UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

Date: 9/10/2012

SUBJECT: Fluazinam. Human Health Risk Assessment to Support New Uses on Soybeans, 

the Melon Subgroup (9-A), and the Pepper/Eggplant Subgroup (8-10B), and to 

Support Registration Review 

PC Code: 129098 DP Barcodes: D397601, D398687, D398690

Decision Nos.: 459601, 459565, 459568 Registration Nos.: 71512-1, 71512-20

Petition Nos.: 1E7959, 2F7977, 8E7506 Regulatory Action: Section 3 Registration and 

Registration Review

Risk Assessment Type: Single Chemical 

Aggregate

Case No.: 7013

TXR No.: NA CAS No.: 79622-59-6

MRID No.: NA 40 CFR: §180.574

FROM: Douglas A. Dotson, Ph.D., Chemist

Karlyn Middleton, M.S., Toxicologist

Zaida Figueroa, M.S., Industrial Hygienist

Registration Action Branch II

Health Effects Division (7509P)

THROUGH: Ed Scollon, Ph.D., Toxicologist

Dennis McNeilly, Chemist

Margarita Collantes, M.S., Biologist

Christina Swartz, Branch Chief

Registration Action Branch II

Health Effects Division (7509P)

TO: Andrew Ertman/Barbara Madden, RM Team 5, RIMUERB

Dominic Schuler/Tony Kish, PM Team 22, Fungicide Branch

Registration Division (7505P)

and

Steven Snyderman/Avivah Jakob, RMIB3

Pesticide Re-evaluation Division (7508P)
Fluazinam Human Health Risk Assessment DP No. D397601

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The Health Effects Division (HED) was requested to evaluate tolerance petitions associated with 

new uses proposed by ISK Biosciences (soybeans) and the Interregional Research Project No. 4

(IR-4, melons and peppers). The attached human health risk assessment addresses dietary, 

aggregate and occupational exposure and risk associated with the proposed uses of fluazinam, 

and there are no risks of concern.

Additional toxicity data required for fluazinam in conjunction with Registration Review have 

been submitted, evaluated and incorporated into the current hazard characterization, endpoint 

and dose selection, and Food Quality Protection Act (FQPA) Safety Factor determination. All of 

the data HED required to support Registration Review have been submitted and the hazard and 

exposure databases are complete.

In order to complete a preliminary risk assessment (PRA) for Registration Review, HED has 

incorporated the new information into the aggregate human health risk assessment for fluazinam. 

There are no dietary, residential or aggregate risks of concern associated with the existing and 

proposed uses. Further, HED has reassessed occupational exposure and risk for the existing uses 

of fluazinam, using the most updated policies, surrogate data, transfer coefficients, and chemicalspecific data submitted for fluazinam. In 2009 HED concluded that because of the relatively low 

volume of incidents and the lack of moderate or severe health effects potentially related to 

fluazinam exposure, no further investigation was required to support the preliminary risk 

assessment.

HED is not recommending any label changes or other mitigation for existing uses in conjunction 

with this risk assessment. Details regarding the risk assessment to support Registration Review 

are provided in Appendix F of the attached document.
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1.0 Executive Summary.......................................................................................................... 5

2.0 HED Recommendations................................................................................................. 10

2.1 Data Deficiencies/Conditions of Registration........................................................... 10

2.2 Tolerance Considerations........................................................................................... 10

2.2.1 Enforcement Analytical Method ........................................................................... 10

2.2.2 International Harmonization................................................................................. 11

2.2.3 Recommended Tolerances...................................................................................... 11

2.2.4 Revisions to Petitioned-for Tolerances.................................................................. 11

2.3 Label Recommendations........................................................................................ 12

3.0 Introduction..................................................................................................................... 12

3.1 Chemical Identity........................................................................................................ 12

3.2 Physical/Chemical Characteristics............................................................................ 12

3.3 Pesticide Use Pattern for Proposed Commodities.................................................... 12

3.4 Anticipated Exposure Pathways................................................................................ 14

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

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

4.1 Toxicology Studies Available for Analysis................................................................ 15

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).............................. 18

4.4.1 Completeness of the Toxicology Database............................................................ 18

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

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 19

4.4.4 Residual Uncertainty in the Exposure Database.................................................. 19

4.5 Toxicity Endpoint and Point of Departure Selections............................................. 20

4.5.1 Dose Response Assessment..................................................................................... 20

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment... 21

4.5.3 Classification of Carcinogenic Potential ............................................................... 21

4.5.4 Summary of Toxicological Doses and Endpoints for Fluazinam ....................... 22

5.0 Dietary Exposure and Risk Assessment........................................................................ 24

5.1 Metabolite/Degradate Residue Profile ...................................................................... 24

5.1.1 Summary of Plant and Animal Metabolism Studies ........................................... 24

5.1.2 Summary of Environmental Degradation ............................................................ 25

5.1.3 Comparison of Metabolic Pathways...................................................................... 25

5.1.4 Residues of Concern Summary and Rationale..................................................... 26

5.2 Food Residue Profile................................................................................................... 27

5.3 Water Residue Profile................................................................................................. 28

5.4 Dietary Risk Assessment ............................................................................................ 29

5.4.1 Description of Residue Data Used in Dietary Assessment .................................. 29

5.4.2 Percent Crop Treated Used in Dietary Assessment............................................. 30

5.4.3 Acute Dietary Risk Assessment ............................................................................. 30

5.4.4 Chronic Dietary Risk Assessment ......................................................................... 30

5.4.5 Cancer Dietary Risk Assessment........................................................................... 30

5.4.6 Summary Table....................................................................................................... 30
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 31

6.1 Residential Handler Exposure and Risk................................................................... 31

6.2 Residential Post-application Exposure ..................................................................... 31

6.2.1 Dermal Post-application Exposure........................................................................ 31

6.2.2 Inhalation Post-application Exposure................................................................... 32

6.3 Combined Residential Risk Estimates...................................................................... 32

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

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

6.6 Residential Bystander Post Application Inhalation Exposure................................ 33

7.0 Aggregate Exposure/Risk Characterization................................................................. 33

7.1 Acute Aggregate Risk ................................................................................................. 34

7.2 Short-/Intermediate-Term Aggregate Risk Estimates ............................................ 34

7.3 Chronic Aggregate Risk ............................................................................................. 35

7.4 Cancer Aggregate Risk............................................................................................... 35

8.0 Cumulative Exposure/Risk Characterization .............................................................. 35

9.0 Occupational Exposure/Risk Characterization ........................................................... 35

9.1 Occupational Handler Exposure/Risk Estimates..................................................... 35

9.2 Occupational Post-application Exposure/Risk Estimates....................................... 37

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates ................ 39

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates..................... 39

10.0 References........................................................................................................................ 41

Appendix A. Fluazinam Toxicology Profile and Additional Information............................ 43

A.1 Toxicology Profile Tables for Fluazinam.................................................................. 43

A.2 Triple Pack Analysis for Fluazinam.......................................................................... 50

A.3 HEC Inhalation Calculations..................................................................................... 52

A.4 Hazard Identification and Endpoint Selection......................................................... 55

Appendix B. International Residue Limit Status Sheet ......................................................... 60

Appendix C. Fluazinam Physical/Chemical Properties ......................................................... 62

Appendix D. Review of Human Research................................................................................ 63

Appendix E. Structures of Fluazinam Metabolites and Degradates of Concern................. 64

Appendix F. Occupational Exposure and Risk Assessment for Registered Uses ................ 66
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1.0 Executive Summary

ISK Biosciences and the Interregional Research Project No. 4 (IR-4) submitted petitions to 

establish tolerances for the fungicide fluazinam in/on soybeans and the commodities of the 

melon and pepper/eggplant subgroups (9-A and 8-10B, respectively). This human health risk 

assessment presents HED’s conclusions with respect to the risk estimates associated with the 

proposed uses as well as all registered uses for fluazinam. The toxicity and exposure databases 

for fluazinam are complete in accordance with the requirements of registration review, and 

therefore this document also serves as HED’s human health risk assessment to support 

registration review. The proposed uses on melons and peppers were evaluated under a joint 

review with Canada’s Pesticide Management Regulatory Agency (PMRA).

Fluazinam (3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2-

pyridinamine) is a preventive contact fungicide with a multi-site fungicidal mode of action. It 

disrupts the production of energy at several metabolic sites within the fungal cell. Fluazinam is a 

protectant fungicide. When it is applied to plants, it remains primarily on the plant surface and 

kills any fungal spores that come into contact with it. It is not taken up to any extent by the plant 

and, unlike systemic fungicides, is not translocated within the plant.

HED has assessed exposures and risks from the registered and proposed uses of fluazinam. The 

end-use product proposed for use on melons, peppers, and soybeans is OMEGA®500F (EPA 

Reg. No. 71512-1), a soluble-concentrate (SC) formulation containing 40% ai fluazinam (4.17 

lbs ai/gal). OMEGA®500F may be applied as a foliar spray using aerial, ground, and handheld 

equipment. It may also be applied via chemigation. The maximum single application rates for 

the proposed uses range from 0.52-0.78 lb ai/A. For melons and peppers, the label allows up to 6 

applications at 0.78 lb ai/A for a total seasonal application rate of 4.68 lb ai/A. The proposed 

PHI for these commodities is 30 days. For soybeans, the label allows up to 2 applications at 0.52 

lb ai/A for a total seasonal application rate of 1.04 lb ai/A. Occupational exposure from use on 

soybeans, melons, and peppers is expected to be of short- to intermediate-term durations.

Hazard Characterization and Endpoint Selection

The 28-day inhalation and immunotoxicity studies required during registration review were 

submitted and evaluated, and the toxicology database for fluazinam is complete.

The liver is a primary target organ following dosing with fluazinam. Numerous liver effects 

were observed in rats, mice, and dogs. Liver effects were also observed in rats following dosing 

via the dermal route. Treatment-related effects were also noted in other organs; however, these 

effects were not regularly observed in all three species or in all studies in a given species. 

No signs of neurotoxicity were observed in an acute neurotoxicity study or in two subchronic 

neurotoxicity studies. However, a neurotoxic lesion described as vacuolization of the white 

matter of the central nervous system (CNS) was observed in subchronic and chronic studies in 

mice and dogs, as well as in special studies in rats. After further investigation, it was determined 

that an impurity was responsible for the appearance of the white matter vacuolization. A 

developmental neurotoxicity (DNT) study containing a lower concentration of the impurity was 
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submitted to address the Agency’s concerns regarding the vacuolization; in the study, there was 

no evidence of vacuolization of the brain or any other treatment-related pathology up to the 

highest dose tested. Because of the lower concentration of the impurity in the technical used in 

the DNT, and because of the absence of the lesion in the study, HED concluded that fluazinam, 

per se, was not responsible for the induction of the lesion. Furthermore, HED is not concerned 

about the presence of the impurity, since the acute and chronic reference doses selected for risk 

assessment are protective of any possible neurotoxic effects resulting from exposure to the 

impurity.

In an immunotoxicity study in mice, significant suppressions of anti sheep red blood cell (antiSRBC) antibody-forming cell assay (AFC) response were demonstrated at the highest dose tested

indicating potential immunotoxicity. However, clear NOAELs and LOAELs were identified for 

the effects seen in the study and the points of departure (PODs) and endpoints selected for risk 

assessment are protective of immunotoxic effects. 

In a subchronic inhalation toxicity study in rats, pulmonary effects were observed at the mid and 

high doses. These effects included dose related increases in lung/bronchial weights and 

increased incidences of alveolar macrophages and peribronchiolar proliferation in both sexes.

There was no evidence of increased quantitative or qualitative susceptibility in a developmental 

toxicity study in rabbits or in a 2-generation reproduction study in rats. In a developmental 

toxicity study in rats, there was no evidence of increased quantitative susceptibility; however, 

there was evidence of increased qualitative susceptibility. Developmental effects were seen in 

the presence of minimal maternal toxicity. The registrant submitted a developmental 

neurotoxicity study (DNT) in rats. There was evidence of increased quantitative susceptibility in 

the DNT study, i.e., offspring effects were seen in the absence of maternal toxicity. The 

registrant also submitted a series of special studies in order to address the issues of increased 

susceptibility and the presence of neurotoxic lesions observed in the toxicological database.

The concern is low for the increased susceptibility seen in the developmental toxicity and DNT 

studies because clear NOAELs were established, dose-responses were well defined, and the most 

sensitive endpoints were used for risk assessment, in order to be protective of the observed 

susceptibility. The required 10x FQPA Safety Factor was reduced to 1x based on 1) the 

completeness of the toxicology database; 2) the lack of neurotoxicity; 3) the lack of residual 

uncertainty for pre- and post natal toxicity; and 4) because the exposure assessment is 

conservative and does not underestimate exposure.

HED’s Cancer Assessment Review Committee (CARC) classified fluazinam as having 

“Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential.” The CARC also determined that the quantification of cancer risk using a non-linear 

approach (i.e., RfD) would adequately account for all chronic toxicity, including carcinogenicity, 

that could result from exposure to fluazinam. 

The dose and endpoint for acute dietary risk assessment (general population) were selected from

an acute neurotoxicity study in which clinical signs including decreased motor activity and soft 

stools observed were observed at high doses. For acute dietary risk assessment for females 13-

49, a developmental toxicity study in rabbits was used, and the endpoint selected was total litter 
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resorptions and skeletal abnormalities. For the chronic dietary risk assessment, the 

carcinogenicity study in mice and the chronic study in dogs were selected as co-critical studies. 

In the mouse, effects seen were mainly in the liver. In dogs, nasal dryness and gastric lymphoid 

hyperplasia were observed. 

Route-specific toxicity studies were available for assessing both dermal and inhalation risks. In 

the dermal study, the endpoint consisted of liver effects, while in the inhalation study the effects 

observed were lung histopathology and increased lung and bronchial weights. For the dermal 

route, the dermal toxicity and dermal absorption studies were used to determine a refined dermal 

equivalent dose (RDD) for assessing short- and intermediate-term dermal exposure. For the 

inhalation route, HED selected the endpoint from the subchronic inhalation toxicity study based 

on portal-of-entry effects (pulmonary). In accordance with current guidance, human equivalent 

concentrations (HECs) and human equivalent doses (HEDs) were calculated, with the HEDs 

being used for risk assessment. The dermal and inhalation studies are protective of the 

developmental effects seen in rats as well as potential neurotoxicity and immunotoxicity. 

The short-/intermediate-term toxicological endpoints for fluazinam are the same for the 

respective routes of exposure. As a result, only short-term dermal and inhalation exposures were 

assessed for occupational and residential scenarios. The resulting short-term risk estimates are 

considered to be protective of intermediate-term exposure and risk.

For acute and chronic dietary and dermal risk assessments, a 100x uncertainty factor was applied 

(10x interspecies factor and 10x intraspecies factor). The 100x factor was used to calculate the 

acute and chronic reference doses (RfDs), which are the same as the respective population 

adjusted doses (PADs). For the dermal assessment, the level of concern (LOC) is a margin of 

exposure (MOE) of 100, based on the combined uncertainty factors. For inhalation risk 

assessments, the LOC is an MOE of 30 based on an interspecies factor of 3x and an intraspecies 

factor of 10x; the interspecies factor was reduced from 10x to 3x, since calculation of human 

equivalent calculations (HECs) accounts for pharmacokinetic (not pharmacodynamic) 

interspecies differences between animals and humans.

Metabolism/Metabolites and Degradates of Concern

The metabolism of fluazinam in primary crops, rotational crops, and animals has been 

adequately delineated. The residue of concern for risk assessment in bulb vegetables as well as 

in root and tuber vegetables is parent fluazinam. For all other plant commodities, the residues of 

concern in plants for risk assessment are fluazinam and its metabolite AMGT. In drinking water, 

the degradates of concern for risk assessment are parent fluazinam and its transformation 

products. In livestock commodities, the residues of concern for risk assessment are fluazinam,

the metabolites known as AMPA, DAPA, and their sulfamate conjugates.

Food Residue Profile

The food use profiles for the registered and proposed commodities are complete and adequate for 

tolerance setting and risk assessment purposes, including registration review. For soybeans, 

melons, and peppers, the registrants submitted adequate field trial and processing data for parent 
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and the metabolite AMGT. For all crops, adequate numbers of trials were performed in the 

recommended NAFTA growing zones. The OECD MRL calculation procedures were used for 

determining appropriate tolerance levels. The recommended tolerances for soybean seed, 

soybean hulls, the melon subgroup, and the pepper/eggplant subgroup are listed in Table 2.2.3.

Adequate analytical methods are available for enforcement of tolerances in plant and livestock 

commodities. In addition, the FDA Multiresidue Methods (MRMs) can serve as a confirmatory

procedure for residues of fluazinam, but not for the metabolites. The necessary analytical 

reference standards for fluazinam are available in the EPA National Pesticide Standards 

Repository.

Dietary Exposure and Risk

Acute and chronic dietary exposure and risk assessments were conducted, including food and 

drinking water contributions from the existing uses as well as the proposed uses. The acute and 

chronic assessments are based on 100% crop treated assumptions and incorporate modeled 

estimated drinking water concentrations (EDWCs) that account for both parent fluazinam and its 

transformation products. Default processing factors were used for all processed commodities for 

which default factors were available. The acute analysis is based on tolerance-level residues for 

all commodities and uses high-end residue estimates for the metabolite AMGT. The chronic 

analysis is based on tolerance-level residues for all commodities except apples. For apples, the 

average field trial value was used. As a result, the acute and chronic exposure and risk estimates 

are considered to be conservative. The acute and chronic dietary risk estimates are below HED’s 

level of concern for all population subgroups, including those comprised of infants and children. 

The acute dietary risk estimate for the general U.S. population is 5.3% of the acute PAD (aPAD). 

The population subgroup with the highest acute dietary risk estimate is Females 13-49, which 

uses 28% of the aPAD. The chronic dietary risk estimate for the general U.S. population is 20% 

of the chronic PAD (cPAD). The most highly exposed population subgroup is All Infants (<1 

year old), which uses 51% of the cPAD. As the chronic dietary endpoint and dose are protective 

of potential cancer effects, cancer dietary risk is also not of concern. Because such conservative 

assumptions were made in the assessments, HED is confident that the acute and chronic dietary

exposure assessments do not underestimate risk to the general U.S. population or any population 

subgroup or life stage.

Residential Exposure and Risk 

The residential exposure database is complete and adequate. There are no proposed residential 

uses; however, there is an existing use of fluazinam on golf course turf. Individuals can be 

exposed when they play golf on treated turf, and therefore a residential dermal post-application 

assessment was previously conducted for golfers. Residential post-application exposure to 

golfers was assessed using the HED Standard Operating Procedures (SOPs) for Residential 

Exposure Assessment (2012), as well as chemical-specific residue data from the turf transferable 

residue (TTR) study. Dermal post-application exposure and risk estimates for golfers resulted in 

MOEs greater than the LOC of 100, and were not of concern (e.g., lowest MOE = 780).
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Aggregate Exposure and Risk

The acute and chronic aggregate risk estimates are equivalent to the corresponding dietary (food 

plus water) risk estimates, which are not of concern. Chronic dietary exposure is considered to 

be a background exposure level to which the short-term residential exposure is added. The shortterm aggregate risk assessments resulted in estimated MOEs of 730 to 970. For fluazinam, the 

LOC for short-term risk is an MOE of 100. As the resulting aggregate MOEs exceed the LOC of 

100, aggregate dietary and residential risk estimates are not of concern.

Occupational

The occupational exposure database is complete and adequate for assessing occupational 

exposure to fluazinam for both the registered and proposed uses.

It is HED policy 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 the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler 

Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., AHETF 

data), and subject to the data protection provisions of FIFRA. Default assumptions established 

by HED’s Science Advisory Council for Exposure were used for parameters such as body

weight, acres treated, and amount handled.

Occupational handler assessments considered both dermal and inhalation short-term exposures. 

The estimates are considered to be protective of intermediate-term exposure and risk. For the 

proposed uses on soybeans, melons, and peppers, all the occupational handler scenarios resulted 

in MOEs equal to or greater than the respective levels of concern at some level of personal 

protective equipment (PPE, e.g., baseline (single layer clothing, no respirator), chemical-resistant 

gloves, double layer clothing), and assuming engineering controls (i.e., enclosed cockpit) for 

aerial applications. Based on the dermal and inhalation risk estimates, no additional PPE or 

other mitigation is needed on the label, either for the existing or proposed uses.

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

inhalation exposure assessment is not being performed for fluazinam at this time. Although a 

quantitative occupational post-application inhalation exposure assessment was not performed, an 

inhalation exposure assessment was performed for occupational handlers (e.g., flaggers). 

Handler inhalation exposure estimates are considered to be protective of occupational postapplication inhalation exposure scenarios. If new policies or procedures are put into place, the 

Agency might revisit the need for a quantitative occupational post-application inhalation 

exposure assessment for fluazinam.

There is potential for dermal exposure during occupational post-application activities, such as 

crop maintenance activities, scouting, irrigation, and harvesting. Chemical-specific dislodgeable 

foliar residue (DFR) studies were submitted by the registrant and reviewed by HED, and the 

results of these studies were incorporated into HED’s review of the existing and proposed uses. 

Post-application dermal exposure and risk estimates for the proposed uses resulted in MOEs 

greater than the LOC of 100 and are not of concern on Day 0 (i.e., 12 hours after application).
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Restricted Entry Interval (REI)

The restricted entry interval (REI) for fluazinam is based on the acute toxicity of the technical 

material. Fluazinam is classified as Toxicity Category I for eye irritation. Under the Worker 

Protection Standard (WPS) for Agricultural Pesticides, active ingredients classified as acute 

Toxicity Category I for any route is assigned a 48-hour REI. Based on the acute toxicity profile 

of fluazinam, the 48-hour REI specified on the OMEGA®500F label is appropriate to protect 

agricultural workers from post-application exposures to fluazinam on melons, peppers, and 

soybeans.

2.0 HED Recommendations

HED recommends in favor of granting the proposed Section 3 use of fluazinam on soybeans, the 

Melon subgroup (9-A), and the Pepper/Eggplant subgroup (8-10B).

2.1 Data Deficiencies/Conditions of Registration

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate GC/ECD method (6148-94-0170-MD-001) is available for enforcing fluazinam 

tolerances on plant commodities. The method was adequately radiovalidated and underwent a 

successful ILV trial. The method was forwarded to BEAD’s Analytical Chemistry Branch 

(ACB) for a TMV trial, and was subsequently determined to be suitable as a toleranceenforcement method. The method LOQ is 0.01 ppm for fluazinam in plant commodities. An 

adequate enforcement method for determination of AMGT is also available. The method is an 

HPLC/UV method entitled “Method Evaluation for the Analysis of AMGT in Grapes.” The 

registrant submitted an adequate ILV for the method. The range of fortification levels and the 

percent recovery values were acceptable.

ISK Biosciences Corporation’s analytical method entitled “Enforcement Method for the Analysis 

of Fluazinam and its Metabolites AMPA and DAPA in Milk and Meat” is adequate as an 

enforcement method for residues of fluazinam, AMPA, and DAPA and their sulfamate 

conjugates in kidney, liver, and fat. The method was successfully validated for fluazinam, 

AMPA, and DAPA in beef kidney, beef liver, and beef fat.

Adequate FDA multiresidue method (MRM) testing data are available for fluazinam and its 

metabolite AMGT. As fluazinam is partially recovered through Sections 302, 303, and 304 of 

PAM Volume I, the MRMs can serve as a confirmatory procedure for residues of fluazinam. 

The FDA MRM methods are not suitable for determining residues of AMGT.
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2.2.2 International Harmonization

There are no harmonization issues between the U.S., Codex, Canada, and Mexico. There are 

currently no Codex MRLs for fluazinam on any commodities including melons, bell peppers, 

non-bell peppers, or soybeans. There are no Canadian or Mexican MRLs for melons or peppers. 

The petition for melons and peppers is being evaluated jointly by the EPA and PMRA, and the

MRLs for melons and peppers will be harmonized between the two countries. There are no 

harmonization issues between the U.S. and Canada with respect to soybean commodities. There 

is a Canadian MRL of 0.10 ppm for edible-podded soybean. There is no need to harmonize this 

MRL with HED’s recommended tolerance of 0.01 ppm for soybean seed because edible-podded 

soybean and soybean seed are different commodities. Edible-podded soybean is an immature 

seed that includes the pod. It is likely to have a higher residue level than soybean seed, which is 

the dried seed alone.

The U.S. and Canadian MRLs are harmonized for all other commodities for which both countries 

have established MRLs (potatoes (0.02 ppm), bushberries (7.0 ppm), Brassica leafy vegetables 

(0.01 ppm), dried shelled peas and beans (Subgroup 6C, except pea, 0.02 ppm), and edible 

podded peas and beans (Subgroup 6A, except pea, 0.10 ppm). Mexico adopts U.S. tolerances 

and/or Codex MRLs for its export purposes.

For the purpose of registration review, no additional tolerance changes are needed to achieve 

harmonization.

2.2.3 Recommended Tolerances

The recommended tolerances are listed in Table 2.2.3, and should be added to the table in 

40CFR §180.574(a)(1): Tolerances are established for residues of fluazinam, 3-chloro-N-[3-

chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2-pyridinamine), including its 

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

tolerance levels is to be determined by measuring only fluazinam.

Table 2.2.3. Tolerance Summary for Fluazinam

Commodity as Proposed by 

Registrant

Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Melon subgroup 9A 0.08 0.07

Pepper/eggplant subgroup 8-10B 0.10 0.09

Soybean, Seed 0.01 0.01 Soybean, seed

Soybean, Hulls 0.02 0.05 Soybean, hulls

2.2.4 Revisions to Petitioned-For Tolerances

The proposed tolerances for soybean hulls, melons, and peppers are different from the tolerances 

recommended by HED. The reason for the differences is that the registrant determined the 

proposed tolerances using the NAFTA tolerance calculator, while Canada and the U.S. agreed to 

use the OECD calculation procedures for melons and peppers. The U.S. is also using the OECD 
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calculation procedures for soybean commodities. Revised Sections F should be submitted by IR4 and the registrant, to reflect HED’s tolerance recommendations. No changes are needed to the 

tolerance expressions.

2.3 Label Recommendations

None

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Fluazinam Nomenclature

Compound Chemical Structure

 

Empirical Formula C13H4Cl2F6N4O4

Molecular Weight 465.1

Common Name Fluazinam

Company Experimental Names Fluazinam, IKF-1216

IUPAC Name 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-α,α,α-trifluoro-2,6-dinitrop-toluidine

CAS Name 3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-

(trifluoromethyl)-2-pyridinamine

CAS Number 79622-59-6

End-use Product/(EP) Omega®

500F Fungicide (EPA Reg. No. 71512-1)

Fluazinam Turf Fungicide (EPA Reg. No. 71512-20)

3.2 Physical/Chemical Characteristics

Fluazinam has a relatively high octanol/water partition coefficient. The log KOW value is 3.56

(KOW = 3,630). Fluazinam has a vapor pressure of 1.73 x 10-7 mm Hg at 25oC. See Appendix C

for a listing of fluazinam’s physical and chemical properties. 

3.3 Pesticide Use Pattern for Proposed Commodities

There is currently a single end-use product (EP) for fluazinam registered in the U.S. for use on 

several food and feed crops. This product is Omega®500F (EPA Reg. No. 71512-1), which is a 

N

N

H

CF3

Cl

Cl

CF3

NO2

O2N
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4.17 lb/gal soluble-concentrate (SC) formulation. ISK Biosciences and IR-4 are proposing to 

add uses on soybeans, the melon subgroup (9A), and the pepper/eggplant subgroup (8-10B) to 

the registered label. The proposed use directions are summarized in Table 3.3.

OMEGA®500F may be applied as a foliar spray using aerial, chemigation (i.e., sprinkler 

irrigation system), ground and handheld equipment. The proposed Restricted Entry Interval 

(REI) is 48 hours for all crops. The Personal Protective Equipment (PPE) statement on the 

proposed label requires applicators, flaggers, and other handlers to wear long-sleeved shirt and 

long pants, socks, chemical-resistant gloves and footwear, and protective eyewear. When mixing

and loading also wear a chemical-resistant apron. Mixers/Loaders must wear a dust/mist 

filtering respirator (MSHA/NIOSH TC-21C) or a NIOSH approved respirator with an N, R, P or 

HE filter.

Table 3.3. Summary of Directions for Proposed Use of Fluazinam on Melons, Peppers and Soybeans

Applic. Timing, 

Type, and Equip.

Formulation 

[EPA Reg. 

No. 71512-1]

Max. Single 

Application

Rate 

(lb ai/A)†

Max. No. of

Applications

per Season

Max. Seasonal 

Application

Rate (lb ai/A)

PHI 

(days)

Use Directions and 

Limitations

Melons (Crop Subgroup 9A)

Broadcast; Ground, 

Chemigation 

(Sprinkler System).

OMEGA®500F 

40% ai, Soluble 

Concentrate 

(4.17 lb ai/gal)

0.78 lb ai/A 

(24 fl oz/A) 6

4.68 lb ai/A 

(144 fl oz/A) 30

Re-treatment Interval = 7-10

days. 

Apply when disease symptoms 

first appear.

Peppers (Crop Subgroup 8-10B)

Broadcast; Ground, 

Chemigation 

(Sprinkler System), 

Soil Drench (at 

transplanting).

OMEGA®500F 

40% ai, Soluble 

Concentrate 

(4.17 lb ai/gal)

0.78 lb ai/A 

(24 fl oz/A)

(0.013 lb 

ai/gal)

6

4.68 lb ai/A 

(144 fl oz/A) 30

Re-treatment Interval = 7-14

days.

Apply as a soil drench at 

transplanting. Foliar applications 

should begin 7 days after 

transplanting.

Soybean

Apply at early bloom 

to full bloom stage of 

development.

Broadcast; Aerial, 

Ground.

OMEGA®500F 

40% ai, Soluble 

Concentrate 

(4.17 lb ai/gal)

0.52 lb ai/A 

(16 fl oz/A) 2

1.04 lb ai/A 

(32 fl oz/A)

Growth 

Stage 

R33

Re-treatment Interval = 10-14 

days (at early pod formation).

For preventive treatment or low 

disease pressure use low rate.

Do not feed hay from treated 

field to livestock or allow 

livestock to graze on treated 

areas.

Do not apply after early pod 

formation.

† Maximum Single Application Rate for Soybeans (lb ai/A) = (1 pint/A)(16 fl oz/1 pint) (4.17 lb ai/gal)(1 gal/128 fl 

oz) = 0.52 lb ai/A. Maximum Single Application Rate for Melons & Peppers (lb ai/A) = (24 fl oz/A) (4.17 lb 

ai/gal)(1 gal/128 fl oz) = 0.78 lb ai/A. Maximum Single Application Rate for Peppers (lb ai/gal) = (0.78 lb ai/A)/(60 

gal/A) = 0.013 lb ai/gal.

The proposed (and current) product label for the 4.17 lb/gal soluble-concentrate (SC) 

formulation specifies that applications are allowed through the following types of irrigation 

systems: center pivot, motorized lateral move, traveling gun, solid set, or portable (wheel move, 

side roll, end tow, or hand move). The label contains the following rotational crop restrictions: 
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“All crops on the label may be replanted immediately after treatment. All other crops may be 

replanted 30 days after the last application.”

The recommended spray volumes are 20-100 gal/A (20-60 gal A for field/row crops) for dilute 

spray applications and 5-10 gal/A for ground and aerial spray applications. As the proposed 

supplemental label states that chemigation (i.e., sprinkler irrigation) will be permitted on melons 

and peppers, chemigation was assessed for the proposed uses. 

3.4 Anticipated Exposure Pathways

Humans might be exposed to fluazinam in food and drinking water because fluazinam may be 

applied directly to row crops and golf course turfgrass. The only residential exposure scenario 

expected for fluazinam is dermal post-application exposure to treated golf course turf. The 

registered and proposed uses also result in the potential for occupational (handler/postapplication) exposures. In addition, applicators might be exposed while handling the pesticide 

prior to application, mixing/loading the pesticide, and during application.

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.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 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 Characterization

Fluazinam is a preventive contact fungicide with a multi-site mode of action. The fungicidal 

mode of action involves disruption of the production of energy at several metabolic sites within 

the fungal cell. Fluazinam is a protectant fungicide. Unlike systemic fungicides, it is not taken 
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up to any extent by the plant, and is not translocated within the plant. When applied to plants it 

remains primarily on the plant surface. The mammalian mode of action is unknown at this time.

4.1 Toxicology Studies Available for Analysis

The toxicology database for fluazinam is complete. The available studies include: subchronic 

oral toxicity studies in rats, mice, and dogs; a chronic oral toxicity study in dogs; carcinogenicity

studies in rats and mice; developmental and reproduction studies in rats and a developmental 

study in rabbits; subchronic dermal and inhalation toxicity studies in rats; and an immunotoxicity

study in mice. There is also a metabolism study in the rat, a complete mutagenicity battery, and 

acute LD50 and neurotoxicity studies (acute, subchronic, and developmental).

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

In the rat metabolism study, overall recovery of the administered radioactivity was acceptable 

(93.10-103.55%). Excretion via the urine was minor. AMPA mercapturate and DAPA, the 

major urinary metabolites, represented only 0.05-0.39% of the administered dose. Radioactivity

in the feces represented most of the administered dose (88.78-100.0%). Identified fecal 

metabolites, however, represented from 11.20-68.59% of the administered dose. For all dose 

groups, most of the fecal radioactivity appeared to reside with unextractable components in the 

post-extraction solids (PES). Further analysis of the PES components using base hydrolysis 

indicated that most of this radioactivity could be attributed to hydrolysis products of AMPA and 

DAPA. PES radioactivity was also greatest for the low-dose group, which was consistent with 

the lower overall accounting of identified metabolites for this group. Approximately 20-25% of 

the aqueous phase of the fecal extraction was identified as a cysteine conjugate of DAPA and 

represented <1% of the administered dose. With the exception of the low-dose group, parent 

compound represented most of the identified radioactivity in the feces. AMPA and DAPA were 

identified in the feces from all dose groups, but these metabolites never represented more than 

5% of the administered dose (except for high-dose female rats where AMPA accounted for 

10.22%).

 

DAPA glucuronide and AMPA mercapturate were the major biliary metabolites, but represented 

<4% of the administered dose. Total biliary radioactivity, however represented 25-34% of the 

administered dose. Analysis of chromatograms indicated that numerous other metabolites were 

present in the bile, but were individually of insufficient quantity to allow for characterization. 

Metabolite profiles from administration of different label positions (pyridyl and phenyl) 

indicated that there was no metabolic cleavage of the ring structures. Minor quantitative 

differences in metabolite recovery were observed between genders, but not of sufficient 

magnitude to suggest biologically relevant differences in the metabolism of fluazinam.

4.2.1 Dermal Absorption

An in vivo dermal absorption study in rats is available for fluazinam that demonstrates low 

dermal absorption of 4%. Additionally, in vitro dermal data are available in rat and human skin, 

along with a dermal toxicity study in rats. In the rat study, liver effects were seen at the lowest 
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observed adverse effects level (LOAEL) of 100 mg/kg/day, with a no observed adverse effects 

level (NOAEL) of 10 mg/kg/day. In an effort to refine the dermal point of departure selected for 

risk assessment, the dermal absorption data and dermal toxicity study were used to calculate a 

refined human dermal equivalent dose that was used for short- and intermediate-term dermal risk 

assessments. To calculate a RDD, in vitro results using rat skin are corrected for any differences 

between in vitro and in vivo absorption rates and species differences between rats and humans. 

This refinement in dermal absorption is important because absorption by human skin is usually

lower than that by rat skin. Accordingly, the combined use of the data from the three studies and 

two testing systems offers greater precision in estimating human dermal absorption, which 

strengthens the reliability of the dermal risk assessment (see Appendix A.2). 

4.3 Toxicological Effects

In subchronic and chronic oral and dermal studies in rats, dogs, and mice, the liver was a primary

target organ. In rats, subchronic exposure resulted in increased liver weights and liver 

histopathology (hepatocyte hypertrophy, sinusoidal chronic inflammation, and necrosis). In 

dogs, increased liver enzymes (alkaline phosphatase), increased liver weights, and 

histopathology (hepatic coagulative necrosis, and bile duct hyperplasia) were observed. In mice, 

increased liver weights, and liver hypertrophy were seen. Liver histopathology (hypertrophy, 

necrosis, brown pigment, and apoptosis) was also noted in maternal animals in a preliminary

developmental toxicity study in rabbits. Chronic exposure in rats led to similar liver effects, 

along with gross lesions (pale, enlarged, pitted, and mottled livers, and accentuated markings on 

the liver) and more pronounced liver histopathology (eosinophilic or basophilic hepatocytes, 

rarefied or vacuolated hepatocytes, altered foci, single cell necrosis, hypertrophy, and fatty 

change). In dogs, liver effects were limited to increased alkaline phosphatase and liver weights 

after long-term exposure. In mice, basophilic and/or eosinophilic vacuolated hepatocytes, 

hepatitis, and brown pigmented macrophages were observed after chronic exposure, with the 

addition of hepatocellular adenomas/carcinomas at the HDT. 

Treatment-related effects were also observed in other organs in subchronic and chronic oral, 

dermal, and inhalation studies in rats, dogs, and mice, but these effects were not regularly noted 

in all three species or in all studies in a given species. In rats, effects observed were decreased 

body weight gain, decreased food consumption, mild anemia, and clinical chemistry alterations 

(increased serum cholesterol, phospholipid, and aspartate aminotransferase). Testicular atrophy

and increased testicular weights (inhalation study), pancreatic exocrine atrophy, increased lung 

weights and increased alveolar adenomatosis, epithelialization, and macrophages were also 

observed. Additionally, thyroid gland follicular cell hyperplasia and an increased incidence of 

thyroid gland follicular cell tumors in male rats, but not in female rats, were seen. In dogs, 

effects included increased salivation and increased nasal dryness, grey mottling of the retina, 

mild anemia, and gastric lymphoid hyperplasia. In mice, increased mortality (at high doses), 

decreased body weight gain, increased serum glucose, increased kidney weights, cystic thyroid 

follicles, and an increased incidence of hepatocellular adenoma/carcinoma (males) were seen. In 

a subchronic inhalation toxicity study in rats, pulmonary effects were observed at the mid and 

high doses. These effects included dose related increases in lung/bronchial weights and 

increased incidences of alveolar macrophages and peribronchiolar proliferation in both sexes. 
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In a developmental toxicity study in rats, there was evidence of increased qualitative 

susceptibility of fetuses to fluazinam; however, there was no evidence of increased quantitative 

susceptibility. Decreased body weights, placental weights, and increased incidences of 

facial/palate clefts, diaphragmatic hernia and delayed ossification (several bone types) were 

observed in fetuses at the HDT. There was also greenish amniotic fluid and increases in late 

resorptions, as well as post-implantation loss. Maternal effects observed at the same dose level 

were decreased body weight gain and food consumption, increased water consumption, and 

increased urogenital staining.

There was no evidence of increased quantitative or qualitative susceptibility in a developmental 

toxicity study in rabbits or in a 2-generation reproduction study in rats. In rabbits, increased 

incidences of total litter resorptions and a slightly increased incidence of fetal skeletal 

abnormalities (e.g. kinked tail tip, fused or incompletely ossified sternebrae, and abnormalities of 

head bones) were seen in fetuses at the HDT. At the same dose, abortions, resorptions, placental 

anomalies, decreased body weight gain and food consumption, and significant liver histopathology were seen in maternal animals. Additionally, treatment-related effects were seen at lower 

doses in maternal animals in the absence of fetal effects. In the rat reproduction study, decreased 

pup weight gain was seen at the HDT in the presence of decreased food consumption and liver 

histopathology in parental animals.

Clinical signs were observed in an acute oral neurotoxicity study in rats; decreases in motor 

activity and soft stools were seen on the day of dosing at the limit dose. These effects were 

attributed to systemic toxicity and were not considered to be evidence of frank neurotoxicity. In 

two subchronic neurotoxicity studies (evaluated together) in rats, no evidence of neurotoxicity

was observed up to and including the HDT. A neurotoxic lesion described as vacuolization of 

the white matter of the CNS was observed initially in long-term studies in mice and dogs; 

however, the lesion is reversible and was later attributed to the presence of an impurity in the 

technical material. The developmental neurotoxicity study was conducted with a technical with 

significantly less of the impurity, and there were no lesions or developmental neurotoxicity

concerns (see section 4.4.2).

In an immunotoxicity study in mice, significant suppressions of anti-SRBC AFC assay response 

were demonstrated at the HDT indicating potential immunotoxicity. However, clear NOAELs 

and LOAELs were identified for the effects seen in the study and the points of departure (PODs) 

and endpoints selected for risk assessment are protective of immunotoxic effects. 

 

Fluazinam is classified as having “Suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential.” This classification was based on some evidence of thyroid 

tumors in male rats and evidence of liver tumors in male mice. The CARC determined that 

quantification of risk using a non-linear approach (i.e., RfD) will adequately account for all 

chronic toxicity, including carcinogenicity, that could result from exposure to fluazinam. 

Fluazinam (technical) has low or mild acute toxicity (Categories III and IV), except for acute eye 

irritation (I) and acute inhalation toxicity (II). 
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4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The proposed and existing use patterns for fluazinam will result in dietary and residential 

exposure to infants and children. Thus, FQPA hazard and exposure considerations were 

addressed in HED’s evaluation of the database. HED recommends that the 10x FQPA Safety 

Factor (for the protection of infants and children) be reduced to 1x. This recommendation is 

supported by the following: 1) the toxicological database for fluazinam is complete with regard 

to pre-and postnatal toxicity, including the required immunotoxicity and neurotoxicity studies 

and the developmental neurotoxicity study, 2) the endpoints and doses selected for risk 

assessment are protective of the qualitative and quantitative susceptibility observed in the 

developmental rat and DNT studies, respectively, and the degree of concern for the susceptibility

is low, 3) although indications of neurotoxicity and immunotoxicity were observed in the 

database, there were clear NOAELs for these effects, and the endpoints and doses for risk 

assessment are protective of the potential effects, 4) the dietary exposure assessments are based 

on high-end health protective residue levels and processing factors for foods, and upper-bound 

assumptions were used to determine exposure through drinking water, and 5) the residential 

assessments were conducted in accordance with standard practices that ensure exposures were 

not underestimated, and further, no residential exposure is expected for children. 

4.4.1 Completeness of the Toxicology Database 

The available toxicity studies are adequate for assessing and characterizing potential pre- and/or 

post-natal susceptibility for infants and children, and the database is complete in accordance with 

the Part 158 data requirements, including route-specific toxicity studies. Acceptable/guideline 

developmental toxicity studies in rats and rabbits, a reproduction study in rats, and a DNT study 

in rats are all available for FQPA assessment.

4.4.2 Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in an acute neurotoxicity study in rats up to 1000 

mg/kg/day. Decreases in motor activity and soft stools were observed on the day of dosing. 

These findings are attributed to systemic toxicity and are not considered to be evidence of frank 

neurotoxicity. However, a neurotoxic lesion described as vacuolization of the white matter of 

the central nervous system (CNS) was observed in subchronic and chronic studies in mice and 

dogs, as well as special studies in rats. After further investigation, it was determined that one 

single impurity, Impurity-5, was solely responsible for the appearance of the white matter 

vacuolization. A developmental neurotoxicity (DNT) study containing a lower concentration of 

Impurity-5 was submitted to address the concerns regarding the vacuolization observed. In the 

study, there was no evidence of vacuolization of the brain or any other treatment-related 

pathology up to the highest dose tested. The DNT study contained a lower concentration of 

Impurity-5 than the maximum concentration of Impurity-5 in technical grade fluazinam. 

Therefore, it was concluded that fluazinam, per se, was not responsible for the induction of this 

lesion. A NOAEL for Impurity-5 was determined that is equivalent to a NOAEL for CNS 

effects of 20 mg/kg/day for technical grade fluazinam. The current acute and chronic reference 

doses selected for risk assessment are lower than the determined NOAEL and protective of any 

possible neurotoxic effects resulting from exposure to Impurity-5.
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4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal 

No evidence of increased quantitative or qualitative susceptibility was seen in a developmental 

toxicity study in rabbits or a reproduction study in rats. However, there was evidence of 

increased qualitative susceptibility of fetuses in the developmental toxicity study in rats. 

Increased incidences of facial/palate clefts and other rare deformities were seen in fetuses in the 

presence of minimal maternal toxicity. A DNT study in rats was submitted to address the 

increased susceptibility as well as the presence of neurotoxic lesions observed after fluazinam 

exposure. In the DNT study, decreases in body weight and body weight gain as well as delayedpreputial separation were observed in pups. These effects were seen in the absence of maternal 

effects, suggesting increased quantitative susceptibility of the offspring.

 

Although there is evidence of increased qualitative susceptibility in the developmental toxicity

study in rats, there are no residual uncertainties with regard to pre- and/or postnatal toxicity

following in utero exposure to rats or rabbits and pre and/or post-natal exposures to rats. 

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

the degree of concern for the effects observed in the developmental rat study is low. There is a 

clear NOAEL for the fetal effects seen, the effects occurred in the presence of maternal toxicity, 

and they were only seen at the highest dose tested. Additionally, the fetal NOAEL of 50 

mg/kg/day identified in the developmental toxicity study in rats is significantly higher than the 

NOAEL used (7 mg/kg/day) to establish the acute reference dose (aRfD, females 13-49);

therefore, the aRfD is protective of any observed fetal effects. 

As previously stated, increased quantitative susceptibility was seen in the DNT study in rats. 

Although the NOAEL determined for the DNT study (2 mg/kg/day) is lower than the NOAEL 

used for acute dietary risk assessment for females 13-49 (7 mg/kg/day), the effects noted in the 

DNT study are attributable to multiple doses and are considered to be post-natal effects. 

Therefore, the study endpoint is not appropriate for assessing acute dietary exposure and risk. 

Additionally, the NOAEL (1.1 mg/kg/day) used for the chronic dietary assessment is lower, and 

is considered to be protective of the effects observed in the DNT study.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with respect to dietary and residential exposure. The dietary

exposure assessments are based on high-end health protective residue levels (that account for 

parent and metabolites of concern), and processing factors. Actual risk from exposure to 

fluazinam will likely be much lower than HED’s risk estimates conducted for the proposed and 

existing uses. Furthermore, conservative, upper-bound assumptions were used to determine 

exposure through drinking water and residential sources, such that these exposures have not been 

underestimated.
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4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The detailed descriptions of the toxicity studies used for selecting toxicity endpoints and points 

of departure for various exposure scenarios are presented in Appendix A.3 of this assessment.

For acute dietary assessment for females 13-49, the endpoint selected for risk assessment was 

increased incidence of total litter resorptions and increased incidence of fetal skeletal 

abnormalities at the LOAEL of 12 mg/kg/day, and the point of departure (POD) was the NOAEL 

of 7 mg/kg/day. For the general population, the acute dietary endpoint was clinical signs (soft 

stools and decreased motor activity) observed at the LOAEL of 1000 mg/kg/day; the POD was 

the study NOAEL of 50 mg/kg/day. The effects observed in the selected studies are considered 

to be attributable to a single dose of fluazinam.

For chronic dietary exposure and risk assessment, the carcinogenicity study in mice and the 

chronic study in dogs were selected as co-critical studies. In both studies, the NOAELs 

determined were approximately 1 mg/kg/day and the LOAELs approximately 10 mg/kg/day. In 

the mouse, effects seen were mainly in the liver (increased pigmented macrophages, eosinophilic 

vacuolated hepatocytes, and liver weights). In dogs, nasal dryness and gastric lymphoid 

hyperplasia were seen. The rat carcinogenicity study was also considered; however, the mouse 

and dog studies provided a lower point of departure. The POD for the chronic dietary

assessment was the NOAEL of 1.1 mg/kg/day from the carcinogenicity study in mice.

For short- and intermediate-term dermal exposure, a refined dermal dose of 24.4 mg/kg/day was 

calculated based on the dermal toxicity study and dermal absorption data. In the dermal toxicity

study, liver effects were seen at the LOAEL of 100 mg/kg/day. Developmental effects were 

noted in developmental toxicity studies at ≥ 12 mg/kg/day. Although the RDD is 24 mg/kg/day, 

it is based on an oral NOAEL that is lower than the dose at which developmental effects were 

seen. The comparable dermal equivalent dose (DED) for the developmental study, using the 

developmental NOAEL of 7 mg/kg/day and a DAF of 4.47% is 155 mg/kg/day. Therefore, the 

RDD is considered protective of potential developmental effects. Additionally, the RDD is 

protective of immunotoxic effects seen in an immunotoxicity study in mice at the LOAEL of 231 

mg/kg/day.

For short- and intermediate-term inhalation exposure, a route-specific 4 week inhalation toxicity

study was used for endpoint and dose selection. In previous risk assessments, the systemic liver 

effects observed in a 7-day inhalation study served as the basis for endpoint and dose selection. 

However, in the 4-week study, a dose related increase in lung and bronchial weights in both 

sexes was observed at the LOAEL of 0.020 mg/L/day. At 0.100 mg/L, there were also increased 

lung and bronchial weights, along with histopathology of the lung (alveolar macrophages, 

peribronchiolar proliferation) in both sexes. The NOAEL is 0.003 mg/L/day. In accordance 

with current guidance, human equivalent concentrations (HECs) and human equivalent doses 

(HEDs) were calculated, with the HEDs being used for risk assessment. The occupational 

inhalation HED is 0.048 mg/kg/day, and the residential inhalation HED is 0.043 mg/kg/day. 

The inhalation POD and endpoint are protective of the developmental effects seen in rats as well 
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as potential neurotoxicity and immunotoxicity since significantly lower PODs were determined 

in the inhalation study. 

The occupational HED is based on an 8-hour working day, and a corresponding 8 hours of 

inhalation exposure. The residential HED takes into account the potential for 24-hour bystander 

exposure via the inhalation route. At the current time, there are no data to quantitatively assess 

inhalation exposure to residential bystanders, and there are no other residential inhalation 

exposure scenarios based on the existing and proposed uses. If sufficient exposure data become 

available to assess potential bystander exposure and risk, the residential HED would be used. 

Based on the proposed use pattern for fluazinam, long-term dermal and inhalation exposures are 

not anticipated.

For acute and chronic dietary and dermal risk assessments, a 100x uncertainty factor was 

applied (interspecies factor of 10x and intraspecies factor of 10x). For dietary assessments, the 

acute and chronic population adjusted doses are therefore For dermal risk assessment, the level 

of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined interspecies 

and intraspecies uncertainty factors. For inhalation risk assessments, the LOC is an MOE of 30 

(interspecies factor of 3x and intraspecies factor of 10x) since human equivalent calculations 

(HECs) were used for risk assessment. The interspecies factor was reduced from 10x to 3x

because the HEC calculation accounts for pharmacokinetic (not pharmacodynamic) interspecies 

differences between animals and humans.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major sources: incidental oral, dermal, and 

inhalation. It must be determined whether or not the individual exposures have the same 

toxicological effects. If they do, then they can be combined. For fluazinam, inhalation and 

dermal routes cannot be combined because the toxicological effects are different.

4.5.3 Classification of Carcinogenic Potential

In accordance with EPA’s Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the 

Cancer Assessment Review Committee (CARC) classified (HED Doc. No.: 014512, March 29, 

2001) fluazinam as having “Suggestive evidence of carcinogenicity, but not sufficient to assess 

human carcinogenic potential,” based on increases in thyroid gland follicular cell tumors in male 

rats and increases in hepatocellular tumors in male mice. Although there is evidence of thyroid 

tumors in male rats and liver tumors in male mice, the NOAEL used (1.12 mg/kg/day) for 

establishing the chronic reference dose is approximately 3-fold lower than the lowest dose that 

induced tumors (3.8 mg/kg/day). The Agency has determined that quantification of cancer risk

using a non-linear approach would adequately account for all chronic toxicity, including 

carcinogenicity, that could result from exposure to fluazinam. 
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The cancer classification is based on the following weight-of-evidence considerations: 

(i) There was some evidence that fluazinam induced an increase in thyroid gland follicular 

cell tumors in male rats, but not in female rats at ≥ 100 ppm (3.8 mg/kg/day). In one 

study in mice, there was clear evidence that an increased incidence of hepatocellular 

tumors observed in male mice was treatment-related at 1000 ppm (107 mg/kg/day). In

another study in mice, there was equivocal/some evidence that fluazinam might have 

induced an increase in hepatocellular tumors in the male mice at ≥ 3000 ppm 

(377mg/kg/day). Increases in hepatocellular tumors observed in the female mice in the 

latter study were not statistically significant, and some occurred at an excessively toxic 

dose level. The thyroid gland follicular cell tumors of concern were seen only in the 

male rats, and the hepatocellular tumors of concern were seen only in the male mice. 

(ii) Fluazinam was negative in mutagenicity assays. In a combined chronic/carcinogenicity

study in rats, increased incidences of thyroid gland follicular cell tumors were observed 

in male rats only. Additionally, in two carcinogenicity studies in mice, increased 

incidences of hepatocellular tumors were observed in male mice only. The CARC 

concluded that there was some evidence that the thyroid tumors observed in the male rats 

were treatment-related. For the liver tumors in mice, the CARC concluded that there was 

clear evidence of treatment-related increases in both benign and malignant liver tumors in 

one study; however, it was concluded that there was only equivocal/some evidence for 

hepatocellular tumors in the other study. There was no evidence of mutagenicity in the 

available mutagenicity battery. 

4.5.4 Summary of Toxicological Doses and Endpoints for Fluazinam for Use in Human 

Health Risk Assessments 

Table 4.5.4.a. Toxicological Doses and Endpoints for Fluazinam for Use in

Dietary and Non-Occupational 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=

50 mg/kg/day

UF: 100x

UFA= 10x

UFH=10x

FQPA SF=1x

Acute RfD =0.5 mg/kg/day

aPAD= 0.5mg/kg/day

Acute Neurotoxicity-Rats.

LOAEL = 1000 mg/kg/day based on 

decreased motor activity and soft stools on 

day of dosing. 

Acute 

Dietary

(Females 

13-49 years 

of age)

NOAEL 

(developmental) = 

7 mg/kg/day

UF: 100x

UFA= 10x

UFH=10x

FQPA SF=1x

Acute RfD =0.07 

mg/kg/day

aPAD = 0.07mg/kg/day

Developmental Toxicity- Rabbits.

Developmental LOAEL = 12 mg/kg/day 

based on increased incidence of total litter 

resorptions and possibly increased 

incidence of fetal skeletal abnormalities.
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Table 4.5.4.a. Toxicological Doses and Endpoints for Fluazinam for Use in

Dietary and Non-Occupational 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

Chronic 

Dietary (All 

Populations)

NOAEL=

1.1 mg/kg/day

(mouse study)

UF: 100x

UFA= 10x

UFH=10x

FQPA SF=1x

Chronic RfD =0.011 

mg/kg/day

cPAD

= 0.011mg/kg/day

Co-critical: Carcinogenicity-Mice.

LOAEL = 10.7 mg/kg/day based on liver 

histopathology and increased liver weight. 

Chronic Dog.

LOAEL = 10 mg/kg/day based on 

marginal increases in the incidence of 

nasal dryness in females and the 

incidence/severity of gastric lymphoid 

hyperplasia in both sexes. 

Dermal 

Short-Term

(1-30 days) 

Dermal NOAEL=

24.4 mg/kg/day

UF: 100x

UFA=10x

UFH=10x

Residential LOC:

MOE = 100 

21-Day Dermal Toxicity-Rats

LOAEL= 100 mg/kg/day based on liver 

effects (increased AST and cholesterol 

levels).

A Refined Dermal Equivalent Dose (RDD) 

of 24.4 mg/kg/day was calculated using the 

dermal POD and dermal absorption data 

(see A.2) 

Inhalation 

Short-Term

(1-30 days) 

NOAEL=

0.003 mg/L 

HEC=

0.0003 mg/L

HED =

0.043 mg/kg/day 

UF: 30x

UFA=3x

UFH=10x

Residential LOC:

MOE = 30

4 week inhalation study in the rat.

LOAEL = 0.020 mg/L based on a dose 

related increase in absolute and relative 

lung/bronchial weights in both sexes. At 

0.100 mg/L, increased lung/bronchial 

weights were also seen , along with lung 

histopathology (alveolar macrophages, 

peribronchiolar proliferation) in both 

sexes.

Cancer 

(oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenicity, but not sufficient to assess human carcinogenic 

potential.”

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). PAD = population adjusted dose (a = acute, c = 

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

= human equivalent concentration; HED = human equivalent dose.
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Table 4.5.4.b. Summary of Toxicological Doses and Endpoints for Fluazinam for Use in

Occupational Human Health Risk Assessments

Exposure/ 

Scenario Point of Departure

Uncertainty/

FQPA Safety 

Factors

Level of Concern for 

Risk Assessment

Study and Toxicological Effects

Dermal 

Short-Term

(1-30 days); 

Intermediate

-Term (1-6 

months) 

Dermal NOAEL=

24.4 mg/kg/day

UF=100x

UFA=10x

UFH=10x

Occupational LOC for 

MOE = 100 

21-Day Dermal Toxicity-Rats

LOAEL= 100 mg/kg/day based on liver 

effects (increased AST and cholesterol 

levels)

A Refined Dermal Equivalent Dose (RDD) 

of 24.4 mg/kg/day was calculated using the 

dermal POD and dermal absorption data 

(see A.2) 

Inhalation 

Short-Term

(1-30 days); 

Intermediate

-Term (1-6 

months) 

NOAEL=

0.003 mg/L 

HEC= 0.001mg/L

HED =

0.048 mg/kg/day 

UF=30X

UFA=3x

UFH=10x

Occupational LOC: 

MOE = 30

4 week inhalation study in the rat.

LOAEL = 0.020 mg/L based on a doserelated increase in absolute and relative 

lung/bronchial weights in both sexes. At 

0.100 mg/L, increased lung/bronchial 

weights were also seen, along with lung 

histopathology (alveolar macrophages, 

peribronchiolar proliferation) in both 

sexes.

Cancer 

(oral, 

dermal, 

inhalation)

Classification: “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic 

potential”

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). MOE = margin of exposure. LOC = level of 

concern. HEC = human equivalent concentration; HED = human equivalent dose.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of fluazinam residues in plants is adequately understood based on metabolism studies 

on potatoes, peanuts, and grapes. The residue of concern in peanuts and root and tuber 

vegetables is parent fluazinam for purposes of both dietary risk assessment and tolerance

enforcement (D272624, W. Cutchin, 4/23/2001). For all other crops, the residues of concern 

include both fluazinam and its metabolite AMGT for purposes of dietary risk assessment. For 

tolerance enforcement, the residues of concern in plants include fluazinam and AMGT for wine 

grapes, but only fluazinam for all other plant commodities.
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The nature of fluazinam residues in rotational crops is adequately understood. Based on the 

absence of metabolites containing the intact fluazinam nucleus, HED has determined that the 

residue of concern in rotational crops is the parent compound, and that rotational crop tolerances 

are not required for fluazinam. The available confined field rotational crop study supports the 

30-day plantback interval (PBI) that is currently listed on the label for crops without direct uses 

of fluazinam.

The nature of the residue in livestock is also understood based on acceptable goat and hen 

metabolism studies. The fluazinam residues of regulatory interest in animal commodities are 

parent plus the metabolites AMPA and DAPA and their sulfamate conjugates.

5.1.2 Summary of Environmental Degradation

The environmental fate studies for fluazinam indicate that the parent compound forms 

transformation compounds that, in most cases, are similar in structure to the parent. Fluazinam 

does not undergo degradation. Instead, it undergoes transformation into a series of products, all 

of which are structurally similar to the parent compound. For modeling drinking water residues, 

the Environmental Fate and Effects Division (EFED) assumed that the physicochemical 

characteristics were similar for both the parent and its products (i.e., the total toxic residue 

approach).

5.1.3 Comparison of Metabolic Pathways

Fluazinam is a secondary amine whose substituents are substituted phenyl and pyridinyl rings. 

The primary metabolic and degradation pathways involve reduction of nitro groups on the 

phenyl ring followed by hydrolysis or conjugation of the various substituents on both rings. Two 

of the primary metabolites and degradates are AMPA and DAPA, and their hydrolysis or 

conjugation products. These compounds are primary metabolites in plants, ruminants, poultry, 

drinking water, and rats.

In plants, fluazinam undergoes reduction of one of the nitro groups to an amine, forming AMPA. 

AMPA can then be conjugated with glutathione, with subsequent degradation of the glutathione 

moiety to cysteine. The AMPA-cysteine conjugate then undergoes transamination, reduction, 

and conjugation with glucose to form AMGT. In addition, both rings of fluazinam appear to be 

labile to ring cleavage, and subsequent degradation of the rings into small fragments occurs. 

These fragments can then be incorporated into a variety of natural plant components.

In ruminants and poultry, the metabolism of [14C]-fluazinam is comparable, and involves 

reduction of one or both nitro groups on the phenyl ring to form AMPA, MAPA, or DAPA. 

Fluazinam also undergoes dehalogenation and hydroxylation of the chlorine on the phenyl ring 

to form HYPA. These compounds can then undergo conjugation with glutathione, and 

subsequent degradation of the glutathione component yields a variety of polar compounds. 

Although the ring structure of the parent molecule remains intact, fluazinam per se was only a 

minor component (≤2.7% TRR) of the [14C]-residues in poultry tissues and eggs, and was not 

detected in ruminant tissues or milk.
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In drinking water, the primary degradates include DCPA, CAPA, DAPA, HYPA, and AMPA. 

Although there are metabolites and degradates in plants, livestock, and drinking water that were 

not found in the rat, these compounds are structurally similar to the parent compound. The 

toxicity of these compounds is considered to be comparable to that of the parent. The 

toxicological endpoints that were selected for fluazinam are expected to be protective for the 

metabolites and degradates.

5.1.4 Residues of Concern Summary and Rationale

HED has concluded that the residue of concern in peanuts and root and tuber vegetables is parent 

fluazinam for purposes of both dietary risk assessment and tolerance enforcement (D272624, W. 

Cutchin, 4/23/2001). For all other crops, the residues of concern include both fluazinam and its 

metabolite AMGT for purposes of dietary risk assessment. For tolerance enforcement, the 

residues of concern in plants include fluazinam and AMGT for wine grapes, but only fluazinam 

for all other plant commodities. AMGT is included in the tolerance for wine grapes because it is 

the only adequate measure of misuse for residues in wine. The parent does not serve as a misuse 

measure in wine because it degrades during the fermentation process. Based on structural 

similarity, AMGT is assumed to have comparable toxicity as the parent and, therefore, is 

included for dietary risk assessment in those crops where it is present at significant levels.

Based on the absence of metabolites containing the intact fluazinam nucleus in rotational crop 

studies, HED has determined that the residue of concern in rotational crops is the parent 

compound, and that rotational crop tolerances are not required for fluazinam. The available 

confined field rotational crop study supports the 30-day plant-back interval (PBI) that is 

currently listed on the label for crops without direct uses of fluazinam.

The fluazinam residues of regulatory interest in animal commodities are parent plus the 

metabolites AMPA and DAPA and their sulfamate conjugates. These metabolites were the 

primary metabolites in the ruminant and poultry metabolism studies. AMPA and DAPA are 

structurally similar to fluazinam. They are the products formed by reduction of one or both nitro 

groups on the phenyl ring to form the mono- and di-amino metabolites. Their toxicity is 

assumed to be comparable to that of the parent compound (D272624, W. Cutchin, 4/23/2001). 

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: grapes Parent fluazinam and AMGT Parent fluazinam and AMGT

Primary Crop: peanuts, 

root/tuber vegetables, 

bulb vegetables 

Parent fluazinam Parent fluazinam

Primary Crop: all 

others

Parent fluazinam and AMGT Parent fluazinam
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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

Rotational Crop N/A Note: Tolerances are not 

required based on the absence 

of residues in rotational crops 

at the requested plant back 

interval.

Livestock Ruminant Parent fluazinam, AMPA, and 

DAPA, and their sulfate 

conjugates

Parent fluazinam, AMPA, and 

DAPA, and their sulfate 

conjugates

Poultry Parent fluazinam, AMPA, and 

DAPA, and their sulfate 

conjugates

Parent fluazinam, AMPA, and 

DAPA, and their sulfate 

conjugates

Drinking Water Fluazinam, CAPA, DAPA, 

DCPA, HYPA, and AMPA

Not Applicable

Under 40 CFR §180.574(a)(1), tolerances are established for residues of fluazinam, 3-chloro-N-

[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2-pyridinamine), including 

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

tolerance levels is to be determined by measuring only fluazinam. The existing tolerances for 

residues in grapes and livestock commodities are listed Under 40 CFR §180.574(a)(2) and (a)(3),

respectively, including the relevant coverage and compliance statements. No changes are needed 

in conjunction with the proposed uses or to support registration review.

5.2 Food Residue Profile

The food use profile for the proposed and registered commodities is adequate and complete for 

tolerance setting and risk assessment purposes (D397721, D. Dotson, 9/7/2012). For soybeans, 

melons, and peppers, the registrants submitted adequate field trial data for parent and the 

metabolite AMGT. For head and leaf lettuce, IR-4 submitted adequate field trial data for the 

metabolite AMGT, which were requested in a previous review (D360840, D. Dotson, 

3/31/2010). Adequate storage stability data were submitted for melons, peppers, and soybean 

forage, hay, and seed. The data indicated that residues were stable over the storage durations 

used in the field trial and processing studies. 

For all crops, adequate numbers of trials were performed in the recommended NAFTA growing 

zones. Residues of parent fluazinam were below the LOQ of 0.01 ppm in all samples of soybean 

seed. Quantifiable residues of fluazinam were found in soybean forage, soybean hay, melons, 

and peppers. The ranges of residues in the samples of these commodities can be found in Table 

5.2. No quantifiable residues of AMGT were found in any samples of any commodities tested, 

including head and leaf lettuce. 
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The registrant submitted a processing study for soybeans. Residues concentrated in soybean 

hulls, and a separate tolerance for the commodity will be needed. Separate tolerances will not be 

needed for soybean oil or meal.

Although soybean seed and hulls are livestock feed items, the current tolerances for livestock 

commodities (0.05 ppm for the fat and meat byproducts of cattle, goats, horses, and sheep) are 

adequate.

Table 5.2 provides a summary of the soybean, cantaloupe, pepper, and lettuce field trial data.

TABLE 5.2. Summary of Fluazinam Field Trial Residue Data 

Commodity Analyte Total

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)

n Sample 

Min.

Sample 

Max.

LAFT1 HAFT2 Median Mean Std. 

Dev.

Soybeans

Soybean Forage Fluazinam 0.99-1.17 29-35 16 0.021 3.73 0.034 3.06 0.427 0.63 0.74

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Soybean Hay Fluazinam 29-35 16 <0.017 5.21 0.028 5.21 0.868 1.41 1.48

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Soybean Seed Fluazinam 56-94 16 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Cantaloupes

Cantaloupe Fluazinam 5.18-5.35 27-32 22 <0.01 0.077 <0.01 0.048 0.01 0.017 0.015

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Peppers (Bell and Non-Bell)

Bell Pepper Fluazinam 4.47-5.45 28-31 18 <0.01 0.038 <0.01 0.030 0.01 0.014 0.007

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Non-Bell 

Pepper

Fluazinam 5.10-5.29 28-31 8 <0.01 0.053 <0.01 0.045 0.01 0.02 0.016

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Lettuce

Head Lettuce AMGT 0.95-1.02 46-52 14 <0.02 <0.02 <0.02 <0.02 0.02 0.02 NA

Leaf Lettuce AMGT 0.97-1.05 20-32 14 <0.02 <0.02 <0.02 <0.02 0.02 0.02 NA

1

 LAFT = lowest average field trial

2

 HAFT = highest average field trial result.

NA = not applicable

The OECD MRL calculation procedures were used for determining appropriate tolerance levels. 

The recommended tolerances for soybean seed, soybean hulls, the melon subgroup, and the 

pepper/eggplant subgroup are listed in Table 2.2.3.

5.3 Water Residue Profile

The drinking water assessment performed by EFED provides EDWCs of fluazinam in surface 

water and in groundwater. The drinking water residue used in the dietary risk assessment was 

provided by EFED (D397602, J. Meléndez, 7/17/2012) and incorporated directly into this dietary

assessment into the food categories “water, direct, all sources” and “water, indirect, all sources.” 

The residues of concern in drinking water for risk assessment are parent fluazinam and its 
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transformation products, including DCPA, CAPA, DAPA, HYPA, and AMPA. The acute and 

chronic EDWCs are based on ground application of fluazinam to turf. The turf use results in 

higher EDWCs than uses on the proposed crops (as well as all other crops). The values are 

provided in Table 5.3, below. The groundwater value was generated using the Screening 

Concentration in Groundwater (SCI-GROW) Model and the surface water values were generated 

using the FQPA Index Reservoir Screening Tool (FIRST) Model. The surface water estimates 

were used for both the acute and chronic assessments because they were higher than the 

groundwater value. For the acute assessment, a value of 226 ppb was used. This value includes 

both parent and degradates. For the chronic assessment, a value of 37.8 ppb was used. This 

value also includes both parent and degradates. For more information about EFED’s drinking 

water models, see http://www.epa.gov/oppefed1/ models/water.

Table 5.3. Maximum Tier 1 Estimated Drinking Water Concentrations Based on Ground

Application of Fluazinam to Turf at a Seasonal Rate of 8.4 lb a.i./A

Source/Model

Fluazinam Total Residues of Fluazinam1

Acute/ppb Chronic/ppb Acute/ppb Chronic/ppb

Surface Water/FIRST 217 21.47 226 2

37.8

Groundwater/SCI-GROW 0.404

1. Including the following transformation products: DCPA, HYPA, CAPA, DAPA, and AMPA.

2.

Exceeds the solubility of fluazinam at pH 7 (71 ppb), but not the solubility at pH 11 (350 ppm).

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

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

conducted using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 3.16 which 

uses food consumption data from the U.S. Department of Agriculture’s National Health and 

Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This dietary

survey was conducted from 2003 to 2008.

The acute analysis is based on tolerance-level residues for all commodities and uses high-end 

residue estimates for the metabolite AMGT. In addition, the acute assessment assumes 100% 

crop treated and incorporates modeled EDWCs that account for both parent fluazinam and its 

transformation products. Default processing factors were used for all relevant processed 

commodities without separate tolerances. Therefore, the resulting exposure and risk estimates 

are considered to be very conservative.

The chronic analysis is based on tolerance-level residues for all commodities except apples. For 

apples, the average field trial value was used. As with the acute assessment, it incorporates highend estimates for AMGT, 100% crop treated assumptions, default processing factors for all

relevant processed commodities without a separate tolerance, and modeled EDWCs that account 

for both parent and transformation products. Again, the resulting exposure and risk estimates are 

considered to be conservative.
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Because such conservative assumptions were made in the assessments, the resulting exposure 

and risk estimates are considered to be conservative as well. HED is confident that the acute and 

chronic dietary exposure assessments significantly overestimate risk to the general U.S. 

population and its various population subgroups.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic assessments were both based on the assumption that 100% of all 

commodities with fluazinam tolerances will be treated.

5.4.3 Acute Dietary Risk Assessment

The acute risk estimates at the 95th percentile of exposure are below HED’s level of concern for 

all population subgroups, including those comprised of infants and children. Generally, HED is 

concerned when risk estimates exceed 100% of the population-adjusted dose (PAD). The acute 

risk estimate for the general U.S. population is 5.3% of the acute PAD (aPAD). The population 

subgroup with the highest acute dietary risk estimate is Females 13-49, which uses 28% of the 

aPAD. Although Females 13-49 use the greatest percent of the aPAD, the population subgroup 

with the highest exposure estimate is Children 1-2. This subgroup uses 21% of the aPAD. The 

reason this subgroup has a higher exposure but a lower estimated risk than Females 13-49 is that 

it has a higher aPAD value than Females 13-49 (0.5 mg/kg/day for Children 1-2 as opposed to

0.07 mg/kg/day for Females 13-49). Since the assessment used an assumption of 100 %CT, the 

risk estimates are being reported at the 95th percentile of exposure. The acute dietary risk 

estimates are given in Table 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

Chronic risk estimates are also below HED’s level of concern for all population subgroups. The 

risk estimate for the general U.S. population is 20% of the chronic PAD (cPAD). The most 

highly exposed population subgroup is All Infants (<1 year old), which uses 51% of the cPAD.

The chronic dietary risk estimates are given in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

Fluazinam is classified as having “suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential.” The CARC determined that quantification of risk using a 

non-linear approach (i.e., RfD) will adequately account for all chronic toxicity, including 

carcinogenicity, that could result from exposure to fluazinam. As a result, a separate dietary

exposure assessment for cancer risk was not performed.
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5.4.6 Summary Table

Table 5.4.6. Summary of Acute and Chronic Dietary Exposure and Risk Estimates for Fluazinam

Population Subgroup

Acute Assessment (95th Percentile) Chronic Assessment

aPAD, 

mg/kg/day

Exposure Estimate, 

mg/kg/day

% aPAD cPAD, 

mg/kg/day

Exposure Estimate, 

mg/kg/day

% cPAD

U.S. Population 0.5 0.026393 5.3 0.011 0.002145 20

All infants 0.5 0.083776 17 0.011 0.004928 45

Children 1-2 yrs* 0.5 0.106710 21 0.011 0.005635 51

Children 3-5 yrs 0.5 0.064022 13 0.011 0.003751 34

Children 6-12 yrs 0.5 0.031323 6.3 0.011 0.002031 18

Youth 13-19 yrs 0.5 0.017332 3.5 0.011 0.001171 11

Adults 20-49 yrs 0.5 0.019148 3.8 0.011 0.001936 18

Adults 50-99 yrs 0.5 0.017495 3.5 0.011 0.002118 19

Females 13-49 yrs* 0.07 0.019721 28 0.011 0.001996 18

*The subpopulations with the highest acute or chronic risk estimates

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure and Risk

The Agency uses the term “Handlers” to describe those individuals who are involved in the 

pesticide application process. A residential handler assessment has not been conducted for 

fluazinam, since the end-use product, Fluazinam Turf Fungicide, limits the application site to 

golf courses only. The proposed label also includes the following statement in the use 

restrictions section: “Do not apply product to home lawns (turf) or any other residential turf.”

6.2 Residential Post-application Exposure

Fluazinam residential post-application scenarios include individuals playing golf on treated turf. 

Children 6 to <11 years old, youths 11 to <16 years old, and adults can potentially be exposed 

when they play golf on treated turf. Post-application residential exposure was assessed using 

default assumptions and transfer coefficients from the HED SOPs for Residential Exposure 

Assessments, (2012), as well as chemical-specific residue data from a turf transferable residue 

(TTR) study (MRID No. 48361527). Although HED typically assesses oral (hand-to-mouth) 

post-application exposure and risk for toddlers playing on treated turf, these exposures are not 

expected for golf course turf, and were therefore not assessed.

6.2.1 Dermal Post-application Exposure

Short-term residential post-application dermal exposures resulting in MOEs greater than or equal 

to 100 are not of concern. Short-term dermal post-application exposure and risk analyses for 

golfers resulted in MOEs greater than the LOC and are not of concern. The highest risk estimate 

(lowest MOE) was for youth golfers aged 6 to <11 years old, with an MOE of 780. A summary

of the residential short-term dermal exposure and risk estimates is shown in Table 6.2.1.
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Table 6.2.1. Residential Post-application Short-term Dermal Exposure and Risk Estimates for Fluazinam

Scenario Application 

Rate

(lb ai/A)

TTR 1

(μg/cm2)

CF TC

(cm2/hr)

ET 

(hrs)

BW 

(kg)

Dose 2 

(mg/kg/day)

Dermal

MOE 3

Golfer

6 to < 11 yrs old 0.7 0.0865 0.001 2,900 4 32 0.031356 780

11 to < 16 yrs old 0.7 0.0865 0.001 4,400 4 57 0.026709 910

Adult 0.7 0.0865 0.001 5,300 4 80 0.022923 1,100

1. Turf Transferable Residues (TTR) = 0.0865 ug/cm2is based on predicted day 0 residue value calculated from chemicalspecific data (MRID No. 48361527).

2. Dermal Dose (mg/kg/day) = [TTR (μg/cm2) x 0.001 (mg/μg) x TC (cm2/hr) x ET (hr/day)]/ BW (kg).

3. Dermal MOE = (NOAEL (24.4 mg/kg/day)) ÷ (Dermal Dose (mg/kg/day)).

6.2.2 Inhalation Post-application Exposure

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment is not being performed for fluazinam at this time primarily because of its vapor 

pressure of 1.73 x 10-7 mm Hg. However, volatilization of pesticides can be a potential source of 

post-application inhalation exposure to individuals in close proximity to 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. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP /meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and might, as appropriate, develop policies and procedures 

to identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency’s risk assessments. If new policies or procedures are put into place, 

the Agency might revisit the need for a quantitative post-application inhalation exposure 

assessment for fluazinam.

6.3 Combined Residential Risk Estimates

HED combines risk values resulting from separate exposure scenarios when it is likely they can 

occur simultaneously based on the use pattern and when the toxicological effects are the same 

across different routes of exposure. Since inhalation post-application exposure is expected to be 

negligible outdoors, and the application of fluazinam is only directed for golf course, incidental 

oral post-application exposure for children is also expected to be negligible. The only route of 

exposure is through the dermal route (i.e., dermal post-application exposure). Therefore,

combined residential exposure assessment for golfers is not required. 

6.4 Residential Risk Estimates for Use in Aggregate Assessment

The residential scenarios and risk estimates identified for use in performing an aggregate 

exposure assessment as part of the fluazinam human health risk assessment are: dermal postapplication exposure resulting from treated golf courses for adults (MOE = 1,100) and for 

children 6 to < 11yrs old (MOE = 780).
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6.5 Spray Drift

Spray drift is always a potential source of exposure to residents in close proximity to spraying 

operations. This is particularly the case with aerial application, but, to a lesser extent, could also 

be a potential source of exposure from the ground application method employed for fluazinam. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, State 

Lead Agencies for pesticide regulation, and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods. 

After the policy is in place, the Agency might impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios.

6.6 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment is not being performed for fluazinam at this time primarily because of its vapor 

pressure (1.73 x 10-7 mm Hg), and the proposed use rates (0.52-0.78 lb ai/A). However, 

volatilization of pesticides might 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.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report and might, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency’s risk assessments. If new policies or 

procedures are developed, the Agency might revisit the need for a quantitative post-application 

inhalation exposure assessment for fluazinam.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposure and 

risk estimates 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 risk estimates themselves can 
Fluazinam Human Health Risk Assessment DP No. D397601

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be aggregated. When aggregating exposures and risks from various sources, HED considers 

both the route and duration of exposure.

7.1 Acute Aggregate Risk

Acute aggregate risk results from exposure to residues in food and drinking water. The acute 

dietary exposure analysis included both food and drinking water. Therefore, acute aggregate risk

estimates are equivalent to the acute dietary risk estimates, as discussed in Section 5.4.3, above. 

All risk estimates are not of concern.

7.2 Short-/Intermediate-Term Aggregate Risk Estimates

For the short-term aggregate risk assessment, the only relevant residential exposure scenario, 

dermal post-application, was combined with background exposure from food and water.

The chronic dietary exposure estimates are the background exposure levels that were added 

directly to the residential dermal post-application exposure estimates. Of the population 

subgroups comprised of adults, the subgroup Adults 50-99 had the highest dietary exposure 

estimate. For the child and youth population subgroups, the dietary groups did not directly

overlap with the representative residential life stages. Specifically, the closest dietary subgroup 

to the residential life stage children 6-<11 was children 6-12, and the closest dietary subgroup to 

the residential life stage youth 12-<16 was youth 13-19. 

The short-term aggregate risk assessments resulted in estimated MOEs of 730 to 970. For 

fluazinam, the LOC for short-term risk is an MOE of 100. As the resulting aggregate MOEs

exceed the LOC of 100, aggregate dietary and residential risk estimates are not of concern. 

Because the background exposure from food and water is so low relative to the dermal exposure 

estimates, the short-term aggregate MOEs are the similar to those estimated for the dermal route 

alone. The aggregate risk estimates are given in Table 7.2.

Table 7.2. Residential Short-/Intermediate-Term Aggregate Risk Calculations

Population

Short- or Intermediate-Term Scenario

NOAEL

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential Postapplication 

Dermal Exposure 

mg/kg/day3

Total 

Exposure4

mg/kg/day

Aggregate 

MOE (food, 

water, and 

residential)

5

Children 6-<11 24.4 100 0.244 0.002031 0.031356 0.033387 730

Youth 11-<16 24.4 100 0.244 0.001171 0.026709 0.027880 880

Adults 24.4 100 0.244 0.002118 0.022923 0.025041 970

1. An UF of 100x was applied to account for interspecies extrapolation (10x) and intraspecies variation (10x). No 

additional uncertainty factors/safety factors are required.

2. Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3. Residential Exposure = Dermal exposure from treated turf (see table 6.2.2). 

4. Total Exposure = Avg Food & Water Exposure + Residential Exposure

5. Aggregate MOE = [NOAEL (24.4 mg/kg/day) ÷ (Avg Food & Water Exposure + Residential Exposure 

(mg/kg/day))]
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7.3 Chronic Aggregate Risk

There are no residential scenarios that result in long-term exposure. As a result, the chronic 

aggregate risk assessment results from long-term exposure to residues in food and drinking water

only. The chronic dietary exposure analysis included both food and drinking water and, 

therefore, the chronic aggregate risk assessment is equivalent to the chronic dietary assessment

discussed in Section 5.4.4, above. All risk estimates are below HED’s level of concern.

7.4 Cancer Aggregate Risk

Fluazinam is classified as having “suggestive evidence of carcinogenicity, but not sufficient to 

assess human carcinogenic potential.” The CARC determined that quantification of risk using a 

non-linear approach (i.e., RfD) will adequately account for all chronic toxicity, including 

carcinogenicity, that could result from exposure to fluazinam. As a result, a separate dietary

exposure assessment for cancer risk was not performed.

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 fluazinam and any other substances, and fluazinam does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this risk assessment, therefore, 

EPA has not assumed that fluazinam 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 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns, current labeling, and the types of equipment and 

techniques that can potentially be used, occupational handler exposure is expected from the 

proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is 

based on the following scenarios: 

• Mixing/Loading Liquids for Groundboom Application,

• Mixing/Loading Liquids for Aerial Application,

• Mixing/Loading Liquids for Chemigation,

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment, 

• Flagging for Aerial Applications, and

• Mixing/Loading/Applying Liquids with Mechanically-Pressurized Handgun Sprayer.
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No handler exposures are expected from applying sprays via chemigation systems.

The maximum single application rate on the proposed label was used to assess all handler 

exposure scenarios (0.52-0.78 lb ai/A). The maximum application rate per acre per season

ranges from 1.04 - 4.68 lb ai/A/yr. The number of applications per year at the maximum single 

application rate ranged from 2-6 depending on the use site.

No data on the number of exposure days per year were provided. For fluazinam, based on the 

proposed use patterns and directions (e.g., 2-6 applications per season with a minimum 7-14 day

spray interval depending on the use), short- and intermediate-term exposures are expected for 

handlers. The estimates are considered to be protective for intermediate-term exposure and risk. 

Long-term exposures are not expected.

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 fluazinam product label directs mixers, loaders, applicators and other handlers to wear:

baseline clothing (i.e., long-sleeved shirt and long pants, socks), chemical-resistant gloves and 

footwear, and protective eyewear. When mixing and loading, handlers must wear a chemicalresistant apron and a dust/mist filtering respirator (MSHA/NIOSH TC-21C) or a NIOSH 

approved respirator with an N, R, P or HE filter.

Detailed descriptions of the occupational handler assessment are available in Z. Figueroa

(D397723, 9/7/2012). The occupational hander exposure and risk estimates rely on generic data 

from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural 

Handler Exposure Task Force (AHETF) database. 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 Table” (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, 

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

of the various sources, can be found at: http://www.epa.gov/pesticides/science/handler-exposuredata.html

In addition to the generic exposure data to assess occupational exposure and risk, HED used 

standard assumptions with respect to the area treated, the hours worked in a day, and the average 

adult body weight (80 kg).

Occupational Handler Non-Cancer Exposure and Risk Estimates

Table 9.1 presents the short-term dermal and inhalation risk estimates for handlers. Since the 

endpoints selected for risk assessment are different for dermal (liver effects) and inhalation (lung 

effects) routes of exposure, the exposure and risk cannot be combined. Therefore, dermal and 

inhalation risks were calculated and presented separately. Exposure estimates for the 

occupational handler scenarios described above resulted in MOEs greater than the respective 
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levels of concern (dermal LOC = 100; inhalation LOC = 30) at some level of PPE and with the 

assumption of an enclosed cockpit (i.e., engineering controls) for aerial applicators.

Handler dermal exposure and risk estimates were not of concern (LOC = 100) with baseline PPE, 

except for the following scenarios which required additional PPE to attain and MOE equal to or 

greater than 100; however, HED notes that these additional PPE are already required on the 

proposed label:

 mixing/loading liquids for groundboom applications to soybeans, which requires the use 

of chemical-resistant gloves,

 mixing/loading liquids for aerial applications to soybeans, which requires the use of 

chemical-resistant gloves + double layer clothing, and

 mixing/loading liquids for chemigation for melons and peppers, which requires the use of 

chemical-resistant gloves. 

Handler inhalation exposure and risk estimates were not of concern (LOC = 30) at the baseline 

PPE (i.e., no respirator) for all of the scenarios. The dermal and inhalation handler risk estimates 

do not require any changes to the PPE listed on the proposed label.

The Agency has evaluated scenarios that might be limited in nature such as flagging during 

aerial applications because engineering controls (i.e., Global Positioning Satellite technology) 

are now predominantly used as indicated by the 1998 National Agricultural Aviation Association 

(NAAA) survey of their membership. It appears, however, that flaggers are still used in 

approximately 10 to 15 percent of aerial application operations. In cases like these, the Agency

strongly encourages the use of the engineering control system, but will continue to evaluate risks 

for flaggers and any other population where a clear exposure pathway exists until the potential 

for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on 

exposure issues and will consider those results as are timely and appropriate.

HED has no data to assess exposure for pilots using open cockpits. The only data available 

represent exposure for pilots in enclosed cockpits. Therefore, pilot exposure and risk estimates

are determined assuming use of engineering control (enclosed cockpits) and baseline attire (i.e., 

long-sleeve shirt, long pants, shoes, and socks). Pilots are not required to wear protective gloves. 

With this level of protection, there are no risk estimates of concern for aerial applicators treating 

melons, peppers, and soybeans with fluazinam in accordance with the proposed label.
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Table 9.1. Short-Term Occupational Handler Exposure and Risk Estimates for Fluazinam

Exposure Scenario Crop or 

Target

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

Mitigation Level Mitigation Level Dose 

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

Mixer/Loader

Liquids for Groundboom 

Applications

(AHETF)

Melons, Peppers 220

(Baseline)

0.219

(No respirator) 0.78 lb ai/A 80 A 0.171 140 0.000171 280

Soybeans 37.6

(Gloves)

0.219

(No respirator) 0.52 lb ai/A 200 A 0.0489 500 0.000285 170

Liquids for Aerial 

Application

(AHETF)

Soybeans 29.1

(Double Layer, Gloves)

0.219

(No respirator) 0.52 lb ai/A 1,200 A 0.228 110 0.00171 30

Liquids for Chemigation

(AHETF)

Melons, Peppers 37.6

(Gloves)

0.219

(No respirator) 0.78 lb ai/A 350 A 0.129 190 0.000748 60

Applicator

Sprays for Groundboom 

Applications

(AHETF)

Melons, Peppers 78.6 

(Baseline)

0.34

(No respirator) 0.78 lb ai/A 80 A 0.061 400 0.000265 180

Soybeans 78.6 

(Baseline)

0.34

(No respirator) 0.52 lb ai/A 200 A 0.102 240 0.000443 110

Sprays for Aerial 

Application

(AHETF)

Soybeans 5

(Engineering Controls -

Enclosed cockpit)

0.068

(Engineering Controls -

Enclosed cockpit)

0.52 lb ai/A 1,200 A 0.039 630 0.000530 90

Flagger

Flagging for Aerial 

Applications 

(PHED)

Soybeans 11

(Baseline)

0.35

(No respirator) 0.52 lb ai/A 350 A 0.025 980 0.000796 60

Mixer/Loader/Applicator

Mechanically-pressurized 

Handgun Sprayer

(PHED)

Peppers (Soil 

Drench) 1,300

(Baseline)

3.9

(No respirator) 0.013 lb ai/gal 1,000 gal 0.211 120 0.000634 80

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2012); includes data from PHED/ORETF/AHETF (Level of Mitigation: Baseline, Gloves, Double Layer, 

Eng. Controls).

2 Based on the proposed crops listed on the registered label (EPA Reg. No. #71512-1).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A) x Area Treated or Amount Handled (A/day or gal/day)/BW (80 kg).

5 Dermal MOE = Dermal NOAEL (24.4 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 100.

6

Inhalation Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A) x Area Treated or Amount Handled (A/day or gal/day)/BW (80 kg).

7

Inhalation MOE = Inhalation NOAEL (0.048 mg/kg/day)/ Inhalation Dose (mg/kg/day); LOC = 30.
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9.2 Occupational Post-application Exposure/Risk Estimates

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment is not being performed for fluazinam at this time primarily because of its vapor 

pressure (1.73 x 10-7 mm Hg), and the proposed use rates (0.52-0.78 lb ai/A). However, 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 (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and might, as appropriate, develop 

policies and procedures to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the Agency’s risk assessments. If new 

policies or procedures are put into place, the Agency might revisit the need for a quantitative 

occupational post-application inhalation exposure assessment for fluazinam.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers, including flaggers. Handler exposure resulting from application of pesticides outdoors 

is likely to result in higher exposure than post-application exposure. Therefore, it is expected 

that these handler inhalation exposure estimates would be protective of most occupational postapplication inhalation exposure scenarios.

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

Occupational workers who enter treated fields to perform post-application activities such as hand 

weeding and scouting might be exposed to fluazinam residues. Based on the use pattern, 

workers might be exposed to short- and intermediate-term exposure durations. Detailed 

descriptions of the occupational post-application dermal assessment are available in Z. Figueroa, 

(D397723, 9/7/2012). 

Transfer Coefficients: It is the policy of HED to use the best available data to assess postapplication exposure. Sources of generic post-application data, used as surrogate data in the 

absence of chemical-specific data, are derived from ARTF exposure monitoring studies, and, as 

proprietary data, are subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting post-application exposure that are used in this assessment, 

known as “transfer coefficients”, are presented in the ExpoSAC Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at: http://www.epa.gov/pesticides/science/postapp-exposure-data.html. 
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Dislodgeable Foliar Residues: Chemical-specific dislodgeable foliar residue (DFR) studies on 

apples (MRID#: 45584203), potatoes (MRID #: 45584202), and peanuts (MRID#: 45584201) 

were submitted and reviewed by HED. The studies demonstrated that dislodgeable foliar residue 

values declined over time. Furthermore, HED concluded that the peanut DFR data serve as the 

best surrogate to assess post-application exposure for all crops when no crop-specific DFR data 

are available, based on available information about the study conditions, region of use, use 

pattern, etc. (M. Collantes, 03/18/2008, D349315). 

Therefore, dermal post-application exposure resulting from application of fluazinam on melons, 

peppers, and soybeans was estimated using the best available surrogate DFR predicted Day-0 

residue value from treated peanuts (0.987 ug/cm2) calculated by a first-order dissipation kinetics 

and decay model. Maximum single application rates were used in this assessment. Day-0 DFR 

values were adjusted by application rate. 

Dermal exposures during post-application activities were estimated using: 1) the maximum 

single application rate on the proposed label for each crop (0.52-0.78 lb ai/A), 2) a standard body

weight for the general population (80 kg), and 3) an average occupational workday of 8 hours 

per day.

Occupational Post-application Non-Cancer Dermal Risk Estimates

A summary of the post-application exposure and risk estimates for the proposed uses is provided 

in Table 9.2.b. Only risk estimates for the highest contact activity are shown below. Postapplication dermal exposure and risk estimates for the scenarios shown below resulted in MOEs 

greater than 100 on the day of application, and are not of concern. All other scenarios involving 

lower contact activities would have higher MOEs and are also not of concern.

Table 9.2.2.b. Short-term Occupational Post-application Exposure and Risk Estimates for Fluazinam

Crop/Site Activities DFR1 Day 0 Dose2 Day 0 MOE3 Day at which 

MOE ≥ LOC

Melons Irrigation (hand set) 0.975 0.1850 130 0

Peppers Irrigation (hand set) 0.975 0.1850 130 0

Soybeans Scouting 0.650 0.0715 340 0

1. Dislodgeable Foliar Residue (DFR) from Treated Peanuts = 0.987 ug/cm2is based on predicted day 0 residue value calculated from chemicalspecific data (MRID No. 455842-01) and then adjusted by application rate. 

2. Daily Dermal Dose = [DFR (μg/cm2) x TC x 0.001 mg/μg x 8 hrs/day]  BW (kg).

3. MOE = NOAEL (24.4 mg/kg/day) / Daily Dermal Dose. 

Restricted Entry Interval

The restricted entry interval (REI) for fluazinam is based on the acute toxicity of technical 

material. Fluazinam is classified as Toxicity Category I for eye irritation. Under the Worker 

Protection Standard (WPS) for Agricultural Pesticides, active ingredients classified as acute 

Toxicity Category I for any of the routes are assigned a 48-hour REI. Based on the acute toxicity

profile of fluazinam, the 48-hour REI specified on the OMEGA®500F label is appropriate to 

protect agricultural workers from post-application exposures to fluazinam on melons, peppers,

and soybeans. 
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10.0 References

D. Dotson, K. Middleton, Z. Figueroa, 3/31/2010, D365940, Fluazinam. Human Health Risk 

Assessment for the Proposed Uses on Apples, Carrots, Lettuce, and the Bulb Onion Subgroup (3-

07A), and a Request for a Reduced Tolerance on the Bushberry Subgroup (13-07B)

D. Dotson, K. Middleton, Z. Figueroa, 2/7/2012, Fluazinam. Human Health Risk Assessment 

for the Section 3 Registration Action on Turfgrass

D. Dotson, 9/7/2012, Fluazinam. Petitions for the Establishment of Tolerances and Registration 

of New Uses on Soybeans, the Melon Subgroup (9-A), and the Pepper/Eggplant Subgroup (8-

10B). Summary of Analytical Chemistry and Residue Data

D. Dotson, 9/7/2012, D397722, Fluazinam, Acute and Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on 

Soybeans, the Melon Subgroup (9A), and the Pepper/Eggplant Subgroup (8-10B)

Z. Figueroa, 2/7/2012, D387284, Fluazinam: Occupational and Residential Exposure 

Assessment for the Proposed Use on Golf Course Turf

J. Melendez, 7/17/2012, D397602, Tier I Estimated Drinking Waters Concentrations of 

Fluazinam and its Transformation Products for the Use in the Human Health Risk Assessment 

for the Registration of the New Uses on Peppers, Eggplant (Subgroup 8-10B), Melons (Subgroup 

9A), and Soybeans

Z. Figueroa, 9/7/2012, D397723, Fluazinam: Occupational and Residential Exposure and Risk 

Assessment for Registration Review and to Support the Registration of Proposed Uses on 

Melons, Peppers, and Soybeans

W. Cutchin, 4/23/2001, D272624, Fluazinam. Decision by Metabolism Assessment Review 

Committee (MARC)

D. Dotson, K. Middleton, S. Oonnithan, 9/2/2009, D362190, Fluazinam Human Health 

Assessment Scoping Document in Support of Registration Review

Fluazinam Final Work Plan for Registration Review, Fluazinam Registration Review Docket ID 

EPA-HQ-OPP-2009-0039

Y. Yang, 4/17/2012, D398060. Fluazinam: Immunotoxicity Study in Mice.

K. Middleton, D393912, Fluazinam: Toxicology Data Evaluation Record for Inhalation Toxicity

Study
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List of Appendices

Appendix A. Toxicology Profile and Additional Data

Appendix B. International Residue Limit Status Sheet

Appendix C. Fluazinam Physical/Chemical Properties

Appendix D. Review of Human Research

Appendix E. Structures of Fluazinam Metabolites and Degradates of Concern

Appendix F. Occupational Exposure and Risk Assessment to Support Registration Review
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Appendix A: Toxicology Profile and Additional Data

A.1. Toxicity Profile Tables for Fluazinam

Table A.1.1. Acute Toxicity Data on Fluazinam (Technical)

Guideline No./ 

Study Type

Test Substance MRID No. Results Toxicity 

Category

870.1100 

Acute oral toxicity 

rats

Technical grade fluazinam 

(lot #109; 95.3%)

42248603 M: LD50 = 4500 mg/kg

F: LD50 = 4100 mg/kg

III

Technical grade fluazinam 

(lot #8412-20; 95.3%)

42248602 M: LD50 >5000 mg/kg

F: LD50 >5000 mg/kg

IV

Technical grade fluazinam 

(lot #1/87; 97.9%)

42248604 M: LD50 >5000 mg/kg

F: LD50 >5000 mg/kg

IV

870.1200 

Acute dermal toxicity

rats

Technical grade fluazinam 

(lot #8303-2; 98.5%)

42248605 M: LD50 >2000 mg/kg

F: LD50 >2000 mg/kg

III

870.1300

Acute inhalation 

toxicity

rats

Technical grade fluazinam 

(lot #109; 95.3%)

42270601 M: LC50 = 0.463 mg/L

F: LD50 = 0.476 mg/L

II

870.2400

Acute eye irritation

rabbits

Technical grade fluazinam 

(lot # SNPE B-1216, No. 

1006; 97.9%)

42248606 Extremely irritating. 

Corneal opacity did NOT 

reverse in 21 days.

I

870.2500 Acute 

dermal irritation

rabbits

Technical grade fluazinam 

(lot # SNPE B-1216, No. 

1006; 97.9%)

42248607 Slightly irritating IV

870.2600 Dermal 

sensitization

guinea pigs

Technical grade fluazinam 

(lot # 1030/91; 96.7%)

42274401 Positive NA

Ultra-purified fluazinam 

(lot #Y910401; 100%)

42248608 Negative NA

Table A.1.2. Acute Toxicity Data on Fluazinam

Guideline No./ 

Study Type

Test Substance MRID No. Results Toxicity 

Category

870.1100 

Acute oral toxicity 

rats

Omega 500F 

(40% fluazinam)

42974907 M: LD50 >5000 mg/kg

F: LD50 >5000 mg/kg

IV

870.1200 

Acute dermal toxicity

rabbits

Omega 500F

(40% fluazinam)

42974908 M: LD50 >2000 mg/kg

F: LD50 >2000 mg/kg

III

870.1300

Acute inhalation 

toxicity

rats

Fluazinam 50% WP a

(51.3% fluazinam)

42311001 M: LC50 = 3.0 mg/L

F: LD50 = 3.4 mg/L

IV

870.2400

Acute eye irritation

rabbits

Omega 500F

(40% fluazinam)

42974910 Slightly irritating III

870.2500 Acute 

dermal irritation

rabbits

Omega 500F

(40% fluazinam)

42974911 Moderately irritating II

870.2600 Dermal Omega 500F 42974912 Positive NA
Fluazinam Human Health Risk Assessment DP No. D397601

Page 44 of 75

Table A.1.2. Acute Toxicity Data on Fluazinam

sensitization

guinea pigs

(40% fluazinam)

a Study satisfies requirement for testing on Omega 500F.

Table A.1.3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline/

Type of Study

Study Title/

Classification /Doses MRID Results

870.3100

90-Day oral toxicity 

rats

M : 0, 0.15, 0.77, 3.8, 38 

mg/kg/day;

F: 0, 0.17, 0.86, 4.3, 44 

mg/kg/day

Acceptable/guideline

42248610 (1984); 

44807214 (1998) NOAEL: Males: 3.8 mg/kg/day; 

Females: 4.3 mg/kg/day

LOAEL Males = 38 mg/kg/day; 

Females = 44 mg/kg/day based on 

increased liver weights and liver 

histopathology in males, and increased 

lung and uterus weights in females.

870.3150

90-Day oral toxicity 

dogs

M & F: 0, 1, 10, 100 

mg/kg/day 

Acceptable/guideline

42248611 (1991); 

44807215 (1998)

NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on 

retinal effects, increased relative liver 

weight, liver histopathology and 

possible increased serum alkaline 

phosphatase in females and possible 

marginal vacuolization of the cerebral 

white matter (equivocal)

870.3200

21-Day dermal 

toxicity

rats

M & F: 0, 10, 100, 1000 

mg/kg/day

Acceptable/guideline

42270602 (1985) Systemic NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on 

increased AST and cholesterol levels in 

clinical chemistry determinations 

(males)

Dermal NOAEL = not identified

LOAEL = 10 mg/kg/day based on 

erythema, acanthosis, and dermatitis

870.3465

4 week inhalation 

toxicity

Concentrations of 0, 

0.003, 0.020, or 0.100 

mg/L

Acceptable/guideline

48571410 NOAEL = 0.003 mg/L 

LOAEL = 0.020 mg/L based on a dose 

related increase in absolute and relative 

lung/bronchial weights in both sexes. 

At 0.100 mg/L, increased lung/bronchial 

weights were also seen, along with lung 

histopathology (alveolar macrophages, 

peribronchiolar proliferation) in both 

sexes.

870.3700a

Prenatal 

developmental 

toxicity 

rats

F: 0,10, 50, 250 

mg/kg/day

Acceptable/guideline

42248613 (1985) Maternal NOAEL = 50 mg/kg/day

LOAEL = 250 mg/kg/day based on 

decreased body weight gain and food 

consumption and increased water 

consumption and urogenital staining

Developmental NOAEL = 50 

mg/kg/day

LOAEL = 250 mg/kg/day based on 

decreased fetal body weights and 

placental weights, increased facial/cleft 

palates, diaphragmatic hernia, and 

delayed ossification in several bone 
Fluazinam Human Health Risk Assessment DP No. D397601

Page 45 of 75

Table A.1.3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline/

Type of Study

Study Title/

Classification /Doses MRID Results

types, greenish amniotic fluid and 

possible increased late resorptions and 

postimplantation loss

870.3700b

Prenatal 

developmental 

toxicity

rabbits

F: 0, 2, 4, 7, 12 

mg/kg/day 

Acceptable/guideline

42248616 (1988) Maternal NOAEL = 4 mg/kg/day

LOAEL = 7 mg/kg/day based on 

decreased food consumption and 

increased liver histopathology.

Developmental NOAEL = 7 mg/kg/day

LOAEL = 12 mg/kg/day based on an 

increase in total litter resorptions and 

possible fetal skeletal abnormalities

870.3700b

Prenatal 

developmental 

toxicity 

rabbits

F: 0, 0.3, 1, 3 mg/kg/day 

Unacceptable/guideline

42248615 (1985); 

42248614 (1984); 

42248617 (1984)

Maternal NOAEL = 3 mg/kg/day

LOAEL = not identified (>3 mg/kg/day)

Developmental NOAEL = 3 mg/kg/day

LOAEL = not identified (>3 mg/kg/day)

870.3800

Reproduction and 

fertility effects

rats

F0 males: 0, 1.5, 7.3, 

36.6 mg/kg/day

F0 females: 0, 1.7, 8.4, 

42.1 mg/kg/day

F1 males: 0, 1.9, 9.7, 

47.3 mg/kg/day

F1 females: 0, 2.2, 10.6, 

53.6 mg/kg/day

Acceptable/guideline

42248619 (1987); 

42208406 (1985); 

42248618 (1986)

Parental/Systemic NOAEL = 1.9 

mg/kg/day

LOAEL = 9.7 mg/kg/day based on liver 

pathology in F1 males

Reproductive NOAEL = 10.6 

mg/kg/day

LOAEL = 53.6 mg/kg/day based on 

decreased number of implantation sites 

and decreased litter sizes to day 4 postpartum for F1 females (F2 litters).

Offspring NOAEL = 8.4 mg/kg/day

LOAEL = 42.1 mg/kg/day based on 

reduced F1 and F2 pup body weight 

gains during lactation.

870.4100a

Chronic toxicity 

rats

M: 0, 1.0, 1.9, 3.9 

mg/kg/day

F: 0, 1.2, 2.4, 4.9 

mg/kg/day

Acceptable/guideline

44839901 (1993); 

44807213

NOAEL = Males: 1.9 mg/kg/day; 

Females: 4.9 mg/kg/day

LOAEL = Males: 3.9 mg/kg/day; 

Females: not identified (>4.9 

mg/kg/day) based on increased 

testicular atrophy in males and no 

effects in females

870.4100b

Chronic toxicity 

dogs

M & F: 0, 1, 10, 50 

mg/kg/day

Acceptable/guideline

42270603 (1987); 

44807219 (1998)

NOAEL = 1 mg/kg/day

LOAEL = 10 mg/kg/day based on 

gastric lymphoid hyperplasia in both 

sexes and nasal dryness in females

870.4300

Combined chronic 

toxicity/carcinogenicity

rats

M: 0, 0.04, 0.38, 3.8, 40 

mg/kg/day

F: 0, 0.05, 0.47, 4.9, 53 

mg/kg/day 

Acceptable/guideline

42248620 (1988); 

44807223 (1999); 

45150201 (2000)

NOAEL = Males: 0.38 mg/kg/day; 

Females: 0.47 mg/kg/day

LOAEL = Males: 3.8 mg/kg/day; 

Females: 4.9 mg/kg/day based on liver 

toxicity in both sexes, pancreatic 

exocrine atrophy in females and 

testicular atrophy in males.

Some evidence of carcinogenicity 
Fluazinam Human Health Risk Assessment DP No. D397601

Page 46 of 75

Table A.1.3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline/

Type of Study

Study Title/

Classification /Doses MRID Results

(thyroid gland follicular cell tumors) 

in male rats, but not in females.

870.4200b

Carcinogenicity 

mice

M: 0, 0.12, 1.1, 10.7, 

107 mg/kg/day

F: 0, 0.11, 1.2, 11.7, 117 

mg/kg/day

Acceptable/guideline

42208405 (1988); 

44807220 (1996)

NOAEL = Males:1.1 mg/kg/day; 

Females: 1.2 mg/kg/day

LOAEL = Males: 10.7 mg/kg/day; 

Females: 11.7 mg/kg/day based on 

increased incidences of brown 

macrophages in the liver of both sexes, 

eosinophilic vacuolated hepatocytes in 

males, and increased liver weight in 

females

Clear evidence of carcinogenicity

(hepatocellular tumors) in male mice, 

but not in females

870.4200b

Carcinogenicity 

mice

M: 0, 126, 377, 964 

mg/kg/day

F: 0, 162, 453, 1185 

mg/kg/day 

Acceptable/guideline

44807222 (1996); 

44807221 (1998); 

45201301 (2000)

NOAEL = Males:<126 mg/kg/day, 

Females: <162 mg/kg/day

LOAEL = Males: 126 mg/kg/day; 

Females: 162 mg/kg/day based on 

increased liver weights and liver and 

brain histopathology in both sexes

Equivocal/some evidence of 

carcinogenicity (hepatocellular 

tumors) in male mice, but not in 

females

870.5100

Bacterial reverse 

mutation assay 

(Ames test)

Up to 2 μg/plate for S. 

typhimurium strains and 

up to 250 μg/plate for E. 

coli (-S9). Up to 100 

μg/plate for S. 

typhimurium strains and 

Up to 500 μg/plate for E. 

coli (+ S9)

Acceptable/Guideline

42270605 (1988) Negative with and without S9 up to 

cytotoxic concentrations. 

870.5100

Bacterial reverse 

mutation assay 

(Ames test)

Up to 1μg/plate for S. 

typhimurium strains and 

up to 250 μg/plate for E. 

coli (-S9) and up to 100 

μg/plate for S. 

typhimurium strains and 

up to 500 μg/plate for E. 

coli (+S9) 

Acceptable/Guideline

42270604 (1989) Negative with and without S9 up to 

cytotoxic concentrations. 

870.5300

In vitro mammalian 

gene mutation assay 

Up to 9 μg/mL (+S9), up 

to 0.3 μg/mL (-S9)

Acceptable/guideline

45261801 (2000) Negative with S9 activation up to 9 

μg/mL. Negative without S9 activation 

up to 0.3 μg/mL.

Compound tested to cytotoxic 

concentrations.

870.5300

In vitro mammalian 

Up to 5 μg/mL (+/-S9) 45156902 (1986) Negative with and without S9 activation 

up to 5 μg/mL. 
Fluazinam Human Health Risk Assessment DP No. D397601

Page 47 of 75

Table A.1.3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline/

Type of Study

Study Title/

Classification /Doses MRID Results

gene mutation assay Acceptable/guideline Compound tested to cytotoxic 

concentrations.

870.5375

In vitro mammalian 

chromosome 

aberration (CHL 

cells)

Up to 9.5 μg/mL (+S9) 

up to 4 μg/mL (-S9) 

Acceptable/guideline

42270606 (1988) Negative with and without S9 up to 

cytotoxic concentrations. Cells 

harvested at 24 and 48 hours in 

nonactivated studies and at 24 hours in 

activated studies.

870.5395

Mammalian 

erythrocyte 

micronucleus test

500, 1000, 2000 mg/kg 

(oral gavage) 

Acceptable/guideline

44807224 (1999) Negative at 24 hour sacrifice (500, 

1000, 2000 mg/kg).

Negative at 24, 48, and 72 hour 

sacrifices (2000 mg/kg).

870.5550

UDS in primary rat 

hepatocytes

Unacceptable/guideline

0.05 to 6.25 μg/mL

45156901 (1984) Negative; however there were several 

serious study deficiencies: treatment 

time shorter than recommended, no data 

supporting the claim of cytotoxicity, 

data variability for major endpoints.

870.5550

Differential 

killing/growth 

inhibition in B. 

subtilis

0.003 to 0.3 μg/disk

(-S9)

0.3 to 30 μg/disk (+S9) 

Unacceptable/guideline

42270607 (1988) Negative, however only one replicate 

plate/dose was used. 

870.6200a

Acute neurotoxicity 

screening battery 

rats

M & F: 0, 50, 1000, 

2000 mg/kg 

Acceptable/guideline

44807210 (1995) Systemic NOAEL = 50 mg/kg

LOAEL = 1000 mg/kg based on soft 

stools and decreased motor activity on 

day of dosing.

Neurotoxicity NOAEL = 2000 mg/kg

LOAEL = not identified (>2000 mg/kg)

870.6200b

Subchronic 

neurotoxicity 

screening battery 

rats

M :0, 21, 69, 74, 149, 

233 mg/kg/day;

F: 0, 23, 81, 89, 175, 

280 mg/kg/day 

Acceptable/guideline

44807217 (1998); 

44807218 (1998)

Neurotoxicity NOAEL = Males: 233 

mg/kg/day; Females: 280 mg/kg/day

LOAEL = not identified (Males: >233 

mg/kg/day; Females: > 280 mg/kg/day) 

870.6300

Developmental 

neurotoxicity

0, 2, 10 or 50 mg/kg/day 

Acceptable/NonGuideline

46534401, 

47018301 and 

47037001. 

Maternal:

NOAEL not established. No toxicity at 

highest dose tested. 

Developmental:

NOAEL = 2 mg/kg/day.

LOAEL = 10 mg/kg/day based on 

decreased pup weight and gain and 

delayed balano-preputial separation. 

870.7485

Metabolism and 

pharmacokinetics

rats

0.5, 50 mg/kg 

Acceptable/guideline

44807233 (1995); 

43521004 thru 

43521008, 

43553001 (1993-

1995)

Only 33-40% of the administered dose 

was absorbed. Most of the administered 

dose was recovered in the feces (>89%). 

Excretion via the urine was minor 

(<4%). Total biliary radioactivity, 

however, represented 25-34% of the 

administered dose, indicating 

considerable enterohepatic circulation. 
Fluazinam Human Health Risk Assessment DP No. D397601

Page 48 of 75

Table A.1.3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline/

Type of Study

Study Title/

Classification /Doses MRID Results

870.7600

Dermal AbsorptionRat

500 g/L (Fluazinam SC) 

and 0.5 g/L (diluted 

Fluazinam SC) for 6 

hours

Acceptable/Guideline

48361513 (2001) The mean absorbed dose for Fluazinam 

SC at 24 hours was 0.38% (18.67 μg 

equiv.cm-2). The dermal delivery was 

0.52% (25.72 μg equiv.cm-2). The mean 

absorbed dose for diluted Fluazinam SC 

at 24 hours was 4.08% (0.153 μg 

equiv.cm-2). The dermal delivery dose 

was 4.47% (0.169 μg equiv.cm-2).

870.7800

ImmunotoxicityMouse

Acceptable/Guideline

0, 1000, 3000 or 7000 

ppm (0, 217.7, 679.0 or 

1684.6 mg/kg/day)

MRID 48708702 

and 48708703 

(2011)

Under conditions of the combined 

studies, the immunotoxicity NOAEL is 

50 ppm (equivalent to 11 mg/kg/day); 

the LOAEL is 1000 ppm (equivalent to 

231 mg/kg/day) based on decreased 

anti-SRBC AFC response. 

The systemic toxicity NOAEL is 7000 

ppm (1684.6 mg/kg/day); the LOAEL 

was not established.

Non-guideline

In Vitro

Percutaneous 

Absorption of 

Radiolabeled 

Fluazinam in Two

Formulations

Through Rat Skin

Fluazinam applied to 13 

rat dermatomed skin 

membranes in vitro in 2 

test formulations; 

Fluazinam SC and 

Diluted Fluazinam SC 

(Fluazinam Suspension 

using in vitro flow 

through diffusion cell 

system. The 

formulations were 

applied to skin for 24 

hours at 10 uL/cm2

giving the nominal dose 

levels of 5000 μg/cm2

and 5 μg/cm.2

48361514 (2000) Dermal delivery of Fluazinam from the 

Fluazinam SC (5000 μg/cm2) was 119 

μg equiv/cm2or 2.36% of the applied 

dose. Of this, only 58 μg equiv/cm2or 

1.16% of the applied dose was absorbed. 

Dermal delivery of Fluazinam from the

Diluted Fluazinam SC (5 μg/cm2) was 

1.88 μg equiv/cm2 or 40.17% of the 

applied dose. Of this, only 0.75 μg 

equiv/cm2 or 15.95% of the applied dose 

was absorbed. For risk assessment 

purposes the dermal delivery dose at 24 

hours will be used since it includes the 

absorbed dose as well as any material 

potentially absorbed (absorbable dose). 

Non-guideline

In Vitro

Percutaneous 

Absorption of 

Radiolabeled

Fluazinam in Two

Formulation 

Through Human 

Skin

Fluazinam applied to 

human dermatomed skin 

membranes in vitro

using a flow through 

diffusion cell system. A 

Suspension Concentrate 

and a Diluted 

Suspension Concentrate 

were used and the 

formulations were 

applied to the skin at 10 

μL.cm-2giving the 

nominal dose levels of 

5000 μg.cm-2 and 5 

μg.cm,-2respectively.

48361515 (2000) Dermal delivery of Fluazinam from the 

Fluazinam SC was 81 ug equiv.cm2or 

1.61% of the applied dose. Of this, only 

8 ug equiv. cm2or 0.15% of the applied 

dose was absorbed. Dermal delivery of 

Fluazinam from the Diluted Fluazinam 

SC was 0.83 ug equiv. cm-2or 16.49% 

of the applied dose. Of this, only 0.10 

ug equiv. cm2or 2.08% of the applied 

dose was absorbed. For risk assessment 

purposes the dermal delivery dose at 24 

hours will be used since it includes the 

absorbed dose as well as any material 

potentially absorbed (absorbable dose). 

Non-guideline

Mechanistic Study 

on Thyroid 

0 50, 1000 and 3000 

ppm for 7 days (0, 3.58, 

71.1, and 212 

48361509 (2004) Decrease in T4 and an increase or 

increasing trend in TSH at 1000 and 

3000 ppm groups. Increase in UDPGT 
Fluazinam Human Health Risk Assessment DP No. D397601

Page 49 of 75

Table A.1.3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline/

Type of Study

Study Title/

Classification /Doses MRID Results

Function in Rats mg/kg/day)

Acceptable/Non-guideline

activity toward 4-nitrophenol in all 

treated groups. Thyroid hypertrophy and 

proliferation at 1000 and 3000 ppm.

Non-guideline

Mechanistic Study 

on Thyroid 

Function and its 

Reversibility in Rats

Main: 0 and 3000 ppm 

for 7 days and sacrificed 

(0 and 222 mg/kg/day)

Recovery: 0 and 

3000ppm then 

reversibility for 7 days

Acceptable/Non-guideline 

48361510 (2005) Decreases in T3 and T4 and an 

increasing trend in TSH in the main 

group after treatment at 3000 ppm. In 

the 3000 ppm recovery group after 7 

days, decrease in T3 noted at almost the 

same level, but no changes in T4 or 

TSH. Increase in UDPGT activity 

toward 4-nitrophenol in main group, 

similar changes in recovery group. 

Thyroid proliferation in main group @ 

HDT, no proliferation in recovery group

Non-guideline

Effects on Hepatic 

Drug-Metabolizing 

Enzyme induction, 

Cell Proliferation 

and Oxidative 

Stress in Mice

0 10, 100 and 1000 ppm 

for 3, 7, and 14 days (0, 

1.38, 13.9, and 140 

mg/kg/day)

Acceptable/Non-guideline

48361511 (2001) Increases in cytochrome P-450 content, 

ECOD and PROD in the 1000 ppm 

group. The 100 ppm group showed an 

increase in ECOD and an increasing 

trend in PROD. Increases in CYP1A 

were seen in the 1000 ppm group. The 

100 ppm group also exhibited an 

increase in CYP2B and an increasing 

trend in CYP1A. Hepatic proliferation 

in1000 ppm group after 7 and 14 days. 

No effect on oxidative stress markers. 

Non-guideline

Additional 

Mechanistic Study 

on Hepatic DrugMetabolizing 

Enzyme induction, 

Cell Proliferation 

and the 

Reversibility of its 

Toxic Effects in 

Mice 

Main: 0 and 1000 ppm 

for 14 days and 

sacrificed (0 and 137 

mg/kg/day)

Recovery: 0 and 

1000ppm (0 and 139 

mg/kg/day) then 

reversibility for 14 days

Acceptable/Non-guideline

48361512 (2005) Increases in P-450 PROD, ECOD after 

14 days at 1000 ppm. Returned to 

normal in the satellite group after 14 

days of recovery at 1000ppm. Increase 

in CYP1A and an increasing trend in 

CYP2B in the main group after 14 days 

at 1000 ppm. In the satellite group after 

14 days at 1000 ppm, still a significant 

increase (but lower) in CYP1A. CYP2B 

returned to normal. No changes in 

hepatic proliferation observed in any 

group. 
Fluazinam Human Health Risk Assessment DP No. D397601

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A.2. Triple Pack Analysis for Fluazinam

Using the available dermal absorption data for fluazinam, a refined dermal dose (RDD) for 

human skin was calculated. A RDD is calculated from a dermal point of departure (POD) and 

triple pack dermal absorption data (in vivo rat, in vitro rat skin, and in vitro human skin) as 

follows: 

Refined Dermal Dose (RDD) = Dermal Equivalent Dose (DED) x (animal in vitro  human in 

vitro)

POD=DED=Dermal NOAEL=10 mg/kg/day

RDD = 10 mg/kg/day x (40.17%  16.49%) = 24.4 mg/kg/day

Additional details of the study results supporting these calculations are shown in the table below:
Fluazinam Human Health Risk Assessment DP No. D397601

Page 51 of 75

Table A.2. Fluazinam Triple Pack Data

Parameters In Vivo Rat In Vitro Rat In Vitro Human Comments

Study ID MRID No. 48361513

TXR No. 0055733

MRID No.48361514

TXR No. 0055733

MRID No.48361515

TXR No. 0055733

Same formulation 

products were tested in 

all three studies. 

Doses are identical in in 

vivo and in vitro rat and 

human studies

Comparable exposure 

periods

DED not required since 

dermal toxicity study 

used.

Calculated a Refined 

Dermal Dose (RDD) to 

modify the dermal 

POD.

Test 

Material

Suspension Concentrate 

(SC)

Diluted Spray Concentrate 

(DSC)

Suspension Concentrate 

(SC)

Diluted Spray Concentrate 

(DSC)

Suspension Concentrate 

(SC)

Diluted Spray Concentrate 

(DSC)

Exposure 

(hours)

6, 24, and 48 hrs post dose 24 24

Doses tested Low (DSC)-

24 hrs

Hi (SC)-24 hrs Low (DSC) Hi (SC) Low (DSC) Hi (SC)

5 μg/cm25000 μg/cm25 μg/cm25000 μg/cm25 μg/cm25000 μg/cm2

% Dermal 

Delivery 

(Absorbed + 

absorbable 

dose)

24 hrs

4.47 0.52 40.17 2.36 16.49 1.61

Risk Values POD = 21 day dermal study-dermal NOAEL of 10 mg/kg/day (LOAEL =100 mg/kg/day) used 

to assess short-, and intermediate-term dermal exposure. Long-term dermal exposure not 

anticipated. 

Dermal 

Equivalent 

Dose (DED)

Dermal toxicity study was used for risk assessment (10 mg/kg/day).

Therefore, DED=POD=10mg/kg/day

Refined 

Dermal Dose 

(based on 

dermal 

delivery 

values)

Diluted Suspension Concentrate (5 μg/cm2)

POD=Dermal NOAEL=10mg/kg/day

DAF (In Vivo rat)= 4.47%

In vitro human dermal absorption= 16.49%) 

In vitro rat dermal absorption= 40.17% 

*Refined Dermal Equivalent Dose(RDD)=DED x (animal in vitro/human in vitro)

POD=DED

RDD= 10 mg/kg/day x 40.17% = 24.4 mg/kg/day

 16.49% 

 Information taken from “ Interim Guidance: Estimating Dermal Absorption Factors for Use In Human Health Risk 

Assessments, Office of Pesticide Programs, June 2010”
Fluazinam Human Health Risk Assessment DP No. D397601

Page 52 of 75

A.3 HEC Inhalation Calculations

In response to the data requirements for registration review, a 4 week repeated dose rat inhalation

toxicity study (MRID 48571410) was conducted to assess the effects of fluazinam via the 

inhalation route. Fluazinam was administered to 10/sex CD rats (nose only) for a total of 6 

hours/day (two 3 hr exposures), 5 days/week, as an aerosol with an average mass medium 

aerodynamic diameter (MMAD) of 4.7 and a geometric standard deviation (σ) of 2.7. The 

LOAEL of 0.020 mg/L is based on a dose related increase in absolute and relative lung/bronchial 

weights in both sexes. The NOAEL is 0.003 mg/L.

RDDR for Fluazinam

Because the respired material used in the inhalation study is an aerosol, the RDDR ratio, which 

incorporates MMAD and σ, is appropriate to use for HEC calculation (table below). The 

“RDDR.exe” software program was used to obtain the RDDR value of 3.1 based on pulmonary

effects as shown below. The inputs for the program are: MMAD=4.7; σ=2.7; BW for CD Rats 

from study report=150g; Standard human BW information (i.e., 70 kg). 

Table A.3. HEC Array for Non-Occupational and Occupational Risk Assessment 

Relevant Study LOAEL

(mg/L)

NOAEL

(mg/L)

Da Dh Wa Wh RDDR HEC 

(mg/L)

inter intra UF

Short-& Intermediate-Term Occupational Exposure

Inhalation – Rat

(4 week)

(MRID 48571410) 

Pulmonary 0.020 0.003 6 8 5 5 0.486 0.001 3 10 NA

Short-& Intermediate-Term Non-Occupational (Residential) Exposure

Inhalation – Rat

(4 week)

(MRID 48571410)

Pulmonary 0.020 0.003 6 24 5 7 0.486 0.0003 3 10 NA

Long Term Exposure: Not appropriate 

Key for Array Tables

LOAEL: Lowest observed adverse effect level

Da: Daily animal exposure (hrs/day)

Wa: Weekly animal exposure (days/week)

RRDR: Regional Deposited Dose Ratio

inter: interspecies extrapolation uncertainty factor

Dh: Anticipated daily human exposure (hrs/day)

Wh: Anticipated weekly human exposure (days/week)

HC: Human Concentration

HEC: Human Equivalent Concentration

intra: intraspecies variation uncertainty factor

UF: Other uncertainty factor(s)
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Calculation of the Human Equivalent Concentration (HEC) and Human Equivalent Dose

Human Equivalent Concentrations

Human Equivalent Doses

Using the HECs calculated, a conversion of the inhalation concentration to a dose (mg/L to 

mg/kg/day) was conducted as follows:

Dose (systemic HEC value) mg/L x A x CF (L/hr/kg) x D (hours) x AF = mg/kg;

Occupational: (0.001 mg/L) x 1 x 6 x 8 x 1 = 0.048 mg/kg/day 

Residential: (0.0003 mg/L) x 1 x 6 x 24 x 1 = 0.043 mg/kg/day

 

Where:

A Absorption: ratio of deposition and absorption in respiratory tract compared to 

absorption by the oral route.

CF Conversion Factor: A L/hr/kg factor which accounts for respiratory volume and body 

weight for a given species and strain (Table 1 of guidance document).

D Duration: Duration of daily animal or human exposure (hours).

AF Activity Factor: Animal default is 1.

When conducting inhalation risk assessments, the magnitude of the UFs applied is dependent on 

the methodology used to calculate risk. For studies in this risk assessment with inhalation animal 

data, UFs are based on the RfC methodology developed by the Office of Research and 

Development (ORD) for the derivation of inhalation reference concentration s (RfCs) and human 

equivalent concentrations (HECs) for use in MOE calculations. As the RfC methodology takes 

into consideration the pharmacokinetic (PK) differences but not pharmacodynamic (PD) 

differences, the UF for interspecies extrapolation may be reduced to 3x (to account for the PD 

differences between animals and humans which are not accounted for in the RfC methodology) 

while the UF for intraspecies variation is retained at 10x. Thus, the UF when using the RfC 

methodology is customarily 30x.

For fluazinam, HED believes exposures can be short- (1-30 days) or intermediate- (1 to 6 

months) term in duration. Long-term exposures are not anticipated for fluazinam. 
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For the short- and intermediate-term scenarios, inhalation data from the 4-week inhalation rodent 

study was most appropriate for determining HECs. In the RfC methodology, different HECs can

be calculated for the same experimental NOAEL because different algorithms are used to derive 

HECs for systemic versus port-of-entry effects. Typically, HECs are calculated separately for 

systemic versus port-of-entry effect. For fluazinam, pulmonary effects were observed and,

therefore, only pulmonary HECs were derived. Time adjustments are traditionally needed for 

non-occupational (bystander) versus occupational exposure scenarios. Traditionally, HECs for 

non-occupational exposure are based on the number of hours an individual might be at home. 

Therefore, the most conservative estimate of hours spent at home would be 24 hours/day and 7 

days/week. In comparison, the average work week for an occupational worker is 8 hours/day

and 5 days/week. The HEC array table reflects the time adjustment in the calculations.

Methodologies for Human-Equivalent Concentration (HEC) Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the 

differences in ventilation rate (MV) but also the physicochemical properties of the inhaled 

compound, the type of toxicity observed (e.g. systemic vs. port of entry) and the pharmacokinetic 

(PK) but not pharmacodynamic (PD) differences between animals and humans. Based on the 

EPA’s RfC guidance (1994), the methodology for RfC derivation is an estimate of the 

quantitative dose-response assessment of chronic non-cancer toxicity for individual inhaled 

chemicals and includes dosimetric adjustment to account for the species-specific relationships of 

exposure concentration to deposited/delivered dose. This adjustment is influenced by the 

physicochemical properties of the inhaled compound as well as the type of toxicity observed 

(e.g. systemic vs. port of entry), and takes into consideration the PK differences between animals 

and humans. Though the RfC methodology was developed to estimate toxicity of inhaled 

chemicals over a lifetime, it can be used for other inhalation exposures (e.g. acute and short-term 

exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition 

that can be applied to shorter duration of exposures provided the assumptions underlying the 

methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity

observed. Thus the derivation of a HEC for inhaled gases is described by the following 

equation:

Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of animal exposure (hrs/day; days/wk)

Danticipated exposure: Anticipated human duration of exposure (hrs/day; days/wk)

RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on 

the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies 

using aerosols characterize particulate exposure by defining the particulate diameter (mass 

median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is 

then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an 

observed inhalation particulate exposure concentration of an animal (A) to the predicted 

HEC = POD *

D 

D 

*

W

W

study * RGDR animal exposure (hrs/ day)

human exposure (hrs/ day)

animal exposure (days / wk)

human exposure (days/ wk)
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inhalation particulate exposure concentration for a human (H) that would be associated with the 

same dose delivered to the region or target tissue.

RDDRr = (RDDr/Normalizing Factor)A

 (RDDr/Normalizing Factor)H 

As with calculations for gases, the regions and potential target tissues are the three respiratory

regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed 

specifically for computing the RDDR from the MMAD and σg defined from an aerosol 

inhalation study. The values for the species-specific parameters used to calculate the RDDR are 

provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations 

and Application of Inhalation Dosimetry.”
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A.4. Hazard Identification and Endpoint Selection

Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Developmental Toxicity Study in Rabbits

MRID No: 46578987

Dose and Endpoint for Risk Assessment: NOAEL= 7 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor)

Comments about Study/Endpoint/Uncertainty Factors: A developmental toxicity study in 

rabbits was used to select the dose and endpoint for establishing the aRfD of 0.07 mg/kg/day. 

The NOAEL of 7 mg/kg/day and the LOAEL of 12 mg/kg/day were based on increased 

incidence of total litter resorptions and a possible increased incidence of fetal skeletal 

abnormalities (including kinked tail tip, fused or incompletely ossified sternebrae, and 

abnormalities of head bones). The skeletal abnormalities observed are considered to be effects 

that could occur after a single dose of fluazinam; thus, the route and duration of exposure are 

appropriate for this population.

Acute RfD (females 13-49) = 

100 ( )

7 / /

UF

mg kg day = 0.07 mg/kg/day

Acute Reference Dose (aRfD) - General Population

Study Selected: Acute Neurotoxicity Study in Rats

MRID No: 44807210

Dose and Endpoint for Risk Assessment: NOAEL= 50 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor)

Study/Endpoint/Uncertainty Factors: An acute oral neurotoxicity study in rats was used to 

select the dose and endpoint for establishing the aRfD of 0.5 mg/kg/day. The NOAEL of 50 

mg/kg/day and the LOAEL of 1000 mg/kg/day were based on soft stools and decreased motor 

activity. In this study there was a large dose spread between the NOAEL (50 mg/kg/day) and the 

LOAEL (1000 mg/kg/day). The true NOAEL is probably much higher than 50 mg/kg/day. This 

study, however, provides the best data available for determining an acute RfD for the general 

population (including infants and children). The route and duration of exposure are appropriate 

for this population. 

Acute RfD (females 13-49) = 

100 ( )

50 / /

UF

mg kg day = 0.5 mg/kg/day
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Chronic Reference Dose (cRfD) 

Studies Selected: A 2-year carcinogenicity study in mice and a 1-year chronic oral study in 

dogs (co-critical studies) were selected to establish the cRfD. The 2-year carcinogenicity study 

in mice, rather than the 1-year chronic oral study in dogs, was used to establish the RfD because 

the treatment-related effects at the LOAEL in the mouse study were related to liver toxicity (the 

regularly observed target organ for fluazinam in many studies); whereas the effects at the 

LOAEL in the dog study were unrelated to liver toxicity. The effects seen in the dog study were 

increased incidence of nasal dryness in females and increased incidence/severity of gastric 

lymphoid hyperplasia in males and females. The NOAELs in the mouse (1.12 mg/kg/day in 

males and 1.16 mg/kg/day in females) and the dog (1 mg/kg/day in males and females) studies 

and the LOAELs in the mouse (10.72 mg/kg/day in males and 11.72 mg/kg/day in females) and 

dog (10 mg/kg/day in males and females) studies were similar. 

 

1

st Study: 2-Year Carcinogenicity Study in Mice 

MRID Nos: 42208405, 44807220, 44807212 

Dose and Endpoint for Risk Assessment: NOAEL= 1.12 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor)

Study/Endpoint/Uncertainty Factors: A 2-year carcinogenicity study in mice was one of two 

co-critical studies used in selecting the dose and endpoint for establishing the cRfD of 0.11 

mg/kg/day. The NOAEL of 1.12 mg/kg/day and the LOAEL of 10.72 mg/kg/day were based on 

increased incidences of brown pigmented macrophages in the liver of both sexes, increased 

incidences of eosinophilic vacuolated hepatocytes in males, and increased liver weights in 

females. The route and duration of exposure are appropriate for this population. 

2

nd Study: 1-Year Chronic Oral Toxicity Study in Dogs

MRID Nos: 42270603, 44807219

Dose and Endpoint for Risk Assessment: NOAEL= 1 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

safety factor)

Study/Endpoint/Uncertainty Factors: A 1-year chronic oral toxicity study in dogs was one of 

two co-critical studies used in selecting the dose and endpoint for establishing the cRfD of 0.11 

mg/kg/day. The NOAEL of 1 mg/kg/day and the LOAEL of 10 mg/kg/day were based on 

marginal increases in the incidence of nasal dryness in females and the incidence/severity of 

gastric lymphoid hyperplasia in both sexes. The route and duration of exposure are appropriate 

for this population. 

Chronic RfD = 

100 ( )

1.1 / /

UF

mg kg day = 0.011 mg/kg/day

Comments: A 2-year chronic feeding/carcinogenicity study in rats (MRID 42248620, 

44807223) was also considered for establishing the cRfD based on a lower NOAEL of 0.38 

mg/kg/day. The next highest dose level tested in this study was 3.8 mg/kg/day in males and 4.9 
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mg/kg/day in females (a 10 fold higher dose). A second 2-year chronic feeding study in rats 

(MRIDs 44839901 and 44807213) was subsequently performed with 2 intermediate dose levels. 

The doses used in the study were 0, 1.0, 1.9, and 3.9 mg/kg/day for males; 0, 1.2, 2.4, and 4.9 

mg/kg/day for females. The NOAEL observed in the second study was 1.9 mg/kg/day for males 

and 4.9 mg/kg/day for females, which is higher than the NOAEL (1.1 mg/kg/day) selected for 

establishing the chronic RfD. Therefore, this study was not chosen for risk assessment. 

Dermal Exposure (Short-, Intermediate-Term) 

Studies Selected: 21-Day Dermal Toxicity Study in Rats, In Vivo Dermal Penetration Study in 

Rats, and In Vitro Dermal Penetration Study in Human and Rat Skin

MRID Nos: 42270602, 48361513-15 

Dose and Endpoint for Risk Assessment: Refined human dermal NOAEL= 24.4 mg/kg/day

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor)

Study/Endpoint/Uncertainty Factors: A 21-day dermal toxicity study in rats was used, along 

with dermal absorption data to refine the point of departure for short- and intermediate-term 

dermal risk assessment. In the dermal toxicity study, the NOAEL of 10 mg/kg/day and the 

LOAEL of 100 mg/kg/day were based on increased aspartate aminotransferase (AST) and 

increased cholesterol levels in males. The route and duration of exposure are appropriate for this 

population. A refined dermal dose of 24.4 mg/kg/day was calculated considering data from the 

available dermal penetration studies in human and rat skin. The data suggests that human skin is 

less permeable than rat skin (see A.2).

Comments: Developmental effects were noted in developmental toxicity studies at ≥ 12 

mg/kg/day. Although the RDD is 24 mg/kg/day, it is based on an oral NOAEL that is lower than 

the dose at which developmental effects were seen. The comparable dermal equivalent dose 

(DED) for the developmental study, using the developmental NOAEL of 7 mg/kg/day and a 

DAF of 4.47% is 155 mg/kg/day. Therefore, the RDD is considered protective of potential 

developmental effects. Additionally, the RDD is protective of immunotoxic effects seen in an 

immunotoxicity study in mice at the LOAEL of 231 mg/kg/day.

Inhalation Exposure (Short-, Intermediate-Term) 

Study Selected: 4 Week Inhalation Study in Rats (test material: Frowncide

WP, containing 51.9% fluazinam) 

MRID No: 48571410

Dose and Endpoint for Risk Assessment: NOAEL= 0.003 mg/kg/day

Uncertainty Factor: 30x (3x interspecies extrapolation, 10x intraspecies variability, 1x FQPA 

Safety Factor)

Inhalation absorption factor (IAF): 100%

Study/Endpoint/Uncertainty Factors: A 4 week inhalation study in rats was used to select the 

dose and endpoint for short- and intermediate-term inhalation exposure. The NOAEL of 0.003 

mg/L and the LOAEL of 0.020 mg/L based on a dose related increase in absolute and relative 

lung/bronchial weights in both sexes. At 0.100 mg/L, increased lung/bronchial weights were 
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also seen, along with lung histopathology (alveolar macrophages, peribronchiolar proliferation) 

in both sexes.

Occupational and Residential Long-Term Dermal and Inhalation Exposures

Based on the proposed use pattern for fluazinam, long-term dermal and inhalation exposures are 

not anticipated.
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Appendix B. International Residue Limit Status Sheet

Table B.1. Summary of U.S. and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

[40 CFR §180.574 (a)(1)]

Plant: fluazinam (3-chloro-N-[3-

chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-

2-pyridinamine)

3-chloro-N-[3-chloro-2,6-dinitro-4-

(trifluoromethyl)phenyl]-5-

(trifluoromethyl)-2-pyridinamine

None

Commodity

Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Apple 2.0

Apple, wet pomace 5.0

Bushberry subgroup 13-07B 7.0 7.0 aronia berries, buffalo currants, Chilean 

guavas, currants, elderberries, European 

barberries, gooseberries, highbush 

blueberries highbush cranberries 

honeysuckle, huckleberries, jostaberries, 

lingonberries, lowbush blueberries, native 

currants, salal berries, saskatoon berries 

(juneberries), sea buckthorn

Carrot, roots 0.70

Ginseng 4.5

Lettuce, head 0.02

Lettuce, leaf 2.0

Onion, bulb, subgroup 3-07A 0.20

Pea and bean, dried shelled, 

except soybean, subgroup 6C, 

except pea

0.02 0.02 Dry (adzuki beans, beans, blackeyed 

peas, broad beans, catjang seeds, 

chickpeas, cowpea seed, guar seeds, kidney 

beans, lablab beans, lima beans, moth 

beans, mung beans, navy beans, pink 

beans, pinto beans, rice beans, southern 

peas, tepary beans, urd beans); grain lupin

Pea and bean, succulent shelled, 

subgroup 6B, except pea

0.04

Peanut 0.02

Potato 0.02 0.02

Turnip, greens 0.01

Vegetable, Brassica leafy, group 

5

0.01 0.01 bok choy Chinese cabbages, broccoli, 

broccoli raab, Brussels sprouts, cabbages, 

cauliflower, Chinese broccoli, chinese 

mustard cabbages, collards,, kale, kohlrabi, 

mustard greens, mustard spinach, napa 

Chinese cabbages, rape greens

Vegetable, legume, ediblepodded, subgroup 6A, except 

pea

0.10 0.1edible podded ( jackbeans, moth beans, 

runner beans, snap beans, soybeans, sword 

beans, wax beans, yardlong beans)

Proposed MRLs

Melon subgroup 9A 0.08

Pepper/Eggplant

Subgroup 8-10B 0.10

Soybean, Seed 0.01 0.1 edible-podded soybeans

Soybean, Hulls 0.05
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Table B.1. Summary of U.S. and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

[40 CFR §180.574(a)(2)]

fluazinam and its metabolite AMGT 

(3-[[4-amino-3-[[3-chloro-5-

(trifluoromethyl)-2-

pyridinyl]amino]-2-nitro-6-

(trifluoromethyl) phenyl]thio]-2-

(beta-D-glucopyranosyloxy) 

propionic acid).

Same as above None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Grape, wine13.0

[40 CFR §180.574(a)(3)] Canada Mexico2 Codex

fluazinam, AMPA (2-(6-amino-3-

chloro-α,α,α-trifluoro-2-nitro-ptoluidino)-3-chloro-5-

(trifluoromethyl) pyridine), DAPA 

(3-chloro-2-(2,6-diamino-3-chloroα,α,α.-trifluoro-p-toluidino)-5-

(trifluoromethyl)pyridine), and their 

sulfamate conjugates.

Same as above None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Cattle, fat 0.05

Cattle, meat byproducts 0.05

Goat, fat 0.05

Goat, meat byproducts 0.05

Horse, fat 0.05

Horse, meat byproducts 0.05

Sheep, fat 0.05

Sheep, meat byproducts 0.05

Proposed MRLs

Milk 0.01

Meat of Cattle, Goat, Horse, and 

Sheep 0.03

Meat Byproducts of Cattle, Goat, 

Horse, and Sheep 0.10

Completed: : M. Negussie; 08/03/2012

1 No US registration as of March 15, 2002 (grape, wine).

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
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Appendix C. Fluazinam Physical/Chemical Properties

Table B.1. Physicochemical Properties of Fluazinam

Parameter Value Reference

Melting Point/Range 115.5°C MRID 42208401

pH 5.85 MRID 43521001

Density (20°C) 1.74 g/cm3 MRID 42208401

Water Solubility (25°C) (pH 5.5): 25 ppb

(pH 7): 71 ppb

(pH 11): 350 ppm

MRID 42208401

Solvent Solubility (25°C) Solvent Solubility (g/L) MRID 42208401

acetone

dichloroethane

ethyl acetate

ethyl ether

hexane

methanol

toluene

645

485

624

168

6.7

162

512

Vapor Pressure (25°C) 1.73 x 10-7 mm Hg

(2.3 x 10-5Pa)

LSS 2000_1973_2LS_rev

Dissociation Constant (pKa) Average pKa = 7.22 in 50% 

ethanol/water (v/v)

MRID 42208401

Octanol/Water Partition Coefficient 

(KOW)

3,630

(Log Kow = 3.56)

MRID 42208401

UV/Visible Absorption Spectrum pH λmax (nm) PMRA Regulatory Note REG2003-

12 5

7

>10

238

239, 342

260, 343, 482

 
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Appendix D. Review of Human Research

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 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force 

(ORETF) database; the Agricultural Re-entry Task Force (ARTF) database; and other registrantsubmitted studies (MRID Nos. 46991302, 45584203, 45584202, and 48361527); are subject to 

ethics review pursuant to 40 CFR 26, have received that review, and are compliant with 

applicable ethics requirements. For certain studies, that review might have included review by 

the Human Studies Review Board. Descriptions of data sources as well as guidance on their use 

can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.
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Appendix E: Structures of Fluazinam Metabolites and Degradates of Concern

Table E.1. Structures of Fluazinam Metabolites and Degradates of Concern

Compound Common Name Structure

Fluazinam

AMGT

Plant Metabolite

AMPA

Livestock Metabolite

Drinking Water Degradate

DAPA

Livestock Metabolite

Drinking Water Degradate

Cl

N

H

CF3

NO2

O2N

N

Cl

F3C

O

OH

OH

OH

HO

O

NH

CF3

O2N

N

F Cl 3C

NH2

S

HOOC

Cl

N

H

CF3

O2N

N

Cl

F3C NH2

Cl

N

H

CF3

N

Cl

F3C NH2

H2N
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Table E.1. Structures of Fluazinam Metabolites and Degradates of Concern

Compound Common Name Structure

CAPA

Drinking Water Degradate

DCPA

Drinking Water Degradate

HYPA

Drinking Water Degradate

N

H

N

O2N

O2N

Cl

CF3

Cl

HOOC

N

H

N

O2N

COOH

Cl

O2N

Cl

HOOC

DCPA

N

H

N

O2N

CF3

HO

O2N

Cl

F3C
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Appendix F.

Occupational Exposure and Risk Assessment to Support Registration Review

With the submission of the two toxicity studies required during registration review, as well as 

additional conditional data requested in conjunction with previously evaluated new use petitions, 

the toxicity and exposure databases for fluazinam are complete. Therefore, the new use 

aggregate human health risk assessment, in combination with the information presented below, 

serves as HED’s risk assessment to support registration review. The new toxicity data have been 

evaluated and incorporated into the hazard characterization, endpoint and dose selection, and 

FQPA Safety Factor determination.

The residue data submitted as a condition of registration are acceptable, and have been 

incorporated in to the dietary exposure and risk estimates, which are not of concern when both 

existing and proposed uses are taken into consideration. In addition, the largely unrefined 

dietary assessments incorporated high end modeled estimates of drinking water exposure. 

The only potential residential exposure scenario results from dermal contact with treated golf 

course turf, and no dermal risks of concern were identified; the most recent policies and 

procedures for assessing residential exposure were used to estimate post-application risk for 

youth and adult golfers. When these exposures were aggregated with background exposure from 

food and water, there were no aggregate risks of concern.

In 2009 HED consulted the OPP Incident Data System (IDS) for poisoning incident data on 

fluazinam to identify potential patterns on the extent and severity of the health effects attributed 

to fluazinam exposure. The IDS includes reports of incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports 

from registrants, other federal and state health and environmental agencies and individual 

consumers. HED concluded that because of the relatively low volume of incidents, and the lack 

of moderate or severe health effects potentially related to fluazinam exposure, no further 

investigation was required to support the preliminary risk assessment.

There were 5 major changes that required HED to reassess occupational exposure and risk for 

the existing uses of fluazinam, for the purpose of registration review:

1) The inhalation endpoint changed from systemic liver effects to the portal-of-entry effects 

for the respiratory system. Based on the results of the new inhalation study, the 

Reference Concentration methodology developed by the Office of Research and 

Development (ORD) was used to calculate human equivalent concentrations (HECs) and 

doses (HEDs) for inhalation risk assessment;

2) Since the effects observed via the inhalation route are different from the effects observed 

following dermal dosing, dermal and inhalation exposures are no longer combined in the

risk assessment;

3) HED has updated the surrogate unit exposures for occupational handlers, which have 

been incorporated in to the risk assessment for occupational handlers (see Occupational 

Pesticide Handler Unit Exposure Surrogate Reference Table). No changes to the label 
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PPE, or other types of mitigation, are required in conjunction with the revised risk 

estimates;

4) HED has used an updated approach to incorporation of dislodgeable foliar residue (DFR) 

data (i.e., use of predicted vs. measured day 0 residue values). Further, HED has revised 

the post-application exposure and risk assessment to reflect the use of the available DFR 

data to assess all registered crops; and

5) HED has incorporated updated transfer coefficients to assess post-application exposure 

associated with re-entry activities such as harvesting, thinning, weeding, and scouting. 

No label changes or mitigation are needed in conjunction with the revised postapplication exposure and risk assessment.

A summary of the occupational scenarios assessed, as well as the updated handler and postapplication exposure and risk estimates for the registered uses, is presented below. The detailed 

assessment, including assumptions used for DFR studies, is presented in Z. Figueroa (D397723, 

9/7/2012).

Table F.1. Summary of Occupational Exposure Scenarios for Fluazinam Registered Uses

EPA Reg. 

No. Crop Application Equipment

Max. 

rate/appl.

(lb ai/A)

No. appl./season 

(Re-Treatment 

Interval)

71512-1

Omega 500F

(40% ai; 4.17 

lb a.i./gal)

Dry Bean & Succulent

Bean Crop

Edible-podded Legume 

Vegetables

Groundboom 0.44 2 (7 days)

Brassica vegetables

(pre-transplant soil 

spray band or bed; 

post-transplant soil 

drench)

Groundboom 1.36

(0.024 lb ai/gal) 1-2 (none)

Bushberry Groundboom, airblast 0.65 6 (7 days)

Carrots Groundboom, aerial, 

chemigation 0.52 4 (7 days)

Lettuce Groundboom, aerial chemigation 0.78 1 (none)

Onions Groundboom, aerial, 

chemigation 0.52 6 (7 days)

Apples Aerial, chemigation, airblast 0.45 10 (7 days)

Ginseng Groundboom 0.78 4 (7 days)

Peanuts Groundboom 0.78 2 (21 days)

Potatoes Groundboom, aerial chemigation 0.26 7 (7 days)

CO 070003

Omega 500F

Potatoes

seed pieces

(at-plant in-furrow

over seed piece)

Groundboom 1.8 1 (none)

71512-20

Fluazinam 

Turf 

Fungicide 

(40% ai; X)

Turf (Golf Course)

Groundboom, handheld 

(backpack, manually-pressurized 

handwand, and mechanicallypressurized handgun sprayers)

0.70 12 (14 days)
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Occupational Handler Exposure and Risk Estimates

Based on the registered use patterns and current labeling, and the types of equipment and 

techniques use for application, the following occupational handler exposures are expected from 

the registered uses. The quantitative exposure/risk assessment developed for occupational 

handlers is based on the following scenarios: 

• Mixing/Loading Liquids for Groundboom Application,

• Mixing/Loading Liquids for Aerial Application,

• Mixing/Loading Liquids for Chemigation,

• Mixing/Loading Liquids for Airblast,

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment, 

• Applying Sprays with Airblast,

• Flagging for Aerial Applications,

• Mixer/Loader/Applicator for Mechanically-Pressurized Handgun Sprayer,

• Mixer/Loader/Applicator for Backpack Sprayer, and

• Mixer/Loader/Applicator for Manually-pressurized Handwand

No handler exposures are expected from applying sprays via chemigation systems. The 

maximum single application rate on the registered label was used to assess all handler exposure 

scenarios.

No data on the number of exposure days per year were provided. Based on the registered use 

patterns and directions, short- and intermediate-term exposures are expected for handlers. As

short- and intermediate-term endpoints and PODs are the same for each exposure route, only 

short-term handler exposures were estimated. The estimates are considered to be protective of 

intermediate-term exposure and risk. Long-term exposures are not expected.

Table F.2 presents the short-term dermal and inhalation risk estimates for occupational handlers. 

The occupational handler scenarios for the existing uses resulted in estimated MOEs greater than 

the respective levels of concern (dermal LOC = 100; inhalation LOC = 30) at some level of PPE 

(e.g., chemical-resistant gloves, double layer clothing with chemical-resistant hat) and assuming 

use of engineering controls (i.e., enclosed cockpit) for aerial applications. Based on the risk 

estimates shown below, no additional PPE or other mitigation is needed on registered labels. 
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Table F.2. Short-Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses.

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb ai)1 Maximum

Application 

Rate2

Area 

Treated or 

Amount 

Handled3

Dermal Inhalation

Mitigation Level Mitigation Level Dose 

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

Mixer/Loader

Liquids for Groundboom 

Applications

(AHETF)

Turf (Golf Course) 220

(Baseline)

0.219

(No respirator) 0.70 lb ai/A 40 0.0770 320 0.000077 620

Potatoes

(Spray)

220

(Baseline)

0.219

(No respirator) 0.26 lb ai/A 80 0.0573 430 0.000057 840

Potatoes 

(at plant in-furrow 

over seed piece)

37.6

(Gloves)

0.219

(No respirator) 1.8 lb ai A 80 0.0676 360 0.00034 120

Dry Bean & 

Succulent Bean Crop, 

Edible-podded

Legume Vegetable

220

(Baseline)

0.219

(No respirator) 0.44 lb ai/A 80 0.0968 250 0.0000964 500

Carrots, Onions 220

(Baseline)

0.219

(No respirator) 0.52 lb ai/A 80 0.1140 210 0.000114 420

Bushberry 220

(Baseline)

0.219

(No respirator) 0.65 lb ai/A 80 0.1430 170 0.000143 340

Ginseng, Peanuts,

Lettuce (Head and 

Leaf)

220

(Baseline)

0.219

(No respirator) 0.78 lb ai/A 80 0.1710 140 0.000171 280

Brassica (Cole) Leafy 

Vegetables

37.6

(Gloves)

0.219

(No respirator) 1.36 lb ai/A 80 0.0511 480 0.000298 160

Liquids for Aerial Application

(AHETF)

Potatoes

220

(Baseline)

0.219

(No respirator) 0.26 lb ai/A 350 0.250 100 0.000249 190

Apples 37.6

(Gloves)

0.219

(No respirator) 0.45 lb ai/A 350 0.074 330 0.000431 110

Carrots, Onions 37.6

(Gloves)

0.219

(No respirator) 0.52 lb ai/A 350 0.085 290 0.000499 100

Lettuce (Head and 

Leaf)

37.6

(Gloves)

0.219

(No respirator) 0.78 lb ai/A 350 0.129 190 0.000748 60

Liquids for Chemigation

(AHETF)

Potatoes 220

(Baseline)

0.219

(No respirator) 0.26 lb ai/A 350 0.250 100 0.000249 190
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Table F.2. Short-Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses.

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb ai)1 Maximum

Application 

Rate2

Area 

Treated or 

Amount 

Handled3

Dermal Inhalation

Mitigation Level Mitigation Level Dose 

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

Apples 37.6

(Gloves)

0.219

(No respirator) 0.45 lb ai/A 350 0.074 330 0.000431 110

Carrots, Onions 37.6

(Gloves)

0.219

(No respirator) 0.52 lb ai/A 350 0.085 290 0.000499 100

Lettuce (Head and 

Leaf)

37.6

(Gloves)

0.219

(No respirator) 0.78 lb ai/A 350 0.129 190 0.000748 60

Liquids for Airblast (AHETF)

Apples 220

(Baseline)

0.219

(No respirator) 0.45 lb ai/A 40 0.0495 490 0.0000493 970

Bushberry 220

(Baseline)

0.219

(No respirator) 0.65 lb ai/A 40 0.0715 340 0.0000711 680

Applicator

Sprays for Groundboom 

Applications

(AHETF)

Turf (Golf Course) 78.6 

(Baseline)

0.34

(No respirator) 0.70 lb ai/A 40 0.02751 890 0.000119 400

Potatoes

(Spray Treatment)

78.6 

(Baseline)

0.34

(No respirator) 0.26 lb ai/A 80 0.0204 1,200 0.0000884 540

Potatoes 

(at plant in-furrow 

over seed piece)

78.6

(Baseline)

0.34

(No respirator) 1.8 lb ai/A 80 0.141 170 0.000613 80

Dry Bean & 

Succulent Bean Crop,

Edible-podded 

Legume Vegetable

78.6

(Baseline)

0.34

(No respirator) 0.44 lb ai/A 80 0.0346 710 0.00015 320

Carrots, Onions 78.6 

(Baseline)

0.34

(No respirator) 0.52 lb ai/A 80 0.0409 600 0.000176 270

Bushberry 78.6 

(Baseline)

0.34

(No respirator) 0.65 lb ai/A 80 0.0511 480 0.000221 220

Ginseng, Peanuts,

Lettuce (Head and 

Leaf) 

78.6 

(Baseline)

0.34

(No respirator) 0.78 lb ai/A 80 0.0613 400 0.000265 180

Brassica (Cole) Leafy 

Vegetables

78.6 

(Baseline)

0.34

(No respirator) 1.36 lb ai/A 80 0.1070 230 0.000463 100

Sprays for Aerial Application Potatoes 5

(Engineering Controls -

0.068

(Engineering Controls -

0.26 lb ai/A 350 0.00569 4,300 0.0000774 620
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Table F.2. Short-Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses.

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb ai)1 Maximum

Application 

Rate2

Area 

Treated or 

Amount 

Handled3

Dermal Inhalation

Mitigation Level Mitigation Level Dose 

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

(AHETF) Enclosed cockpit) Enclosed cockpit)

Apples 5

(Engineering Controls -

Enclosed cockpit)

0.068

(Engineering Controls -

Enclosed cockpit)

0.45 lb ai/A 350 0.00985 2,500 0.000134 360

Carrots, Onions 5

(Engineering Controls -

Enclosed cockpit)

0.068

(Engineering Controls -

Enclosed cockpit)

0.52 lb ai/A 350 0.01140 2,100 0.000155 310

Lettuce (Head and 

Leaf)

5

(Engineering Controls -

Enclosed cockpit)

0.068

(Engineering Controls -

Enclosed cockpit)

0.78 lb ai/A 350 0.0171 1,400 0.000233 210

Sprays for Airblast 

Applications

(AHETF)

Apples 1,480

(Double Layer + 

Chemical-resistant Hat, 

Gloves)

4.71

(No respirator) 0.45 lb ai/A 40 0.333 500 0.00106 50

Bushberry 1,480

(Double Layer + 

Chemical-resistant Hat, 

Gloves)

4.71

(No respirator) 0.65 lb ai/A 40 0.481 350 0.00153 30

Flagger

Flagging for Aerial 

Applications 

(PHED)

Potatoes

11

(Baseline)

0.35

(No respirator) 0.26 lb ai/A 350 0.0125 2,000 0.000399 120

Apples 11

(Baseline)

0.35

(No respirator) 0.45 lb ai/A 350 0.0216 1,100 0.000689 70

Carrots, Onions 11

(Baseline)

0.35

(No respirator) 0.52 lb ai/A 350 0.0250 980 0.000796 60

Lettuce (Head and 

Leaf)

11

(Baseline)

0.35

(No respirator) 0.78 lb ai/A 350 0.0375 650 0.0012 40

Mixer/Loader/Applicator

Backpack Sprayer

(MRID 44339801) Turf, Golf Course

8260

(Baseline)

2.58 

(Baseline) 0.0175 lb ai/gal 5 gals 0.00903 2,700 0.00000282 17,000

Manually-pressurized 

Handwand

(PHED)

Landscape, Outdoor 

Areas

100000

(Baseline)

30

(Baseline) 0.0175 lb ai/gal 5 gals 0.109 220 0.0000328 1,500

Mechanically-pressurized Turf, Golf Courses 1140 1.9 0.70 lb ai/A 5 A 0.050 490 0.0000831 580
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Table F.2. Short-Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses.

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb ai)1 Maximum

Application 

Rate2

Area 

Treated or 

Amount 

Handled3

Dermal Inhalation

Mitigation Level Mitigation Level Dose 

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

Handgun Sprayer (Liquids)

(ORETF)

(Broadcast) (Baseline) (Baseline)

Mechanically-pressurized 

Handgun Sprayer (Liquids)

(PHED)

Brassica (Cole) Leafy 

Vegetables (Soil 

Drench)

390

(Single Layer, Gloves)

3.9

(No respirator) 0.024 lb ai/gal 1,000 gal 0.117 210 0.00117 40

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2012); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, Gloves, Eng. Controls).

2 Based on the registered labels (EPA Reg. No. 71512-1 and EPA Reg. No. 71512-20).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A) x Area Treated or Amount Handled (A/day or gal/day)/BW (80 kg).

5 Dermal MOE = Dermal NOAEL (24.4 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 100.

6

Inhalation Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A) x or Amount Handled (A/day or gal/day) /BW (80 kg).

7

Inhalation MOE = Inhalation NOAEL (0.048 mg/kg/day)/ Inhalation Dose (mg/kg/day); LOC = 30.
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Occupational Post-Application Exposure and Risk Estimates

Post-Application Inhalation 

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

inhalation exposure assessment for the existing uses is not being performed for fluazinam at this 

time; handler inhalation exposure estimates are considered to be protective of occupational postapplication inhalation exposure scenarios. If new policies or procedures are put into place, the 

Agency might revisit the need for a quantitative occupational post-application inhalation 

exposure assessment for fluazinam.

Post-Application Dermal 

Short- and intermediate-term dermal exposures are expected for workers conducting postapplication activities on agricultural crops. The standard values recommended for use in 

predicting post-application exposure that are used in this assessment, known as “transfer 

coefficients,” are presented in the ExpoSAC Policy 3 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at: http://www.epa.gov/pesticides/science/postapp-exposure-data.html. 

Chemical-specific dislodgeable foliar residue (DFR) studies on apples (MRID 45584203), 

potatoes (MRID 45584202), and peanuts (MRID 45584201) were submitted and reviewed by 

HED. The studies demonstrated that dislodgeable foliar residue values declined over time. 

HED concluded that the peanut DFR data would serve as the best surrogate to assess postapplication exposure for all crops when no crop-specific DFR data were available based on 

information about the study conditions, region of use, use pattern, etc. (M. Collantes, 

03/18/2008, D349315). Therefore, the peanut DFR data were used as a surrogate to assess 

dermal post-application exposure resulting from application of fluazinam on ginseng, Brassica

(cole) leafy vegetables, succulent edible podded and dry beans, carrots, bushberries, lettuce, 

onions, and peanuts. The apple and potato DFR studies were used to assess post-application 

exposure for the respective crops, and a chemical-specific turf-transferable residue (TTR) study

was used to assess dermal exposure to treated turf.

Maximum single application rates were used based on the registered labels (EPA Reg. No. 

#71512-1 and EPA Reg. No. #71512-20). Residue values were adjusted by application rate, 

when applicable. 

Post-application Exposure and Risk Estimates – Agricultural Crops

A summary of the post-application exposure and risk estimates for the registered agricultural 

uses is provided in Table F.3. 
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Table F.3. Short-term Occupational Post-application Exposure and Risk Estimates for Fluazinam Registered Uses.

Crop/Site Activities DFR1

(μg/cm2)

Day 0 Dose2

(mg/kg/day) Day 0 MOE3 Day at which MOE ≥ LOC

DFR Data on Treated Peanuts (MRID 45584201)

Brassica (Cole) 

Leafy Vegetables

Transplanting 1.70 0.0391 620 0

Scouting 1.70 0.0561 430 0

Hand Weeding 1.70 0.2380 100 0

Irrigation (hand set) 1.36 0.2580 100 2

Ginseng

Weeding, Hand 0.975 0.0068 3,600 0

Scouting 0.975 0.0205 1,200 0

Harvesting, Hand 0.975 0.1070 230 0

Irrigation (hand set) 0.975 0.1850 130 0

Succulent Edible 

Podded and Dry 

Beans

Hand weeding 0.550 0.00385 6,300 0

Scouting 0.550 0.01160 2,100 0

Scouting 0.550 0.06050 400 0

Irrigation (hand set) 0.550 0.10500 230 0

Carrots

Hand Weeding 0.650 0.00455 5,400 0

Scouting 0.650 0.01370 1,800 0

Harvesting, Hand 0.650 0.0715 340 0

Irrigation (hand set) 0.650 0.1240 200 0

Bushberry

Hand Weeding 0.812 0.00568 4,300 0

Transplanting 0.812 0.01870 1,300 0

Harvesting, Hand 0.812 0.08930 270 0

Irrigation (hand set) 0.812 0.1540 160 0

Lettuce

Hand Weeding 0.975 0.00683 3,600 0

Scouting 0.975 0.02050 1,200 0

Transplanting 0.975 0.02240 1,100 0

Harvesting, Hand 0.975 0.10700 230 0

Irrigation (hand set) 0.975 0.18500 130 0

Onions

Scouting 0.650 0.0215 1,100 0

Hand Weeding 0.650 0.0910 270 0

Irrigation (hand set) 0.650 0.1240 200 0

Weeding, Hand 0.582 0.2440 100 1

Peanuts

Hand Weeding 0.975 0.0068 3,600 0

Scouting 0.975 0.0205 1,200 0

Irrigation (hand set) 0.975 0.1850 130 0

DFR Data on Potatoes (MRID 45584202)

Potatoes

Hand Weeding 0.232 0.00162 15,000 0

Scouting 0.232 0.00405 5,000 0

Irrigation (hand set) 0.232 0.00441 550 0

DFR Data on Apple Trees (MRID 45584203)

Apples

Orchard 

Maintenance, 

Propping, Hand 

Weeding, Thinning 

Fruit, Bird Control 

0.017 0.00017 140,000 0

Transplanting 0.017 0.00039 62,000 0

Scouting, Hand 

Pruning, Training 0.017 0.00099 25,000 0

Harvesting, Hand 0.017 0.00238 10,000 0

Thinning, Fruit 0.017 0.00061 4,000 0

1. Dislodgeable Foliar Residue (DFR) from Treated Peanuts = 0.987 μg/cm2is based on predicted day 0 residue value calculated from chemicalspecific data (MRID No. 45584201) and then adjusted by application rate. Dislodgeable Foliar Residue (DFR) from Potatoes = 0.429 μg/cm2

is based on predicted day 0 residue value calculated from chemical-specific data (MRID No. 45584202) and then adjusted by application rate. 

Dislodgeable Foliar Residue (DFR) from Apples = 0.0471 μg/cm2is based on predicted day 0 residue value calculated from chemical-specific 

data (MRID No. 45584203) and then adjusted by application rate. 

2. Daily Dermal Dose = [DFR (μg/cm2) x TC x 0.001 mg/μg x 8 hrs/day]  BW (80 kg).

3. MOE = NOAEL (24.4 mg/kg/day) / Daily Dermal Dose. 
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Short- and intermediate-term post-application risk estimates were not a concern on day 0 (i.e., 12 

hours following application) for most activities. Based on HED’s post-application exposure 

calculations, the following crops reached a dermal MOE of 100 within 48 hours of application,

which is in accordance with the current label REI:

• Onions resulted in a MOE of 100 or greater within 1 day (24 hours after application) for hand 

weeding activities; 

• Brassica (cole) leafy vegetables resulted in an MOE of 100 or greater within 2 days (48 hours 

after application) for irrigation (hand set) activities.

The REI specified on the proposed label is based on the acute toxicity of fluazinam technical 

material. Fluazinam is classified as Toxicity Category I for eye irritation. Under the Worker 

Protection Standard for Agricultural Pesticides, active ingredients classified as acute toxicity

category I for any of these routes are assigned a 48-hour REI. Based on the acute toxicity profile 

of fluazinam, the 48-hour REI specified on the OMEGA®500F label is appropriate to protect 

agricultural workers from post-application exposures to fluazinam. 

Dermal Post-application Exposure and Risk Estimate – Turf (Golf Course)

Dermal post-application exposure for turf was previously assessed (D398546, Z. Figueroa,

2/7/2012). A summary of the post-application exposure and risk estimate for turf is provided in 

Table F.4. The post-application dermal exposure estimate resulted in an MOE greater than 100 

and was not of concern.

Table F.4. Short-Term Occupational Post-application Exposure and Risk Estimate Using Chemical-Specific 

Data for Fluazinam on Turf (Golf Course)

Crop/Site Activities TTR1

(μg/cm2)

Day 0 Dose2

(mg/kg/day) Day 0 MOE3 Day X at which MOE ≥ 

LOC

Turf/Sod Maintenance, 

Harvesting, Slab

Transplanting/

Planting

0.0865 0.0320 760 0

1. Turf Transferable Residue (TTR) = 0.0865 μg/cm2is based on predicted day 0 residue value calculated from chemical-specific 

data (MRID No. 48361527).

2. Chemical-Specific Dermal Dose = [TTR (μg/cm2) x TC (cm2/hr) x 0.001 mg/ug x 8 hrs/day]  BW (80 kg).

3. Chemical-Specific MOE = NOAEL (24.4 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 100. 

The Worker Protection Standard (WPS) requirements, such as REI, apply when this product is 

used on agricultural crops. However, turf grasses on golf courses are not within the scope of 

WPS. Therefore, HED concurs with the non-agricultural use requirement listed on the label 

which states: “Do not enter or allow others to enter the area until treatments have dried.” The 

statement included in the proposed label is considered to be appropriate.