test compound necessitated estimating a NOAEL for this study. The 

estimated NOAEL is 50% of 30 mg/kg/day (200 ppm diet) or 15 mg/kg/day. Also, the estimated 

LOAEL is 50% of 49.5 mg/kg/day (330 ppm diet) or 25 mg/kg/day.

The LOAEL for fluridone in mice is 25 mg/kg/day based on increased incidence of hepatic 

centrilobular hypertrophy. The NOAEL is 15 mg/kg/day.

This 90-day oral toxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirements for a 90-day oral toxicity study in the mouse (OCSPP 870.3100; OECD 408). The 

study was reported in 1978. The diet analysis indicated that the concentration of the test 

compound in treatment diet decreased overtime. The report did not show how rapidly the 

concentration of the test diet deteriorated. Using the decrease found at 3 month (50% drop) was 
Fluridone Human Health Risk Assessment DP No. 423464

Page 56 of 83

a conservative approach. In addition, the report did not indicate how frequently diet was 

prepared and how long it was stored prior to offering to the test mice. 

870.3150 90-Day Oral Toxicity – Dog MRID 00082344

In a 90-day oral toxicity study (MRID No. 00082344), fluridone (98.6% a.i. Lot # 597-B29-

200C) was administered to 4 beagle dogs/sex/dose in capsules at doses of 0, 50, 100, or 200 

mg/kg/day. No adverse, treatment-related effects were observed on survival, clinical signs, body 

weight, body weight gain, food consumption, hematology, bone marrow analysis, urinalysis, 

organ weights, gross pathology, or microscopic pathology. 

The LOAEL for fluridone in dogs is not established and the NOAEL is equal or greater 

than 200 mg/kg/day (HDT).

This 90-day oral toxicity study is classified Acceptable/Non-Guideline and does not satisfy the 

guideline requirements for a 90-day oral toxicity study in the dog [OCSPP 870.3150 (§82-1b)]. 

Although the results reported were valid for the doses tested, the study is classified non-guideline 

because no adverse effects were observed at the high dose (200 mg/kg/day). Dose selection for 

the 90-day study was based on a slight body weight reduction observed at 200 mg/kg/day in a 

range finding study. This minor body weight effect is not indicative of an adverse response to 

treatment and suggests the animals could have tolerated a higher dose in the 90-day study. 

However, another 90-day guideline non-rodent study is not required at this time because the 

toxicological data requirements are satisfied by the 1-year feeding study in dogs (MRID No. 

00103336). [NOTE: This study was classified as minimum (acceptable) in the previous review 

(TXR No. 000824).]

870.3200 21/28-Day Dermal Toxicity – Rat MRID 00103299

In a 21-day dermal toxicity study (MRID No. 00103299), groups of New Zealand white rabbits 

(5/sex/dose group) received Fluridone 4AS (Lot No.: #X-36339; purity: 44.5% a.i.) by dermal 

application at doses of 0, 192, 384 or 768 mg/kg/day for 21 days (6 hours/day and 5 days/week). 

No adverse, treatment-related effects were observed on survival, clinical signs, body weight, 

body weight gain, food consumption, hematology, clinical chemistry, organ weights, or gross or 

histological pathology.

Localized dermal reactions included the following:

Animals in the 192 mg/kg/day group (20% formulation) showed transient, slight erythema in 

9/10 animals, accompanied by slight desquamation. 

Animals in the 384 mg/kg/day group (40% formulation) showed moderate, well-defined 

erythema, slight edema and mild desquamation, and epidermal fissures in 3/10 rabbits. 

Animals in the 768 mg/kg/day group (80% formulation) showed moderate to severe 

erythema with epidermal fissures in 8/10 rabbits, accompanied by slight edema.
Fluridone Human Health Risk Assessment DP No. 423464

Page 57 of 83

Differences in the dermal response between abraded and non-abraded skin were not statistically 

significant.

The LOAEL for systemic toxicity was not established. The NOAEL was 768 mg/kg/day.

The LOAEL for dermal toxicity was 192 mg/kg/day based on transient, slight erythema in 

9/10 animals accompanied by slight desquamation. The NOAEL for dermal toxicity was 

not established.

This 21-day dermal toxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirement for a 21-day dermal toxicity study (82-2) in the rabbit.

870.3465 90-Day Inhalation – Rat

Waived by HASPOC (TXR 0057221)

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat MRID 00159963

In a developmental toxicity study (MRID No. 00159963), 25 presumed pregnant Crl:CD® (SD) 

rats per group were administered Fluridone (purity: 99.5%; batch/lot No.: 414DT4) by oral 

gavage in 10% acacia solution at doses of 0, 100, 300, or 1000 mg/kg/day on gestation days 

(GD) 6-15, inclusive. On GD 20, dams were sacrificed and necropsied, and gravid uterine 

weights and the numbers of fetuses, early and late resorptions, total implantations and corpora 

lutea were recorded. All fetuses were weighed, sexed, and subjected to external examination 

followed by fresh dissection. Approximately one-half of the fetuses from each litter terminated 

on GD 20 were fixed in Bouin’s solution for visceral examination, and the remaining fetuses 

were eviscerated and processed for skeletal examination. 

Maternal Toxicity

One dam (#2061) on 300 mg/kg/day was found dead on GD 10 (after receiving 4 doses) 

apparently as a consequence of an injury during dosing. Autopsy revealed dark-red, collapsed 

lungs, surrounded by fibrin and fluid. There were 15 implantation sites in utero. 

In mid- and high-dose groups, dose-related significant decreases in the body weight gain and 

food consumption were recorded during the first half of the treatment period (days 6 to 10), but 

weight gain rebounded during the latter half (days 11 to 15) of the treatment period. In the highdose group, adjusted overall net weight gain (minus gravid uterine weight) during the posttreatment period remained significantly depressed (20% less than controls). In addition, higher 

incidences of alopecia was observed only in the 1000 mg/kg/day group (5 rats vs. 0, 1, and 1 rat 

at 0, 100, and 300 mg/kg/day, respectively). 
Fluridone Human Health Risk Assessment DP No. 423464

Page 58 of 83

Necropsy findings in sacrificed dams (hydronephrosis, empty stomach and gastrointestinal tract, 

infantile uterine horn, etc.) were evenly distributed and of low incidence in all groups with no 

compound relationship.

Therefore, the LOAEL for maternal toxicity was 300 mg/kg/day based on reduced body 

weight gains and food consumption; NOAEL for maternal toxicity was 100 mg/kg/day.

 

Developmental Toxicity

There were no differences between the control group and the all treated groups for number of 

females pregnant, corpora lutea, number of implant per pregnancy, % of live fetuses or % 

resorptions. No dead fetuses were observed in any group. 

At 1000 mg/kg/day, mean fetal weight (males = 3.25 g; females = 3.04 g) was significantly 

decreased as compared with controls (male= 3.66 g; females 3.53 g). In female fetuses at 1000 

mg/kg/day, rudimentary ribs (T-13, T-14, L-1) in seven litters and delayed ossification of 

sternebrae and pelvic girdle in two litters were observed.

Renal cavitation and ureter dilatation were reported at a higher incidence than controls in the 

mid- and high-dose groups, but these fetal variations have been observed in higher incidences in 

controls from other studies conducted by the same laboratory. One high-dose fetus had a 

shortened right hindlimb (micromelia) and associated skeletal defects, while two high-dose 

fetuses from a separate litter had hernias and one of these had hypoplastic lungs.

Therefore, the LOAEL for developmental toxicity was 1000 mg/kg/day based on decreased 

fetal weight, increased incidences of rudimentary ribs, and delayed ossification in 

sternebrae and pelvic girdle; NOAEL for developmental toxicity was 300 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the requirements for a 

developmental toxicity study [OCSPP: 870.3700a (83-3a)] in rats.

870.3700b Prenatal Developmental Toxicity Study – Rabbit MRID 00103302

In a developmental toxicity study (MRID No. 00103302), fluridone (lot no.:X-29478; purity: 

99.5% a.i.) in 10% acacia solution was administered daily by oral gavage to pregnant female 

Dutch Belted rabbits (15/sex/dose) on days 6-18 of gestation at dose levels of 0, 125, 300, or 750 

mg/kg/day. The rabbits were observed for signs of toxicity and body weight and food 

consumption values were recorded. On day 28 of gestation, the rabbits were sacrificed and 

necropsied and the numbers of fetuses, early and late resorptions, total implantations and corpora 

lutea were recorded. The fetuses were removed, weighed, sexed, and examined for external 

anomalies. They were then processed for visceral or skeletal evaluation.

Maternal Toxicity

No deaths were observed in the control and 125 mg/kg/day (LDT) groups. One female in the 

300 mg/kg/day group was found dead on day 23 of gestation. An acute upper respiratory tract 
Fluridone Human Health Risk Assessment DP No. 423464

Page 59 of 83

infection and focal acute pneumonia were observed at necropsy. Two animals were found dead 

on day 23 in the 750 mg/kg/day group. No diagnosis was reported for one; the other female was 

diagnosed as having an acute upper respiratory tract infection and acute pneumonia. No other 

signs of toxicity were observed in any of the surviving animals during the study.

There were no differences between the control group and low-dose group for the body weight 

gain and mean food consumption during the treatment period. 

In the mid-dose group, a slight loss in the body weight, the body weight gain, and mean food 

consumption during the treatment period were slightly reduced when compared to the controls, 

however, the difference was not statistically significant. At the mid- and high-dose levels, 

increased incidence of abortions was also seen (detailed below).

The mean body weight changes during the treatment period at high dose-level was significantly 

reduced (-2.3%; p<0.05) when compared to the controls (+4.9%). Mean food consumption 

during the treatment period and post-treatment period of the high-dose animals were 62% and 

77% of the control values, respectively.

In addition, treatment related increased incidences of abortions was observed at both the midand high-doses. Since maternal toxicity was also observed at these doses (reduced body weight 

and food consumption), the increased incidence of abortions seen at mid- and high-dose levels 

was considered to be secondary to the maternal effects.

Therefore, the LOAEL for maternal toxicity was 300 mg/kg/day based on increased 

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

NOAEL for maternal toxicity was 125 mg/kg/day.

Developmental Toxicity

No dead fetuses were observed in any group and the mean fetal body weights of all treatment 

groups were comparable to the control group. A dose-related decrease in the ratio of live fetuses 

to implantation sites was evident. The ratios were 0.96, 0.95, 0.80, and 0.65 for control, low-, 

mid- and high-dose groups, respectively.

The reproduction findings showed that 4 of 14 mid-dose and 6 of 11 high-dose pregnant rabbits 

aborted between days 20 and 25 of gestation. The number of high-dose rabbits successfully 

maintaining pregnancy until day 28 of gestation was reduced by deaths and abortions when 

compared to the control group. Thirteen of the 13 control rabbits reached day 28 of gestation, 

whereas, only 5 of the 11 high-dose rabbits were still pregnant by day 28 of gestation. The mean 

number of resorptions/litter was increased two and one half fold when the mid-dose (1.5) was 

compared to the controls (0.6), however, this difference was not statistically significant. At highdose, the mean number of resorptions/litter (3.0) was significantly increased (p<0.05) when 

compared to the controls (0.6).

One control and one high-dose fetus each had multiple abnormalities, however, these 

abnormalities were considered spontaneous and not related to fluridone. In addition, the control 
Fluridone Human Health Risk Assessment DP No. 423464

Page 60 of 83

fetus was observed to have hair lip, omphalocelle, and absent forepaws and hindlimbs. The 

high-dose fetus was observed to have exencephally, omphalocele, rudimentary ear, and 

rudimentary forelimbs without digits. No visceral abnormalities were observed in either the 

control or treatment groups. An increase in the percentage of fetuses with 13th ribs was observed 

in the high-dose level as compared to controls, however, the percentage of fetuses with 13th ribs 

was comparable to the historical controls. There were increased incidences of unidentified 

thickened rib and sternebral variations in the high-dose level. 

Therefore the LOAEL for developmental toxicity was 300 mg/kg/day based on increased 

incidences of abortions; NOAEL for developmental toxicity was 125 mg/kg/day. 

This study is classified as Acceptable/Guideline and satisfies the requirements for a 

developmental toxicity study [OCSPP: 870.3700b (83-3b)] in rabbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat MRID 00103304

In a 3-generation reproduction study (MRID 00103304), fluridone (99.5% a.i., lot # X-29478) 

was administered to 25 Fischer 344 rats/sex/dose in the diet at concentrations of 0, 200, 650, or 

2000 ppm. The mean calculated intake of fluridone during the growth phases over the 3 

generations were 10.6-11.1, 35.5-36.6, or 111.9-112.3 mg/kg/day for males and 12.4-13.2, 40.4-

44, or 128-131.4 mg/kg/day for females. Two litters were produced by each generation, and the 

animals were administered test or control diet continuously for at least 10 weeks prior to mating, 

throughout mating, gestation, lactation, and until necropsy. The F2 generation parents were 

mated three times and histopathologic examination was conducted on selected F3b progeny and 

the teratology phase of the study was conducted on the F3c litters. The F3a pups were 

terminated at weaning because of poor viability in all treatment groups, however, the report 

stated that “No cause was determined for the loss of significant numbers of F3a pups between 

days 1 and 7 postpartum.”

For low- and mid-dose F0 females, there were two deaths resulting from the room temperature 

reaching 380C. One control F2 female died, but cause of death was not evident. There were no 

treatment-related effects on body weights and food consumption during the growth phase in any 

of the three generations. Also, fluridone did not produce clinical signs of toxicity in the animals 

in any of the generation. The absence of parental toxicity indicates that optimal dietary levels of 

the test material were not used, thus compromising the sensitivity of the test.

The maternal body weights and body weight gains of the fluridone-treated females were 

comparable to those of the control females on days 0 to 20 of gestation and on day 21 of 

lactation during all generations (F1, F2, F3a, and F3b). Also, in the teratology phase (F3c) of the 

study, no dose-related differences were observed in the body weights at days 0, 7, 14, and 20 of 

gestation, nor were any observed for the weight gains from day 0 to day 20 of gestation. The 

LOAEL for maternal toxicity was not determined; NOAEL for maternal toxicity was equal 

or greater than 2000 ppm (112 mg/kg/day, HDT). 
Fluridone Human Health Risk Assessment DP No. 423464

Page 61 of 83

The test chemical did not significantly affect any of the reproductive parameters. Therefore, the 

NOAEL for reproductive toxicity is equal to or greater than 2000 ppm (112 mg/kg/day, 

HDT) and the LOAEL is not established. 

Fluridone significantly depressed the body weights (90.7% of controls; p<0.05) on lactation day 

21 of the 2,000 ppm F2 pups. A comparison of the pup weight gain from day 1 to day 21 of 

lactation indicated a dose-related trend toward decreased weight gain among the fluridonetreated pups, however, the differences were not statistically significant. Therefore, the NOAEL 

for offspring toxicity is 650 ppm (36 mg/kg/day) and the LOAEL is 2000 ppm (112

mg/kg/day, HDT) based on decreased pup weight (on lactation day 21).

For developmental toxicity phase of the study, F3c developmental toxicity data shows that there 

were no evidence of embryolethality, altered fetal growth, or developmental alteration. 

Therefore, the LOAEL for developmental toxicity was not determined; NOAEL for 

developmental toxicity was equal or greater than 2000 ppm (112 mg/kg/day, HDT). 

This study is classified as Acceptable/Guideline and satisfies the guideline requirements for a 

2-generation reproductive study in the rat (OCSPP 870.3800; OECD 416). However, the 

teratology phase of the study is classified as Unacceptable/Guideline and does not satisfy the 

requirements for a developmental toxicity study [OCSPP: 870.3700 (83-3a)] in rats because the 

highest dietary level failed to produce maternal toxicity. A separate acceptable guideline rat 

developmental study (MRID 00159963) was submitted that satisfied the guideline requirement 

for a developmental toxicity study.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat MRID 00103305/00103251

There were three studies conducted concurrently and reported as combined 

chronic/carcinogenicity study (MRID 00103305 and 00103251). For these three studies 

fluridone (Lot No: D36-Y25-091; purity: 97.2% a.i.) was administered to Fischer 344 rats 

(75/sex/dose) in the diet at levels of 0, 200, 650, or 2000 ppm. Corresponding daily intake of test 

material for the two-year studies were 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 first study was a one year study consisting of 15 

rats/sex/dose and the other two studies were 2-year study each consisting of 30 

rats/sex/dose/study.

None of the animals in the one-year study died prior to the 12-month sacrifice. For the 2-year 

studies, the mortality rate through week 77 was 10% or less for all test groups. However, from 

week 78 (18 months) through the remainder of the study, increase in mortality occurred in highdose males (87% vs 20-32% in the other male groups). Mortality rates among female groups 

were similar to the control until the last month of the study, when an increase in mortality 

occurred among high-dose females (37% vs 23% in the controls).

No treatment-related effect was seen at 200 ppm (7.65 mg/kg/day).
Fluridone Human Health Risk Assessment DP No. 423464

Page 62 of 83

The mid-dose males (25.15 mg/kg/day) at final sacrifice exhibited decreased body weights 

(92% of controls; p<0.05), decreased eosinophil counts, and increased absolute and relative liver 

and kidney weights as compared to controls. 

In the high-dose animals (80.8 mg/kg/day), treatment related toxicity observed includes 

decreased body weights and food consumption and pale eyes and thin appearance in both sexes, 

increased incidences of chromorhinorrhea, anorexia, and cloudy eyes in males.

At final sacrifice, the mean erythrocyte counts, hemoglobin, mean corpuscular hemoglobin 

concentration and hematocrit values from high-dose males were significantly lower (p<0.05) 

than control values. In high-dose females, only hemoglobin levels was significantly lower than 

the control values.

The high-dose males had increased levels of nucleated erythrocytes and neutrophil count and a 

decreased levels of lymphocyte and eosinophil counts when compared to controls at study 

termination. Also, statistically significant increases in total leukocyte count were noted in highdose males and females. 

BUN and creatinine levels in both sexes were significantly higher than the controls. 

Necropsy findings observed at final sacrifice were increased incidence of small testes noted in 

the high-dose group. The mean testes weight of high-dose males was lower than control values, 

but the relative testes weight was not significantly different from controls. In addition, there was 

an increased dose-related trends in number of enlarged, pale and/or granular kidneys (in males 

and females). In addition, there was increased number of opaque, cloudy, pale, red, or ulcerated 

eyes (in males) and increased number of skin nodules or masses (in females). 

At interim and final sacrifices, both absolute and relative liver and kidney weights and relative 

spleen weights in the high dose males and females were significantly higher than controls.

Examination of the renal cortex by electron microscopy showed necrosis in albumin precipitate 

in 1/4 high-dose male and necrosis in 2/4 high-dose females.

Histopathologic findings showed that incidence of atrophy of the testes and ocular keratitis were 

increased in high-dose males. Incidences of epidermal inclusion cysts (non-neoplastic retention 

of keratin in the skin) were increased in treated animals of both sexes. Also the incidences of 

skin papillomas were increased in treated animals of both sexes, however, the skin papillomas do 

not represent an oncogenic response to fluridone treatment because of the following reasons: 

1) statistical analyses were conflicting;

2) skin papillomas do not represent a life-threatening lesion; 

3) the majority of “masses” grossly identified in this study were minute in size (“wart-like”); and

4) there is no hint these could have undergone malignant transformation.
Fluridone Human Health Risk Assessment DP No. 423464

Page 63 of 83

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

females). The LOAEL for systemic toxicity was 650 ppm (25.15 in males and 30.11 

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

increased absolute and relative liver and kidney weights.

The tumor issue of this study was peer reviewed by the HED Cancer Assessment Review 

Committee (TXR 007726, July 15 and October 7, 1985). The committee evaluated the available 

data and concluded that the data did not provide evidence for the carcinogenicity of fluridone in 

rats.

Dosing was considered adequate in this study based on increased mortality, decreased body 

weight and food consumption, increased liver and kidney weights, changes in hematology 

parameters, changes in clinical chemistry parameters (increased BUN, creatinine, bilirubin), 

increased incidence of chromorhinorrhea, anorexia, and cloudy and pale eyes observed at highdose (80.8 mg/kg/day). In addition, there were changes in morphology of erythrocytes 

(increased incidences of nucleated erythrocytes, leukocyte and neutrophil counts), changes in 

total and differential leukocyte counts (increased leukocyte counts and decreased lymphocyte 

and eosinophil counts). Also, fluridone treatment at high-dose resulted in increased incidences 

of small testes and enlarged, pale and/or granular kidneys. Also increased incidences of opaque, 

cloudy, pale, red, or ulcerated eyes, skin nodules or masses, atrophy of testes, ocular keratitis, 

and epidermal inclusion cyst observed at high-dose.

This study is classified as Acceptable/Guideline and satisfies the Subdivision F guideline 

requirements for a combined chronic toxicity/carcinogenicity study (83-5) in rats.

870.4100b Chronic Toxicity – Dog MRID 00103336

In a chronic toxicity study (MRID No. 00103336), 4 beagle dogs/sex/dose were orally 

administered fluridone (98.1% a.i.; Lot # D36-Y93-107) in gelatin capsules at doses of 0, 75, 

150, or 400 mg/kg/day for 52 weeks. 

There were no deaths during the study and no treatment-related ophthalmic findings were noted 

at the termination of the study. No differences that could be attributed to compound 

administration were evident in any of the urinalysis, hematologic parameters, and gross or 

histopathologic examinations. Also, fluridone did not induce hepatic mixed-function oxidase 

activity. Dose-related emesis occurred in females only (0/4 controls, 2/4 low-dose, 3/4 middose, and 4/4 high-dose), however, sporadic occurrence of this finding precludes assessment of 

its biological significance. 

No treatment-related effects were found in the low-dose animals.

In the 150 mg/kg/day group, body weight gain was slightly lower (4-6%; statistically not 

significant) in males as compared to the controls over the last two months of the study. 

In the 400 mg/kg/day group, body weight gain was slightly lower (6-10%; statistically not 

significant) in males and females as compared to the controls over the last two months of the 
Fluridone Human Health Risk Assessment DP No. 423464

Page 64 of 83

study. Also, alkaline phosphatase activity in female dogs was statistically significantly elevated 

(approximately 2-3 times of control) beginning at the 5th week and continuing to the study 

termination. No increase in alkaline phosphatase activity was found in the males. Additional 

findings in the high-dose females were significantly increased absolute liver weights (118% of 

controls, p<0.05) and increase in the relative liver weights (not statistically significant). A 

potential hepatotoxic effect of fluridone in this study is consistent with previous findings: 

elevated alkaline phosphatase activity was observed at 200 mg/kg (HDT) in a 3-month oral 

toxicity study in dogs and elevated alkaline phosphatase activity and increased relative liver 

weights were observed at 400 mg/kg (HDT) in a 2 week oral pilot study in dogs. 

The LOAEL is 400 mg/kg/day based on significant increases in absolute liver weights and 

increases in alkaline phosphatase activity in female dogs. The NOAEL is 150 mg/kg/day. 

(In the original DER, the LOAEL was conservatively estimated at 150 mg/kg/day based on the 

slight weight loss in males and the trend towards increased alkaline phosphatase activity (120-

170% of the control values) in females.

This chronic study in the dog is classified Acceptable/Guideline and satisfies the guideline 

requirement for a chronic oral study in the dog [OCSPP 870.4100b; OECD 452].

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - Rat

Study is detailed under guideline 870.4100a 

870.4200b Carcinogenicity (feeding) – Mouse MRID 00103252/00103335

There were three studies conducted concurrently and reported as carcinogenicity study (MRID 

00103335 and 00103252). In these 3 studies, fluridone (Lot No: D36-Y25-091; purity: 97.2% 

a.i.) was administered to ICR mice (120/sex/dose in controls; 80/sex/dose in treated groups) in 

the diet at levels of 0, 33, 100, or 330 ppm (equivalent to 0, 5, 15 or 50 mg/kg/day based on a 

conversion factor of 1 ppm = 0.15 mg/kg/day). The first study was a one year study consisting 

of 15 mice/sex/dose. In the 2 two-year studies, the control groups consisted of 60 mice/sex/study 

and each of the dosed groups consisted of 40 mice/sex/study. 

Mortality among the control and dosed animals in the one- and two-year studies were similar. 

No treatment-related effect was seen at 33 (low-dose) and 100 (mid-dose) ppm. Overall, no 

dose-related changes in hematology parameters were apparent for 300 (high-dose) ppm males 

and females. For high-dose females of the first 2-year study (M-9407), hematology data showed 

statistically significant decreases in hemoglobin, packed cell volume, and monocyte counts 

compared to controls. For high-dose males, a significant decrease in the lymphocyte counts and 

a significant increase in the neutrophil counts were observed. However, these parameters were 

not reduced in the second 2-year study (M-9417). 
Fluridone Human Health Risk Assessment DP No. 423464

Page 65 of 83

The high-dose males showed statistically significant increases in alkaline phosphatase (134 

and 209% of controls at 12 and 24 months, respectively) (study M-9407). The combined data 

from 2 two-year studies indicated a significant increase (157% of controls) in alkaline 

phosphatase activity in the high-dose group males as compared to controls. 

Absolute organ weights for males and females showed no compound-related effects at interim 

and final sacrifices. In the high-dose females, relative liver weights were significantly higher 

than controls at interim sacrifice but this was not supported by the absolute liver weights. 

Gross examination showed no compound related effects in any tissue. Histopathological 

examination at final sacrifice showed a slight but significant (p<0.05) increase in 

hepatocellular hyperplasia for the high-dose males (2, 2, 4, and 6 cases in control, low-, mid-, 

and high-doses). A slight increase in hepatic focal atypia (not defined in the final study report) 

was also noted for high-dose females (0, 1, 2, and 2 cases in control, low-, mid-, and high-doses).

The report indicated an increased incidence of fibrosarcomas of the skin in the high-dose 

females. The tumor issue of this study was peer reviewed by the HED Cancer Assessment 

Review Committee (TXR 007726, July 15 and October 7, 1985). The committee concluded that 

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

The NOAEL for systemic toxicity was 100 ppm (15 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.

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

compared to controls.

Dosing was considered adequate in this study based on increase in alkaline phosphatase activity 

and increased incidence of hepatocellular hyperplasia for the high-dose males.

This study is classified as Acceptable/Guideline and satisfies the Subdivision F guideline 

requirements for a carcinogenicity study (83-2) in mice.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, gene mutation

MRID 00255339

Not mutagenic

Cytogenetics

Guideline 870.5375, In vivo

mammalian cytogenics – sister 

chromatid exchange in CHO

MRID 00070942

Not mutagenic

Other Genotoxicity
Fluridone Human Health Risk Assessment DP No. 423464

Page 66 of 83

Guideline 870.5550, Unscheduled DNA 

damage/repair

MRID 00070942

Not mutagenic

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study - Hen

Not required

870.6200 Acute Neurotoxicity Screening Battery MRID 48939603

In an acute neurotoxicity study (MRID 48939603), groups of 6-week-old Crl:CD(SD) rats

(10/sex/dose) were given a single oral gavage dose of fluridone (98.02% a.i.; Lot no. 

MAR11BE011) in 5% Acacia in deionized water at doses of 0 (vehicle control), 125, 650, or 

2000 mg/kg bw and observed for 14 days. Functional observation battery (FOB) and locomotor 

activity data were recorded for all animals prior to the initiation of dose administration, on Day 0 

at the time of peak effect (approximately 4 hours following dose administration), and on Days 7 

and 14. Animals were sacrificed on Day 15 and perfused in situ. Brain weights and brain 

dimensions were recorded. A neuropathological evaluation of selected tissues from the central

(CNS) and peripheral nervous systems was performed on 5 animals/sex in the control and 2000 

mg/kg groups.

Treatment with fluridone did not affect clinical signs, mortality, gross necropsy findings, 

neuropathology, brain weight, or brain dimensions.

Dose-related changes in FOB parameters were observed in males and females at 125, 650 and 

2000 mg/kg bw of fluridone. These changes were transient, occurring only on Day 0, and often 

disappeared by Day 7 or 14. 

Anomalies in a multitude of FOB parameters was observed in the 2000 mg/kg group. Home 

cage observations revealed clonic convulsions (repetitive movement of mouth and jaws) (2 

males; 5 females) and cage biting (2 males; 3 females). Open-field observations included gait 

abnormality (hunched body: 2 males; 5 females) and one male also exhibiting bizarre/stereotypic 

behavior (repetitive turning of head from side to side). Sensory observations revealed a number 

of animals had no reaction or response to approach (3 rats each), touch (3 rats each), startle (4 

males; 2 females), and/or tail pinch (4 males; 3 females). Air righting reflex was also impaired 

(slightly uncoordinated: 2 males; 2 females; landing on their side: 1 male; 2 females). One highdose female exhibited no hindlimb extension. Physiological observations found a longer 

catalepsy time in males only (2.4 vs. 0.4 seconds for controls), mainly due to 2 rats with long 

times. Females had reduced body temperature compared to controls (35.8 vs. 37.1°C for 

controls). Lastly, motor activity was reduced. Although mean cumulative total activity counts 

were not affected, mean cumulative ambulatory activity counts were decreased (p<0.05) in males 

(325 vs. 500 counts for controls) and females (521 vs. 828 counts for controls). 
Fluridone Human Health Risk Assessment DP No. 423464

Page 67 of 83

Similar effects were observed in male and female rats at 650 mg/kg bw on Day 0 but generally 

occurred at a much lower incidence and were mostly limited to minor FOB anomalies. These 

effects included: clonic convulsions (1 female), cage biting (1 female), gait abnormality 

(hunched body; 1 male), no response/reaction to approach (4 males; 1 female), touch (4 males; 1 

female), startle (3 males), and/or tail pinch (3 males), and abnormal righting reflex (landing on 

its side; 1 female). Males from the 650 mg/kg/day dose group also exhibited longer catalepsy 

time outside the historical control range, which was considered a more serious neurotoxic 

response relative to the other FOB anomalies. Both males and females experienced a reduction in 

mean ambulatory counts concurrent with the behavioral anomalies. 

Changes in FOB parameters on Day 0 were also noted in males and females at 125 mg/kg bw 

although many of the changes, similar to the 650 mg/kg/day dose group, occurred at a low 

incidence and were relatively minor anomalies. These effects included gait abnormality (hunched

body) and uncoordinated air righting reflex (both in same female), and no reaction/response to 

approach (4 males; 1 female), touch (3 males; 2 females), startle (2 males), and/or tail pinch (1 

male). At the 125 mg/kg/day dose, cumulative total and ambulatory motor activity counts were 

not affected. 

Male and female rats from all dose groups exhibited depressed body weight gain (5-25% less 

than controls) during the two weeks after treatment. The impact of depressed body weight gain 

on absolute body weight was negligible (all dose groups were comparable to controls on Day 0, 

7 and 14); therefore, the body weight gain depression was not considered adverse. Food 

consumption was not recorded.

The changes in FOB parameters in combination with significant depression of cumulative 

ambulatory activity counts was considered evidence of an adverse response at the mid and high 

doses. In the absence of a corroborative effect on motor activity, the FOB effects at the low dose 

were not considered adverse because the effects were limited to minor behavior aberrations not 

anticipated to impact quality of life and were of low incidence. 

The LOAEL is 650 mg/kg bw based on decreased ambulatory counts and the prevalence of 

FOB anomalies in males and females. The NOAEL is 125 mg/kg/day.

This neurotoxicity study is classified as Acceptable/Guideline and satisfies the guideline 

requirement for an acute neurotoxicity study in rats (OCSPP 870.6200; OECD 424). 

870.6200 Subchronic Neurotoxicity Screening Battery

Waived by HASPOC (TXR 0056853)

870.6300 Developmental Neurotoxicity Study

Not required

A.4.8 Metabolism
Fluridone Human Health Risk Assessment DP No. 423464

Page 68 of 83

870.7485 Metabolism – Rat MRID 00103261/00103262

MRID 00103261

In a rat metabolism study (MRID No. 00103261), Fischer 344 rats (5 animals/sex/group) 

received a single oral gavage dose of 14C-labeled fluridone (Lot No. 553-897-200; purity not 

provided) at 10, 100, 250, 500 or 1000 mg/kg for urine and fecal elimination study. For both 

biliary elimination (13 males) and tissue distribution (15 animals/sex) studies, Fischer 344 rats 

received a single oral gavage dose of 14C-labeled fluridone at 100 mg/kg/day.

The urine and fecal elimination study indicates that fluridone 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 in the urine and feces were 78-

90% and 87-97% of administered dose in males and females, respectively. Doses of 1000 

mg/kg/day were eliminated less rapidly than doses between 10 and 500 mg/kg/day. Over a 3-day 

period, the radioactivity recovered in the urine was 4-14% and 11-19% of the dose in males and 

females, respectively. The radioactivity recovered in feces was 72-79% and 68-85% of the dose 

in males and females, respectively. 

The tissue distribution study showed that there was no indication of bioaccumulation in any 

tissue or organ after administration of each of the five dosage regimens. The study showed that 

the highest tissue to plasma ratios were found in liver, kidney, ileum, and colon. The tissue to 

plasma ratios following 4, 24, and 96 hours after dosing ranged 11-43 for liver, 6-18 for kidney, 

2-15 for ileum, and 1-9 for colon. Nearly 90% of the radioactivity present in tissues was cleared 

by 96 hours after dosing.

The bile contained 61% of the total radioactivity administered 2 days after dosing. 

MRID No. 00103262

In a biliary elimination study and identification of bile metabolites (MRID No. 00103262), 

Fischer 344 rats (5 males) received a single oral gavage dose of 14C-labeled fluridone at 100 

mg/kg/day. An average of 44 and 66% of the administered dose was eliminated in rat bile within 

24 and 48 hours after dosing, respectively. The radioactivity eliminated in the bile consisted of 

unidentified highly polar metabolites (55.5% of the total bile radioactivity; approximately 37% 

of administered dose), fluridone (12%; 8% of dose) and the 4-hydroxyphenyl fluridone (9%; 6% 

of dose). The identity of fluridone and the 4-hydroxyphenyl fluridone were confirmed by gas 

chromatography-mass spectrometry (GC-MS). 

The unidentified metabolites (55.5% of the total bile radioactivity) consisted of the following 

components: polar metabolites remained at the origin of the chromatograms in the 2nd ethyl 

acetate extract (6% of the bile radioactivity) and 3rd ethyl acetate extract (15.7% of the bile 

radioactivity) and radioactive components in the aqueous phase (33.8% of the bile radioactivity) 

which were not hydrolyzed by 2N HCl. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 69 of 83

The results of these studies indicated that 14C-labeled fluridone was absorbed, and much of it was 

metabolized. Majority of the radioactivity eliminated via feces (approximately 70%). No tissue 

accumulation was seen.

These combined rat metabolism studies are classified Unacceptable/Non-guideline. Although 

the results of these studies provide good understanding of metabolism of this chemical most of 

the administered radioactivity in feces was not identified. [Comments: It is noted that in the 

previous DERs, the major metabolism study (MRID: 00103261) was classified as core 

minimum. The biliary elimination study (MRID: 00103262) was classified as supplementary 

because polar metabolites which constituted the bulk of the metabolites were not identified.]

870.7485 Metabolism – Rat MRID 44265101

Male and female rats (5/sex) were administered either a single oral low dose of labeled fluridone 

at a nominal dose of 10 mg/kg, a multiple oral low dose of unlabeled fluridone at 10 mg/kg once 

daily for 14 days followed by a single labeled fluridone dose at 10 mg/kg on day 15, or a single 

oral high dose of labeled fluridone at a nominal dose of 1000 mg/kg. Two animals of each 

gender were administered a dose of 1% vehicle (carboxymethyl cellulose) to act as controls. A 

majority of the administered dose in the single oral low dose, multiple oral low dose, and single 

oral high dose was eliminated in feces (79-92%). Lower levels were detected in urine (9-15%, 

sum of urine and cage rinse) over 7 days following dosing. Most of the elimination occurred 

within the first 24 hours post-dose for the single and multiple oral low dose regimens, whereas 

complete elimination of the single oral high dose required 72 hours. Excretion profiles of urine 

and feces were considered dose dependent because a significantly higher amount of fecal 

elimination occurred at the single high dose. The profiles did not vary significantly between 

genders. Although tissue residues were low (~0.3-0.7%), the highest residues levels were most 

often found in liver and kidney. Tissues from animals receiving the high dose showed 

proportionally higher residue levels than those from the other two groups. Overall recovery of 

the administered dose amounted to between 93% and >100% for all three dose groups. The 

major components in the excreta were fluridone (single low dose = 4.49%, multiple low dose = 

5.61%, single high dose = 56.6%) and fluridone metabolites (single low dose = 62.9%, multiple 

low dose = 55.9%, single high dose = 32.4%) produced primarily by ring hydroxylation and Ndemethylation. Fourteen metabolites were identified in the feces and urine including: Parent 

compound (3.89-60.26%), Non-polar [(Fluridone)2-S-SO)] (3.18-6.05%), Fluridone (CF3Ø-SH) 

(0.23-2.99%), Fluridone-[Ø-(OH-SCH3)] (0.20-2.76%), Fluridone–(Ø-SH) (0.26-2.67%), 

Desmethyl-Fluridone (2.62-4.42%), (Ø-OH)-Fluridone (1.55-5.09%), Fluidone-(Ø-OH) (0.35-

2.39%), (Ø-OH)-Desmethyl-Fluridone (1.03-7.92%), (CF3Ø-OH)-Desmethyl-Fluridone (1.34-

2.94%), (CF3Ø-OH, Ø-OH)-Fluridone (0.77-4.89%), polar metabolites (4 isomeric products 

4.34-19.56%), and two unidentified metabolites (1st metabolite – 4.63%-9.81%, 2nd metabolite –

1.06-9.34%). Percentage range covers all dose groups from both male and female excreta.

This metabolism study is classified as Acceptable/Guideline and satisfies the guideline 

requirement for a metabolism study in rats (OCSPP 870.7485; OECD 417).

870.7600 Dermal Absorption – Rat
Fluridone Human Health Risk Assessment DP No. 423464

Page 70 of 83

No study submitted. A 39% dermal absorption factor was estimated from the ratios of LOAELs 

of a 21 day dermal toxicity study & a developmental toxicity study in rabbits. 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity MRID 48939601

In an immunotoxicity study (MRID 48939601), fluridone (98.02%, a.i., Batch No. 

MAR11BE011) was administered to CD-1 female mice (10/group) in the diet at concentrations 

of 0, 200, 400, or 1000 ppm (equivalent to 0, 43.5, 89.1, and 205.4 mg/kg bw/day, respectively) 

for 28 days. A concurrent positive control group received the basal diet, but was administered 50 

mg/kg bw/day cyclophosphamide monohydrate (CPS) by IP injecttion on study days 24-27. 

During the study, clinical signs of toxicity were monitored daily, and body weight and food 

consumption were monitored weekly. On Day 24, all mice were sensitized with 1 × 108 sheep 

red blood cell (sRBC). The mice were sacrificed on day 28, the spleen, thymus, and liver 

removed and weighed, and spleen cells suspension were prepared for plaque forming cells (PFC) 

assay. 

There were no treatment-related effects on clinical signs, morbidity, mortality, body weights, or 

organ weights (liver, spleen and thymus) in any treated group compared to the control. 

The systemic NOAEL was 1000 ppm (equivalent to 205.4 mg/kg bw/day), the highest dose 

tested; the LOAEL was not identified.

There were no statistically significant differences in treated groups when compare to the vehicle 

control group for PFC responses. High inter-individual variability was noted in all the treatment 

groups as well as in the control group. Evaluation of the individual animal data of this study did 

not show any trend or distribution that would demonstrate significant suppression of anti-SRBC 

PFC response. Positive control group had statistically significant decrease of the antibody 

response. This confirmed the ability of the test system to detect immuno-suppressive effects and 

confirmed the validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database 

for fluridone does not reveal any evidence of immunotoxicity. The overall weight of evidence 

suggests that the chemical does not directly target the immune system. Under HED guidance a 

NK cell activity assay is not required at this time.

The immunotoxicity NOAEL was 1000 ppm (equivalent to 205.4 mg/kg bw/day); the

LOAEL was not identified. 

This immunotoxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirement for an immunotoxicity study (OCSPP 870.7800) in mice. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 71 of 83

Appendix B. Physical/Chemical Properties

Table B1. Physico-Chemical Properties

Parameter Value Reference

Molecular Weight 329.3 Molecular Formula: C18H14F3NO

Water solubility (20°C) 8.3 mg/L (20°C) MRID 49368504

Solvent solubility (20°C to 25°C) 5-10 g/L NIH

Vapor pressure (25°C) <9.77 x 10-8 torr (25°C)

Tomlin, 2003 (The Pesticide 

Manual, 13th Ed. p.476, BCPC 

Publications, Hampshire) 

Dissociation constant, pKa None at pH 1.0 -12.9 MRID 49368504 

Octanol/water partition coefficient, log KOW

(25°C) 2.54 MRID 49368504 

Soil Half-life (or other relevant information 

from EFED Drinking water assessment)

No evidence of 

degradation 

MRID 49385701 
Fluridone Human Health Risk Assessment DP No. 423464

Page 72 of 83

Appendix C. Review of Human Research

Human Studies Review

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) 

database; and the Residential SOPs; are (1) subject to ethics review pursuant to 40 CFR 26, (2) 

have received that review, and (3) are compliant with applicable ethics requirements. For certain 

studies, the ethics review may have included review by the Human Studies Review Board. 

Descriptions of data sources, as well as guidance on their use, can be found at the Agency 

website10. 

 10 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposuredata and http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-postapplication-exposure
Fluridone Human Health Risk Assessment DP No. 423464

Page 73 of 83

Appendix D. International Tolerances and MRLs

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.420:

(a) General. Compliance with the tolerance levels 

specified in this paragraph is to be determined by 

measuring only the sum of fluridone, 1-methyl-3-

phenyl-5-(3-(trifluoromethyl)phenyl)-4(1H)-

pyridinone, and its bound residues, calculated as the 

stoichiometric equivalent of fluridone

None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Crayfish 0.5

Fish 0.5

US 40 CFR 180.420 Canada Mexico1 Codex

(2) Compliance with the tolerance levels specified in 

this paragraph is to be determined by measuring only 

fluridone, 1-methyl-3-phenyl-5-(3-

(trifluoromethyl)phenyl)-4(1H)-pyridinone

None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Cattle, fat 0.05

Cattle, kidney 0.1

Cattle, liver 0.1

Cattle, meat 0.05

Cattle, meat byproducts 0.05

Egg 0.05

Goat, fat 0.05

Goat, kidney 0.1

Goat, liver 0.1

Goat, meat 0.05

Goat, meat byproducts 0.05

Hog, fat 0.05

Hog, kidney 0.1

Hog, liver 0.1

Hog, meat 0.05

Hog, meat byproducts 0.05

Horse, fat 0.05

Horse, kidney 0.1

Horse, liver 0.1

Horse, meat 0.05

Horse, meat byproducts 0.05

Milk 0.05

Poultry, fat 0.05

Poultry, kidney 0.01

Poultry, liver 0.01

Poultry, meat 0.05

Poultry, meat byproducts 0.05

Sheep, fat 0.05

Sheep, kidney 0.1
Fluridone Human Health Risk Assessment DP No. 423464

Page 74 of 83

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Sheep, liver 0.1

Sheep, meat 0.05

Sheep, meat byproducts 0.05

Completed: M. Negussie; 07/23/15 

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US Canada Mexico2 Codex

40 CFR 180.420:

Plant/Livestock: 1-methyl-3-phenyl-5-(3-

(trifluoromethyl)phenyl)-4(1H)-pyridinone

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Cotton, undelinted seed 0.1

Cotton, gin byproducts 0.1

Completed: M. Negussie; 05/18/2015

1 Includes only commodities of interest for this action. Tolerance values are HED recommendations and not those 

proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Fluridone Human Health Risk Assessment DP No. 423464

Page 75 of 83

Appendix E. NMF Exposure and Risk Assessment

Summary

N-methylformamide (NMF) is a possible degradate of fluridone. Under laboratory conditions, 

using a light source that does not mimic the sun, photolysis of fluridone in water led to the 

formation of NMF. The Agency is unaware of any evidence that supports the formation of NMF 

in the environment from photolysis of fluridone. However, a screening assessment is considered 

for fluridone using extremely conservative assumptions: 100% conversion of fluridone to NMF, 

the possibility that NMF can reach the ground water, and a 10X uncertainty factor due to the lack 

of toxicity data. 

Fluridone is registered for use as an aquatic herbicide and is proposed for pre-emergent treatment 

of cotton. These treatments may result in fluridone reaching surface water sources of drinking 

water. There is a potential for fluridone to be found in ground water via several natural 

processes. There may also potential for residential post-application exposure to NMF while 

swimming in fluridone-treated water. 

The toxicology profile for NMF is limited to one developmental study in rats and rabbits that 

was reported in the literature, and substantial uncertainty surrounds the toxicity of NMF in 

mammals. Toxicological endpoints were selected for acute (females 13-49 years old) and chronic

dietary exposures, and for short-term residential incidental oral, dermal, and inhalation 

exposures. An acute RfD was established for the female 13-49 subpopulation based on decreased 

fetal viability and body weight and increased incidence of skeletal malformations. This acute 

effect was not appropriate for the general population. For all other endpoints, the POD was 10 

mg/kg/day (NOAEL) and the LOAEL was 75 mg/kg/day for rats and 50 mg/kg/day for rabbits 

based on based on body weight loss during gestation. The same three uncertainty factors were 

applied to each exposure scenario: 10x for interspecies extrapolation (UFA), 10x for intraspecies 

variation (UFH), and 10x to account for the lack of NMF toxicity studies (FQPA SF). 

Acute and chronic dietary exposure assessments were conducted for NMF in drinking water; 

NMF is not a residue of concern in food. Estimated drinking water concentrations (EDWCs)

assumed 100% conversion of fluridone to NMF. There were no acute or chronic dietary risk 

estimates of concern for NMF in drinking water for any of the population subgroups assessed (all 

risk estimates <100% aPAD or cPAD).

The proposed new use on cotton is not anticipated to result in residential exposures to NMF; 

however, the existing aquatic uses of fluridone could result in exposure to NMF for swimmers. 

The residential post-application exposure assessment assessed adults and children (3 to < 6 years 

old) who may be exposed to NMF while swimming in treated water (dermal, inhalation and 

incidental ingestion exposure routes). There were no risks of concern for swimmers for the 

individual routes (i.e., all NMF MOEs ≥ 1000). Since all the routes of exposure are based on the 

same effect, the exposures can be combined across routes. The combined MOEs for adults and 

children are also not of concern (i.e., all NMF combined MOEs ≥ 1000).
Fluridone Human Health Risk Assessment DP No. 423464

Page 76 of 83

There are no acute or chronic residential exposure scenarios; therefore the acute and chronic 

aggregate risks for NMF are equivalent to the acute and chronic risk estimates, respectively. The 

acute and chronic dietary exposure estimates for NMF in drinking water are not of concern (risk 

estimates are < 100% of the aPAD or cPAD for all population subgroups assessed). 

Short-term aggregate risk assessments for NMF are necessary, since there is potential for 

residential exposure to NMF from the aquatic uses. For the short-term aggregate risk assessment, 

potential residential exposures (dermal, inhalation, and incidental ingestion exposure from 

swimming in treated waters) were combined with drinking water exposures. The short-term 

aggregate MOEs for NMF for adults and children are greater than the level of concern (LOC = 

1000) and are, therefore, not of concern. Intermediate-term residential exposures are not likely 

because of the intermittent residential exposure to NMF; therefore, an intermediate-term 

aggregate risk assessment is not required. 

Occupational exposure to NMF is not anticipated since NMF only forms in water due to the 

photolysis of fluridone. In addition, the proposed use on cotton is for pre-plant or pre-emergent 

use; therefore, occupational post-application dermal exposures to residues on foliage are not 

expected. For the aquatic uses of fluridone, occupational post-application exposure of workers 

to previously treated water bodies is expected to be negligible, since post-application activities 

are not anticipated for occupational workers post-treatment. 

Chemical Identity

Table E.1. Test Compound Nomenclature

Chemical Structure

Common name N-methyl formamide (NMF)

CAS registry number 123-39-7

CAS name Formamide, N-methylTable E.2. Summary of Toxicological Doses and Endpoints for NMF for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure

Scenario

Point of 

Departure

Uncertainty 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(Females 13-

49 years)

NOAEL = 

10 

mg/kg/day

UFA=10x

UFH=10x

UFDB=10x

aRfD = 0.01 

mg/kg/day

Developmental Toxicity in Rats and Rabbits 

LOAEL = 75 mg/kg/day for rats and 50 

mg/kg/day for rabbits based on decreased fetal 

viability and weight; increased incidence of 

skeletal malformations
Fluridone Human Health Risk Assessment DP No. 423464

Page 77 of 83

Table E.2. Summary of Toxicological Doses and Endpoints for NMF for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure

Scenario

Point of 

Departure

Uncertainty 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

population 

including 

infants and 

children)

A dose and endpoint were not selected for this population group because the acute effects 

observed in the developmental toxicity study in rats and rabbits were not applicable to the 

general population.

Chronic 

Dietary

NOAEL= 

10 

mg/kg/day

UFA=10x

UFH=10x

UFDB=10x

cRfD = 0.01 

mg/kg/day

Developmental Toxicity in Rats and Rabbits 

LOAEL = 75 mg/kg/day for rats and 50 

mg/kg/day for rabbits based on body weight 

loss during gestation 

Incidental Oral

Short-Term

NOAEL= 

10 

mg/kg/day

UFA=10x

UFH=10x

UFDB=10x

MOE = 1000 Developmental Toxicity in Rats and Rabbits 

(same as chronic dietary) 

Dermal

Short-Term

NOAEL= 

10 

mg/kg/day

UFA=10x

UFH=10x

UFDB=10x

MOE = 1000 Developmental Toxicity in Rats and Rabbits 

(same as chronic dietary)

Inhalation

Short-Term

NOAEL= 

10 

mg/kg/day

UFA=10x

UFH=10x

UFDB=10x

MOE = 1000 Developmental Toxicity in Rats and Rabbits 

(same as chronic dietary)

Cancer (oral, 

dermal, and 

inhalation)

No evidence of mutagenicity or carcinogenicity was observed in the single study available.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

Dietary Exposure and Risk Assessment
Fluridone Human Health Risk Assessment DP No. 423464

Page 78 of 83

NMF remains a residue of concern in drinking water unless acceptable aqueous photolysis data 

are submitted that demonstrate otherwise (Orrick; 2015, D423846). Concentrations of NMF 

were found in an aqueous photolysis study (Mosier and Saunders, 1982; MRID 125743) where 

up to 74% of the applied amount of fluridone was converted to NMF. However, this study 

utilized lamps that are known to produce irradiation different from that of natural sunlight. 

Consequently, this study was classified as unacceptable. NMF may or may not be a 

photodegradate in water under natural conditions. Fluridone did not readily photolyze on soil. If 

NMF forms, it will do so in surface water and potentially migrate to ground water. NMF appears 

to be stable to photolysis and hydrolysis, since it was found to increase in concentration at study 

termination, 30 days after treatment. 

Concentrations of NMF in drinking water were estimated assuming NMF conversion efficiency 

of 100%, and by adjusting for the ratio of the fluridone molecular weight of 329 to the NMF 

molecular weight of 59. The drinking water residue for NMF was assumed to be 0.006 ppm [(34 

or 32 ppb * 59 g/mol) / 329 g/mol]. This estimate of NMF concentration is very conservative,

because it is unknown if exposure occurs at all, the conversion rate of fluridone to NMF is 

unknown, and the highest drinking water estimate for fluridone was used (which occurs in 

ground water).

 

Acute and chronic dietary exposure assessments were performed for NMF using the DEEM 

FCID model. Only drinking water was included in the dietary analysis; NMF is not a residue of 

concern in food. Acute dietary (drinking water) risks were determined for females 13-49 years 

old (the only population subgroup for which an acute toxicological endpoint was identified). The 

resulting risk estimate was 3.3% of the aPAD at the 95th percentile of exposure. Chronic dietary 

(drinking water) risks were determined for the general population and all population subgroups. 

The most highly exposed population subgroup was infants (<1 year old), with a risk estimate of 

3.2 % of the cPAD. These risk estimates are all well below 100% of the PAD and are not of 

concern. The risk estimates are summarized in table E.3 below.

Table E.3. Summary of Dietary Drinking Water Exposure and Risk Estimates for 

NMF

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/da

y)

% cPAD

General U.S. 

Population N/A N/A 0.000126 1.3

All Infants (<1 year 

old) N/A N/A 0.000324 3.2*

Children 1-2 years old N/A N/A 0.000181 1.8

Children 3-5 years old N/A N/A 0.000153 1.5

Children 6-12 years old N/A N/A 0.000110 1.1

Youth 13-19 years old N/A N/A 0.000092 < 1

Adults 20-49 years old N/A N/A 0.000125 1.3

Adults 50+ years old N/A N/A 0.000124 1.2
Fluridone Human Health Risk Assessment DP No. 423464

Page 79 of 83

Table E.3. Summary of Dietary Drinking Water Exposure and Risk Estimates for 

NMF

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/da

y)

% cPAD

Females 13-50 years 

old 0.000332 3.3 0.000125 1.2

*The highest exposed population subgroup

Residential Exposure and Risk Assessment

Since NMF may be formed in water via photolysis, residential exposures to NMF are anticipated 

for the aquatic uses of fluridone in order to be protective of possible exposures. No NMF 

exposure is anticipated from the proposed agricultural uses of fluridone. Post-application 

exposure to NMF in aquatic environments (i.e., adult and child swimmers) has been assessed 

according to HED’s November 2015 Draft Aquatic Use SOP. The quantitative exposure/risk 

assessment for residential post-application exposures is based on the following scenarios: 

• Adults and children (3 to <6 years old) swimming in treated water (dermal, inhalation

and incidental ingestion)

Residential Post-Application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the Draft 2015 

Aquatic Use SOP.

Application Rate: Concentrations of NMF were estimated assuming NMF conversion efficiency 

of 100%, and by adjusting for the ratio of the fluridone molecular weight of 329 g/mol to the 

NMF molecular weight of 59 g/mol. A maximum concentration of 150 ppb (0.15 mg/L) was 

assumed for the fluridone assessment, therefore, a concentration of 27 ppb (0.027 mg/L) was 

used to assess aquatic exposure to the degradate, NMF.

Exposure Duration: Residential exposure is expected to be short-term in duration. 

Residential Post-Application Non-Cancer Exposure and Risk Equations

The algorithms used to estimate residential non-cancer post-application exposure and dose can 

be found in the Draft November 2015 Aquatic Use SOP.

Combining Non-Cancer Exposure and Risk Estimates

Since dermal, inhalation and incidental oral exposure routes share a common toxicological 

endpoint, exposure estimates have been combined for those routes. 

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

For NMF, the combined MOE for adult swimmers is 4,400,000 and for child swimmers is 

530,000; therefore, there are no risk estimates of concern (LOC = 1000). 
Fluridone Human Health Risk Assessment DP No. 423464

Page 80 of 83

Table E.4. Residential Post-application Non-cancer Exposure and Risk Estimates for NMF.

Lifestage

Post-application Exposure 

Scenario Application 

Rate1

Dose 

(mg/kg/day)2 MOEs3

Combined Routes

(X indicates 

included in 

Combined MOE)

Combined MOEs

(LOC = 1000) Use Site Route of 

Exposure

Adult

Aquatic

Dermal

27 ppb

(0.027 mg/L)

2.7E-7 36,000,000 X

4,400,000 Inhalation 2.06E-8 490,000,000 X

Incidental 

Ingestion 1.96E-6 5,100,000 X

Child (3 to 

<6 years 

old)

Dermal 9.7E-7 10,000,000 X

530,000 Inhalation 1.22E-7 82,000,000 X

Incidental 

Ingestion 1.78E-5 560,000 X

1 Based on application of fluridone and conversion to NMF.

2 Dose (mg/kg/day) equations:

• Inhalation Dose (mg/kg/day) = [Concentration in water (0.027 mg/L) * Dimensionless Henry’s law constant (8.21E-07) * CF (1000 

L/m3

) * IR (0.64 m3/hr for adults and 0.32 m3/hr for children) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW (69 kg 

for adults and 19 kg for children).

• Dermal dose (mg/kg/day) = [Concentration in water (0.027 mg/L) * Permeability constant (0.00039) * Surface area (19,500 cm2 for 

adults and 7,600 cm2 for children) * Exposure time (0.1 hr for adults and 0.25 hr for children)] / BW (69 kg for adults and 19 kg for 

children).

• Incidental ingestion dose (mg/kg/day) = [Concentration in water (0.027 mg/L) * Ingestion rate (0.05 L/hr) * Exposure time (0.1 hr for 

adults and 0.25 hr for children)] / BW (69 kg for adults and 19 kg for children).

3 MOE = POD (10 mg/kg/day) ÷ Dose (mg/kg/day).

4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

Table E.5 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for NMF.

• The recommended residential exposure for use in the adult aggregate assessment reflects 

dermal and incidental oral exposures from post-application exposure to aquatic 

applications.

• The recommended residential exposure for use in the child (3 to <6 years old) aggregate 

assessment reflects dermal and incidental oral exposures from post-application exposure 

to aquatic applications.

Table E.5. Recommendations for the Residential Exposures for the NMF Aggregate Assessment.

Lifestage Exposure 

Scenario

Dose (mg/kg/day)1 MOE (LOC = 1000)2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Swimming 2.7E-7 2.06E-8 1.96E-6 2.3E-6 36,000,000 490,000,000 5,100,000 4,400,000

Child (3 to 

<6 years old) Swimming 9.7E-7 1.22E-7 1.78E-5 1.9E-5 10,000,000 82,000,000 560,000 530,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral 

(where applicable).

2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental 

Oral MOE), where applicable.
Fluridone Human Health Risk Assessment DP No. 423464

Page 81 of 83

Aggregate Exposure and Risk Assessment

Acute: There are no acute residential exposure scenarios; therefore, the acute aggregate risk is

equivalent to the acute dietary risk estimate. The acute dietary risk estimate for NMF in drinking 

water is not of concern to HED (<100% aPAD) for females 13-49 years old (the only population 

subgroup for which an acute toxicological endpoint has been identified).

Short-term: Short-term aggregate risk assessments for NMF are necessary since there is 

potential for residential exposure to NMF from the aquatic uses, and data are presented in Table 

E.6. For the short-term aggregate risk assessment, potential residential exposures were 

combined with average drinking water exposures. See Table E.5 for information on the 

residential risk estimates that are recommended for use in the aggregate assessment for NMF. 

The short-term residential exposure estimates were aggregated with the chronic dietary (drinking 

water) exposure to provide a worst-case estimate of short-term aggregate risk for adults and

children. The short-term aggregate MOEs for adults and children are greater than the LOC of 

1000 for NMF, and are therefore not of concern. 

Table E.6. Short-Term Aggregate Risk Calculations for NMF

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Drinking 

Water 

Exposure 

mg/kg/day3

Residential 

Exposure 

mg/kg/day4

Total 

Exposure 

mg/kg/day5

Aggregate 

MOE (food, 

water, and 

residential)6

Adult 10 1000 0.01 0.000125 0.0000023 0.000127 79,000

Child 10 1000 0.01 0.000324 0.000019 0.000343 29,000 1 LOC based on the standard inter- and intra-species uncertainty factors, in addition to a 10x database uncertainty factor; total UF 

= 1000. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Chronic Dietary (drinking water) exposure for females (13-49 years old) and all infants less than 1 years old (see Table E.3.). . 4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure], where applicable. 

5 Total Exposure = Average Drinking Water Exposure + Residential Exposure. 6 Aggregate MOE = [NOAEL (10 mg/kg/day)/ (Total Exposure, mg/kg/day)]. 

Intermediate-term: Intermediate-term residential exposures are not likely because of the 

intermittent residential exposure to NMF; therefore, an intermediate-term aggregate risk 

assessment is not required.

Chronic: There are no chronic residential exposure scenarios; therefore, the chronic aggregate 

risk is equivalent to the chronic dietary risk estimate. The chronic dietary (drinking water) risk

estimates for NMF are not of concern to HED (<100% cPAD) for the general U.S. population 

and all population subgroups.

Occupational Exposure and Risk Assessment

Occupational exposure to NMF is not anticipated since NMF is only suspected to form in water 

due to the photolysis of fluridone. In addition, the proposed use on cotton is for pre-plant or preemergent use; therefore, occupational post-application dermal exposures to residues on foliage 
Fluridone Human Health Risk Assessment DP No. 423464

Page 82 of 83

are not expected. For the aquatic uses of fluridone, occupational post-application exposure of 

workers to previously treated water bodies is expected to be negligible, since post-application 

activities are not anticipated for occupational workers post-treatment. 
Fluridone Human Health Risk Assessment DP No. 423464

Page 83 of 83

Addendum: Executive Summary for the Toxicity Study

Prenatal Developmental Toxicity Study – Rat and Rabbit MRID 49719001

Kelich SL, MD Mercieca, RC Pohland. 1995. Developmental toxicity of N-methylformamide 

administered by gavage to CD rats and New Zealand white rabbits. Fundam. Appl. Toxicol.

27(2): 239-246. MRID 49719001. 

N-Methylformamide (NMF) is a metabolite of dimethylformamide (DMF), a solvent with wide 

applications in the chemical industry. The potential developmental toxicity of NMF was 

evaluated in CD rats and New Zealand white rabbits. Pregnant rats and rabbits were dosed once 

daily by gavage on Gestation Days 6-15 and 6-18, respectively. Doses for rats were 0, 1, 5, 10, or 

75 mg/kg; doses for rabbits were 0, 5, 10, or 50 mg/kg. Cesarean sections were performed on rats 

and rabbits on Gestation Days 20 and 29, respectively. No treatment-related maternal deaths or 

clinical signs occurred in either species. Body weight gain and food consumption were depressed 

in rats given 75 mg/kg and rabbits given 50 mg/kg. Fetal viability was reduced at 75 mg/kg in 

rats and at 50 mg/kg in rabbits. In rats, a significant increase in the incidence of malformations 

including cephalocele and sternoschisis was observed in fetuses from the 75 mg/kg group. In 

addition, a developmental delay was indicated by reduction of fetal weight and by a significant 

increase in the occurrence of incomplete ossification of various skeletal structures. In the rabbit, 

fetal body weight was reduced at 50 mg/kg. Malformations observed at 50 mg/kg included 

gastroschisis, cephalocele, domed head, flexed paw, and skull and sternum anomalies. The 

lowest-observed-adverse-effect levels for maternal and developmental toxicity in the rat and 

rabbit were 75 and 50 mg/kg, respectively. The no-observed-adverse-effect level for maternal 

and developmental toxicity in the rat and rabbit was 10 mg/kg.