1 of 32 

 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION

MEMORANDUM

DATE: 10/13/10 

SUBJECT: Flutolanil: Human Health Risk Assessment for Flutolanil on Brassica Leafy 

Vegetables (Crop Group 5) and Turnip Greens. 

 

PC Code: 128975 DP Barcode: D370200

Decision No.: 419258 Registration No.: 10163-247

Petition No.: 856744 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical Case No.: NA

TXR No.: NA CAS No.: 66332-96-5

MRID No.: NA 40 CFR: §180.484

FROM: Kristin Rury, Risk Assessor 

 Stephen Funk, Senior Science Advisor 

Amelia Acierto, Chemist 

 Risk Assessment Branch III (RAB3) 

 Health Effects Division (7509P) 

THROUGH: Paula Deschamp, Branch Chief 

 Risk Assessment Branch III (RAB3) 

 Health Effects Division (7509P) 

TO: Barbara Madden/Laura Nollen, RM #5 

 Risk Integration, Minor Use and Emergency Response Branch (RIMUERB) 

 Registration Division (7505P) 

The Health Effects Division (HED) has conducted a human health risk assessment for the fungicide 

flutolanil to estimate the risk to human health that will result from proposed and registered uses of 

flutolanil. The Interregional Research Project No. 4 (IR-4) has submitted a petition proposing the 

establishment of permanent tolerances for Brassica (Cole) leafy vegetables (crop group 5) and turnip 

greens. 

HED has conducted a human health risk assessment for these proposed uses. This HED document 

provides a summary of the findings from the data evaluation and subsequent assessment of human 

health risk resulting from this submission. The dietary exposure assessment was conducted by 

Kristin Rury (DP#371494, 9/10/2010). The residue chemistry data were reviewed and analyzed by 

Stephen Funk (DP#381713, 9/7/2010) and Amelia Acierto (DP#371493, 5/12/2010). The drinking 
 2 of 32 

water assessment was conducted by Larry Liu (DP#370201, 7/12/2010) of OPP’s Environmental Fate 

and Effects Division (EFED).
 3 of 32 

Table of Contents 

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

2.0 Ingredient Profile..........................................................................................................................7

2.1 Summary of Registered/Proposed Uses...................................................................................7

2.2 Structure and Nomenclature ....................................................................................................8

2.3 Physical and Chemical Properties............................................................................................9

3.0 Hazard Characterization/Assessment ...........................................................................................9

3.1 Hazard and Dose-Response Characterization..........................................................................9

3.1.1 Database Summary...............................................................................................................9

3.1.3 Metabolism.........................................................................................................................10

3.1.4 Dose-Response...................................................................................................................11

3.2 FQPA Safety Factor Considerations......................................................................................11

3.2.1 Evidence of Neurotoxicity..................................................................................................11

3.2.2 Evidence of Immunotoxicity..............................................................................................11

3.2.3 Pre-and/or Postnatal Toxicity: Determination of Susceptibility .......................................11

3.2.4 Safety Factor for Infants and Children...............................................................................12

3.3 Hazard Identification and Toxicity Endpoint Selection ........................................................12

3.4 Endocrine Disruption.............................................................................................................13

4.0 Dietary Exposure/Risk Characterization ....................................................................................14

4.1 Pesticide Metabolism and Environmental Degradation.........................................................14

4.1.1 Metabolism in Primary Crops and Livestock.....................................................................14

4.1.2 Metabolism in Rotational Crops ........................................................................................15

4.1.3 Analytical Methodology.....................................................................................................15

4.1.4 Environmental Degradation ...............................................................................................16

4.1.5 Drinking Water Residue Profile.........................................................................................16

4.1.6 Food Residue Profile..........................................................................................................17

4.1.7 Proposed Tolerances and Recommended Tolerances........................................................19

4.1.8 International Residue Limits ..............................................................................................20

4.2 Dietary Exposure and Risk ....................................................................................................21

5.0 Residential (Non-Occupational) Exposure and Risk..................................................................21

6.0 Aggregate Risk Assessments and Risk Characterization ...........................................................21

7.0 Cumulative Risk Characterization/Assessment..........................................................................22

8.0 Occupational Exposure/Risk Pathway .......................................................................................22

9.0 Data Needs/Label Recommendations.........................................................................................22

9.1 Toxicology .................................................................................................................................23

9.2 Residue Chemistry ......................................................................................................................23

9.2.1 Residue Enforcement Analytical Methods ...........................................................................23

9.2.2 Proposed Tolerances .............................................................................................................23

Appendix A: Chemical Structures ...................................................................................................24

Appendix B: Toxicology.................................................................................................................26

Appendix C: Toxicology Study Requirements Rationale................................................................31
 4 of 32 

1.0 Executive Summary 

Flutolanil, N-[3-(1-methylethoxy)phenyl]-2-(trifluoromethyl)benzamide, is a systemic benzanilide 

fungicide with both preventative and curative actions against powdery scab, Spogospora 

subterranean, Rhizoctonia solani (the causal agent of limb/pod rot in peanuts), sheath blight in rice, 

black scurf in potato, wirestem in Brassica (Cole) leafy vegetables and turnip greens, and black scurf, 

Rhizoctonia solani, and crown rot in ginseng. Flutolanil is also effective in controlling white mold in 

peanuts and rust diseases in several crops. 

Flutolanil is currently registered for application to peanuts, potatoes, and rice, and as a seed treatment 

for soybean and cotton. Tolerances have been established for these commodities as well as 

tolerances for inadvertent residues for soybean and wheat commodities as rotational crops and 

tolerances for ruminant commodities. Non-food uses of flutolanil include turf, greenhouse, nursery, 

and potted ornamentals. 

Use Profile

The proposed uses on Brassica (Cole) leafy vegetables (crop group 5) and turnip greens are 

summarized in Table 2.1. These proposed uses/tolerances result in new dietary exposures. 

The flutolanil end-use product (EP) relevant to this registration action is Monocut 70-DF, EPA 

registration number 10163-301. This dry flowable (DF) formulation contains 70% active ingredient 

(ai). The flutolanil technical product relevant to this registration is Flutolanil Technical, EPA 

registration number 10163-247. 

The petitioner (IR-4) wishes to amend the product labels to incorporate new uses on Brassica (Cole) 

leafy vegetables (crop group 5) and turnip greens. 

Proposed Tolerances 

The proposed tolerances are for residues of the fungicide flutolanil and the metabolite desisopropyl, 

flutolanil (also known as M-4) in/on the following raw agricultural commodities (RACs): 

Vegetable, brassica, leafy group 5.............................. 0.11 ppm 

Turnip Greens............................................................. 0.11 ppm 

Hazard Profile 

The toxicology database is considered complete with the exception of newly required studies for 

acute neurotoxicity (OPPTS Guideline 870.6200a), subchronic neurotoxicity (OPPTS Guideline 

870.6200b), and immunotoxicity (OPPTS Guideline 870.7800). The toxicological database has been 

reviewed and is considered adequate for the overall hazard profile, endpoint selection, and 

determination of susceptibility of infants and children as required by the Food Quality Protection Act 

(FQPA). 

In general, the toxicology studies conducted on flutolanil demonstrate few or no biologically 

significant toxic effects at relatively low-dose levels in animal studies and only mild or no toxic 

effects at high doses. The subchronic and chronic toxicity studies showed that at high dose levels ( >

400 mg/kg/day) the frequently observed effects of flutolanil were liver effects (characterized by 
 5 of 32 

increased liver weight in rats and enlarged livers and hepatic glycogen deposition in dogs) and 

decreases in body weight. Flutolanil is not neurotoxic, carcinogenic, nor mutagenic. Flutolanil is 

not a developmental or reproductive toxicant at limit doses (1,000 mg/kg/day). There is no evidence 

of increased susceptibility of rat or rabbit fetuses to in utero exposure or rat pups to in utero and postnatal exposure to flutolanil. No toxic effects were observed in studies in which flutolanil was 

administered by the dermal routes of exposure. 

Only a chronic dietary endpoint was identified for flutolanil. HED selected a chronic reference dose 

(RfD) of 0.50 mg/kg/day (No Observed Adverse Effect Level (NOAEL) = 50 mg/kg/day; 

Uncertainty Factor = 100). This chronic RfD is based on the chronic oral toxicity study in dogs in 

which increased incidences of clinical signs (emesis, salivation, and soft stool) occurred following 65 

weeks of exposure. 

HED classified flutolanil as “not likely to be carcinogenic to humans” based on the absence of a 

significant tumor increase in two adequate rodent carcinogenicity studies. 

The potential for increased susceptibility of infants and children from exposure to flutolanil was 

evaluated as required by FQPA. The FQPA Safety Factor (SF) for flutolanil was reduced to 1X 

because there was no increased sensitivity to fetuses as compared to maternal animals in the 

developmental rat and rabbit studies and no increased sensitivity to pups as compared to adults in a 

multi-generation reproduction study in rats. 

Dietary Exposure 

A chronic aggregate dietary exposure and risk assessment was conducted using the Dietary Exposure 

Evaluation Model (DEEM-FCIDTM), Version 2.03, which uses food consumption data from the U.S. 

Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-

1996 and 1998. An acute dietary risk assessment was not conducted, as an acute dietary endpoint 

was not identified. 

The chronic dietary analysis included tolerance level residues, 100% crop treated (CT) estimates, and 

processing factors (default). The estimated drinking water concentration (EDWC) was incorporated 

directly into the dietary assessment (1 in 10 yr annual mean, 8.5 ppb). 

The assessment concluded that the chronic dietary exposure estimates are well below HED’s level of 

concern (<100% cPAD) for the general U.S. population and all population subgroups. The chronic 

dietary exposure is estimated for the U.S. population at 1% of the cPAD and for the most highly 

exposed population subgroup, children 1-2 years old, at 1.5% of the cPAD. 

Since toxicological endpoints have only been identified for chronic oral exposures, aggregate 

exposure and risk assessments include only chronic dietary food and water sources of exposure. The 

aggregate chronic risk estimates were below the Agency’s level of concern for all population 

subgroups. 

Occupational Exposure

Workers may be exposed to flutolanil during mixing, loading, applying, and postapplication 

activities. Based on the proposed application rates and use scenarios, short- and intermediate-term 
 6 of 32 

occupational exposures may occur. However, since short- and intermediate-term endpoints have not 

been established, an occupational exposure assessment is not required. Chronic occupational 

exposure is not expected; thus, chronic occupational exposure risk assessments are also not required. 

Under the Worker Protection Standard (WPS) for Agricultural Pesticides, active ingredients 

classified as acute Toxicity Categories III or IV for these routes are assigned a 12-hour Restricted 

Entry Interval (REI). Therefore, the 12-hour REI that appears on the proposed label is adequate. 

Residential Exposure 

No residential uses are being requested at this time. 

There are existing non-occupational/residential uses associated with flutolanil. Registered products 

include several for use on turf grass and potted ornamentals which, if not specifically prohibited 

through label directions, could be used in a residential/public site. Although potential residential 

handler and post-application exposures exist, assessments were not conducted because no dermal, 

oral (incidental), or inhalation toxicological endpoints attributable to short- or intermediate-term 

exposures have been identified, and the current use patterns do not indicate long-term exposure (6 or 

more months of continuous exposure) potential. However, should HED identify new regulatory 

endpoints for risk assessment purposes for flutolanil in the future, then non-occupational/residential 

exposures may need to be assessed.

Conclusions

HED recommends for the establishment of tolerances for Brassica (Cole) leafy vegetables (crop 

group 5) and turnip greens. Residues from the field trials were determined by a data collection 

method that might understate the residue by measuring only flutolanil and its metabolite M4. In the 

case of the dataset for these crops, HED believes the tolerances are adequate for Brassica (Cole) leafy 

vegetables. A confined rotational crop study indicated that residues in lettuce, a crop similar to the 

Brassica (Cole) leafy vegetables, determined by the enforcement method (common moiety) were 

0.08 ppm. This is in agreement with the results of the subject field trials, where the combined 

residues of flutolanil and its metabolite, M4, were <0.1 ppm. 

There are no residue chemistry, toxicology, and/or exposure issues that would preclude granting 

tolerances and registrations for the requested use of flutolanil on Brassica (Cole) leafy vegetables 

(crop group 5) and turnip greens. However, registrations should be made conditional pending 

adequate resolution of issues associated with the fulfillment of new toxicology data requirements. 

Recommended Tolerances Including Revisions to Petitioned For Tolerances 

HED recommends modification of the tolerance expressions for flutolanil according to the new 

compliance/measurement policy (Interim Guidance on Tolerance Expressions, Steve Knizner, May 

27, 2009) to read as follows: 

“HED recommends that the tolerance definition entry in 40 CFR 180.484 be revised as follows: 

(a) General. Tolerances are established for residues of the fungicide flutolanil, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only flutolanil and its metabolites 

converted to 2-(trifluoromethyl) benzoic acid and calculated as flutolanil, in or on the commodity. 
 7 of 32 

Vegetable, brassica, leafy group 5.............................. 0.11 ppm 

Turnip Greens............................................................. 0.11 ppm 

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.eh.doe.gov/oepa/guidance/justice/eo12898.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 USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) 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, nondietary 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 postapplication 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. 

EPA Review of Human Research 

Occupational and residential exposure analyses were considered unnecessary. Therefore, this risk 

assessment does not rely on data from Pesticide Handlers Exposure Database (PHED) and Outdoor 

Residential Exposure Task Force (ORETF) studies in which adult human subjects were intentionally 

exposed to a pesticide or other chemical. 

2.0 Ingredient Profile 

 2.1 Summary of Registered/Proposed Uses 

Flutolanil is currently registered for application to peanuts, potatoes and rice and for use as a soybean 

and cotton seed treatment. This petition is associated with a FIFRA Section 3 amendment of the 

registration of the EP, Moncut® 70DF Fungicide (EPA Reg. No. 10163-301), a DF formulation 

containing 70% flutolanil to include new uses on Brassica (Cole) leafy vegetables crop group 5, and 

turnip greens as a single in-furrow spray over the seeds at the time of seeding or as directed spray at 

the base of the transplants at the time or immediately after transplanting at the rate of 0.70 – 0.75 lb 

ai/A. All applications are to be made using ground equipment. The use of adjuvant is prohibited. 

The use of flutolanil is at-plant or at-transplant and is not related to a specific preharvest interval 

(PHI), as reflected in the wide preharvest intervals of 56-106 days for mature broccoli flower heads, 

62-138 days for mature cabbage heads, and 31-63 days for mustard greens in the field trials. 
 8 of 32 

Maintenance pesticides and fertilizers are proposed as necessary to produce commercial quality 

crops. The proposed use directions for flutolanil as an in-furrow or directed spray to transplants for 

Brassica (Cole) leafy vegetables and turnip greens are presented in Table 2.1. 

Table 2.1. Summary of Directions for Use of Flutolanil 

Trade 

Name 

Application 

Timing 

Application 

Rate 

(lb ai/A) 

Max. No. 

Applic. 

per Season

RTI1

(days) 

Max. Seasonal 

Applic. Rate 

(lb ai/A) 

PHI2

(days) 

Use Directions and other 

Limitations3

Brassica (Cole) Leafy Vegetables Crop Group 5, and Turnip Greens. 

Moncut ® 

70DF 

in-furrow at 

planting or 

directed spray 

at the base of 

transplants at 

time of 

transplant or 

immediately 

after 

transplanting 

0.77 1 none 0.70 – 0.78 Not 

specified

Applications to be made in a 

minimum of 3 gal/A using 

ground equipment. 

Do not use adjuvant 

1

RTI = retreatment interval 

2

PHI = preharvest interval 

3

Use of oil as carrier or addition of other additives to the finished spray is prohibited. 

 2.2 Structure and Nomenclature 

The nomenclature of flutolanil is summarized in Table 2.2. 

Table 2.2. Flutolanil Nomenclature

Chemical structure 

N

H

O

CH3

CH3

O

CF3

Common name Flutolanil 

Company experimental name N/A 

IUPAC name α,α,α-trifluoro-3’-isopropoxy-o-toluanilide 

CAS name N-[3-(1-methylethoxy)phenyl]-2-(trifluoromethyl)benzamide 

CAS registry number 66332-96-5 

End-use product (EP) Moncut 70 DF SC Fungicide (70%% flutolanil); EPA Reg. No. 10163-301) 

Chemical structure of 

common moiety determined 

by enforcement method 

O

CF3

OH

2-trifluoromethylbenzoic acid (2-TFBA) 
 9 of 32 

 2.3 Physical and Chemical Properties 

The physicochemical properties are summarized in Table 2.3. The chemical names and structures of 

flutolanil and its transformation products are presented in Appendix A.

Table 2.3.1. Physicochemical Properties of Flutolanil. 

Parameter Value Reference 

Melting range 100.4-103.8 °C 

pH 5.69 

Density 1.325 @ 20-25

Water solubility 6.53 mg/L at 20 °C 

Solvent solubility at 20 °C 

Methanol 232 g/L 

n-Hexane 0.9 g/L 

Vapor pressure 4.87 x 10-8 mm Hg at 25 °C 

Dissociation constant, pKa Not applicable 

Octanol/water partition 

coefficient, Log(KOW) 

log POW = 3.74 

DP#s 190584 and 190586, 3/24/94, 

J. Garbus; MRID 42606601 

UV/visible absorption spectrum Not available 

3.0 Hazard Characterization/Assessment 

3.1 Hazard and Dose-Response Characterization 

3.1.1 Database Summary 

A summary of the hazard assessment of flutolanil is provided below. Additional details may be 

found in the 2000 Human Health Risk Assessment (A. Lowit, DP#268880, 9/11/00) and the 2007 

Human Health Risk Assessment (F. Fort, DP#335050, 11/27/07). The acute toxicity of flutolanil 

technical is summarized in Appendix B (Table B.1.) and the toxicity profile of flutolanil is shown in 

Appendix B (Table B.2.). The following study types were considered. 

• Subchronic: 21-day dermal toxicity (rat), 90-day oral toxicity (rat, dog), 

• Developmental: rat and rabbit developmental toxicity studies (rat, rabbit), 

• Reproduction: two-generation reproduction study (rat), 

• Chronic: oral chronic toxicity (dog), combined chronic toxicity/carcinogenicity (rat), 

carcinogenicity (mouse), and 

• Other: mutagenicity battery, metabolism. 

As there are no new toxicity data associated with this current action, the hazard characterization and 

endpoint selection from the previous risk assessment can be applied directly to this action. 

The existing flutolanil database is considered adequate for hazard characterization, endpoint 

selection, and assessment. However, the revised Toxicology Data Requirements for Conventional 
 10 of 32 

Pesticides [40 CFR §158.340] now include studies which are better able to detect any potential 

immunotoxicity or neurotoxicity. These new study requirements are: 

• Acute neurotoxicity [OPPTS Guideline 870.6200a], 

• Subchronic neurotoxicity [OPPTS Guideline 870.6200b], and 

• Immunotoxicity [OPPTS Guideline 870.7800]. 

 

For flutolanil, the above studies are not available, and they are required under the new rule. 

Based on the available toxicity database and the Agency's current practices, the inhalation risk for 

flutolanil was not assessed. The Agency may, as appropriate, re-examine and develop new policies 

and procedures for conducting inhalation risk assessments. If any new policies or procedures are 

developed, the Agency may revisit the need for an inhalation toxicity study for flutolanil and/or reexamine the inhalation toxicity risk assessment. 

 3.1.2 Toxicological Effects

The toxicology studies conducted on flutolanil demonstrate few or no biologically significant toxic 

effects. Liver effects in rats included increases in absolute and relative liver weight in the absence of 

clinical chemistry and/or histopathology findings. In dogs, there was an elevation in alkaline 

phosphatase and cholesterol levels together with dose-related increases in absolute and relative liver 

weights, slightly enlarged livers, and an increase in severity of glycogen deposition. The increased 

liver weights are considered to be an adaptive response to flutolanil treatment and not an adverse 

effect. Based on the lack of evidence of carcinogenicity and the lack of evidence of mutagenicity, 

flutolanil is classified as “not likely to be carcinogenic to humans.” 

Evaluation of the available data for flutolanil did not reveal any clinical signs, clinical chemistry 

changes, and/or histopathology to indicate that it is neurotoxic or that it targets the immune system. 

It is not a developmental or reproductive toxicant. No maternal, reproductive, or developmental 

toxicity was observed at the limit dose (1000 mg/kg/day). There was no evidence for increased 

susceptibility of rat or rabbit fetuses to in utero exposure or rat pups to post-natal exposure to 

flutolanil. No toxic effects were observed in studies in which flutolanil was administered by the 

dermal route of exposure at the limit dose. Further, there is no developmental or reproductive concern 

at dose levels that do not exceed the limit dose. For these reasons, it is concluded that no short-term, 

intermediate-term, or long-term dermal risk assessment is required. 

3.1.3 Metabolism 

The available metabolism data show that with single dose oral administration, flutolanil is not 

completely absorbed and 40% of the administered radioactivity was eliminated in urine and similar 

percentage was eliminated in feces. With repeated dosing, absorption was improved as shown by 

70% of the administered dose eliminated in urine, while approximately 30% in feces. The absorbed 

flutolanil was eliminated rapidly in the urine and the majority of the urinary elimination occurred 

within 24 hours post dose. There was no appreciable concentration remaining in any tissue. The 

major metabolite was reported to be M-4. The parental chemical was found to account for the 

majority of the radioactivity eliminated in the feces. 
 11 of 32 

3.1.4 Dose-Response 

The HED flutolanil risk assessment team previously reevaluated the flutolanil database and 

reaffirmed the lack of an appropriate endpoint for the acute RfD and reduction of the FQPA safety 

factor to 1X. Previous (HED) risk assessments utilized a cRfD of 0.87 mg/kg/day based on the 2-

year combined chronic toxicity/carcinogenicity study in rats (Hazard Identification Assessment 

Review Committee (HIARC) October 14, 1999). However, more recently the team identified an 

endpoint from the 2-year chronic dog study as providing a more appropriate endpoint for the chronic 

RfD. This is based on the conclusion that the liver effects are considered to be an adaptive, nonadverse response in the absence of clinical chemistry or histopath findings (chronic rat study). In the 

chronic dog study, the increased incidence of clinical signs (emesis, salivation, and soft stool) at 250 

mg/kg/day (LOAEL) occurred following 65 weeks of exposure. The flutolanil risk assessment team 

then selected a chronic RfD of 0.5 mg/kg/day (NOAEL of 50 mg/kg/day; 10X interspecies factor; 

10X intraspecies factor; 1X FQPA SF). 

No adverse effects were identified from oral or dermal exposure for dosing up to 90 days. In a 90 

day oral dosing of rats study, no treatment-related changes in ophthalmoscopic, hematological, 

clinical chemistry, gross pathology, or histopathology parameters were observed. A 21-day rat 

dermal study showed a systemic LOAEL of 1000 mg/kg/day (limit dose). There is no appropriate 

endpoint for either short-term or intermediate-term incidental oral assessment based on the lack of 

adverse effects following these exposure durations. 

3.2 FQPA Safety Factor Considerations

The database for flutolanil is adequate for FQPA consideration. 

3.2.1 Evidence of Neurotoxicity 

A thorough evaluation of the available toxicology database on flutolanil (including open literature) 

revealed no clinical signs, clinical chemistry changes, organ weights, and histopathology indicating 

possible neurotoxicity. Included were studies conducted at high doses between 500 mg/kg/day and a 

1000 mg/kg/day dose (limit dose), where signs of neurotoxicity were not detected. Based on this 

analysis, a database uncertainty factor (UF) is not needed to account for the missing neurotoxicity 

studies on flutolanil at this time. 

3.2.2 Evidence of Immunotoxicity 

None of the available submitted or open literature studies suggested that flutolanil produces 

hematological effects, effects on the thymus or spleen indicative of potential immunotoxicity. In 

addition, in most of the repeated oral dosing studies, flutolanil did not produce any adverse effects at 

the limit dose (1000 mg/kg). At this time, a database uncertainty factor is not needed to account for 

the missing immunotoxicity study. 

3.2.3 Pre-and/or Postnatal Toxicity: Determination of Susceptibility 

There is no evidence of increased susceptibility. There was no increased sensitivity to fetuses as 

compared to maternal animals in the developmental rat and rabbit studies and no increased sensitivity 

to pups as compared to adults in a multi-generation reproduction study in rats. 
 12 of 32 

3.2.4 Safety Factor for Infants and Children 

There was no evidence of increased susceptibility of rat or rabbit fetuses to in utero exposure or rat 

pups to post-natal exposure to flutolanil. Flutolanil is not a developmental or reproductive toxicant. 

No maternal, reproductive, or developmental toxicity was observed at the limit dose. 

EPA has determined that reliable data show the safety of infants and children would be adequately 

protected if the FQPA SF were reduced to 1X. That decision is based on the following findings: 

1. The toxicity database for flutolanil is complete except for acute and subchronic neurotoxicity 

and immunotoxicity studies. Recent changes to 40 CFR part 158 make acute and subchronic 

neurotoxicity testing (OPPTS Test Guideline 870.6200), and immunotoxicity testing (OPPTS 

Test Guideline 870.7800) required for pesticide registration. However, the available data for 

flutolanil do not suggest that the compound produces hematological or thymus/spleen organ 

effects indicative of immunotoxicity. Further, there is no evidence of neurotoxicity in any 

study in the toxicity database for flutolanil. Therefore, EPA does not believe that conducting 

neurotoxicity and immunotoxicity studies will result in a NOAEL lower than the NOAEL of 

50 milligrams/kilogram/day (mg/kg/day) already established for flutolanil. Consequently, an 

additional database UF does not need to be applied. 

2. There is no indication that flutolanil is a neurotoxic chemical and there is no need for a 

developmental neurotoxicity study or additional UFs to account for neurotoxicity. 

3. There is no evidence that flutolanil results in increased susceptibility in in utero rats or rabbits 

in the prenatal developmental studies or in young rats in the 2-generation reproduction study. 

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

exposure assessments were performed based on 100% CT and tolerance-level residues. EPA 

made conservative (protective) assumptions in the ground water and surface water modeling 

used to assess exposure to flutolanil in drinking water. Residential exposure does not pose a 

concern for flutolanil because (1) chronic residential exposure is not expected; and (2) 

although short-term or intermediate-term residential exposure may occur, no relevant adverse 

effects were identified for dermal, incidental oral, or inhalation exposure related to residential 

use. These assessments will not underestimate the exposure and risks posed by flutolanil. 

3.3 Hazard Identification and Toxicity Endpoint Selection 

The toxicity endpoints and doses for risk assessment were selected based upon the available toxicity 

data and the use exposure information on flutolanil. The toxicological doses and endpoints selected 

for various exposure scenarios are summarized in Table 3.3. 
 13 of 32 

Table 3.3. Summary of Toxicological Doses and Endpoints for Flutolanil for Use in Dietary and NonOccupational Human Risk Assessments 

Exposure 

Scenario 

Point of 

Departure 

Uncertainty/ 

FPQA 

Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

 Acute Dietary 

(All populations) 

No appropriate toxicological endpoint attributable to a single exposure (dose) was identified 

from the oral toxicity studies including developmental toxicity studies in rats and rabbits. This 

risk assessment is not required. 

Chronic Dietary 

(All populations) 

NOAEL= 

50 

mg/kg/day 

 

UFA=10X 

UFH=10X 

FQPA SF =

1X 

cRfD = 

0.5 mg/kg/day 

cPAD = 

0.5 mg/kg/day 

2-year Chronic study in dogs. 

MRID no. 40342922 

LOAEL = 250 mg/kg/day based on increased 

incidence of clinical toxic signs (emesis, 

salivation, and soft stool) 

Incidental Oral, 

Short- and 

Intermediate-Terms; 

Dermal and 

Inhalation, Short 

and intermediate 

terms 

No appropriate endpoint was identified in the database for these durations of exposure. 

Dermal and 

Inhalation 

Long-term 

The current use pattern does not indicate long-term inhalation exposure potential. 

Cancer (oral, 

dermal, inhalation) 

Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant 

tumor increases in two adequate rodent carcinogenicity studies. 

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). RfD = reference dose. MOE = margin of exposure. LOC = 

level of concern. PAD = Population adjusted dose. 

3.4 Endocrine Disruption 

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening 

Program (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, and 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 
 14 of 32 

related effects caused by the substance, and establish a dose-response relationship between the dose 

and the E, A, or T effect. 

 

EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide 

active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential 

for human exposure through pathways such as food and water, residential activity, and certain postapplication agricultural scenarios. This list should not be construed as a list of known or likely 

endocrine disruptors. 

Flutolanil is among the group of 58 pesticide active ingredients on the initial list to be screened under 

the EDSP. The Agency will review the EDSP Tier 1 data and any “other scientifically relevant 

information” submitted in response to test orders. Based on this review the Agency will determine 

the need for additional testing. For further information on the status of the EDSP, the policies and 

procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit 

our website: http://www.epa.gov/endo/. 

4.0 Dietary Exposure/Risk Characterization 

References: 

Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the 

Section 3 Registration Action (Brassica Leafy Vegetables, Crop Group 5). K. Rury, DP#371494, 

9/10/10. 

Petition for Establishment of Tolerances for Use on Brassica (Cole) Leafy Vegetables Crop Group 5 

and Turnip Greens. Summary of Analytical Chemistry and Residue Data. A. Acierto, DP#371493, 

5/12/10. 

Petition for Establishment of Tolerances for Use on Brassica (Cole) Leafy Vegetables Crop Group 5 

and Turnip Greens. Summary of Analytical Chemistry and Residue Data. S. Funk, DP#381713: 

Revision of DP# 371493, 9/07/10. 

Estimated Environmental Concentrations (EECs) of Flutolanil on Sugar Beets, Brassica Leafy 

Vegetables, Turnip Greens, and Ginseng. L. Liu, D370201, DP#376798, 7/21/10. 

4.1 Pesticide Metabolism and Environmental Degradation 

4.1.1 Metabolism in Primary Crops and Livestock 

No new plant metabolism data were submitted in conjunction with the subject petitions. The nature 

of the residue in plants is adequately understood based on acceptable metabolism studies submitted 

previously on rice, cucumber leaves, and peanuts. Flutolanil is metabolized via O-deisopropylation, 

hydroxylation, and methylation to yield N-(3'-hydroxyphenyl)-2-(trifluoromethyl)benzamide (M4), 

and N-(4'-hydroxy-3'-methoxy)phenyl-2-(trifluoromethyl)benzamide (M7). Most of the metabolites 

are found bound or conjugated. The major identified components in plants were parent and 

metabolite M4. HED’s Metabolism Committee concluded that the parent compound and metabolites 

containing the common moiety, 2-trifluoromethyl benzanilide, need to be included in the tolerance 

expression. 
 15 of 32 

No livestock metabolism data were submitted in conjunction with the subject petition since there are 

no livestock feed commodities associated with the proposed uses. 

See Appendix A for chemical structures of flutolanil and metabolites. 

4.1.2 Metabolism in Rotational Crops 

The nature of the residue in rotational crop commodities is adequately understood based on an 

acceptable confined rotational crop study with lettuce, radish, and oat/sorghum conducted with [U14C-aminophenoxy]flutolanil. The major residue components were flutolanil and metabolites M-4 

and M-5 (N-[3',4'-(dihydroxy)phenyl]-2- (trifluoromethyl)benzamide). The residues of concern for 

tolerance expression and dietary risk assessment for rotational crops are flutolanil and metabolites 

containing the common moiety, 2-trifluoromethyl benzanilide. 

4.1.3 Analytical Methodology 

A gas chromatography-mass spectrometry (GC/MS) enforcement method (AU/95R/04) originally 

submitted by AgrEvo USA Company has undergone a successful independent validation with 

nutmeat, peanut and hay, rice grain, milk, eggs, beef muscle, and beef fat. The method was found 

adequate for data collection based on acceptable recovery data. Method AU/95R/04 analyzes for the 

flutolanil residues of concern for tolerance expression and risk assessment. However, it was noted 

that a confirmatory method is required because the method is a common moiety method. In addition, 

HED noted that the method must be rewritten to include instructions for analysis of additional crops 

including cotton and soybeans. 

Nichino America submitted a liquid chromatography-mass spectrometry (LC/MS/MS) method XAM65 as a data collection method and proposed this method to replace the AU/95R/04 enforcement 

method. The proposed XAM-65 method was not found acceptable as a data collection method and 

not suitable as a replacement for the enforcement method because it may not determine the flutolanil 

residues of concern for the tolerance expression and dietary risk assessment. The AU/95R/04 

analytical method would be expected to determine higher residues of flutolanil-derived residues, 

since it determines all metabolites converted to 2-TFBA (including M-2, M-3, and M-7 (Appendix 

A)) in addition to flutolanil and M-4 (F. Fort, DP#335050, 11/26/07). Method XAM-65 is acceptable 

as a confirmatory enforcement method (S. Funk, DP#364462, 01/25/10). 

HED recommends for the establishment of tolerances for Brassica (Cole) leafy vegetables (crop 

group 5) and turnip greens. Although residues from the field trials were determined by a data 

collection method that in general might understate the residue by measuring only flutolanil and its 

metabolite M4, in the case of the data set for these crops HED believes the tolerances are adequate 

for Brassica (Cole) leafy vegetables. The use is at-plant/at-transplant to the soil and is therefore very 

similar to the conditions of a rotational crop trial. A confined rotational crop study indicated that 

residues in lettuce, a crop similar to the Brassica (Cole) leafy vegetables, determined by the 

enforcement method (common moiety) were 0.08 ppm. This is in agreement with the results of the 

subject field trials, where the combined residue of flutolanil and metabolite M4 were <0.1 ppm. 

Flutolanil was proposed for use on ginseng but ginseng has been removed from the revised Section F. 

HED notes for possible future requests that ginseng samples must be analyzed by the common moiety 
 16 of 32 

method. Other acceptable approaches would be (1) to demonstrate that the common moiety method 

(AU/95R/04) and the LC/MS/MS method XAM-65 yield similar quantitative results on a variety of 

crop matrices with incurred residues; OR (2) to demonstrate that method XAM-65 modified to use 

the extraction solvents of the plant metabolism studies, including a new extract hydrolysis step gives 

similar results as unmodified method XAM-65. 

4.1.4 Environmental Degradation 

Flutolanil has a very low solubility, has a low propensity to volatilize, is resistant to hydrolysis, and 

practically resistant to photolysis. Flutolanil is relatively resistant to aerobic and anaerobic 

degradation in soils and aquatic environments with half-lives of more than 200 days in soils and 

greater than one year in water. 

Flutolanil and the most significant transformation product DIP (desisopropyl flutolanil) do have the 

potential to leach based on their Koc values. Flutolanil and its degradate DIP, may be transported to 

surface water through erosion of soil particles containing bound residues or dissolved in runoff water. 

In all fate studies, no major transformation products were identified. In the aerobic soil metabolism 

study, three minor degradates were identified. 3'-hydroxy- 2-trifluoromethyl-benzanilide (DIP) was 

formed at no more than 3% of the applied. Two other degradates were formed in minor amounts 

(<1%): 3'-methoxy-2-trifluoromethyl-benzanilide (MDP) and 4'-hydroxy-3-methoxy-2-

trifluoromethyl-benzanilide (HMD). Flutolanil was observed to degrade faster under anaerobic 

conditions during the flooded stage of the study. Two minor degradates not identified under aerobic 

conditions were observed: 3'-(hydroxymethy1ethoxy)-2-trifluoromethyl-benzanilide (HIP) and 4'-

hydroxy-3'-isopropoxy-2-triflouromethyl-benzanilide (HFT). 

4.1.5 Drinking Water Residue Profile 

There is no established Maximum Contaminant Levels for residues of flutolanil in drinking water. 

No health advisory levels for flutolanil in drinking water have been established. 

EFED does not have monitoring data available to perform a quantitative drinking water risk 

assessment for flutolanil at this time. Therefore, the Agency is presently relying on computergenerated estimated drinking water concentrations (EDWCs). Ground and surface water exposure 

estimates for use of flutolanil on rice were provided by EFED (L. Liu, D3702101, D376798, 

7/21/2010). For surface water and ground water, EDWCs were generated from Pesticide Root Zone 

Model and Exposure Analysis Modeling System (PRZM-EXAMs) and from a Tier I Screening 

Concentration In Ground Water (SCI-GROW) analysis, respectively. At the time the EDWCs were 

generated, flutolanil was proposed for use on sugar beets, Brassica (Cole) leafy vegetables, turnip 

greens and ginseng, with the highest application rate for flutolanil proposed on ginseng. The mean 

surface water concentration of 8.5 ppb from application to ginseng was entered as a conservative 

point estimate in the chronic residue file editor for DEEM-FCIDTM. While the proposed use of 

flutolanil on ginseng has been withdrawn, the drinking water analysis incorporating the use of 

flutolanil on ginseng was used in the dietary assessment as a conservative, screening level analysis. 
 17 of 32 

Table 4.1.5. Summary of Estimated Surface Water and Ground water Concentrations for Flutolanil.

Scenario Surface Water Conc., ppb a Ground water Conc., ppb b

Acute 12.7 

Chronic (non-cancer) 8.5 

0.7 

a

 From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on ... 

b

 From the SCI-GROW model. 

4.1.6 Food Residue Profile 

IR-4 has submitted magnitude of residue data for cabbage, mustard greens, broccoli and ginseng in 

support of the requested uses and proposed tolerances. The results from these studies are 

summarized below: 

Cabbage (MRID#47832601) 

IR-4 submitted crop field data for cabbage from nine field trials conducted in the United States 

during the 2005 growing season. Mature cabbage heads were harvested 62-138 days after treatment 

and analyzed for residues of flutolanil [N-[3-(1-methylethoxy)-phenyl]-2-(trifluoromethyl)-

benzamide] and its metabolite M-4 [N-(3’hydroxyphenyl)-2-(trifluoromethyl)bezamide]. Adequate 

storage stability data are available to support the storage conditions and durations of the cabbage field 

samples. No residues of flutolanil or M-4 were detectable in any of the treated field samples above 

the calculated lowest level of method validation (LLMV) (0.05 ppm) following 62-138 days after 

treatment. No residues were found in any of the untreated control samples. 

Mustard Greens (MRID#47832602)

IR-4 submitted crop field trial data on mustard greens from 10 trials conducted during the 2006 

growing season. The number and geographical distribution of the supervised field trials on mustard 

greens are adequate. The storage stability data are also adequate to support the storage conditions 

and durations of the field samples. No residues of flutolanil or metabolite M-4 were detectable above 

the LLMV (0.05 ppm) in any of the treated samples except samples from the California trial (CA67) 

where 0.05 and 0.06 ppm of flutolanil were found in 2 treated samples. 

Broccoli (MRID#47832602)

IR-4 submitted crop field trial data on broccoli from 11 field trials conducted across the United States 

during the 2006 growing season. The number and geographical distribution of the supervised field 

trials on broccoli are adequate. 

Residues of flutolanil or metabolite M-4 were not detected above the LLMV (0.05 ppm) in any of the 

treated and untreated samples except samples from the Ohio trial (OH*11) where ~0.02 ppm 

flutolanil residue was found in the control sample and apparent residues at or below the calculated 

LOD (0.01 and 0.009 ppm) were found in the treated samples. 

 No residues of flutolanil or metabolite M-4 were detectable above the LLMV in any of the treated 

samples or untreated samples except for the samples from Ohio (OH#11) where apparent flutolanil 

residues of 0.02 ppm were found in the untreated control and 0.01 and 0.009 ppm in the treated 

samples. 
 18 of 32 

The available data are adequate to support the sample storage conditions and intervals from the 

broccoli field trials. 

Ginseng (MRID#47832602)

IR-4 submitted crop field trial data on ginseng from 3 field trials in Wisconsin during the 2006 

growing season. 

Flutolanil residues in the treated samples ranged from 0.65 – 2.17 ppm. Residues of M-4 were not 

detected above the LLMV (0.05 ppm) in any of the treated samples except in one treated sample 

(MI17 trial) where apparent residues of about 0.02 ppm were found. No detectable residues were 

found in the untreated samples except for a sample that was verified to have been switched. 

The available data are adequate to support the sample storage conditions and intervals for ginseng 

roots. 

Field Trials

Table 4.1.6 summarizes the residue data in the field trials of flutolanil on cabbage, mustard greends, 

broccoli and ginseng. 

TABLE 4.1.6. Summary of Residue Data on Cabbage, Mustard Greens, Broccoli and Ginseng Field 

 Trials with Flutolanil.

Commodity Total Applic. Residue Levels (ppm)

Rate 

 (lb ai/A) 

PHI 

(days) 

Analyte 

n Min. Max. HAFT1 Median 

(STMdR) 

Mean 

(STMR)

Std. 

Dev. 

Flutolanil 18 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA 2 Cabbage 0,72 – 0.788 62 - 

138 M-4 18 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA 

 Total <0.10 <0.10 <0.01 <0.05 <0.05 NA 

Greens, Flutolanil 20 < 0.05 < 0.05 0.06 < 0.05 < 0.055 0/007 

Mustard 

0,195– 0.784 31 - 

63 M-4 20 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA 

 Total 20 <0.1 <0.11 <0.11 <0.1 <0.105 NA 

Broccoli 0,411 – 0.775 54 - Flutolanil 23 < 0.05 < 0.05 <0.05 < 0.05 < 0.05 NA 

106 M-4 22 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA 

 Total 20 <0.1 <0.1 <0.1 <0.01 <0.1 NA 

Ginseng 0,674 – 0.717 61 Flutolanil 6 0.65 2.17 1.80 1.25 1.28 0.52 

M-4 6 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA2

 Total 6 <0.07 <2.22 <1.85 <1.30 <1.32 NA 

1 HAFT = Highest Average Field Trial. 

2

 NA = not applicable. 

For the requested minor uses on Brassica (cole) leafy vegetables (crop group 5), turnip greens, and 

ginseng (in the original request), there was a major issue that precluded granting Section 3 

registration of Moncut® 70DF and permanent tolerances for the proposed crops (A. Acierto, 

DP#371493, 5/12/2010). The data collection method used determines flutolanil (M1) and metabolite 

M4 only and may not adequately determine the total residue as currently defined for tolerance 

enforcement. The current residue definition includes flutolanil and all metabolites converted to the 

common moiety 2-trifluoromethyl benzanilide via harsh base hydrolysis of the extract. 
 19 of 32 

The at-plant trials with cabbage, broccoli, and mustard greens yielded residues of <0.05 ppm each of 

flutolanil and M4, or <0.1 ppm total. 

Although the total residue as defined for tolerance enforcement was not determined, there is 

supplemental information that demonstrates that for the Brassica (Cole) leafy vegetables situation the 

residues will be below the limit of quantitation of the data collection method (<0.10 ppm). In a 

confined rotational crop study (G. Kramer, DP#193608, 08/03/1993), aminophenoxy-ring-labeled 

14C-flutolanil was applied to soil at a rate of 2.4 lb ai/A. Lettuce, a leafy vegetable, was seeded into 

the treated soil 30 days later. At normal harvest, the extractable TRR of the lettuce leaves was 0.09 

ppm, including 0.03 ppm free and 0.05 ppm conjugated radiolabeled residue. Analysis of the lettuce 

by the common moiety enforcement method yielded 0.08 ppm. This is comparable to the proposed atplant use of flutolanil for Brassica (Cole) leafy vegetables and turnips, where flutolanil is applied infurrow at seeding at a rate of 0.78 lb ai/acre or to the base of transplants at 0.78 lb ai/acre. Thus, the 

results of the Brassica (Cole) leafy vegetable field trials with residues <0.10 ppm and the confined 

rotational crop study with residues of 0.08 ppm are in agreement. 

Storage Stability 

Storage stability data submitted previously are adequate to support the sample storage conditions and 

intervals for cabbage, mustard greens, broccoli and ginseng roots submitted in conjunction with this 

petition. However, the petitioner is reminded that zero-day data should be submitted in future 

petitions as required in Guideline OPPTS 860.1300. 

4.1.7 Proposed Tolerances and Recommended Tolerances 

HED previously concluded that the residues of concern for tolerance expression and dietary risk 

assessment for crops are flutolanil and metabolites containing the common moiety, 2-trifluoromethyl 

benzanilide. HED recommends modification of the tolerance expressions for flutolanil according to 

the new compliance/measurement policy (Interim Guidance on Tolerance Expressions, Steve 

Knizner, May 27, 2009) to read as follows: 

“HED recommends that the tolerance definition entry in 40 CFR 180.484 be revised as follows: 

(a) General. Tolerances are established for residues of the fungicide flutolanil, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only flutolanil and its metabolites 

converted to 2-(trifluoromethyl) benzoic acid and calculated as flutolanil, in or on the commodity. 

Table 4.1.7. Tolerance Summary for Flutolanil 

Commodity Proposed Tolerance 

(ppm) 

Recommended 

Tolerance (ppm) 

Comments 

Correct Commodity Definition

Brassica leafy vegetables 

(crop group 5), 0.11 0.1 

Turnip greens 0.11 0.1 

Until the regulations have been 

finalized in the Federal Register to 

move turnip greens from the leaves 

of root and tuber vegetables crop 

group (group 2) to the Brassica leafy 

greens subgroup 5B, a separate 
 20 of 32 

Table 4.1.7. Tolerance Summary for Flutolanil 

Commodity Proposed Tolerance 

(ppm) 

Recommended 

Tolerance (ppm) 

Comments 

Correct Commodity Definition

tolerance is needed at the same level 

as the Brassica Leafy Greens, 

subgroup 5B.1

1 Memorandum, B. Schneider, 6/14/02. 

4.1.8 International Residue Limits 

Codex Maximum Residue Limits (MRLs) are established for residues of flutolanil in rice 

commodities at 1-10 ppm, and in livestock commodities at 0.05-0.2 ppm. No Canadian or Mexican 

MRLs have been established.
 21 of 32 

4.2 Dietary Exposure and Risk 

A chronic dietary exposure assessment (using tolerance-level residues and assuming all crops are 

treated (100 %CT) and using default concentration factors for processed commodities) was 

conducted for the general U.S. population and various population subgroups. The results reported in 

Table 4.2 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. Tolerance-level 

residues, 100 % CT, and DEEMTM 7.81 default processing factors were used to determine the chronic 

dietary exposure and risk estimates. This assessment showed that for all included commodities, the 

chronic risk estimates were below the Agency’s level of concern (<100% cPAD) for the general U.S. 

population (<1% of the cPAD) and all population subgroups (<2% cPAD) listed in Table 4.2. The 

most highly exposed population subgroup was children 1 – 2 years of age at 1.5% of the cPAD. 

Table 4.2 Summary of Dietary (Food and Drinking Water) Exposure and Risk for 

 Flutolanil 

Chronic Dietary 

Population Subgroup Dietary Exposure 

(mg/kg/day) % cPAD 

General U.S. Population 0.003127 <1 

All Infants (< 1 year old) 0.007005 1.4 

Children 1-2 years old 0.007530 1.5 

Children 3-5 years old 0.006337 1.3 

Children 6-12 years old 0.004258 <1 

Youth 13-19 years old 0.002850 <1 

Adults 20-49 years old 0.002818 <1 

Adults 50+ years old 0.001964 <1 

Females 13-49 years old 0.002418 <1 

5.0 Residential (Non-Occupational) Exposure and Risk 

There are non-occupational uses associated with flutolanil. Non-occupational handlers may mix, 

load and apply flutolanil products to turf grass. Although residential (non-occupational) exposure 

exists, an assessment was not conducted since no toxicological endpoint attributable to short- or 

intermediate-term route of exposure have been identified, and the current use pattern does not 

indicate long-term exposure (6 or more months of continuous exposure) potential. 

6.0 Aggregate Risk Assessments and Risk Characterization 
 22 of 32 

In accordance with the FQPA, the Agency must consider aggregate 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, the Agency considers both the route and 

duration of exposure. In the case of flutolanil, aggregate risk assessments were performed for chronic 

aggregate exposure (food + drinking water) only. Short- and intermediate-term aggregate risk 

assessments were not performed because toxicological endpoints from dermal and inhalation 

exposures were not identified. Additionally, the Agency does not expect residential exposure 

durations that would result in long term exposures. A cancer aggregate risk assessment was also not 

performed because flutolanil is not carcinogenic. 

The chronic aggregate risk assessment takes into account average exposure estimates from dietary 

consumption of flutolanil (food and drinking water) and residential uses. However, due to the use 

patterns, no chronic residential exposure is expected. Therefore, the chronic aggregate risk 

assessment will consider exposure from food and drinking water only. The chronic dietary exposure 

estimates in Table 4.2 for food and drinking water are below HED’s level of concern (<100% cPAD) 

for the general U.S. population (<1% of the cPAD) and all population subgroups (< 1.5% cPAD). 

Therefore, the chronic aggregate risk associated with the proposed and registered uses of flutolanil 

does not exceed HED’s level of concern for the general U.S. population or any population subgroups. 

7.0 Cumulative Risk Characterization/Assessment 

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 flutolanil 

and any other substances and flutolanil 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 

flutolanil 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/.

8.0 Occupational Exposure/Risk Pathway 

Workers may be exposed to flutolanil during mixing, loading, applying, and postapplication 

activities. Based on the proposed application rates and use scenarios, short- and intermediate-term 

occupational exposures may occur. However, since short-and intermediate-term endpoints have not 

been established, an occupational exposure assessment is not required. Chronic occupational 

exposure is not expected; thus, chronic occupational exposure risk assessments are also not required. 

9.0 Data Needs/Label Recommendations 
 23 of 32 

9.1 Toxicology 

The revised Toxicology Data Requirements for Conventional Pesticides [40 CFR §158.340] now 

includes studies which are better able to detect toxicities that are outside the scope of standard 

subchronic and chronic assays. These new study requirements are: 

 Acute neurotoxicity [OPPTS Guideline 870.6200a]; 

 Subchronic neurotoxicity [OPPTS Guideline 870.6200b]; 

 Immunotoxicity [OPPTS Guideline 870.7800] 

See Appendix C. 

9.2 Residue Chemistry 

HED has examined the residue chemistry database for flutolanil (A. Acierto, DP#371493, 05/12/10). 

There are no residue chemistry issues that would preclude granting an unconditional registration of 

the end-use product Moncut® 70DF (EPA Reg. No.10163-301) for at-plant/at-transplant use in/on 

Brassica (Cole) leafy vegetables crop group 5 and turnip greens. 

The available data, which reflect a single in-furrow or directed spray at the base of transplants of 

Brassica (Cole) leafy vegetables crop group 5, and turnip greens, combined with the data from the 

confined rotational crop study, will support the proposed new minor uses. Although the residues 

resulting from the proposed uses were determined by a method that does not comply with the current 

residue definition and that might understate the residue, a confined rotational crop study conducted at 

3X the proposed rate for Brassica (Cole) leafy vegetables and turnip greens yielded residues of 0.08 

ppm in a leafy vegetable (lettuce), where the samples were analyzed by the existing enforcement 

method. 

9.2.1 Residue Enforcement Analytical Methods 

Ginseng has been removed from the revised Section F. HED notes for possible future requests that 

ginseng samples must be analyzed by the common moiety method. Other acceptable approaches 

would be (1) to demonstrate that the common moiety method (AU/95R/04) and the LC/MS/MS 

method XAM-65 yield similar quantitative results on a variety of crop matrices with incurred 

residues; OR (2) to demonstrate that method XAM-65 modified to use the extraction solvents of the 

plant metabolism studies and including a new extract hydrolysis step gives similar results as 

unmodified method XAM-65. 

9.2.2 Proposed Tolerances 

HED recommends that the tolerance definition entry in 40 CFR 180.484 be revised as follows: (a) 

General. Tolerances are established for residues of the fungicide flutolanil, including its metabolites 

and degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only flutolanil and its metabolites converted to 2-

(trifluoromethyl) benzoic acid and calculated as flutolanil, in or on the commodity. 
 24 of 32 

Appendix A: Chemical Structures 

 

Table A. Chemical Names and Structures of Flutolanil and Metabolites. 

Common name; 

Company code 

Chemical name Chemical structure 

Flutolanil; M1 N-[3'-(1-methylethoxy)phenyl]-2-

(trifluoromethyl)benzamide 

N

H

O

CH3

CH3

O

CF3

M-2 N-[4'-hydroxy-3'-(1-

methylethoxy)phenyl]-2-

(trifluoromethyl) benzamide 

N

H

O

CH3

CH3

O

CF3

OH

M-3 N-[3'-(2-hydroxy-1-methylethoxy) 

phenyl]-2-

(trifluoromethyl)benzamide 

N

H

O

CH3

O

CF3

OH

M-4 N-(3'-hydroxyphenyl)-2-

(trifluoromethyl)benzamide 

N

H

OH

O

CF3
 25 of 32 

Table A. Chemical Names and Structures of Flutolanil and Metabolites. 

Common name; 

Company code 

Chemical name Chemical structure 

M-5 N-[3',4'-(dihydroxy)phenyl]-2- 

(trifluoromethyl) benzamide 

N

H

OH

O

CF3

OH

M-6 N-(3'-methoxy)phenyl -2-

(trifluoromethyl)benzamide 

N

H

O

O

CF3

CH3

M-7 N-(4'-hydroxy-3'-methoxy)phenyl -

2-(trifluoromethyl)benzamide 

N

H

O

O

CF3

CH3

OH

M-11 2-[[3-[2-(trifluoromethyl)benzoyl]-

amino]phenoxy]propanoic acid 

N

H

O

CH3

O

CF3

O

HO

2-TFBA: 2-trifluoromethyl benzoate 

O

CF3

OH
 26 of 32 

Appendix B: Toxicology 

B.1 Toxicology Data Requirements 

The requirements (40 CFR 158.500) for food use for flutolanil are in Table B.1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used. 

Table B.1. Toxicology Data Requirements for Food Use 

Test 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 (Rat)................................................... 

870.3150 Oral Subchronic (Dog) ................................................. 

870.3200 21-Day Dermal ............................................................. 

870.3250 90-Day Dermal ............................................................. 

870.3465 90-Day Inhalation ......................................................... 

yes 

yes 

no 

no 

no 

yes 

yes 

yes 

- 

- 

870.3700a Developmental Toxicity (Rat) ...................................... 

870.3700b Developmental Toxicity( Rabbit) ................................. 

870.3800 Reproduction ................................................................ 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (Rat).................................................. 

870.4100b Chronic Toxicity (Dog) ................................................ 

870.4200a Oncogenicity (Rat) ....................................................... 

870.4200b Oncogenicity (Mouse) .................................................. 

870.4300 Chronic/Oncogenicity (Rat).......................................... 

yes 

yes 

yes 

yes 

yes 

1 

yes 

1 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial.................... 

870.5375 Mutagenicity—Gene Mutation - mammalian............... 

870.5385 Mutagenicity—Structural Chromosomal Aberrations .. 

870.5395 Mutagenicity—Micronucleus ....................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotox. (Hen) ................................... 

870.6100b 90-Day Neurotoxicity (Hen)......................................... 

870.6200a Acute Neurotox. Screening Battery (Rat)..................... 

870.6200b 90 Day Neuro. Screening Battery (Rat)........................ 

870.6300 Develop. Neuro............................................................. 

no 

no 

yes 

yes 

no 

- 

- 

no 

no 

- 

870.7485 General Metabolism...................................................... 

870.7600 Dermal Penetration ....................................................... 

870.7800 Immunotoxicity ............................................................ 

yes 

no 

yes 

yes 

2 

no 

Special Studies for Ocular Effects................................................... no - 

1 = a chronic/onocgenicity study is available for the rat, thus separate chronic and oncogenicity are not necessary. 

2 = study classified as unacceptable. 
 27 of 32 

Table B.2. Acute Toxicity of Flutolanil Technical1

GDLN Study Type MRID nos. Results Tox Category

§81-1 Acute Oral 40342905 LD50 > 10,000 mg/kg IV 

§81-2 Acute Dermal 40342906 LD50 > 2,000 mg/kg III 

§81-3 Acute Inhalation 40342910 LC50 > 5.98 mg/L (4 hours) IV 

§81-4 Primary Eye Irritation 40342912 Minimal irritation IV 

§81-5 Primary Skin Irritation 40342915 Not a dermal irritant IV 

§81-6 Dermal Sensitization 40342917 Not a dermal sensitizer N/A 

 1 All studies were conducted on technical grade flutolanil, 98% purity. 

Table B.3. Toxicity Profile of Flutolanil Technical 

Guideline No./ 

Study Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870.3100 (82-1) 

90-day Oral 

Toxicity Rat - diet 

40342919 (1986)/ 

Acceptable-Guideline/ 

0, 500, 4000, 20000 ppm 

(M: 0, 37, 299, 1512 

mg/kg/d; F: 0, 44, 339, 

1743 mg/kg/d) 

NOAEL = 1512 mg/kg/day (HDT), 

LOAEL = not established. 

At 1512 mg/kg/day (HDT): increased absolute liver weights 

(males), increased relative liver weights (males and 

females), slight decrease in body weights (males) and slight 

increases in absolute, and relative thyroid/parathyroid 

weights were observed. No treatment-related changes in 

ophthalmoscopic, hematological, clinical chemistry, gross 

pathology, or histopathology parameters were observed. 

Therefore, the increased liver weights are considered to be 

an adaptive response to flutolanil treatment. 

870.3150 (82-1) 

90-day Oral 

Toxicity In 

Nonrodents (Dog) - 

gelatin capsule 

40342920 (1986)/ 

Acceptable-Guideline/ 0, 

80, 400, 2000 mg/kg/d 

NOAEL = 80 mg/kg/day, 

LOAEL = 400 mg/kg/day based on enlarged livers and 

increased severity of hepatic glycogen deposition in both 

males and females. 

At 2000 mg/kg/day (HDT), an elevation in alkaline 

phosphatase and cholesterol levels and slight increases in 

absolute and relative thyroid/parathyroid weights were 

observed. 

870.3200 (82-2) 

21-day Dermal 

Toxicity - Rat 

41841205 (1991)/ 

Acceptable-Guideline/ 0, 

1000 mg/kg/d 

Systemic NOAEL= 1000 mg/kg/day (limit dose), 

Systemic LOAEL > 1000 mg/kg/day. 

Dermal irritation NOAEL= 1000 mg/kg/day (limit dose), 

Dermal irritation > 1000 mg/kg/day. 

870.3250 

90-day Dermal 

Toxicity 

Not available Not available. 
 28 of 32 

Guideline No./ 

Study Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870.3465 

90-day Inhalation 

Toxicity 

Not available Not available. 

870.3700a(83-3a) 

Prenatal 

Developmental In 

Rat - oral gavage 

41850804(1987)/ 

Acceptable-Guideline/0, 

40, 200, 1000 mg/kg/d 

Maternal NOAEL = 1000 mg/kg/day, 

LOAEL > 1000 mg/kg/day. 

Developmental NOAEL= 1000 mg/kg/day, 

LOAEL > 1000 mg/kg/day. 

870.3700b(83-3b) 

Prenatal 

Developmental In 

Rabbit - oral gavage 

40342924(1987)/ 

Acceptable-Guideline/ 

0,40,200,1000 mg/kg/d 

Maternal NOAEL= 1000 mg/kg/day, 

LOAEL > 1000 mg/kg/day. 

Developmental NOAEL = 1000 mg/kg/day, 

LOAEL > 1000 mg/kg/day. 

870.3800(83-4) 

Reproduction And 

Fertility Effects In 

Rat - 2 Generation - 

diet 

41850805(1992)/ 

Acceptable-Guideline/ 

0,200,2000,20000 ppm 

(M: 0,16,159,1625 

mg/kg/d; 

F: 0,19,190,1936 

mg/kg/d) 

Parental/Systemic NOAEL = 1000 mg/kg/day, 

LOAEL > 1000 mg/kg/day. 

Reproductive NOAEL = 1000 mg/kg/day, 

LOAEL > 1000 mg/kg/day. 

Offspring NOAEL = 1000 mg/kg/day, 

LOAEL > 1000 mg/kg/day. 

870.3800(83-4) 

Reproduction And 

Fertility Effects In 

Rat - 3 Generation - 

diet 

40342923(1982)/ 

Unacceptable/ 0, 1000, 

10000 ppm (M: 0, 63, 

661 mg/kg/d; F: 0, 86, 

880 mg/kg/d) 

Parental/Systemic NOAEL = 661 mg/kg/day, 

LOAEL > 661 mg/kg/day. 

Reproductive NOAEL = 661 mg/kg/day, 

LOAEL > 661 mg/kg/day. 

870.4100a 

Chronic Toxicity 

Rodents 

See combined chronic / 

carcinogenicity study 

available (see below) 

 

870.4100b (83-1) 

Chronic Toxicity 

Dogs- gelatin 

capsule 

40342922(1982)/ 

Acceptable-Guideline/ 0, 

50, 250, 1250 mg/kg/d 

NOAEL = 50 mg/kg/day, 

LOAEL = 250 mg/kg/day based on increased incidence of 

clinical toxic signs (emesis, salivation, and soft stool) 

observed from the 65th week. 

At 1250 mg/kg/day (HDT), increased incidence of clinical 

toxic signs (from the 65th week), decreased body weight 

gains (from 82nd week in males and from 81st week in 

females) and decreased food consumption (from 79th week 

in males and from 74th week in females) were observed. 

No treatment-related changes in ophthalmoscopic, 

hematological, clinical chemistry, organ weights, gross 

pathology, or histopathology parameters were observed. 

870.4300 

 (83-1 & 83-5) 

Chronic/ 

Carcinogenicity 

Rats - diet 

40342921 (1982)/ 

Acceptable-Guideline/ 

0, 40, 200, 2000, 10000 

ppm 

(M: 0, 2, 9, 87, 460 

mg/kg/d F: 0, 2, 10, 103, 

NOAEL = 460 mg/kg/day, 

LOAEL = not established. 

At 460 mg/kg/day (HDT), increased absolute and relative 

liver weights (males and females) were observed in the 

absence of clinical chemistry or histopathology findings. 

Therefore, the increased liver weights are considered to be 
 29 of 32 

Guideline No./ 

Study Type 

MRID No. (year)/ 

Classification /Doses 

Results 

536 mg/kg/d) an adaptive response to flutolanil treatment. 

870.4300(83-2) 

Carcinogenicity 

Mice - diet 

41850803(1990)/ 

Acceptable-Guideline/ 0, 

300, 1500, 7000, 30000 

ppm (M: 

0,32,162,735,3333 

mg/kg/d; F: 0, 34, 168, 

839, 3676 mg/kg/d) 

NOAEL = 735 (M) and 168 (F) mg/kg/day, 

LOAEL = 3333 (M) and 839 (F) mg/kg/day based on 

decreased body weight gains. 

Gene Mutation 

870.5375 (84-2), In

vitro Chromosomal 

Aberration Assay in 

Cultured 

Mammalian Cell 

40342925(1986)/ 

Acceptable-Guideline/0, 

37, 75, 150 uM/plate 

Positive finding, flutolanil induced chromosomal aberrations 

in cultured Chinese hamster lung cells in the presence of 

metabolic activation (S9). 

Gene Mutation 

870.5100 (84-2), 

Reverse Mutation 

Assay 

40342926(1981)/ 

Acceptable-Guideline/0, 

10, 50, 100, 500, 1000, 

5000, 10000, 25000 

ug/plate. 

Negative (with and without S-9 metabolic activator) at doses 

up to 25 mg/plate in the increase in revertant colonies using 

Salmonella strains TA98, TA10, TA1535, TA1537, and 

TA1538 and in the E. Coli WP2 uvrA strain. 

Gene Mutation 

870.5375 (84-2), 

Gene Mutation in 

Cultured 

Mammalian Cells 

(Mouse Lymphoma 

Cells) 

41841207(1989)/ 

Acceptable-Guideline/0, 

6, 15, 30, 60, 80, 100 

ug/mL. 

Negative (either in the presence or absence of S9 activation) 

for the induction of forward mutations at the TK+/- locus in 

L5178Y mouse lymphoma cells. 

Cytogenetics 

870.5395 (84-2), 

Mouse 

Micronucleus 

40342927(1983)/ 

Acceptable-Guideline/0, 

6400, 8000, 10000 mg/kg 

either in a single dose or 

10 gm/kg/day over 4 days 

by gastric intubation to 

BDF1 mice 

(6/sex/group). 

Negative up to a dose of 10000 mg/kg in the induction of 

micronuclei in the bone marrow erythrocytes of male and 

female mice. 

Cytogenetics 

870.5385 (84-2), 

Mammalian Cells in 

Culture 

Cytogenetics Assay 

in Human 

Lymphocytes 

42606628(1990)/ 

Acceptable-Guideline/0, 

120, 250, 500, 1000 

ug/mL. 

Negative in the structural chromosome assay. There was no 

significant increase in the frequency of aberrations with any 

treatment levels, either with or without activation. 

Other Genotoxicity 

Effects 84-2, In

Vitro Unscheduled 

DNA Synthesis 

41841206(1989)/ 

AcceptableNonguideline/0, 2.67, 27, 

53, 80 ug/mL. 

Negative in the induction of unscheduled DNA synthesis in 

primary rat hepatocytes. 
 30 of 32 

Guideline No./ 

Study Type 

MRID No. (year)/ 

Classification /Doses 

Results 

Assays in Primary 

Rat Hepatocytes 

870.6200a 

Acute Neurotoxicity 

Screening Battery 

Not available Not available. Required. 

870.6200b 

Subchronic 

Neurotoxicity 

Screening Battery 

Not available Not available. Required. 

870.6300 

Developmental 

Neurotoxicity 

Not available Not available. Conditionally required. 

870.7485 

Metabolism And 

Pharmacokinetics -

Rat 

42606602(1992)/ 

Acceptable-Guideline/ 

single oral dose of 20 and 

1000 mg/kg and 

repeated oral doses of 20 

mg/kg for 14 days 

No appreciable tissue levels of flutolanil at study termination 

(168 hours post-dose). 

20 mg/kg: urine (40%) and feces (40% of dose). 

Repeated dose of 20 mg/kg: urine (70%) and feces (10%) 

1000 mg/kg: urine (10%) and feces (66-78%) 

Urinary metabolite by TLC: M-4 [N-(3'-hydroxyphenyl)-2-

(trifluoromethyl) benzamide] 

Fecal metabolite by TLC: Mainly parent chemical with 

limited conversion to M-4. 

870.7600 

Dermal penetration 

- Rat 

Not available Not available. 

 870.7800 

Immunotoxicity 

Not available. Immunotoxicity Required. 
 31 of 32 

Appendix C: Toxicology Study Requirements Rationale 

Guideline Number: 870.6200 

Study Title: Neurotoxicity Battery (Acute and Subchronic Studies) 

Test Substance: Flutolanil

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for 

registration of a pesticide (food and non-food uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential adverse 

effects on the nervous system from exposure to pesticide chemicals. The Agency believes that the 

guideline studies are inadequate in their assessment of behavioral effects and do not use optimal 

methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and 

characterize these potential effects more fully, a battery of more sensitive testing is required. The 

objective of this neurotoxicity battery testing is to evaluate the incidence and severity of the functional 

and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The 

acute neurotoxicity study is required to detect possible effects resulting from a single exposure. The 

subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or longterm exposures. 

 

Practical Utility of the Data 

How will the data be used? 

The acute and subchronic neurotoxicity studies provide critical scientific information needed to 

characterize potential hazard to the human population on the nervous system from pesticide exposure. 

These studies can provide data on a wide range of functional tests for evaluating neurotoxicity 

including sensory effects, neuromuscular effects, learning and memory and histopathology of the 

nervous system For example, animal studies with organophosphorous chemicals have shown 

neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase inhibition) of concern in rodents 

and non-rodents. These animal studies can be used to select endpoints and doses for use in risk 

assessment of all exposure scenarios and are considered a primary data source for reliable reference 

dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks 

for a number of chemicals (e.g., organophosphates and carbamates) where neurotoxicity was the most 

sensitive endpoint of concern. 

How could the data impact the Agency's future decision-making? 

If the acute or subchronic neurotoxicity studies show that flutolanil poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessment for flutolanil 

may need to be revised to reflect the magnitude of potential risk derived from the new data. 

 

If the Agency does not have this data, a 10X database uncertainty factor may be applied when 

conducting a risk assessment using the currently available studies. 
 32 of 32 

OPPTS Guideline Number: 870.7800 

Study Title: Immunotoxicity 

Test Substance: Flutolanil

Rationale for Requiring the Data 

 The immunotoxicity study is a new data requirement under 40CFR §158 as a part of the data 

requirements for registration of a pesticide (food and non-food uses). 

 The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity 

testing, and is designed to evaluate the potential of a repeated chemical exposure to produce adverse 

effects (such as suppression) on the immune system. Immunosuppression is a deficit in the ability of the 

immune system to respond to a challenge of bacterial or viral infections, such as tuberculosis (TB), 

Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly 

complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to 

characterize a pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ 

weights, and histopathology in routine chronic or subchronic toxicity studies may offer useful 

information on potential immunotoxic effects, these endpoints alone are insufficient to predict 

immunotoxicity. 

Practical Utility of the Data 

How will the data be used? 

 Immunotoxicity studies provide critical scientific information needed to characterize potential 

hazard to the human population on the immune system from pesticide exposure. Since epidemiologic 

data on the effects of chemical exposures on immune parameters are limited, and are inadequate to 

characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most 

sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses 

for use in risk assessment of all exposure scenarios, and are considered a primary data source for 

reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity 

in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) 

among developmental, reproductive and endocrinologic toxicities. Additionally, the EPA has 

established an oral reference dose (RfD) for tributyltin oxide (TBTO), based on observed 

immunotoxicity in animal studies (IRIS, 1997). 

How could the data impact the Agency's future decision-making? 

 If the immunotoxicity study shows that the test material poses either a greater or a diminished 

risk than that given in the interim decision’s conclusion, the risk assessments for the test material may 

need to be revised to reflect the magnitude of potential risk derived from the new data. 

 If the Agency does not have these data, a 10X database UF may be applied for conducting a risk 

assessment from the available studies.