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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 3/31/2010

SUBJECT: 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).

PC Code: 129098 DP Barcodes: D365940, D365945, D371444

Decision Nos.: 411458, 412727 Registration No.: 71512-1

Petitions: 8E7506, 9E7570, and 9F7571 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical 

Aggregate

Case No.: NA

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

MRID Nos.: NA 40 CFR: §180.574

 

FROM: Douglas Dotson, Ph.D., Chemist

Karlyn Middleton, Toxicologist

Zaida Figueroa, Industrial Hygienist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Richard Loranger, Senior Scientist

Christina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Division (7509P)

TO: Laura Nollen/Barbara Madden, RM Team 5, RIMUERB

John Bazuin/Tony Kish, PM Team 22, Fungicide Branch

Registration Division (7505P)
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Table of Contents

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

2.0 Ingredient Profile............................................................................................................ 12

2.1 Summary of Registered/Proposed Uses................................................................ 12

2.2 Structure and Nomenclature ................................................................................. 14

2.3 Physical and Chemical Properties......................................................................... 14

3.0 Hazard Characterization/Assessment........................................................................... 15

3.1 Hazard and Dose-Response Characterization....................................................... 15

3.1.1 Database Summary ................................................................................... 15

3.1.1.1 Studies Available and Considered ............................................. 16

3.1.1.2 Mode of Action.......................................................................... 16

3.1.2 Toxicological Effects................................................................................ 16

3.1.3 Dose-response ........................................................................................... 17

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................................. 18

3.3 FQPA Considerations ........................................................................................... 19

3.3.1 Evidence of Neurotoxicity ........................................................................ 19

3.3.2 Developmental Toxicity Studies............................................................... 20

3.3.3 Reproductive Toxicity Study .................................................................... 20

3.3.4 Additional Information from Literature Sources...................................... 21

3.3.5 Pre-and/or Postnatal Toxicity ................................................................... 21

3.3.5.1 Determination of Susceptibility................................................. 21

3.3.5.2 Degree of Concern Analysis and Residual Uncertainties.......... 21

3.4 FQPA Safety Factor for Infants and Children ...................................................... 22

3.5 Hazard Identification and Toxicity Endpoint Selection........................................ 23

3.5.1 Acute Reference Dose (aRfD) - Females 13-49 ....................................... 23

3.5.2 Acute Reference Dose (aRfD) - General Population................................ 23

3.5.3 Chronic Reference Dose (cRfD)............................................................... 24

3.5.4 Dermal Absorption.................................................................................... 25

3.5.5 Dermal Exposure (Short- and Intermediate-Term)................................... 25

3.5.6 Inhalation Exposure (Short- and Intermediate-Term)............................... 26

3.5.7 Level of Concern for Margin of Exposure................................................ 27

3.5.8 Recommendation for Aggregate Exposure Risk Assessments................. 27

3.5.9 Classification of Carcinogenic Potential................................................. 27

3.5.10 Summary of Toxicological Doses and Endpoints for Fluazinam........... 28

3.6 Endocrine disruption............................................................................................. 29

4.0 Public Health and Pesticide Epidemiology Data.......................................................... 30

5.0 Dietary Exposure/Risk Characterization ..................................................................... 30

5.1 Pesticide Metabolism and Environmental Degradation............................................. 30

5.1.1 Metabolism in Primary Crops................................................................... 30

5.1.2 Metabolism in Rotational Crops............................................................... 31

5.1.3 Metabolism in Livestock........................................................................... 31

5.1.4 Analytical Methodology ........................................................................... 31

5.1.5 Environmental Degradation...................................................................... 32

5.1.6 Comparative Metabolic Profile................................................................. 34

5.1.7 Toxicity Profile of Major Metabolites and Degradates of Concern ......... 34
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5.1.8 Pesticide Metabolites and Degradates of Concern.................................... 35

5.1.9 Drinking Water Residue Profile................................................................ 36

5.1.10 Food Residue Profile............................................................................... 36

5.1.11 International Residue Limits................................................................... 39

5.2 Dietary Exposure and Risk ........................................................................................ 39

5.2.1 Acute Dietary Exposure/Risk ..................................................................... 39

5.2.2 Chronic Dietary Exposure/Risk .................................................................. 39

5.2.3 Cancer Dietary Risk.................................................................................... 40

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information.......................... 40

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 40

7.0 Aggregate Risk Assessments and Risk Characterization............................................ 41

7.1 Acute Aggregate Risk........................................................................................... 41

7.2 Short-Term Aggregate Risk.................................................................................. 41

7.3 Intermediate-Term Aggregate Risk ...................................................................... 41

7.4 Long-Term Aggregate Risk .................................................................................. 41

7.5 Cancer Risk........................................................................................................... 42

8.0 Cumulative Risk Characterization/Assessment........................................................... 42

9.0 Occupational Exposure/Risk Pathway.......................................................................... 42

9.1 Agricultural Handler Exposure and Risk.............................................................. 42

9.1.1 Data and Assumptions for Handler Exposure Scenarios............................ 43

9.1.2 Handler Exposure and Risk ........................................................................ 45

9.2 Postapplication Exposure and Risk....................................................................... 50

9.2.1 Data and Assumptions for Postapplication Exposure Scenarios ................ 50

9.2.2 Postapplication Exposure and Risk............................................................. 54

9.2.3 Postapplication Risk Characterization ........................................................ 54

10.0 Data Needs and Label Recommendations.................................................................... 55

10.1 Toxicology ............................................................................................................ 55

10.2 Residue Chemistry................................................................................................ 55

10.3 Occupational and Residential Exposure ............................................................... 57

References:................................................................................................................................... 58

Appendix A: Toxicology Assessment ....................................................................................... 59

A.1 Toxicology Data Requirements ................................................................................ 59

A.2 Toxicity Profiles........................................................................................................ 60

A.3 Executive Summaries................................................................................................ 65

Appendix B: Tolerance Summary Table ................................................................................. 66
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1.0 Executive Summary

The active ingredient (ai), fluazinam, is a preventive contact fungicide with a multi-site mode of 

action. It disrupts the production of energy at several metabolic sites within the fungal cell. 

Interregional Research Project #4 (IR-4) has submitted petitions (PP#s 8E7506 and 9E7570) 

proposing the use of OMEGA®500F, a soluble-concentrate formulation containing 40% 

fluazinam on head lettuce, leaf lettuce, carrots, and the Onion, bulb, subgroup, 3-07A. In 

addition, ISK Biosciences Corporation submitted a tolerance petition for the use of fluazinam on 

apples (PP# 8E7506). Finally, IR-4 submitted a request to revise the established 7.0-ppm 

tolerances for fluazinam residues in/on the Bushberry subgroup (13B) and other bushberry type 

crops. IR-4 requested that the revised tolerance be established for the updated Bushberry

subgroup 13-07B.

This document assesses the toxicology database, the residue chemistry aspects, the dietary, 

residential, and occupational exposures and risks that would result from the proposed uses of the 

product. OMEGA®500F may be applied as a foliar spray using aerial, chemigation, 

groundboom, and airblast equipment. Based on the product labels, handler exposures are 

expected to be short- and intermediate-term in duration.

Toxicology

In subchronic and chronic oral and dermal toxicity studies in rats, dogs, and mice, the liver 

appeared to be the primary target organ. Liver effects included changes in clinical chemistry, 

increased absolute and/or relative liver weights, gross lesions, and a variety of histopathological 

lesions. 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 a developmental toxicity study in rats there was evidence of increased qualitative 

susceptibility (skeletal abnormalities/facial/palate clefts in fetuses vs. decreases in body weight 

gain/food consumption in maternal animals) of fetuses to fluazinam; however, there was no 

evidence of increased quantitative susceptibility. 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 an acute neurotoxicity study in rats, there were decreases in motor activity and soft stools at 

high doses (1000 mg/kg/day); however, in two subchronic neurotoxicity studies (evaluated 

together) there were no signs of neurotoxicity observed at doses up to 280 mg/kg/day. A 

neurotoxic lesion described as vacuolation of the white matter of the central nervous system was 

observed in studies in mice and dogs. This lesion was found to be reversible and is attributed to 

an impurity (Impurity-5). Based on the level of this impurity in technical grade fluazinam, the 

risk assessment for the parent compound is protective of effects from the impurity.
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A developmental neurotoxicity study in rats and a series of special studies were submitted that

address the issues of increased susceptibility in the developmental toxicity study and the 

presence of neurotoxic lesions observed in the toxicological database. As a result, there are no 

residual uncertainties with regard to pre- and/or postnatal toxicity, and no additional safety 

factors are needed. HED recommends that the FQPA Safety Factor be reduced to 1x for dietary

and dermal exposure risk assessments. For inhalation exposure risk assessment, a 10x safety

factor has been retained to account for the lack of histopathology evaluation in a 7-day inhalation 

study (currently used for risk assessment) and the use of the study in evaluating intermediateterm (6 months) inhalation exposure. Additionally, a subchronic (28-day) inhalation toxicity

study is required. 

 

The Cancer Assessment Review Committee (CARC) classified fluazinam as having “Suggestive 

evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” The 

CARC determined that quantification of human cancer risk using a linear low-dose (Q1*) 

extrapolation approach is not required, and the cRfD (0.011 mg/kg/day) is protective of potential 

cancer effects.

As a result of new data requirements in the 40 CFR Part 158 for conventional pesticide 

registration, an immunotoxicity study is required for fluazinam. HED has concluded that the 

available data show no evidence of effects on the immune system. Therefore, a database 

uncertainty factor is not needed for the absence of this study.

Metabolic Profile

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

on potatoes, peanuts, and grapes. The Agency previously concluded that the residue of concern 

in peanuts and root and tuber vegetables is fluazinam per se for purposes of both dietary risk 

assessment and tolerance enforcement. For all other crops, the residues of concern include both 

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

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

only fluazinam for all other plant commodities.

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 plant-back 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.
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Residues in Drinking Water

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 resemble the parent by way of their chemical structure. For modeling of 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).

Residue Chemistry Profile

An adequate gas chromatography with electron capture detection (GC/ECD) method (6148-91-

0170-MD-001) is available for determination of fluazinam residues in crop matrices. The 

method was deemed to be suitable for tolerance enforcement after it successfully completed the 

routes required for an enforcement method including radiovalidation, independent laboratory

validation (ILV), and tolerance method validation (TMV). Samples collected from the 

magnitude of the residue and storage stability studies were analyzed for residues of fluazinam 

using various GC/ECD methods based on, and revised slightly from, the plant enforcement 

method. The GC/ECD methods are adequate for data collection based on acceptable method 

recovery data. The lowest limit of method validation (LLMV) was 0.01 ppm in all tested 

commodities except in carrots where the LLMV was 0.02 ppm. An enforcement method for 

determination of AMGT, a residue in the tolerance for wine grapes, is also available.

PTRL Method 1676W was the data-collection method used for the analysis of samples collected 

from the dairy cattle feeding study. The method is written for LC/MS/MS analysis of fluazinam, 

AMPA, and DAPA in bovine milk and tissues, and for GC/MS analysis of DAPA in milk only. 

The limit of quantitation was 0.01 ppm for each analyte in milk, muscle, fat, liver, and kidney. 

Preliminary method validation data showed that Method 1676W adequately recovered residues 

of fluazinam, AMPA, and DAPA in milk, muscle, and fat. However, poor and/or marginal 

recoveries were obtained for AMPA and DAPA residues in kidney and liver. Method 1676W 

was marginally validated by an independent laboratory during the third trial and following 

modifications to make the method more rugged. For the purpose of developing an animal 

enforcement method, radiovalidation data are required to determine whether the method can 

detect aged residues. HED forwarded Method 1676W to ACB/BEAD for a tolerance method 

validation (TMV) because the method encountered difficulties in the ILV (e.g., three attempts for 

successful validation and/or marginal recoveries with wide variability and high coefficient of 

variation). ACB/BEAD reported that the lab that performed the ILV made major modifications 

to the original method. As a result, HED requested that the registrant submit a revised method 

that incorporated the revisions made by the ILV lab. ISK Biosciences revised the method and resubmitted it. ACB/BEAD performed a cursory review of the revised method. The registrant 

incorporated the modifications made by the ILV lab. However, the revision eliminated the 

cleanup steps that were in the original method, and the only recovery data for the revised method 

were data provided by the ILV lab. ACB/BEAD was concerned that the elimination of the 

cleanup steps could lead to dirty samples which would, in turn, lead to analytical problems, such 

as interference. ACB/BEAD performed no further validation of the method. As the revised 
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method contains major revisions to the original method, and ACB/BEAD believes it is very

likely that the revised method still is not adequate for sample analysis or tolerance enforcement, 

HED recommends that the registrant submit an ILV of the revised method.

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. Multiresidue 

method testing data are required for the regulated metabolites, AMPA and DAPA, in animals.

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

samples collected from the magnitude of the residue studies on apples, carrots, lettuce, and 

onions.

The residue data from the cattle feeding study are not adequate to satisfy data requirements. The 

feeding study data (adjusted for residue decline) along with the calculated dietary burdens for 

beef cattle (0.04 ppm) and dairy cattle (1.27 ppm) indicate that tolerances are needed for the 

combined residues of fluazinam and its metabolites DAPA and AMPA in the fat and meat 

byproducts of cattle and other ruminants at 0.05 ppm to support the proposed uses on apples and 

carrots and the established tolerances on potatoes and peanuts. However, no tolerances are 

required for milk and meat of ruminants, as the expected combined residues in these matrices are 

below the combined method limit of quantitation (LOQ) of 0.03 ppm for the regulated 

compounds. Based on the transfer coefficients for livestock tissues and the relatively low dietary 

burden for swine of 0.003 ppm for fluazinam, tolerances for hog commodities are not needed. A 

poultry feeding study is not required at this time because of the low dietary burden for poultry

(0.005 ppm).

The submitted field trial data for fluazinam on head lettuce, leaf lettuce, bulb onions, carrots, and 

apples are acceptable and support the proposed uses. Adequate numbers of trials were conducted 

in the appropriate geographic regions at ~1x the maximum proposed rate using a representative 

FlC formulation, and the appropriate samples were collected from each test at the proposed PHI. 

However, no residue data were provided on AMGT residues in lettuce. Although AMGT residue 

data on lettuce are still required for purposes of dietary risk assessment, the available data 

support tolerances of 0.02 ppm for head lettuce and 2.0 ppm for leaf lettuce. HED accounted for 

AMGT residues in lettuce in the current risk assessment using a ratio obtained from plant 

metabolism data. The field trial data also support a tolerance of 0.20 ppm for the Bulb onion 

subgroup (3-07A). The tolerance spreadsheet (Guidance for Setting Pesticide Tolerances Based 

on Field Trial Data SOP) was used for determining appropriate tolerance levels. Because of 

data deficiencies associated with Method 1676W, the cattle feeding study, and the apple 

processing study, HED does not recommend in favor of tolerances for apple and carrot 

commodities.

After reevaluating the available residue data for blueberries, HED concludes that the residue data 

for fluazinam from the blueberry field trials are distributed lognormally. As a result, the 

recommended tolerance for the revised Bushberry subgroup, 13-07B is 7.0 ppm, which is 

equivalent to the current tolerance for Subgroup 13B.
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The apple processing study is not adequate to satisfy data requirements. In apples, the 

metabolite AMGT is a residue of concern for risk assessment. In the processing study there were 

no quantifiable residues of AMGT in raw apples. In several of the field trials that were 

performed, however, raw apples contained AMGT residues at, or above, the limit of quantitation. 

In a few cases, residues of AMGT were comparable to those of the parent fluazinam. Canadian 

and U.S. residue chemistry guidelines both stipulate that in the processing study, if residues in 

the raw agricultural commodity (RAC) are below the LOQ, but quantifiable residues occurred in 

the RAC in field trials performed at the maximum requested label rate, that the processing study

should be conducted at exaggerated rates in order to ensure that quantifiable residues will be 

present in the RAC. Quantifiable residues are needed in the RAC in order to determine a reliable 

concentration factor. As a result, the processing study needs to be repeated at a sufficiently high 

rate that residues of both parent and AMGT are quantifiable in the RAC. In the event that the 

potential for phytotoxicity exists, the application rate does not need to be greater than the rate at 

which phytotoxicity occurs.

Tolerance Harmonization

There are currently no established Codex, Canadian, or Mexican maximum residue limits 

(MRLs) for fluazinam on apples, carrots, lettuce, onions, or berry crops. Therefore, there are no 

harmonization issues for the requested tolerances.

Dietary Exposure

HED performed the acute and chronic dietary exposure analyses based on conservative 

assumptions. Both assessments incorporate 100% crop treated (CT) assumptions and modeled 

estimated drinking water concentrations (EDWCs). The acute assessment is based on tolerance

level residues. The chronic assessment is based on an average field trial value for apples and 

tolerance level residues for all other commodities. HED considers the resulting acute and 

chronic exposure and risk estimates to be high-end and very conservative. The acute risk 

estimates 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 4.1% of the acute PAD (aPAD). The population subgroup with the highest risk 

estimate is Females 13-49 years of age, which uses 20% of the aPAD. The 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 14% of the chronic PAD (cPAD). The population subgroup 

with the highest risk estimate is All Infants less than one year old, which uses 40% of the cPAD. 

The CARC determined that the cRfD is protective of cancer effects. As a result, a dietary

exposure assessment for cancer risk is not necessary.

Residential Exposure

Fluazinam has no residential uses, and no occupational uses at residential sites are being 

requested in this petition; therefore, no residential risk assessment has been conducted. 
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Aggregate Exposure

The acute aggregate risk of exposure to fluazinam is equivalent to the acute dietary risk. Acute 

dietary risk estimates are not of concern for the general U.S. population or any population 

subgroup. There are no residential uses for fluazinam; therefore, no short- or intermediate-term 

aggregate risk assessments were performed. As there are no residential uses for fluazinam, 

dietary (food + water) consumption is the only source of exposure to fluazinam that is expected 

to result in chronic exposure. Therefore, the long-term aggregate exposure and risk estimates are 

equivalent to the chronic dietary exposure and risk estimates. The chronic aggregate risk 

estimates are below HED’s level of concern for all population subgroups.

The CARC determined that the cRfD is protective of cancer effects. Cancer risk resulting from 

exposure to fluazinam is not of concern.

Occupational Handler Risk

No chemical-specific handler exposure data were submitted in support of this registration. HED 

data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 was used to assess 

handler exposures (HED Science Advisory Council for Exposure (ExpoSAC), SOP No. 7, 

January 1999).

The maximum application rate for each exposure scenario is presented as the worst-case 

scenario. All handler scenarios resulted in MOEs greater than the level of concern (MOEs > 100 

for dermal and > 1,000 for inhalation) with some level of risk mitigation. HED recommends that 

all label requirements for PPE are followed and expanded to all handlers. 

Occupational Postapplication Risk

Based on the Agency’s current practices, a quantitative postapplication inhalation exposure 

assessment is not being performed for fluazinam at this time. However, volatilization of 

pesticides might be a potential source of postapplication inhalation exposure to individuals in 

close proximity to locations where pesticide applications are made. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its FIFRA 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 the way to incorporate postapplication 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 postapplication inhalation exposure 

assessment for fluazinam.

Chemical-specific dislodgeable foliar residue (DFR) studies on apples (MRID 45584203) and 

peanuts (MRID 46991302) were submitted and reviewed by HED. For this assessment, peanut 

DFR data were used as surrogate data to assess postapplication exposure for lettuce, onions, and 

carrots. 
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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 these routes are assigned a 48-hour REI. 

Postapplication MOEs were estimated for “Day 0” exposure (i.e., the day of application). In 

cases where the MOE was less than the level of concern (LOC) of 100 on Day 0, residue 

dissipation data/assumptions were used to determine the day for which the risk would be not of 

concern (i.e., MOE of 100 or greater). Based on HED’s postapplication exposure calculations, 

the dermal risks for apples and onions, and for certain activities on carrots were greater than 100 

within 48 hours, which is in accordance with the current label REI. Apple and onion 

postapplication dermal risks were 100 or greater within 12 hours of application. Carrot

postapplication dermal risks were 100 or greater within 48 hours of application for low to 

medium contact activities (i.e. hand weeding, irrigation, and scouting).

However, carrots did not reach a MOE of 100 or greater for high contact activities (i.e., hand 

harvesting) until day 6. Furthermore, lettuce did not reach a MOE of 100 or greater for medium 

contact activities (i.e., irrigation, scouting) until day 8 and for high contact activities (i.e., hand 

harvesting) until day 12. Risks from these activities are of concern until the specified intervals 

have elapsed. HED recommends that the Registration Division ensure that the appropriate REI 

is provided on all registered labels.

Environmental Justice Considerations

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

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

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

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups,

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, nondietary exposures based on home-use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

postapplication are evaluated. Further considerations are currently under evaluation as OPP has 

committed resources and expertise to the development of specialized software models and the 

refinement of current methodologies and policies that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups. To ensure 
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that this risk assessment is consistent with scientific standards and policies under development, 

HED might refine the risk assessment components for all registered uses in the future.

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 studies, which comprise the 

Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) 

Database, have been determined to require a review of their ethical conduct, have received that 

review, and have been determined to be ethical.

Conclusions/Recommendations

HED concludes that there is a reasonable certainty that no harm will result to the general U.S. 

population, any population subgroup, or occupational workers through the establishment of the

recommended tolerances on head lettuce, leaf lettuce, or the Bulb onion subgroup (3-07A).

HED recommends in favor of the establishment of the following tolerances: lettuce, head at 0.02 

ppm; lettuce, leaf, at 2.0 ppm; and Onion, bulb, subgroup 3-07A, at 0.20 ppm. Refer to Table 

B.1., in Appendix B for a complete list of the proposed and recommended tolerances associated 

with these tolerance petitions.

HED recommends that the tolerance expressions for fluazinam be revised as stated in Appendix 

B.

An analytical reference standard for the AMGT metabolite is not available. RD should request 

that the registrant submit this standard to the EPA’s National Pesticide Repository as soon as 

possible. 

Although residues in or on apples, carrots, and animal commodities were included in this risk 

assessment, HED cannot recommend in favor of tolerances for these commodities at the present 

time because of deficiencies in the livestock residue analytical method, the cattle feeding study, 

and the apple processing study. These data deficiencies are outlined in Section 10.0, Data Needs 

and Label Recommendations, and are discussed in detail in Sections 5.1.4 and 5.1.10 of this 

document.

Prior to the establishment of tolerances, RD should request that the registrant provide the 

following:

(1) A revised Section F in which a tolerance of 0.2 ppm is proposed for Onion, bulb, 

subgroup 3-07A, and a tolerance of 7.0 ppm is proposed for Bushberry, subgroup 13-07B

(2) Revised labels in which the use directions for all the subject crops (including apples and 

carrots) include a prohibition against addition of adjuvants to the spray mixture

(3) Revised labels that specify the appropriate REIs
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(4) Revised labels in which the required PPE is expanded to all handlers (i.e., workers 

conducting flagger-related activities should wear the same PPE as applicators in order to 

reduce exposures).

These requirements are outlined in greater detail in Section 10.0, Data Needs and Label 

Recommendations.

HED recommends that the following data be made conditions of registration:

(1) Field trial data for AMGT residues in lettuce

(2) An immunotoxicity study for fluazinam

(3) A subchronic (28-day) inhalation toxicity study for fluazinam.

These requirements are outlined in greater detail in Section 10.0, Data Needs and Label 

Recommendations.

2.0 Ingredient Profile

Fluazinam (Omega 500F Agricultural Fungicide) is a non-systemic, preventive, contact 

fungicide of the phenyl-pyridinamine class, with a multi-site mode of action. It disrupts the 

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

fungicide. That is, when applied to plants, it remains primarily on the plant surface, is not taken 

up to any extent by the plant, and is not translocated within the plant.

2.1 Summary of Registered/Proposed Uses

Fluazinam is currently registered in the U.S. for use on ginseng, peanuts, potatoes, turnip greens, 

Crop Group 5 (Brassica leafy vegetables), Subgroup 6A (except pea), Subgroup 6B (except pea), 

Subgroup 6C (except pea), the Bushberry subgroup (13B), and other bushberries that are 

included in Subgroup 13-07B but not 13B. Tolerances range from 0.01 ppm for the Brassica

leafy vegetables and turnip greens to 7.0 ppm for the Bushberry subgroup and other bushberries. 

In addition, there is a tolerance of 3.0 ppm for residues in/on wine grapes (no U.S. registration). 

These tolerances are listed in 40 CFR 180.574. The current tolerance petitions include apples, 

carrots, head lettuce, leaf lettuce, and the Bulb onion subgroup (3-07A). In addition, IR-4 

submitted a request to revise the established 7.0-ppm tolerance for fluazinam residues in/on the 

Bushberry subgroup (13B) and other bushberry type crops by reducing it to 4.5 ppm. IR-4 

requested that the revised tolerance of 4.5 ppm be established for the updated Bushberry

subgroup 13-07B.

IR-4 and ISK Biosciences are proposing the use of a formulation containing 4.17 pounds per 

gallon (lb/gal) of fluazinam (Omega 500F Agricultural Fungicide; EPA Registration No. 

71512-1) on the proposed crops. This end-use product (EP) is formulated as a flowablesuspension concentrate (FlC). Copies of the proposed labels were provided, and the proposed 

uses on the requested crops are summarized in Table 2.1, below.
Page 13 of 67

Table 2.1. Summary of Directions for Use of Fluazinam.

Applic. Timing; Type; 

and Equipment

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations1

Apple

Broadcast foliar 

applications prior to 

or during disease

development;

Ground and aerial

equipment 

4.17 lb/gal 

FlC

[71512-1]

0.33-

0.45 10 4.50 28

Apply in a minimum 

of 5 gal/A (both 

ground and aerial 

equipment). The 

minimum RTI is 7 

days.

Bulb Onion Subgroup 3-07A

Broadcast foliar 

applications prior to 

or during disease

development;

Ground equipment 

4.17 lb/gal 

FlC

[71512-1]

0.52 6 3.12 7

Apply in a minimum 

of 5 gal/A. The 

minimum RTI is 7 

days.

Carrot

Directed band to the 

crop prior to or 

during disease

development;

Ground equipment 

4.17 lb/gal 

FlC

[71512-1]

0.52 4

2.08

(implied) 7

Apply in a minimum 

of 30 gal/A. The 

minimum RTI is 7 

days.

Lettuce (Head and Leaf)

Broadcast or banded 

foliar application or 

soil drench 

application at 

thinning;

Ground equipment

4.17 lb/gal 

FlC

[71512-1]

0.52-

0.99 1 1.0

50 - head 

lettuce;

30 - leaf 

lettuce

Apply in a minimum 

of 50 gal/A. 

1

 A 48-hour restricted entry interval is specified. 

The current (and proposed) product label for the 4.17 lb/gal FlC formulation specifies that 

applications are allowed through the following types of irrigations 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: all crops on the label 

may be replanted immediately after treatment. All other crops can be replanted 30 days after the 

last application.
Page 14 of 67

2.2 Structure and Nomenclature

TABLE 2.2. Test Compound Nomenclature

Compound Chemical Structure

 

N

N

H

CF3

Cl

Cl

CF3

NO2

O2N

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 (USA); Allegro® 500F (Canada)

2.3 Physical and Chemical Properties

TABLE 2.3 Physicochemical Properties of Fluazinam

Parameter Value Reference

Melting Point/Range 115-117°C The e-Pesticide Manual (13th

Edition) Version 3.1

pH 5.85 MRID #43521001

Density (25°C) 1.02 g/cm3 LSS 2000_1973_2LS_rev

Water Solubility (25°C) (pH buffered to 5) 0.131 mg/L

(pH buffered to 7) 0.157 mg/L

(pH buffered to 9) 3.384 mg/L

LSS 2000_1973_2LS_rev
Page 15 of 67

TABLE 2.3 Physicochemical Properties of Fluazinam

Parameter Value Reference

Solvent Solubility (25°C) Solvent Solubility (g/L) LSS 2000_1973_2LS_rev

acetone

dichloromethane

ethyl acetate

ethyl ether

hexane

methanol

octanol

toluene

853

675

722

231

8

192

41

451

Vapor Pressure Temp (°C) Vap. Press. (Pa) LSS 2000_1973_2LS_rev

25

35

45

2.3 x 10-5

1.3 x 10-4

6.7 x 10-5

Dissociation Constant (pKa) Average pKa = 7.22 in 50% 

ethanol/water (v/v)

LSS 2000_1973_2LS_rev

Octanol/Water Partition Coefficient 

(Log KOW)

1.08 x 104(Log Kow = 4.03) LSS 2000_1973_2LS_rev

UV/Visible Absorption Spectrum pH λmax (nm) Regulatory Note REG2003-12

5

7

>10

238

239, 342

260, 343, 482

 

3.0 Hazard Characterization/Assessment 

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The toxicity profile for fluazinam can be characterized for potential carcinogenic, mutagenic, 

developmental, and reproductive effects. However, an immunotoxicity study is required as a 

result of new data requirements in the 40 CFR Part 158 for conventional pesticide registration. 

Additionally, a subchronic (28-day) inhalation toxicity study is required. A 7-day inhalation 

toxicity study was used for short-and intermediate-term inhalation risk assessments; however, 

this study did not include histopathology evaluation. As a result, a 10x safety factor has been

retained to account for the lack of histopathology evaluation, as well as the use of the 7-day

study for intermediate-term (6 months) inhalation exposure risk assessment. The submittal of

the required subchronic inhalation study could potentially result in the removal of the database 

uncertainty factor.
Page 16 of 67

3.1.1.1 Studies Available and Considered (Animal, Human, General Literature)

The following studies were submitted: 

1. Subchronic toxicity studies in rats and dogs, 

2. Chronic/carcinogenicity study in rats, 

3. Carcinogenicity study in mice, 

4. Chronic toxicity study in dogs, 

5. Developmental toxicity studies in rats and rabbits, 

6. Reproduction study in rats

7. Acute, subchronic, and developmental neurotoxicity studies in rats

8. Dermal toxicity study in rats 

9. Mutagenicity battery (including Bacterial reverse assay, Mammalian cell mutation, In 

vitro chromosome aberration, Micronucleus assay, and unscheduled DNA synthesis 

in cultured mammalian cells) 

10. Metabolism study in rats. 

3.1.1.2 Mode of action

Fluazinam is a preventive contact fungicide with a multi-site mode of action. It disrupts the 

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

fungicide. That is, when applied to plants, it remains primarily on the plant surface. It is not 

taken up to any extent by the plant, and is not translocated within the plant as are systemic 

fungicides.

3.1.2 Toxicological Effects

The liver appeared to be a primary target organ in subchronic and chronic oral and dermal 

toxicity studies in rats, dogs, and mice. Signs of liver toxicity included changes in clinical 

chemistry (e.g. increased serum alkaline phosphatase, increased aspartate aminotransferase), 

increased absolute and/or relative liver weights, increased incidences of gross lesions (e.g. pale, 

enlarged, pitted, mottled, accentuated markings), and a variety of histopathological lesions. 

Microscopic liver lesions included eosinophilic/basophilic hepatocytes, rarefied or vacuolated 

hepatocytes, altered hepatocytic foci, hepatocytic single cell necrosis, hypertrophy, fatty 

changes, increased brown pigmented macrophages, sinusoidal chronic inflammation, 

pericholangitis, and bile duct hyperplasia. 

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 and food consumption, mild anemia, increased serum cholesterol, 

phospholipid, and aspartate aminotransferase, testicular atrophy, increased testicular and lung 

weights, pancreatic exocrine atrophy, increased alveolar adenomatosis, epithelialization and 

macrophages, thyroid gland follicular cell hyperplasia, and an increased incidence of thyroid 

gland follicular cell tumors in male rats, but not in female rats. In dogs, effects included 

increased salivation, nasal dryness, grey mottling of the retina, mild anemia, increased serum 

alkaline phosphatase and gastric lymphoid hyperplasia. In mice, increased mortality (at high 
Page 17 of 67

doses), decreased body weight gain, increased glucose, increased kidney weights, cystic thyroid 

follicules, and an increased incidence of both benign and malignant hepatocellular liver tumors 

(males) were seen. 

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. Fetal exposure of 250 mg/kg/day resulted in decreases in body weights and 

placental weights, increased incidences of facial/palate clefts, diaphragmatic hernia, and delayed 

ossification in several bone types. There was also greenish amniotic fluid and increases in late 

resorptions, as well as postimplantation loss. Maternal effects observed at the same dose level 

were decreases in body weight gain and food consumption, increases in water consumption and 

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 an acute oral neurotoxicity study in rats, decreases in motor activity and soft stools were 

observed on the day of dosing at 1000 mg/kg/day. These effects were considered to be due to 

systemic toxicity and not a result of frank neurotoxicity. In two subchronic neurotoxicity studies 

in rats that were evaluated together there were no signs of neurotoxicity observed up to a dose of 

280 mg/kg/day. A neurotoxic lesion described as vacuolation of the white matter of the central 

nervous system (CNS) was observed initially in long-term (1-2 year) chronic studies in mice and 

dogs. This vacuolation was also observed later upon careful re-examination of the CNS, in 

shorter-term (4-week to 90-day) subchronic studies in mice and dogs. This lesion was observed 

during the histopathology examination of several tissues of the CNS and occurred most 

frequently in the brain (sections of cerebrum and/or sections of cerebellum, pons, medulla, and 

midbrain) and less frequently in the cervical spinal cord. This lesion is reversible and is 

attributed to an impurity, Impurity 5 (see section 3.3.2.). 

 

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

assess human carcinogenic potential.” This classification is based on increases in thyroid gland 

follicular cell tumors in male rats and increases in hepatocellular tumors in male mice. The 

Agency has determined that quantification of human cancer risk using a linear low-dose (Q1*) 

extrapolation approach is not required and the cRfD (0.011 mg/kg/day) is protective of potential 

cancer effects.

3.1.3 Dose-response

Although treatment-related effects were noted in other organs, liver toxicity was the primary

effect noted in the toxicology database for fluazinam. Liver effects were observed in the 

majority of toxicity studies in rats. In subchronic studies, effects included increased liver 

weights, increased aspartate aminotransferase, and liver pathology (fatty change) at doses ≥ 9.7 

mg/kg/day. Effects were mainly observed at the highest doses tested (HDT). For those studies 

with liver toxicity noted in mid-doses, higher doses did not result in a significant increase in liver 

toxicity. However, chronic exposure did result in more severe liver toxicity (pigmented 

macrophages and vacuolation) at lower doses (3.8 mg/kg/day). Similar effects (including 

adenomas) were observed in mice after chronic exposure at ≥ 126 mg/kg/day, with severity of 

toxic effects increasing with dose. Additionally, liver effects were also noted in toxicity studies 
Page 18 of 67

in dogs and rabbits. In dogs, increased liver weights and alkaline phosphatase, along with 

hyperplasia were observed at the HDT of 100 mg/kg/day after subchronic exposure. After 

chronic exposure, liver effects were limited to increased alkaline phosphatase at the HDT of 50 

mg/kg/day. Significant liver toxicity (hypertrophy, necrosis, brown pigment, apoptosis, etc.) was 

also noted in adult animals in a developmental rabbit study at ≥ 7 mg/kg/day. 

As the liver was the target organ for fluazinam in several studies, liver toxicity observed in a 

carcinogenicity study in mice was selected for chronic dietary exposure risk assessment. The 

chronic reference dose of 0.011 mg/kg/day was calculated based on liver effects observed at the 

LOAEL of 10 mg/kg/day (NOAEL=1.1 mg/kg/day). For acute dietary exposure of females 13-

49, toxic effects relevant to females and attributable to a single dose were selected. Increased 

incidences of total litter resorptions and fetal skeletal abnormalities were observed in a 

developmental toxicity study in rabbits at the LOAEL of 12 mg/kg/day (NOAEL= 7 mg/kg/day). 

As a result, the developmental study was used to calculate the acute reference dose (aRfD) of 

0.07 mg/kg/day. Developmental effects were also observed in the young in developmental rat 

studies; however, they occurred at much higher doses (≥ 250 mg/kg/day) than developmental 

effects seen in rabbits. In a reproduction study, offspring effects were limited to decreased body

weight gain. For the general population, the aRfD of 0.5 mg/kg/day was based on a LOAEL of 

1000 mg/kg/day (NOAEL=50mg/kg/day) from an acute neurotoxicity study in rats; adverse 

effects seen were decreases in motor activity and soft stools on the day of dosing. These effects 

were not observed in subchronic neurotoxicity studies. For short- and intermediate-term dermal 

and inhalation risk assessments, route specific studies were used based on liver effects. For 

dermal, a 21-day dermal toxicity study in rats was used based on effects observed at the LOAEL 

of 100 mg/kg/day (NOAEL=10 mg/kg/day). For inhalation, a 7-day inhalation study in rats was 

used with a LOAEL of 3.87 mg/kg/day (NOAEL of 1.38 mg/kg/day).

 

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Overall recovery of the administered radioactivity (reported in MRID Nos. 43521006, 43521007, 

and 43521008) was acceptable (93-104%). 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 (89-

100%) as determined by review of MRIDs 43521006, 43521007, and 43521008. 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%). 
Page 19 of 67

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

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

34% of the administered dose (MRIDs 43521006, 43521007, and 43521008). Analysis of 

chromatograms indicated that numerous other metabolites were present in the bile, but 

individually were 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 IKF-1216.

3.3 FQPA Considerations

3.3.1 Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in an acute neurotoxicity study (MRID 44807210) in 

rats up to 1000 mg/kg/day. Systemic effects observed were decreases in motor activity and soft 

stools on the day of dosing. In two subchronic neurotoxicity studies (MRIDs 44807217 and

44807218), evaluated together, no signs of neurotoxicity or systemic effects were observed at 

doses up to 280 mg/kg/day. A neurotoxic lesion described as vacuolation of the white matter of 

the CNS was observed initially in long-term (1-2 year) chronic studies in mice and dogs. This 

vacuolation was also observed later upon careful re-examination of the CNS, in shorter-term (4-

week to 90-day) subchronic studies in mice and dogs. This lesion was observed during 

histopathological examination of several tissues of the CNS and occurred most frequently in the 

brain (sections of cerebrum and/or sections of cerebellum, pons, medulla, and midbrain) and less 

frequently in the cervical spinal cord. Although this lesion was also observed in control animals, 

the increased incidence and/or severity of the lesion in treated animals was clearly treatmentrelated and dose-related. Further investigation of this lesion in a series of special studies 

demonstrated the same lesion could also be induced in rats. In the special studies, the following 

observations were made:

1. Fluazinam, per se, was not responsible for the induction of this lesion. An analysis of the 

effects of impurities present in technical grade fluazinam revealed that one single impurity, 

Impurity 5, was solely responsible for the appearance of white matter vacuolation. 

2. No significant differences in susceptibility or in incidence or severity of vacuolation of 

the white matter of the CNS were observed among species (mice, dogs, or rats). Similarly, 

no significant differences were attributed to sex.

3. White matter vacuolation in the CNS was reversible. Electron microscopy of the white 

matter (cerebellum) of mice treated with technical grade fluazinam indicated that treatmentrelated effects were confined to the myelin sheaths. Large vacuoles were observed in the 

intramyelin sheaths because of the accumulation of fluid between the sheaths. The nucleus 

and mitochondria in oligodendroglia were observed to remain intact, which suggested that 

there was no damage to these cells. The myelin sheaths appeared to recover completely 

during a recovery period of up to 56 days.
Page 20 of 67

4. There appears to be a non-linear dose-response with a clear threshold below which no 

effect occurs. It was concluded that a LOAEL of 0.1 mg/kg/day and a NOAEL of 0.02 

mg/kg/day for CNS effects could be established for Impurity 5. 

A developmental neurotoxicity study (MRID 46534401) was submitted that addresses the 

concerns regarding the white matter vacuolation observed in the subchronic and chronic studies 

in mice and dogs, as well as the increased qualitative susceptibility seen in the developmental rat 

study. In the study, there was no evidence of vacuolation of the brain or any other treatmentrelated pathology seen in dams or pups up to 50 mg/kg/day. Treatment-related effects observed 

in pups were decreases in body weight and body weight gain (lactation), and delayed preputial 

separation seen in the absence of maternal toxicity. 

As previously stated, the brain lesions (vacuolation of the brain and nerve tissue) observed are

attributed to Impurity 5. The level of Impurity 5 in the DNT study was 0.09%. At the current 

maximum concentration of Impurity 5 in technical grade fluazinam of 0.1% (Memo, D272455, I. 

Gairola, 5/18/2001), the NOAEL for CNS effects of 0.02 mg/kg/day for Impurity 5 is equivalent 

to a NOAEL for CNS effects of 20 mg/kg/day for technical grade fluazinam. The aRfDs (0.07 

and 0.5 mg/kg/day) and cRfD (0.011 mg/kg/day), as well as risk assessments for dermal (10 

mg/kg/day) and inhalation (1.38 mg/kg/day + additional 10x safety factor) exposures are set at 

doses much lower than 20 mg/kg/day. Therefore, they are protective of any possible neurotoxic 

effects resulting from exposure to Impurity 5. 

Based on the results of the developmental neurotoxicity study and the overall weight of the 

evidence, additional neurotoxicity studies are not needed. 

3.3.2 Developmental Toxicity Studies

In a developmental toxicity study in rats, decreased body weight gain and food consumption, as 

well as increased water consumption and urogenital staining were observed in maternal animals 

at the LOAEL of 250 mg/kg/day (NOAEL= 50 mg/kg/day). Additionally, at 250 mg/kg/day,

developmental effects observed were decreases in fetal body and placental weights, increases in 

facial and palate clefts, diaphragmatic hernia, and delayed ossification. There were also slight 

increases in late resorptions and postimplantation loss. In the developmental toxicity study in 

rabbits, maternal effects included decreases in food consumption and liver histopathology at the 

LOAEL of 7 mg/kg/day (NOAEL=4 mg/kg/day). In fetuses, skeletal anomalies and an increased 

incidence of total litter resorptions were noted at 12 mg/kg/day (NOAEL=7 mg/kg/day).

3.3.3 Reproductive Toxicity Study

In a 2-generation reproduction study in rats, liver pathology (periacinar hepatocytic fatty

changes) was observed in parental F1 males at the LOAEL of 9.7 mg/kg/day (NOAEL=1.9

mg/kg/day). Reproductive toxicity was seen in F1 females (F2 litters) at the LOAEL of 53.6 

mg/kg/day (NOAEL=10.6 mg/kg/day) as a decreased number of implantation sites and decreased 

litter sizes up to day 4 post partum. At the LOAEL of 42.12 mg/kg/day (NOAEL=8.4 
Page 21 of 67

mg/kg/day), developmental effects observed were limited to decreased body weight gain during 

lactation for both F1 and F2 pups. 

3.3.4 Additional Information from Literature Sources

A PubMed literature search identified the existence of an open literature article that suggests that 

fluazinam might have immunotoxic potential. The reference for this article is:

A. Draper, et al., 2003, Occupational Asthma from Fungicides Fluazinam and Chlorothalonil, 

Occupational and Environmental Medicine 60:76-77.

Fluazinam is a skin sensitizer; thus, it is a potential inhalation allergen with the potential to cause 

asthma. Although the cited study demonstrates that fluazinam causes asthmatic symptoms, the 

asthma effect might be related to the sensitization potential for this chemical. Consequently, 

asthmatic symptoms might only be detected in a small population of people who might develop 

hypersensitivity as a result of chronic exposure to small amounts of the chemical in an industrial 

setting. Therefore, the development of asthma in the general population is not anticipated. 

Furthermore, the product label requires that mixer/loaders wear dust/mist or NIOSH approved 

respirators. HED recommends that this requirement be expanded to all handlers of fluazinam.

3.3.5 Pre-and/or Postnatal Toxicity

3.3.5.1 Determination of Susceptibility

Evidence of increased qualitative susceptibility of fetuses to fluazinam was observed in the 

developmental toxicity study in rats. In this study, increased incidences of facial/palate clefts 

and other rare deformities in the fetuses were observed in the presence of minimal maternal 

toxicity. A developmental neurotoxicity study in rats was submitted to address the increased 

susceptibility, as well as the presence of neurotoxic lesions observed after fluazinam exposure. 

In the developmental neurotoxicity study, decreases in body weight and body weight gain and a 

delay in completion of balano-preputial separation were observed in pups. These effects were 

seen in the absence of maternal effects, suggesting increased quantitative susceptibility of the 

offspring.

3.3.5.2 Degree of Concern Analysis and Residual Uncertainties for Pre- and/or

 Postnatal Susceptibility

The purposes of the Degree of Concern analysis are: (1) to determine the level of concern for the 

effects observed when considered in the context of all available toxicity data; and (2) to identify

any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors 

to be used in the risk assessment. If residual uncertainties are identified, then HED determines 

whether these residual uncertainties can be addressed by a FQPA safety factor and, if so, the size 

of the factor needed.

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

toxicity study in rats, there are no residual uncertainties with regard to pre- and/or postnatal 
Page 22 of 67

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 

for fluazinam, the degree of concern for the effects observed in the 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 NOAEL of 50 mg/kg/day

identified in this developmental toxicity study in rats is significantly higher than the NOAEL 

used (7 mg/kg/day) to establish the acute Reference Dose (aRfD) of 0.07 mg/kg/day (females 13-

49); thus, the aRfD is protective of any potential developmental effects. 

Increased quantitative evidence of susceptibility was observed in a developmental neurotoxicity

study in rats (MRID 46534401). In pups, there were decreases in body weight and body weight 

gain during lactation, and delayed preputial separation observed at 10 mg/kg/day (NOAEL=2 

mg/kg/day). Although the NOAEL of 2 mg/kg/day is lower than that used for the aRfD for 

females 13-49 (7 mg/kg/day), the effects noted in the developmental neurotoxicity study are 

attributable to multiple doses and are considered to be post-natal effects. Therefore, the study 

endpoint is not appropriate for acute dietary exposures. The cRfD of 0.011 mg/kg/day is based 

on a lower NOAEL of 1.1 mg/kg/day, and is considered to be protective of potential 

developmental effects. 

3.4 FQPA Safety Factor for Infants and Children

After evaluating the toxicological and exposure data, the fluazinam risk assessment team 

recommends that the FQPA SF be reduced to 1x for dietary and dermal exposure risk 

assessments based on the following: 

 The toxicological database for fluazinam is complete in regard to pre- and postnatal 

toxicity and neurotoxicity. 

 The degree of concern is low regarding the qualitative susceptibility observed in the 

developmental toxicity study and neurotoxic lesions in studies in rats, mice, and dogs. 

Additionally, there are no residual uncertainties with regard to pre- and/or postnatal 

toxicity or neurotoxicity, and no additional factors are needed.

 An immunotoxicity study is now required as a result of new data requirements in the 40 

CFR Part 158 for conventional pesticide registration. However, based on the available 

data fluazinam shows no evidence of treatment-related effects on the immune system. 

The Agency does not believe that conducting a study will result in a lower point of 

departure (PoD) than that currently selected for overall risk assessment and, therefore, a 

database uncertainty factor (UFDB) is not needed to account for the lack of the study. 

 The acute and chronic dietary exposure assessments are based on the assumption that 

100% of all commodities with fluazinam tolerances will be treated with fluazinam. In 

addition, the acute assessment is based on tolerance level residues for all commodities 

and the chronic assessment is based on tolerance level residues for all commodities 

except apples, for which the average field trial value was used. These assumptions result 

in very high-end estimates of dietary exposure.
Page 23 of 67

 Estimated drinking water concentrations in both the acute and chronic dietary exposure 

assessments are based on values generated by models and modeling parameters that are 

designed to provide conservative, health protective, high-end estimates of water 

concentrations.

 No residential uses are registered or proposed at this time. 

A 7-day inhalation study is currently being used for short- and intermediate-term inhalation risk

assessments. A 10x database safety factor has been retained for these scenarios to account for 

the lack of histopathology evaluation in the inhalation study, as well as its use in evaluating 

intermediate-term (6 months) inhalation exposure.

3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1 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)

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 possibly 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. Uncertainty factors (100x) include: 10x interspecies 

extrapolation and 10x intraspecies variability.

Acute RfD (females 13-49) = 

100 ( )

7 / /

UF

mg kg day = 0.07 mg/kg/day

3.5.2 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)

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 
Page 24 of 67

mg/kg/day and the LOAEL of 1000 mg/kg/day were based on soft stools and decreased motor 

activity. Because of the large dose spread in this study 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) in that the route and duration of exposure are 

appropriate for this population. Uncertainty factors (100x) include: 10x interspecies 

extrapolation and 10x intraspecies variability.

Acute RfD (general population) = 

100 ( )

50 / /

UF

mg kg day = 0.5 mg/kg/day

3.5.3 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 (increased incidence of nasal dryness in females and increased 

incidence/severity of gastric lymphoid hyperplasia in males and females) were unrelated to liver 

toxicity. The NOAELs in the mouse and dog studies were similar. The LOAELs in the mouse 

and dog studies were also similar. The NOAELs in the mouse study were 1.12 mg/kg/day in 

males and 1.16 mg/kg/day in females. In the dog study, the NOAEL was the same for males and 

females: 1 mg/kg/day. The LOAELs in the mouse study were 10.72 mg/kg/day in males and 

11.72 mg/kg/day in females. In the dog study, the LOAEL was the same for males and females: 

10 mg/kg/day. 

 

1

st Study: 2-Year carcinogenicity study in mice 

MRID No: 42208405, 44807220, 44807212 

Dose and Endpoint for Risk Assessment: NOAEL= 1.12 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

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. Uncertainty 

factors (100x) include: 10x interspecies extrapolation and 10x intraspecies variability.

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)
Page 25 of 67

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. Uncertainty factors (100x) include: 10x interspecies extrapolation and 10x 

intraspecies variability.

Chronic RfD = 

100 ( )

1.1 / /

UF

mg kg day = 0.011 mg/kg/day

Comments: A 2-year chronic feeding/carcinogenicity study in rats (MRIDs 42248620 and

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 

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. 

3.5.4 Dermal Absorption

A dermal absorption study is not available for fluazinam. A dermal absorption factor of 25% 

was estimated by comparing the LOAEL from a 21-day dermal toxicity study in rats (42270602) 

to the LOAEL from a 4-week range-finding feeding study in rats (44807213) based on a 

common endpoint (liver toxicity). In the dermal toxicity study, liver effects observed were 

increased aspartate aminotransferase (AST) and increased cholesterol levels in males at the 

LOAEL of 100 mg/kg/day (NOAEL=10 mg/kg/day). In the range-finding study, effects 

included increased serum phospholipids in females, increased total cholesterol in males and 

females, increased relative liver weights in females, liver hypertrophy in males, as well as 

decreased body weight gain and decreased food consumption in females at the LOAEL of 26.4 

mg/kg/day in males (25.9 mg/kg/day in females) and the NOAEL of 5.1 mg/kg/day in males (5.3 

mg/kg/day in females). 

Estimated Dermal = Oral LOAEL x 100 = 25 mg/kg/day x 100 = 25% 

Absorption Factor Dermal LOAEL 100 mg/kg/day

3.5.5 Dermal Exposure (Short- and Intermediate-Term) 

Study Selected: 21-Day dermal toxicity study in rats

MRID No: 42270602

Dose and Endpoint for Risk Assessment: NOAEL= 10 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)
Page 26 of 67

Study/Endpoint/Uncertainty Factors: A 21-day dermal toxicity study in rats was used to 

select the dose and endpoint for short- and intermediate-term dermal exposure. The NOAEL of 

10 mg/kg/day and the LOAEL of 100 mg/kg/day were based on increased AST and increased 

cholesterol levels in males. The route and duration of exposure are appropriate for this 

population. Uncertainty factors (100x) include: 10x interspecies extrapolation and 10x 

intraspecies variability.

Comments: Developmental effects were noted in developmental toxicity studies at ≥ 12 

mg/kg/day; however, as the endpoint chosen for dermal risk assessments is based on a lower 

NOAEL (10 mg/kg/day) it is considered to be protective of potential developmental effects.

3.5.6 Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected: 7-Day range-finding inhalation study in rats (test material: Frowncide

WP, containing 51.9% fluazinam) 

MRID No: 42248621

Dose and Endpoint for Risk Assessment: NOAEL= 1.38 mg/kg/day

Uncertainty Factor: 1000x (10x interspecies extrapolation, 10x intraspecies variability, 10x 

database uncertainty factor)

Study/Endpoint/Uncertainty Factors: A 7-day range-finding inhalation study in rats was used 

to select the dose and endpoint for short- and intermediate-term exposure. The NOAEL of 

0.011 mg/L (2.76 mg/kg/day in males and 2.97 mg/kg/day in females) and the LOAEL of 0.032 

mg/L (7.93 mg/kg/day in males and 8.50 mg/kg/day in females) were based on slightly

increased testicular weights (males) and slightly increased liver weights (females). The test 

material used in the inhalation study was not technical grade fluazinam, but a formulation 

containing approximately 52% fluazinam (Frowncide WP). Consequently, the NOAEL from 

the study (0.011 mg/L or 2.76 mg/kg/day in males and 2.97 mg/kg/day in females) was reduced 

by half to account for this decreased concentration (i.e. adjusted NOAEL = 1.38 mg/kg/day for 

males and 1.48 mg/kg/day for females). As a result, for inhalation risk assessment a NOAEL of 

1.38 mg/kg/day was used. A histopathology examination was not performed in the study, and it 

is possible that the true NOAEL could be lower than that demonstrated in the study. A safety 

factor of 10x was retained to account for the lack of histopathology evaluation in the inhalation 

studies. This factor also addresses the use of a short-term (7 day) study to evaluate 

intermediate-term inhalation exposure. Uncertainty factors (1000x) include: 10x interspecies 

extrapolation, 10x intraspecies variability, and 10x database uncertainty factor. The 7-day

range-finding inhalation study is the most appropriate route to use for evaluating inhalation risk. 

The target organ in the study is the liver, as seen in several other studies in the toxicology

database. The submittal of the required subchronic inhalation study might result in the removal 

of the 10x database uncertainty factor.

 

Comments: Developmental effects were noted in developmental toxicity studies at ≥ 12 

mg/kg/day; however, as the endpoint chosen for inhalation risk assessments is based on a lower 

NOAEL (1.38 mg/kg/day) it is considered to be protective of potential developmental effects.
Page 27 of 67

3.5.7 Level of Concern for Margin of Exposure

Table 3.5.7. Summary of Levels of Concern for Risk Assessment.

Route Short-Term (1 - 30 Days) Intermediate-Term (1 - 6 Months) Long-Term (> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 N/A

Inhalation 1000 1000 N/A

3.5.8 Recommendation for Aggregate Exposure Risk Assessments

As per the Food Quality Protection Act (FQPA, 1996), EPA must aggregate (add) exposure from 

food, drinking water, and residential exposures. When there are potential residential exposures, 

EPA must consider exposure from three major routes: oral, dermal, and inhalation. As there are 

no registered or proposed residential uses for fluazinam, a residential exposure assessment is not 

needed; furthermore, the aggregate assessment is limited to risk resulting from the dietary (food 

+ water) route of exposure. 

When conducting occupational risk assessments, HED combines dermal and inhalation 

exposures if the toxicity studies demonstrate the toxicological effects are the same for both 

exposure routes. In previous fluazinam risk assessments, HED did not combine dermal and 

inhalation exposures. For the current assessment, HED considered combining exposure from 

these routes because the effects observed at the LOAEL were related to liver toxicity in the 

route-specific dermal and inhalation toxicity studies. However, the toxic effects were not 

identical in these studies. In the dermal study, liver effects included increased cholesterol and 

aspartate aminotransferase (AST) levels, which were observed at the mid and high doses. 

However, at the mid-dose, which was originally considered to be a LOEL (lowest observed 

effect level), the increases were relatively mild and would likely be dismissed if re-evaluated 

under current policy. These effects would be considered to be treatment-related but not adverse. 

The high dose tested in the dermal toxicity study is more reflective of a true LOAEL because

more pronounced liver effects were seen (i.e., significantly increased liver weights, AST, and 

cholesterol, as well as hypertrophy). In the inhalation study, the liver effects were limited to 

increased liver weights and were also mild; however, in the absence of histopathology

evaluations these effects were considered to be adverse, and they served as the basis for the 

LOAEL. Additionally, a 10x safety factor was retained for the inhalation route of exposure to 

account for the lack of histopathology data in the inhalation toxicity study. As the endpoints 

selected for both dermal and inhalation exposure assessments are considered to be very 

conservative, combining exposure from these routes is not considered to be appropriate for the 

current assessment.

3.5.9 Classification of Carcinogenic Potential

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

Cancer Assessment Review Committee (CARC) classified 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 
Page 28 of 67

tumors in male mice (HED Doc. No.: 014512, March 29, 2001). The Agency has determined 

that quantification of human cancer risk using a linear low-dose (Q1*) extrapolation approach is 

not required, and the cRfD of 0.011 mg/kg/day is protective of potential cancer effects.

The cancer classification was 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 some equivocal evidence that fluazinam might have 

induced an increase in hepatocellular tumors in the male mice at ≥ 3000 ppm (377

mg/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.

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

Risk Assessments

Table 3.5a 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

UFA= 10x

UFH=10x

FQPA SF=1x

Total UF=100x

Acute RfD =0.5 

mg/kg/day

aPAD

= 0.5 mg/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

UFA= 10x

UFH=10x

FQPA SF=1x

Total UF=100x

Acute RfD =0.07 

mg/kg/day

aPAD

= 0.07 mg/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.

Chronic 

Dietary (All 

Populations)

NOAEL= 1.1 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF=1x

Total UF=100x

Chronic RfD 

=0.011 mg/kg/day

cPAD

= 0.011 mg/kg/day

Carcinogenicity-Mice.

LOAEL = 10.7 mg/kg/day based 

on liver histopathology and 

increased liver weight. 

Cancer (oral, 

dermal, 

inhalation)

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

carcinogenic potential.” The cRfD is protective of cancer effects.

.

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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = 

reference dose. N/A = not applicable. 
Page 29 of 67

Table 3.5b Summary of Toxicological Doses and Endpoints for Fluazinam for Use in Occupational Human 

Health Risk Assessments

Exposure/

Scenario

Point of Departure Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal 

Short-Term

(1-30 days); 

IntermediateTerm (1-6 

months) 

NOAEL (systemic) 

10 mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE 

= 100 

21-Day dermal, rats.

Systemic LOAEL = 100 mg/kg/day 

based on increased cholesterol, 

increased aspartate aminotransferase.

Inhalation 

Short-Term

(1-30 days)

Inhalation study 

NOAEL= 1.38 

mg/kg/day 

UFA=10x

UFH=10x

UFDB=10x

IAF=100%

Occupational 

LOC for MOE 

= 1000

7-Day inhalation, rats.

LOAEL = 3.97 mg/kg/day based on 

increased liver weights (females) and 

increased testicular weights.

Inhalation 

IntermediateTerm (1-6 

months) 

Inhalation study 

NOAEL= 1.38 

mg/kg/day 

UFA=10x

UFH=10x

UFDB/UFS

=10x

IAF=100%

Occupational 

LOC for MOE 

= 1000

7-Day inhalation, rats.

LOAEL = 3.97 mg/kg/day based on 

increased liver weights (females) and 

increased testicular weights.

Cancer (oral, 

dermal, 

inhalation)

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

carcinogenic potential.” The cRfD is protective of cancer effects.

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

key data (i.e., lack of a histopathological examination). MOE = margin of exposure. LOC = level of concern. IAF=inhalation 

absorption factor.

3.6 Endocrine disruption

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

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) might have an effect in humans or wildlife similar to an effect produced 

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

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

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

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

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

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

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

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

to establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 
Page 30 of 67

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Fluazinam is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines, and the Tier 1 screening battery, please visit EPA’s website: 

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

4.0 Public Health and Pesticide Epidemiology Data

No public health/epidemiology data were used in developing this risk assessment. 

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

The nature of the residue in plants has been adequately delineated, based on acceptable potato, 

peanut, and grape metabolism studies that were reviewed previously (D257115; William 

Cutchin; 5/21/2001). The metabolism of fluazinam appears to be similar in potatoes, peanuts, 

and grapes. 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. Subsequent degradation of the rings into small fragments 

occurs and these fragments can then be incorporated into a variety of natural plant components. 

HED concluded that the residue of concern (ROC) in peanuts as well as root and tuber 

vegetables (for both tolerance expression and dietary risk assessment purposes) is the parent 

compound only (D272624; William Cutchin; 4/23/2001). In wine grapes, both parent and 

AMGT are included in the ROC for tolerance expression and risk assessment. Additionally, 

HED determined that data generated for potential new uses on other crops (with the exception of 

root and tuber, and bulb vegetables) should include analyses for both parent and AMGT. The 

residues of regulatory interest in primary crops are listed in Table 5.1.b.

The registrant submitted an apple metabolism study (MRID 46991301); however, HED has not 

reviewed it. In the event that the registrant resolves the data deficiencies associated with the 

apple petition and re-submits it, the apple metabolism study should be reviewed.
Page 31 of 67

5.1.2 Metabolism in Rotational Crops

Regulatory requirements pertaining to fluazinam residues in rotational crops have been fulfilled, 

and the rotational crop restrictions on the proposed label are adequate. An adequate confined 

rotational crop study was previously reviewed (Memo, D212612, G. Herndon, 9/5/1995) in 

conjunction with a time-limited tolerance petition for use on peanuts. The available data indicate 

that neither fluazinam nor any of its structurally related metabolites are likely to be detectable in 

rotational root crops or leafy vegetables planted ≥30 days (≥68 days for small grains and all other 

crops) following a 2.0 lb ai/A soil application of fluazinam. 

5.1.3 Metabolism in Livestock

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

metabolism studies (Memo, D257115, W. Cutchin; 5/21/2001). The metabolism of [14C]-

fluazinam in ruminants and poultry is similar, 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. HED has determined 

that the fluazinam residues of regulatory interest in animals are parent plus the metabolites 

AMPA and DAPA as well as their sulfamate conjugates.

 

5.1.4 Analytical Methodology

Tolerance Enforcement Method for Plant Commodities

The tolerance-enforcement method for fluazinam in crops is entitled: Fluazinam: Method for 

the Analysis in Peanut Nut Meat (Method 6148-94-0170-MD-001). The method is based on gas 

chromatography with electron capture detection (GC/ECD) and is adequate for enforcement of 

tolerances in crop matrices. The method was deemed to be suitable for tolerance enforcement 

after it successfully completed the routes required for an enforcement method including 

radiovalidation, independent laboratory validation (ILV), and tolerance method validation 

(TMV). Samples collected from the magnitude of the residue in plants and storage stability

studies were analyzed for residues of fluazinam using various GC/ECD methods based on, and 

revised slightly from, the plant enforcement method. The GC/ECD methods are adequate for 

data collection based on acceptable method recovery data. The lowest limit of method validation 

(LLMV) was 0.01 ppm in all tested commodities except in carrots where the LLMV was 0.02 

ppm.

An enforcement method for determination of AMGT, a residue in the tolerance expression for 

wine grapes, is also available. HED recommended in a previous memorandum (Memo, 

D335640, W. Drew, 8/22/07) that a previously submitted HPLC/UV method undergo an ILV 

trial, and potentially, a TMV trial by the ACB. This method is based on Method Evaluation for 
Page 32 of 67

the Analysis of AMGT in Grapes (MRID 45593101). HED has agreed to accept the recovery

data generated by IR-4 for AMGT residues in blueberries as the ILV.

Tolerance Enforcement Method for Animal Commodities

An enforcement method for determination of the fluazinam residues of concern in livestock 

commodities is not available. PTRL Method 1676W was the data-collection method used for the 

analysis of samples collected from the dairy cattle feeding study. The method is written for 

LC/MS/MS analysis of fluazinam, AMPA, and DAPA in bovine milk and tissues, and for 

GC/MS analysis of DAPA in milk only. The limit of quantitation was 0.01 ppm for each analyte 

in milk, muscle, fat, liver, and kidney. Preliminary method validation data showed that Method 

1676W adequately recovered residues of fluazinam, AMPA, and DAPA in milk, muscle, and 

fat. However, poor and/or marginal recoveries were obtained for AMPA and DAPA residues in 

kidney and liver. Method 1676W was marginally validated by an independent laboratory during 

the third trial and following slight modifications to make the method more rugged. For the 

purpose of developing an animal enforcement method, radiovalidation data are required to 

determine whether the method can detect aged residues. HED forwarded Method 1676W to 

ACB/BEAD for a tolerance method validation (TMV) because the method encountered 

difficulties in the ILV (e.g., three attempts for successful validation and/or marginal recoveries 

with wide variability and high coefficient of variation). ACB/BEAD reported that the lab that 

performed the ILV made major modifications to the original method. As a result, HED 

requested that the registrant submit a revised method that incorporated the revisions made by the 

ILV lab. ISK Biosciences revised the method and re-submitted it. ACB/BEAD performed a 

cursory review of the revised method. The registrant incorporated the modifications made by the 

ILV lab. However, the revision eliminated the cleanup steps that were in the original method, 

and the only recovery data for the revised method were data provided by the ILV lab. 

ACB/BEAD was concerned that the elimination of the cleanup steps could lead to dirty samples 

which would, in turn, lead to analytical problems, such as interference. ACB/BEAD performed 

no further validation of the method. As the revised method contains major revisions to the 

original method, and ACB/BEAD believes it is very likely that the revised method still is not 

adequate for sample analysis or tolerance enforcement, HED recommends that the registrant 

submit an ILV for the revised method.

5.1.5 Environmental Degradation

Reference: Tier I Estimated Drinking Waters Concentrations (EDWCs) of Fluazinam and its 

Transformation Products for the Use in the Human Health Risk Assessment for the Registration 

of the Following New Food Uses: Lettuce, Apples, Carrots and Bulb Vegetables (Crop Subgroup 

3-07A), D360713, J. Melendez, 2/24/2010

Based on the properties of fluazinam, applications are likely to reach the target (i.e., the crop), 

but drift is also possible. Fluazinam has a low vapor pressure and a moderate Henry’s Law 

constant. As a result of the fact that it appears to show relatively short half lives in aquatic media 

and it binds to soils, EFED believes that the chemical would not volatilize substantially.
Page 33 of 67

Fluazinam appears to degrade at moderate to low rates in aerobic soils. However, in high pH 

solutions or in aquatic media, both aerobic and anaerobic, it is more rapidly transformed into 

other compounds of similar backbone structure. Fluazinam can be photolyzed relatively rapidly 

(2.5 days) to form a tricyclic compound (G-504). The total fluazinam residues, fluazinam and 

its transformation products (DCPA, CAPA, DAPA, AMPA, and HYPA) are persistent in most 

environments (stable to hydrolysis at all pHs, aerobic aquatic metabolism 51-71 days, relatively

stable in anaerobic aquatic environment) and are likely to reach aquatic media as a totality

through runoff. As fluazinam does not substantially alter its backbone structure in the 

environment, but instead, goes through a slight transformation of functional groups, EFED 

considered parent and transformation products together when making assessments.

Parent fluazinam and two transformation products, HYPA and CAPA, have relatively low 

mobility, indicating a relatively low potential for groundwater contamination. At this time, 

EFED has two newly submitted terrestrial field dissipation studies that are in review.

Fluazinam shows a potential to bioaccumulate in fish (BCF=1220x for whole fish; ≥67% of 

residues depurated in 21 days).

The fate and transport characterization is summarized in Table 5.1.a.

Table 5.1.a. Summary of Fluazinam Environmental Degradates

STUDY TYPE

DEGRADATE and MAXIMUM CONCENTRATION

CAPA, G-504, HYPA AMPA, MAPA, DAPA, DCPA (% applied) SOURCE

Hydrolysis CAPA 34% at 28 days

pH 7; 84-85% at 20 days 

at pH 9

– – MRID: 42208412.

Aqueous Photolysis G-504 was 14.0-17.1% 

by 7-10 days

_ – MRID: 444807312, 

43521009, 45584204.

Soil Photolysis HYPA, detected > dark 

control

AMPA detected > dark 

control

– MRID: 44807313, 

45584204.

Aerobic Soil Metabolism HYPA, MAPA and DAPA detected (in the SL soils, applied at 1 kg/ha) MRID: 42208413, 

42208414.

Anaerobic Soil Metabolism HYPA was 11.0% at 60 

days for the SL flooded 

at 30 days

MAPA was 29.8% at 14 

days for the SL flooded 

at zero time

– MRID: 42208413, 

42208414.

Aerobic Aquatic Metabolism CAPA 12.6% at 72 hr DAPA: 19.0% by 240 hr DCPA: 11.3% at 24 hr MRID: 44807314.

Anaerobic Aquatic Metabolism AMPA 24.2% at 0.2 day DAPA: 32.7% at day 30 SDS-67200 39.6% by 

day 14

MRID: 43521010.

Terrestrial Field Dissipation MAPA, CAPA, and HYPA were monitored; however, there were problems 

with the storage stability data for the degradates.

MRID: 44807318, 

44807320, 44807316, 

44807319, 44807317.
Page 34 of 67

5.1.6 Comparative Metabolic Profile

Data depicting the metabolism of fluazinam in plants and animals, as well as data on 

environmental degradates, have been submitted to the Agency. In rats, fluazinam metabolism 

involves hydroxylation followed by conjugation. The major urinary metabolites identified were 

AMPA mercapturate and DAPA at 0.05-0.39% of administered dose (AD). Radioactivity in the 

feces represented most of the AD (89-100%); however, metabolites identified represented only 

11-69% the AD. Fecal radioactivity (all dose groups) appeared to reside with unextractable 

components in the post-extraction solids (PES), which upon further analysis was attributed to 

hydrolysis products of AMPA and DAPA. Approximately 20-25% of the aqueous phase of the 

fecal extraction was identified as a cysteine conjugate of DAPA and represented <1% of the AD.

With the exception of the low-dose group (greatest PES radioactivity), 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 

AD (except for high-dose female rats where AMPA accounted for 10%). DAPA glucuronide 

and AMPA mercapturate were the major biliary metabolites (<4% of the AD). 

The metabolism of [14C]-fluazinam in ruminants and poultry is similar, 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.

 

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.

The primary metabolites in the plant and livestock metabolism studies are accounted for in the 

rat metabolism study. The reduction products, AMPA and DAPA, and their hydrolysis or 

conjugation products are the primary metabolites in plants, ruminants, poultry, and rats. 

 

5.1.7 Toxicity Profile of Major Metabolites and Degradates of Concern

There is no toxicology information available on fluazinam metabolites and degradates. 
Page 35 of 67

5.1.8 Pesticide Metabolites and Degradates of Concern

Table 5.1.b 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

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

For this current risk assessment, HED continues to consider the residues of concern to be those 

that have been established previously. At a meeting held on 11/28/2000, HED concluded that 

the residue of concern (ROC) in potatoes and peanuts (for both tolerance expression and dietary 

risk assessment purposes) was the parent compound only (Memo, D272624, W. Cutchin,

4/23/2001). HED has extended this determination to bulb vegetables as well. In wine grapes, 

both parent and AMGT were included in the ROC for tolerance expression and risk assessment. 

Additionally, HED determined that data generated for potential new uses on other crops (with 

the exception of root and tuber and bulb vegetables) should include analyses for both parent and 

AMGT. 

The fluazinam residues of regulatory interest in animals were determined by HED to be parent 

plus the metabolites AMPA and DAPA and their sulfamate conjugates. 

Estimated drinking water concentrations (EDWCs) were calculated for total fluazinam residues 

because the environmental fate studies indicated that the parent compound forms transformation 

compounds (CAPA, DAPA, DCPA, HYPA, and AMPA) which are similar in structure to the 

parent (under most conditions). Given that HED is unable to conclude that all these degradates 

are significantly less toxic than the parent, the drinking water assessment is based on total 

residues of fluazinam and its major degradates.
Page 36 of 67

5.1.9 Drinking Water Residue Profile

The drinking water residue values used in the dietary risk assessments were provided by the 

Environmental Fate and Effects Division (EFED; D360713, J. Meléndez, 2/24/2010) and 

incorporated directly into the dietary assessments 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 transformation products, including DCPA, CAPA, 

DAPA, AMPA, and HYPA. The acute and chronic EDWCs are based on ground application of 

fluazinam to apples. The values are provided in Table 5.1.c, 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 117 

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

value of 19.8 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 5.1.c. Maximum Tier I Estimated Drinking Water Concentrations

Drinking Water Source (Model Used) USE (Rate Modeled) Maximum Estimated Drinking Water 

Concentration (EDWC; ppb)

Groundwater

(SCI-GROW) Total Residues of Fluazinam

(including parent)

Apples

(4.5 lb a.i./A/season)

Acute and Chronic 0.216

Surface Water

(FIRST) Total Residues of Fluazinam

(including parent)

Apples

(4.5 lb a.i./A/season)

Acute 117*

Chronic 19.8

* This value exceeds the solubility of fluazinam at pH 7 (71 ppb), but is lower than the solubility at pH 11.

5.1.10 Food Residue Profile

Reference: Fluazinam. Petitions for the Establishment of Tolerances and Registration of New 

Uses on Apples, Carrots, Lettuce, and Bulb Onion Subgroup (3-07A), and a Request for a 

Reduced Tolerance on Bushberry Subgroup (13-07B). Summary of Analytical Chemistry and 

Residue Data, D360840; D. Dotson, 3/31/2010

Data Collection Analytical Methods

Samples collected from the magnitude of the residue and storage stability studies were analyzed 

for residues of fluazinam using various GC/ECD methods based on, and revised slightly from, 

the plant enforcement method (Method (6148-94-0170-MD-001, discussed above). The 

GC/ECD methods are adequate for data collection based on acceptable method recovery data. 

The lowest limit of method validation (LLMV) was 0.01 ppm in all tested commodities except in 

carrots where the LLMV was 0.02 ppm.
Page 37 of 67

An enforcement method for determination of AMGT, a residue in the tolerance expression for

wine grapes, is also available. HED recommended in a previous memorandum (Memo, 

D335640, W. Drew, 8/22/07) that a previously submitted HPLC/UV method undergo an ILV 

trial, and potentially, a TMV trial by the ACB. This method is based on Method Evaluation for 

the Analysis of AMGT in Grapes (MRID 45593101). HED has agreed to accept the recovery

data generated by IR-4 for AMGT residues in blueberries as the ILV.

PTRL Method 1676W was the data-collection method used for the analysis of samples collected 

from the dairy cattle feeding study. The method is written for LC/MS/MS analysis of fluazinam, 

AMPA, and DAPA in bovine milk and tissues, and for GC/MS analysis of DAPA in milk only. 

The limit of quantitation was 0.01 ppm for each analyte in milk, muscle, fat, liver, and kidney. 

Preliminary method validation data showed that Method 1676W adequately recovered residues 

of fluazinam, AMPA, and DAPA in milk, muscle, and fat. However, poor and/or marginal 

recoveries were obtained for AMPA and DAPA residues in kidney and liver. Method 1676W 

was marginally validated by an independent laboratory during the third trial and following slight 

modifications to make the method more rugged. For the purpose of developing an animal 

enforcement method, radiovalidation data are required to determine whether the method can 

detect aged residues. HED forwarded Method 1676W to ACB/BEAD for a tolerance method 

validation (TMV) because the method encountered difficulties in the ILV (e.g., three attempts for 

successful validation and/or marginal recoveries with wide variability and high coefficient of 

variation). ACB/BEAD reported that the lab that performed the ILV made major modifications 

to the original method. As a result, HED requested that the registrant submit a revised method 

that incorporated the revisions made by the ILV lab. ISK Biosciences revised the method and resubmitted it. ACB/BEAD performed a cursory review of the revised method. The registrant 

incorporated the modifications made by the ILV lab. However, the revision eliminated the 

cleanup steps that were in the original method, and the only recovery data for the revised method 

were data provided by the ILV lab. ACB/BEAD was concerned that the elimination of the 

cleanup steps could lead to dirty samples which would, in turn, lead to analytical problems, such 

as interference. ACB/BEAD performed no further validation of the method. As the revised 

method contains major revisions to the original method, and ACB/BEAD believes it is very

likely that the revised method still is not adequate for sample analysis or tolerance enforcement, 

HED recommends that the registrant submit an ILV for the revised method.

Storage Stability

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

samples collected from the magnitude of the residue studies on apples, carrots, lettuce, and 

onions. As residues of fluazinam were found to be stable in tested crop matrices, storage 

stability corrections do not need to be applied to the recommended tolerances for fluazinam 

residues in/on apples, carrots, lettuce, and onions. Storage stability data for the fluazinam 

metabolite AMGT in apple commodities were also submitted, and showed that residues in wet 

apple pomace were reasonably stable for 12 months, but declined to an average corrected 

recovery of 58-63% at the 19-month interval, 61% at the 32-month interval, and 33% at the 37-

month interval. The submitted storage stability data for bovine milk, meat, and meat byproducts 

showed mixed results. However, HED is not currently recommending in favor of tolerances for 

animal commodities.
Page 38 of 67

Residues in Meat, Milk, Poultry, and Eggs 

The residue data from the cattle feeding study are not adequate to satisfy data requirements. The 

feeding study data (adjusted for residue decline) along with the calculated dietary burdens for 

beef cattle (0.04 ppm) and dairy cattle (1.27 ppm) indicate that tolerances are needed for the 

combined residues of fluazinam and its metabolites DAPA and AMPA in the fat and meat 

byproducts of cattle and other ruminants at 0.02 ppm to support the proposed uses on apples and 

carrots and the established tolerances on potatoes and peanuts. However, no tolerances are 

required for milk and meat of ruminants. Based on the transfer coefficients for livestock tissues 

and the relatively low dietary burden for swine of 0.003 ppm for fluazinam, tolerances for hog

commodities are not needed. A poultry feeding study is not required at this time because of the 

low dietary burden for poultry (0.005 ppm).

Magnitude of the Residue in Plants

The submitted field trial data for fluazinam on head lettuce, leaf lettuce, bulb onions, carrots, and 

apples are acceptable and support the proposed uses. Adequate numbers of tests were conducted 

in the appropriate geographic regions at ~1x the maximum proposed rate, and the appropriate 

samples were collected from each test at, or close to, the proposed PHI. Samples from all the 

field trials were analyzed for fluazinam residues using an adequate GC/ECD method, and the 

storage stability data support the sample storage durations for these crops. However, no residue 

data were provided on AMGT residues in lettuce. Although AMGT residue data on lettuce are 

still required for purposes of dietary risk assessment, the available data support tolerances of 0.02 

ppm for head lettuce and 2.0 ppm for leaf lettuce. HED accounted for AMGT residues in lettuce 

in the current risk assessment by using a ratio obtained from plant metabolism data. The field 

trial data also support a tolerance of 0.20 ppm for the Bulb onion subgroup (3-07A). The 

tolerance spreadsheet (Guidance for Setting Pesticide Tolerances Based on Field Trial Data

SOP) was used for determining appropriate tolerance levels. Because of data deficiencies 

associated with Method 1676W, the cattle feeding study, and the apple processing study, HED 

does not recommend in favor of tolerances for apple and carrot commodities.

Processing Studies

The registrant submitted a processing study for apples. This study is not adequate to satisfy data 

requirements. In apples, the metabolite AMGT is a residue of concern for risk assessment. In 

the processing study there were no quantifiable residues of AMGT in raw apples. In several of 

the field trials that were performed, however, raw apples contained AMGT residues at, or above, 

the limit of quantitation. In a few cases, residues of AMGT were comparable to those of the

parent fluazinam. Canadian and U.S. residue chemistry guidelines both stipulate that in the 

processing study, if residues in the raw agricultural commodity (RAC) are below the LOQ, but 

quantifiable residues occurred in the RAC in field trials performed at the maximum requested 

label rate, that the processing study should be conducted at exaggerated rates in order to ensure 

that quantifiable residues will be present in the RAC. Quantifiable residues are needed in the 

RAC in order to determine a reliable concentration factor. As a result, the processing study

needs to be repeated at a sufficiently high rate that residues of both parent and AMGT are 
Page 39 of 67

quantifiable in the RAC. In the event that the potential for phytotoxicity exists, the application 

rate does not need to be greater than the rate at which phytotoxicity occurs.

Rotational Crop Studies

Regulatory requirements pertaining to fluazinam residues in rotational crops have been fulfilled, 

and the rotational crop restrictions on the proposed label are adequate. 

5.1.11 International Residue Limits

There are currently no established Codex, Canadian, or Mexican maximum residue limits 

(MRLs) for fluazinam on apples, carrots, lettuce, onions, or berry crops. Therefore, there are no 

harmonization issues for the requested tolerances.

5.2 Dietary Exposure and Risk

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

were conducted using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 2.03 

which uses food consumption data from the U.S. Department of Agriculture’s Continuing 

Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

5.2.1 Acute Dietary Exposure/Risk

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 estimated drinking water concentrations (EDWCs) that 

account for both parent fluazinam and its transformation products. Therefore, the resulting 

exposure and risk estimates are considered to be very conservative. The acute risk estimates 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 PAD. The 

acute risk estimate for the general U.S. population is 4.1% of the aPAD. The population 

subgroup with the highest risk estimate is Females 13-49, which uses 20% of the aPAD.

5.2.2 Chronic Dietary Exposure/Risk

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 assumes high-end 

estimates for AMGT, 100% crop treated, and incorporates modeled EDWCs that account for 

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

considered to be conservative. Chronic risk estimates are below HED’s level of concern for all 

population subgroups. The risk estimate for the general U.S. population is 14% of the cPAD. 

The most highly exposed population subgroup is All Infants (<1 year old), which uses 40% of 

the cPAD.
Page 40 of 67

5.2.3 Cancer Dietary Risk

The CARC determined that the cRfD is protective of cancer effects. As a result, a dietary

exposure assessment for cancer risk is unnecessary.

Table 5.2. Summary of Acute and Chronic Exposure and Risk Estimates for Fluazinam

Population 

Subgroup

Acute Assessment (95th Percentile) Chronic Assessment

aPAD, 

mg/day

Exposure Estimate, 

mg/day

% aPad cPAD, 

mg/day

Exposure Estimate, 

mg/day

% cPAD

U.S. Population 0.5 0.020332 4.1 0.011 0.001530 14

All infants 0.5 0.086600 17 0.011 0.004411 40

Children 1-2 yrs 0.5 0.098940 20 0.011 0.004064 37

Children 3-5 yrs 0.5 0.063647 13 0.011 0.002789 25

Children 6-12 yrs 0.5 0.022625 4.5 0.011 0.001374 13

Youth 13-19 yrs 0.5 0.013076 2.6 0.011 0.000813 7.4

Adults 20-49 yrs 0.5 0.012952 2.6 0.011 0.001346 12

Adults 50+ yrs 0.5 0.012761 2.6 0.011 0.001488 14

Females 13-49 yrs 0.07 0.014124 20 0.011 0.001394 13

Actual dietary exposures and risks from fluazinam will likely be much lower than the values 

generated in the acute and chronic analyses. The analyses indicate that dietary exposure 

considerations would not preclude establishing the proposed tolerances for fluazinam.

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information

Anticipated Residues

The acute analysis is based on tolerance-level residues for all commodities, and the chronic 

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

average field trial value was used. Both assessments assume high-end estimates for AMGT and 

incorporate modeled EDWCs that account for both parent and transformation products. 

Percent Crop Treated

The acute and chronic assessments are both based on the assumption that 100% of all crops with 

fluazinam tolerances will be treated with fluazinam.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Currently, there are no registered or proposed residential uses for fluazinam; thus, there is no 

exposure via this pathway and an assessment was not conducted.
Page 41 of 67

Spray Drift

Spray drift is always a potential source of exposure to residents living in close proximity to 

spraying operations. This situation is particularly the case with aerial application. However, to a 

lesser extent, spray drift resulting from the ground application of fluazinam could also be a 

potential source of exposure. The Agency has been working with the Spray Drift Task Force (a 

membership of U.S. pesticide registrants), EPA Regional Offices, State Lead Agencies for 

pesticide regulation, and other parties to develop the best spray drift management practices. 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, and is developing a policy on how to apply

appropriately 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 offtarget drift risks associated with pesticide application.

7.0 Aggregate Risk Assessments and Risk Characterization

7.1 Acute Aggregate Risk

Acute aggregate risk consists of risks resulting from exposure to residues in food and drinking 

water alone. The acute dietary exposure analysis included both food and drinking water. As a 

result, the acute aggregate risk assessment is equivalent to the acute dietary risk assessment

discussed in Section 5.2.1, above. All risk estimates are below HED’s level of concern.

7.2 Short-Term Aggregate Risk

Short-term exposures result from residential uses. As there are no residential uses for fluazinam, 

short-term aggregate risk assessments were not conducted.

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposures result from residential uses. As there are no residential uses for 

fluazinam, intermediate-term aggregate risk assessments were not conducted.

7.4 Long-Term Aggregate Risk

The chronic aggregate risk assessment consists of risks resulting from exposure to residues in 

food, drinking water, and residues resulting from residential applications. As there are no 

residential uses for fluazinam, chronic aggregate risk consists of risks resulting from exposure to 

residues in food and drinking water alone. The chronic dietary exposure analysis included both 

food and drinking water. As a result, the chronic aggregate risk assessment is equivalent to the 

chronic dietary risk assessment discussed in Section 5.2.2, above. All risk estimates are below 

HED’s level of concern. 
Page 42 of 67

7.5 Cancer Risk

The CARC determined that the cRfD is protective of cancer effects. Cancer risk resulting from 

exposure to fluazinam is not of concern.

8.0 Cumulative Risk Characterization/Assessment

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information concerning the 

cumulative effects” of a particular pesticide's residues and “other substances that have a common 

mechanism of toxicity.”

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 tolerance action, 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 Pathway

Reference: Fluazinam: Occupational and Residential Risk Assessment for Proposed Use of 

Fluazinam on Apples, Carrots, Lettuce (Head and Leaf), and Onions (Bulb), D371446, Z. 

Figueroa, 3/30/2010.

9.1 Agricultural Handler Exposure and Risk 

The proposed occupational uses of fluazinam are for control of certain fungi in apples, carrots, 

lettuce (head and leaf), and onions (bulb). This document assesses occupational exposures and 

risks from the proposed uses of the product OMEGA®500F, a soluble-concentrate formulation 

containing 40% ai fluazinam. OMEGA®500F may be applied as a foliar spray using aerial, 

chemigation, groundboom, and airblast equipment. Based on the product labels, handler 

exposures are expected to be short- and intermediate-term in duration. 

Application methods, maximum application rates, and use sites are summarized in Table 2.1. 

The quantitative exposure/risk assessment for occupational handlers is based on the use pattern 

and the following exposure scenarios: 
Page 43 of 67

Mixer/Loaders

1. Mixing/loading liquid concentrates to support aerial applications,

2. Mixing/loading liquid concentrates to support chemigation applications,

3. Mixing/loading liquid concentrates to support groundboom applications,

4. Mixing/loading liquid concentrates to support airblast applications,

Applicators

5. Applying sprays with aircraft (enclosed cockpit),

6. Applying sprays with groundboom equipment,

7. Applying sprays with airblast equipment, and 

Flaggers

8. Flagging to support aerial spray applications.

9.1.1 Data and Assumptions for Handler Exposure Scenarios

Unit Exposures:

Chemical-specific data for assessing exposure during pesticide handling activities were not 

submitted to the Agency in support of these tolerance petitions. It is HED policy to use data 

from the Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures 

for regulatory actions when chemical-specific data are not available (HED ExpoSAC, SOP No. 

7, January 1999). For flaggers, the unit exposure value for the first level of mitigation (i.e., 

single layer, gloves) is considered to be of low confidence because of the small number of 

replicates used in determining the unit exposure value.

Mitigation Approaches:

There are three basic risk mitigation approaches considered appropriate for controlling 

occupational exposure. These include administrative controls, use of personal protective 

equipment (PPE), and the use of engineering controls. Occupational handler exposure 

assessments were completed by HED using baseline, PPE, and engineering controls.

The baseline clothing level for occupational exposure scenarios is generally an individual 

wearing long pants, a long-sleeved shirt, shoes, socks, no chemical-resistant gloves, and no 

respirator. The first level of mitigation generally applied is PPE, which may include addition of 

chemical resistant-gloves, an additional layer of clothing, and/or a respirator. The next layer of 

mitigation considered in the risk assessment process is the use of appropriate engineering 

controls, which, by design, attempt to eliminate the possibility of human exposure. Examples of 

commonly used engineering controls include enclosed cockpits or tractor cabs, closed 

mixing/loading systems, and water-soluble packets.

The proposed label has PPE recommendations that include:

 Applicators and other handlers wear coveralls worn over long-sleeved shirt, long 

pants, socks, protective eyewear, and chemical-resistant gloves and footwear;
Page 44 of 67

 Mixer/loaders or handlers conducting cleaning activities wear a chemical-resistant 

apron; and,

 Mixer/loaders wear a dust/mist or NIOSH approved respirator.

Baseline clothing level was used as a starting point to calculate handler exposures. Depending 

on the need for additional dermal or inhalation protection, additional PPE is added to obtain an 

MOE higher than the LOC. However, HED recommends that all label requirements be followed 

and expanded to all handlers. Because of the low confidence there is in the unit exposure data 

for flaggers, workers conducting flagger-related activities should wear the same PPE as the 

applicators in order to reduce exposures.

 

Acres Treated:

The acres treated per day for each scenario are shown in Table 9.1. The values are based on 

HED ExpoSAC SOP No. 9.1 and the equipment used.

Application Rate:

Maximum application rates for all proposed uses are shown in Table 9.1.

Body Weight:

The average adult body weight of 70 kg was used for short- and intermediate-term dermal and 

inhalation calculations because the effects were not sex-specific.

Absorption Factors:

A dermal absorption factor was not used in the calculation of the dermal dose in this instance 

because the toxicity endpoint is derived from a dermal study rather than extrapolated from an 

oral study.

As the short- and intermediate-term inhalation POD was based on an inhalation study, no

inhalation absorption factor is necessary to estimate inhalation exposures for short-and 

intermediate-term durations. 

Equations and Calculations:

Daily Exposure: Daily handler exposures are estimated for each applicable handler task with the 

application rate, the amount of acres treated or gallons applied in a day, and the applicable unit 

exposure using the following formula:

Daily Exposure (mg ai/day) = Unit Exposure (μg ai/lb ai handled) x Application Rate (lbs ai/A or gal) x

Daily Amount Handled (A or gal/day) x Conversion Factor (mg/1,000 μg)
Page 45 of 67

Where: 

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is 

 available for dermal absorption or amount inhaled that is available for 

 inhalation absorption,

Unit Exposure = Unit exposure value (μg ai/day),

Application Rate = Normalized application rate based on a logical unit treatment (lb ai/acre), and 

Daily Amount Handled = Normalized application area based on a logical unit treatment such as acres or

 gallons (A/day or gal/day). 

Daily Dose: Daily dose (inhalation or dermal) was calculated by normalizing the daily dermal or 

inhalation exposure value by body weight. 

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day)/Body Weight (kg)

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given 

 scenario (mg pesticide active ingredient/kg body weight/day),

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is 

 available for dermal absorption or amount inhaled that is available for 

 inhalation absorption, and

Body Weight = Body weight determined to represent the population of interest in a risk

 assessment.

Margin of Exposure (MOE): The daily dermal dose and daily inhalation dose received by 

occupational handlers were compared to the appropriate POD (i.e., NOAEL) to assess the risk to 

occupational handlers for each exposure route. All MOE values were calculated separately for 

dermal and inhalation exposure levels using the following formula:

MOE = NOAEL (mg/kg/day)

 Average Daily Dose (mg/kg/day)

Where:

MOE = Margin of exposure value used by HED to represent risk or how close a 

 chemical exposure is to being of concern (unitless),

ADD = Average daily dose (ADD) is absorbed dose received from exposure to pesticide, and

NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred in the 

 study.

9.1.2 Handler Exposure and Risk

HED’s level of concern for the MOE is defined by the uncertainty factors that are applied to the 

assessment. HED applies a 10x factor to account for interspecies extrapolation and a 10x factor 

to account for intraspecies sensitivity. The uncertainty factor that has been applied to 

occupational risk assessments is 100x for short- and intermediate-term dermal exposures. An 
Page 46 of 67

additional 10x uncertainty factor was added to short- and intermediate inhalation exposures, 

because of the absence of key data (i.e., lack of a histopathological examination). 

As discussed in Section 3.5.8, although liver effects were observed in both the dermal and 

inhalation route-specific toxicity studies, both endpoints are considered to be very conservative,

and combining exposures from these routes is not considered to be necessary. Nevertheless, 

HED did calculate the combined risk estimate for the worker with the highest exposure (i.e., the 

mixer/loader for aerial or chemigation treatment of lettuce). The total risk estimate was 

determined using the aggregate risk index approach because there are different levels of concern 

for the two routes. This risk estimate was greater than one and, therefore, not of concern. As a 

result, the dermal and inhalation risk estimates as shown in Table 9.1 were not combined. 

Summaries of the risks for occupational handlers are included in Table 9.1. The maximum 

application rate for each exposure scenario is presented as the worst-case scenario. All handler 

scenarios resulted in MOEs greater than the level of concern (MOEs > 100 for dermal and >

1,000 for inhalation) at some level of risk mitigation. 

Dermal

For the scenarios listed below, short- and intermediate-term dermal MOEs did not exceed HED’s 

level of concern (MOEs > 100) at the baseline attire level of mitigation (long-sleeved shirt, long 

pants, shoes, and socks):

• Applying sprays with groundboom equipment to carrots, onions, and lettuce; 

• Flagging for aerial spray applications for apples, carrots, onions, and lettuce; and

• Applying sprays via airblast equipment to apples.

For the scenarios listed below, short- and intermediate-term dermal MOEs exceeded HED’s level

of concern (MOEs < 100) at the baseline attire level of mitigation (long-sleeve shirt, long pants, 

shoes, and socks). However, MOEs were greater than 100 and not of concern to HED with 

baseline attire plus chemical-resistant gloves:

• mixing/loading liquid concentrates for aerial applications to carrots, apples, and onions;

• mixing/loading liquid concentrates for chemigation applications to carrots, apples, and 

onions; 

• mixing/loading liquid concentrates for groundboom applications to carrots, onions, and 

lettuce; and

• mixing/loading liquid concentrates for airblast applications to apples.

For the scenarios listed below, short- and intermediate-term dermal MOEs exceeded HED’s level

of concern (MOEs < 100) with the use of baseline attire plus chemical-resistant gloves. 

However, MOEs were greater than 100 and not of concern to HED with the double layer body

attire (coveralls worn over long-sleeve shirt and long pants) plus chemical-resistant gloves:

• mixing/loading liquid concentrates for aerial applications to lettuce (MOE = 90 with 

baseline + gloves; MOE = 120 with double layer attire +gloves); and 
Page 47 of 67

• mixing/loading liquid concentrates for chemigation applications to lettuce (MOE = 90 

with baseline + gloves; MOE = 120 with double layer attire + gloves).

Only engineering control (enclosed cockpit) data are available to assess dermal risks to handlers 

operating aircraft. The dermal risks do not exceed HED’s level of concern for pilots using 

enclosed cockpits and wearing baseline attire. 

Inhalation

For the scenarios listed below, short- and intermediate-term inhalation risks did not exceed 

HED’s level of concern (MOEs > 1,000) at the baseline level of mitigation (no respirator):

• mixing/loading liquid concentrates for groundboom applications to carrots, onions, and 

lettuce;

• mixing/loading liquid concentrates for airblast applications to apples; 

• applying sprays with groundboom equipment to carrots, onions, and lettuce; 

• applying sprays with airblast equipment to apples; and

• flagging for aerial spray applications to apples, carrots, and onions.

For the scenarios listed below, short- and intermediate-term inhalation risks exceeded HED’s 

level of concern (MOEs < 1,000) at the baseline level of mitigation. However, MOEs were 

greater than 1000 and not of concern to HED with a quarter-face dust/mist respirator:

• mixing/loading liquid concentrates for aerial applications to carrots, apples, onions, and 

lettuce;

• mixing/loading liquid concentrates for chemigation applications to carrots, apples, 

onions, and lettuce; and

• flagging for aerial spray applications to lettuce.

Only engineering control (enclosed cockpit) data are available to assess short- and intermediateterm inhalation risks to handlers operating aircraft. The short- and intermediate-term inhalation 

risks do not exceed HED’s level of concern for pilots using enclosed cockpits and wearing no 

respirator.
Page 48 of 67

Table 9.1. Short- and Intermediate-Term Occupational Handler Dermal and Inhalation Exposure and Risk for Fluazinam

Exposure 

Scenario

Crop or 

Target

App 

Ratea

(lb ai/A)

Acres 

Treated 

Dailyb

Unit Exposurec,d

MOEs

Dermal LOC = 100

Inhalation LOC = 1,000

Baseline 

Dermal

mg/lbai

PPE-G

Dermal

mg/lb ai

PPE-G, 

DL

Dermal

mg/lb ai

Baseline 

Inhalation

μg/lb ai

80%

PPE-R 

Inhalation

Baseline 

Dermale

PPE-G

Dermale

PPE-G, DL

Dermale

Baseline 

Inhalationf

80%

PPE-R 

Inhalation f

Mixer/Loader

Mixing/Loading 

Liquid 

Concentrates for 

Aerial 

Applications

Carrot, Onion 0.52 350 2.9 0.023 0.017 1.2 0.24 1.3 170 230 440 2,200

Apple 0.45 350 2.9 0.023 0.017 1.2 0.24 1.5 190 260 510 2,500

Lettuce 0.99 350 2.9 0.023 0.017 1.2 0.24 0.7 90 120 230 1,200

Mixing/Loading 

Liquid 

Concentrates for 

Chemigation 

Applications

Carrot, Onion 0.52 350 2.9 0.023 0.017 1.2 0.24 1.3 170 230 440 2,200

Apple 0.45 350 2.9 0.023 0.017 1.2 0.24 1.5 190 260 510 2,500

Lettuce 0.99 350 2.9 0.023 0.017 1.2 0.24 0.7 90 120 230 1,200

Mixing/Loading 

Liquids 

Concentrates for 

Groundboom 

Applications

Carrot, Onion 0.52 80 2.9 0.023 0.017 1.2 0.24 5.8 730 990 1,900 9,700

Lettuce 0.99 80 2.9 0.023 0.017 1.2 0.24 3 380 520 1,000 5,100

Mixing/Loading 

Liquid 

Concentrates for 

Airblast 

Applications

Apple 0.45 40 2.9 0.023 0.017 1.2 0.24 13 1,700 2,300 4,500 22,000

Applicator

Applying Sprays 

via Aerial 

Equipment

Carrot, Onion 0.52 350

0.005 

(eng. 

control)

No Data No Data

0.068 

(eng. 

control)

No Data

770

(eng. 

control)

No Data No Data

7,800

(eng. 

control)

No Data

Apple 0.45 350

0.005 

(eng. 

control)

No Data No Data

0.068 

(eng. 

control)

No Data

890

(eng. 

control)

No Data No Data

9,000

(eng. 

control)

No Data
Page 49 of 67

Table 9.1. Short- and Intermediate-Term Occupational Handler Dermal and Inhalation Exposure and Risk for Fluazinam

Exposure 

Scenario

Crop or 

Target

App 

Ratea

(lb ai/A)

Acres 

Treated 

Dailyb

Unit Exposurec,d

MOEs

Dermal LOC = 100

Inhalation LOC = 1,000

Baseline 

Dermal

mg/lbai

PPE-G

Dermal

mg/lb ai

PPE-G, 

DL

Dermal

mg/lb ai

Baseline 

Inhalation

μg/lb ai

80%

PPE-R 

Inhalation

Baseline 

Dermale

PPE-G

Dermale

PPE-G, DL

Dermale

Baseline 

Inhalationf

80%

PPE-R 

Inhalation f

Lettuce 0.99 350

0.005 

(eng. 

control)

No Data No Data

0.068 

(eng. 

control)

No Data

400

(eng. 

control)

No Data No Data

4,100

(eng. 

control)

No Data

Applying Sprays 

via Groundboom 

Equipment

Carrot, Onion 0.52 80 0.014 0.014 0.011 0.74 0.148 1,200 1,200 1,500 3,100 16,000

Lettuce 0.99 80 0.014 0.014 0.011 0.74 0.148 630 630 800 1,600 8,200

Applying Sprays 

via Airblast

Equipment

Apple 0.45 40 0.360 0.240 0.220 4.50 0.900 110 160 180 1,200 6,000

Flagger g

Flagging for 

Aerial Sprays 

Applications

Carrot, Onion 0.52 350 0.011 0.012 0.010 0.35 0.070 350 320 350 1,500 7,600

Apple 0.45 350 0.011 0.012 0.010 0.35 0.070 400 370 400 1,800 8,800

Lettuce 0.99 350 0.011 0.012 0.010 0.35 0.070 180 170 180 800 4,000

a. Application Rates based on proposed uses on labels for fluazinam.

b. Science Advisory Council Policy No. 9.1

c. Unit Exposures based on PHED Version 1.1. Engineering control unit exposure for applying sprays via aerial equipment = enclosed cockpit. 

d. Baseline Dermal: Long-sleeve shirt, long pants, and no gloves. 

Baseline plus Gloves Dermal (PPE-G): Baseline plus chemical-resistant gloves. DL is the addition of double layer body attire.

Baseline Inhalation: No respirator. PPE – R 80% = A quarter-face dust/mist respirator (that provides a 5-fold (80%) protection factor).

Those risks specified as engineering control (eng. control) represent enclosed cockpit application. 

e. Dermal MOE = NOAEL (10 mg/kg/day) / dermal daily dose (mg/kg/day). Level of concern = 100.

Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/acre) x acres treated / body weight (70 kg).

f. Inhalation MOE = NOAEL (1.38 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 1000.

Inhalation Dose (mg/kg/day) daily unit exposure (μg/lb ai) x application rate (lb ai/acre) x acres treated / body weight (70 kg). 

g. The PPE-G unit exposure for flaggers is considered to be of low confidence because of the small number of replicates used in determining the unit exposure value. HED recommends that all handlers 

follow label PPE.
Page 50 of 67

9.2 Postapplication Exposure and Risk

9.2.1 Data and Assumptions for Postapplication Exposure Scenarios

Inhalation

Based on the Agency’s current practices, a quantitative postapplication inhalation exposure 

assessment is not being performed for fluazinam at this time. However, volatilization of 

pesticides might be a potential source of postapplication inhalation exposure to individuals in 

close proximity to locations where pesticide applications are made. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its FIFRA 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 the way to incorporate postapplication 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 postapplication inhalation exposure 

assessment for fluazinam.

Dermal 

Chemical-specific dislodgeable foliar residue (DFR) studies on apples (MRID 45584203) and 

peanuts (MRID 46991302) were submitted and reviewed by HED. The peanut dislodgeable 

foliar residue (DFR) data were previously used as surrogate data to assess post application 

exposure for all crops when no crop-specific DFR data were available (Memo, D346976, M. 

Collantes, 2/27/2008). As indicated below, a linear regression analysis was conducted of the 

individual foliar residue values collected immediately after the last application through the last 

day of sampling for peanuts (42 DAT), which resulted in a regression (R2) of 0.962. Regressions 

close in value to 1.0 are a good indication of direct correlation between actual and predicted

residues. 

For this assessment, peanut DFR data were used as surrogate data to assess postapplication 

exposure for lettuce, onions, and carrots. The apple DFR data were used to assess 

postapplication exposure for apples. A summary of each study is provided below. In addition to 

the DFR data, maximum dermal transfer coefficients from the Science Advisory Council for 

Exposure Policy Number 3.1: Agricultural Transfer Coefficients, August 2000, (summarized in 

Table 9.2.a, below) and the following assumptions were used in the postapplication assessment:

 Max Application Rate= 0.52 lb ai/A for carrots and onions; 0.45 lb ai/A for apples; 

0.99 lb ai/A for lettuce

 Exposure Duration = 8 hours per day

 Body Weight = 70 kg, and 

 Dermal Absorption = Not applicable
Page 51 of 67

Table 9.2.a. Anticipated Postapplication Activities and Dermal Transfer Coefficients

Proposed Crops Policy Crop 

Group Category

Exposure 

Potential

Transfer 

Coefficients 

(cm2/hr)

Activities

Carrots Vegetable, “root”

Low 300 hand weeding, irrigation, and 

scouting

High 2,500 hand harvest

Onion Vegetable, “root” Low 300 hand weeding, irrigation, and 

scouting

Lettuce Vegetable, leafy

Low 500 hand weeding, thinning

Medium 1,500 irrigation, scouting

High 2,500 hand harvest

Apple Tree, “fruit” 

deciduous

Low 1,000 hand weeding, irrigation, and 

scouting

High 1,500 hand harvesting, propping, training, 

hand pruning

Very High 3,000 thinning

 Summary of Dislodgeable Foliar Residue Study on Peanut (MRID 45584201)

This study was designed to determine the dissipation of dislodgeable foliar residues (DFR) of 

fluazinam applied to peanut fields located in Sampson County near Garner, North Carolina 

(EPA Region 2). Two applications of Fluazinam 500F, a flowable liquid formulation 

containing 41.5% fluazinam as the ai, were made to peanut crops. The target application rate 

was 0.79 lbs ai/A for each application which was the maximum label use rate. The total 

application rate for both applications was 1.58 lb ai/A. Applications were made as a foliar 

broadcast spray at a spray volume of about 20 gallons per acre (GPA). Samples were 

collected before the first application and at the following time periods thereafter: 

immediately, 7 days, 14 days, and 21 days. Samples were also collected at the following 

time periods after the second (final) application: immediately, 8 hours, and 1, 2, 4, 7, 10, 14, 

21, 28, 35, and 42 days. At each sampling interval, triplicate samples were collected from 

the control plot and from the treated plot. Field-fortified samples using leaf samples from the 

control plot were prepared on days 7, 14, and 35 after the second application to evaluate the 

stability of the field samples during shipping and storage.

Fluazinam residue values were not corrected for field fortification or concurrent percent 

recoveries by the Registrant. The DFR residues were corrected by HED using the average 

field fortification recovery from the fortification level closest to the DFR value (63.2% for 

low level fortification and 62.2% for high level fortification). 
Page 52 of 67

The highest average DFR value occurred immediately after the first application (1.56 

μg/cm2). The residues then declined to 0.0085 μg/cm2by 21 days after the first application 

(21DAT1). The average residues after the final application were highest immediately after 

that application (1.29 μg/cm2). Following the second application, residues declined to 0.013 

μg/cm2 by 42 days after treatment (42 DAT2). All residue values remained above the LOQ 

out to the last day of sampling. Rainfall occurred throughout the entire sampling period, with 

the first rainfalls after application occurring 3 days after the first application and 3 days after 

the last application. 

A linear regression analysis was conducted using the natural logarithm of the individual 

foliar residue values collected immediately after the last application through the last day of 

sampling (42 DAT). The estimated half-life life value for fluazinam was 6.30 days (R2= 

0.962). 

Upon review of the data, HED determined that for days 0-2, the actual measured (raw) DFR 

data were more protective than the predicted DFR values, which would potentially

underestimate residue values and risk of exposure. Therefore, measured DFR values were 

used to assess post application exposure for days 0 through 2.

 Summary of Dislodgeable Foliar Residue Study on Apple (MRID 45584203)

This study was designed to determine the dissipation of dislodgeable foliar residues (DFR) of 

fluazinam applied to apple trees at a test site in Concord, Ohio. Fluazinam 500F, a flowable 

liquid formulation containing 41.1% fluazinam as the ai, was applied as a foliar directed 

spray using an airblast sprayer to two plots consisting of five apple trees each. One plot 

received a single application at the reported recommended rate (0.4 lb ai/A) and the other 

plot received a single application at three times the reported recommended rate (1.2 lb ai/A).

A third plot was used to collect untreated (control) samples. Samples were collected prior to 

the application and at intervals from 1 hr to 35 days after the application. At each sampling 

interval, triplicate samples were collected from the control plot and from the treated plots.

Field-fortified samples and storage stability samples were not prepared for this study.

HED and the registrant calculated DFR values in μg/cm2by dividing the corrected residue 

found in each sample by the total surface area of each sample (400 cm2). Residue values that

dropped below the limit of quantitation (LOQ) were assigned a value of 1⁄2LOQ. 

For both treatment plots, the highest average residue was observed 1 hour after application 

(0.071 μg/cm2for the 1x plot and 0.086 for the 3x plot). The average residue dropped to 

below the LOQ (0.00005 μg/cm2) by day 28 for the 1x plot and day 35 for the 3x plot. A 

significant drop in residues between the Day 2 and Day 4 sampling intervals was seen in both 

plots. From day 2 to day 4, the average residue dropped from 0.053 μg/cm2 to 0.0086 μg/cm2

in the 1x plot and from 0.056 μg/cm2to 0.0059 μg/cm2in the 3x plot. 
Page 53 of 67

A linear regression analysis was conducted using the natural logarithm of the individual 

foliar residue values. The estimated half-life values for fluazinam from the 1x and 3x plots 

were 3.06 days (R2= 0.937) and 2.93 days (R2= 0.931), respectively.

The significant drop in day 4 residues was the result of a heavy thunderstorm with at least 

0.33 inches of rain that occurred on the night before the day 4 sampling interval. The rainfall 

did not significantly affect the overall dissipation curve, but it did result in predicted residues 

on day 0 (0.045 μg/cm2for 1x rate and 0.046 μg/cm2for 3x rate) that were lower than the 

actual residue on day 0 (0.071 μg/cm2for 1x rate and 0.086 for 3x rate).

For purposes of this assessment, HED chose to use the actual residues on day 0, rather than 

the predicted residues on day 0. HED believes that this analysis provides a more realistic 

assessment of actual residue decline. 

Equations/Calculations:

The following equations were used to calculate risks for workers performing postapplication 

activities:

Adjusted DFR (μg/cm2) = Study DFR (μg/cm2) x crop application rate (lb ai/A)

 Study application rate (lb ai/A)

Daily Dermal Dose t (mg/kg-day) = DFRt (μg/cm2) x 1E-3 mg/μg x Tc (cm2/hr) x DA x ET (hrs)

BW (kg)

Where,

t = number of days after application day (days)

DFRt = dislodgeable foliage residue on day t (μg/cm2)

Tc = transfer coefficient (cm2/hr)

 DA = dermal absorption factor (unitless)

ET = exposure time (hr/day)

BW = body weight (kg)
Page 54 of 67

9.2.2 Postapplication Exposure and Risk

The postapplication exposure associated with the use of fluazinam is summarized in Table 9.2.b.

Table 9.2.b. Occupational Postapplication Exposure and Risk for Fluazinam

Crop Activity

Application 

Rate

(lb ai/A)

Transfer

Coefficienta

(cm2/hr)

Normalized 

DFR b

(μg/cm2)

Short- and Intermediate-Term

Daily Dermal 

Dosec

(mg/kg/day)

MOE 

on 

Day 

0

d

Days after 

Application 

until MOE 

≥100

Carrots

Hand weeding, 

irrigation, and 

scouting 0.52

300 0.860 0.0295 340 0

Hand harvest 2,500 0.340 0.0971 41 6

Onions

hand weeding, 

irrigation, and 

scouting

0.52 300 0.860 0.0295 340 0

Lettuce

Hand weeding, 

thinning

0.99

500 1.637 0.0939 110 0

Irrigation, scouting 1,500 0.520 0.0892 35 8

Hand harvest 2,500 0.330 0.0943 21 12

Apples

Hand weeding, 

irrigation, and 

scouting

0.45

1,000 0.080 0.0091 1100 0

Hand harvesting, 

propping, training, 

hand pruning

1,500 0.080 0.0137 730 0

Thinning 3,000 0.080 0.0274 360 0

a. Transfer coefficients and associated activities from ExpoSAC Policy Memo #003.1 “Agricultural Transfer 

Coefficients,” 8/17/2000.

b. DFR = Dislodgeable Foliar Residue from the submitted studies, adjusted to compensate for difference in application 

rates (AR) between study and actual label application rates.

c. Daily Dermal Dose = [(DFR x Tc x Dermal Absorption x 8-hr Exposure Time)] / [(CF: 1000 μg/mg) x (70-kg Body 

Weight)].

d. MOE = NOAEL/Daily Dose (Short- and intermediate-term Dermal NOAEL = 10 mg/kg/day).

9.2.3 Postapplication Risk Characterization

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 for Agricultural Pesticides, active ingredients classified as acute toxicity

category I for any of these routes are assigned a 48-hour REI. 
Page 55 of 67

Postapplication MOEs were estimated for “Day 0” exposure (i.e., the day of application). In 

cases where the MOE was less than the LOC of 100 on Day 0, residue dissipation 

data/assumptions were used to determine the day for which the risk would be not of concern (i.e., 

MOE of 100 or greater). Based on HED’s postapplication exposure calculations, the dermal 

risks for all proposed crops were greater than 100 within 48 hours, which is in accordance with 

the current label REI.

• Apple and onion postapplication dermal risks were 100 or greater within 12 hours of 

application; 

• Carrot postapplication dermal risks were 100 or greater within 48 hours of application for 

low to medium contact activities (i.e. hand weeding, irrigation, and scouting).

However, carrots did not reach a MOE of 100 or greater for high contact activities (i.e., hand 

harvesting) until day 6. Furthermore, lettuce did not reach a MOE of 100 or greater for medium 

contact activities (i.e., irrigation, scouting) until day 8 and for high contact activities (i.e., hand 

harvesting) until day 12. Risks from these activities are of concern until the specified intervals 

have elapsed. HED recommends that the Registration Division ensure that the appropriate 

REI is provided on all registered labels.

10.0 Data Needs and Label Recommendations

10.1 Toxicology

As a result of new data requirements in the 40 CFR Part 158 for conventional pesticide 

registration, an immunotoxicity study is required for fluazinam. Additionally, a subchronic (28-

day) inhalation toxicity study is required. HED recommends that these studies be made a 

condition of registration for the proposed uses. 

10.2 Residue Chemistry

No major deficiencies were noted in the current petitions that would preclude establishing 

permanent tolerances for fluazinam residues of concern on head lettuce; leaf lettuce; Onion, 

bulb, subgroup 3-07A; and Bushberry, subgroup 13-07B. In addition, the deficiency listed 

below for lettuce field trials needs to be resolved as a condition of registration. A revised 

Section F is needed as detailed below (860.1550).

Because of major data deficiencies, HED does not recommend in favor of the establishment of 

tolerances for apples or carrots. HED also does not recommend in favor of tolerances for animal 

commodities. The data deficiencies associated with the apple and carrot petitions are discussed 

below.
Page 56 of 67

List of Deficiencies

860.1200 Directions for Use

• The use directions for all the subject crops (lettuce, onions, bushberries, apples, 

and carrots) should include a prohibition against addition of adjuvants to the spray

mixture.

The following deficiency applies to both existing and proposed uses of fluazinam

860.1650 Submittal of Analytical Reference Standards

• An analytical reference standard for the AMGT metabolite is not available. RD 

should request that the registrant submit this standard to the EPA’s National 

Pesticide Repository as soon as possible.

List of Deficiencies by Petition 

PP# 8E7506 (Lettuce, Onion, Bushberry Subgroup)

860.1500 Crop Field Trials

• Samples from the lettuce field trial need to be analyzed for residues of AMGT. 

The residue data should also be supported by data depicting the frozen storage 

stability of AMGT in the lettuce samples. HED recommends that these data be 

made a condition of registration for the use on lettuce.

860.1550 Proposed Tolerances

• The registrant should submit a revised section F in which a tolerance of 0.2 ppm 

is proposed for Onion, bulb, subgroup 3-07A, and a tolerance of 7.0 ppm is 

proposed for Bushberry, subgroup 13-07B.
Page 57 of 67

PP#s 9E7570 (Carrots) and 9F7571 (Apples)

860.1340 Residue Analytical Methods

• At the present time, an analytical method is not available for enforcement of 

fluazinam tolerances in animal commodities. The registrant should submit an 

ILV of the revised method. This method needs to be adequate for analysis of 

parent fluazinam as well as the metabolites AMPA and DAPA in animal 

commodities for which tolerances will be established.

• If the registrant resolves the data deficiencies associated with the apple and carrot 

petitions and re-submits the tolerance petitions, multiresidue method testing data 

will be required for the regulated animal metabolites, AMPA and DAPA.

860.1480 Meat, Milk, Poultry, and Eggs

• The residue data from the cattle feeding study are not adequate to satisfy data 

requirements. To support tolerances for apples and carrots, the registrant needs to 

submit a new cattle feeding study. When this study is repeated, the samples need 

to be analyzed as soon as possible after sacrifice in order to minimize degradation 

of residues.

860.1520 Processed Food and Feed (Applies Only to Apple Petition) 

• The apple processing study is not adequate to satisfy data requirements. The 

processing study needs to be repeated at a sufficiently high rate that residues of 

both parent and AMGT are quantifiable in the RAC. In the event that the 

potential for phytotoxicity exists, the application rate does not need to be greater 

than the rate at which phytotoxicity occurs.

 

10.3 Occupational and Residential Exposure

HED recommends that the Registration Division ensure that the appropriate REI is provided on 

all registered labels. HED also recommends that the PPE required on the label be expanded to 

all handlers. Workers conducting flagger-related activities should wear the same PPE as 

applicators in order to reduce exposures.
Page 58 of 67

REFERENCES:

Fluazinam: Human Health Risk Assessment for Proposed Use on Edible-Podded Beans, Shelled 

Succulent and Dried Beans, Brassica Leafy Vegetables, Bushberries, and Ginseng. PC Code: 

129098, Petition No: 6E7139, DP Barcode: D334949, K. Bailey, et al., 8/22/2007

Fluazinam. Petitions for the Establishment of Tolerances and Registration of New Uses on 

Apples, Carrots, Lettuce, and Bulb Onion Subgroup (3-07A), and a Request for a Reduced 

Tolerance on Bushberry Subgroup (13-07B). Summary of Analytical Chemistry and Residue 

Data, D360840, D. Dotson, 3/31/2010

Fluazinam: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk 

Assessments for the Section 3 Registration Action on Apples, Carrots, Head Lettuce, Leaf 

Lettuce, and the Bulb Onion Subgroup (3-07A), D374522, D. Dotson, 3/31/2010

Tier I Estimated Drinking Waters Concentrations (EDWCs) of Fluazinam and its Transformation 

Products for the Use in the Human Health Risk Assessment for the Registration of the Following 

New Food Uses: Lettuce, Apples, Carrots and Bulb Vegetables (Crop Subgroup 3-07A), 

D360713, J. Melendez, 2/24/2010

Fluazinam: Occupational and Residential Risk Assessment for Proposed Use of Fluazinam on 

Apples, Carrots, Lettuce (Head and Leaf), and Onions (Bulb), D371446, Z. Figueroa, 3/30/2010
Page 59 of 67

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for a food use for fluazinam are in Table A.1. Use of the 

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

Table A.1 Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity........................................................

870.1200 Acute Dermal Toxicity...................................................

870.1300 Acute Inhalation Toxicity...............................................

870.2400 Primary Eye Irritation.....................................................

870.2500 Primary Dermal Irritation...............................................

870.2600 Dermal Sensitization ......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)................................................

870.3150 Oral Subchronic (nonrodent)..........................................

870.3200 21/28-Day Dermal..........................................................

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

870.3465 28-Day Inhalation...........................................................

yes

yes

yes

no

yes

yes

yes

yes

---

no

870.3700a Developmental Toxicity (rodent) ...................................

870.3700b Developmental Toxicity (nonrodent) .............................

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

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)...............................................

870.4100b Chronic Toxicity (nonrodent).........................................

870.4200a Oncogenicity (rat)...........................................................

870.4200b Oncogenicity (mouse) ....................................................

870.4300 Chronic/Oncogenicity ....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

870.5300 Mutagenicity—Gene Mutation - mammalian.................

870.5375 Mutagenicity—Structural Chromosomal Aberrations....

870.5395 Mutagenicity—Mammalian Erythrocyte Micronucleus.

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity. (hen)...............................

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

870.6200a Acute Neurotoxicity Screening Battery (rat)..................

870.6200b 90 Day Neurotoxicity Screening Battery (rat)................

870.6300 Develop. Neurotoxicity ..................................................

no

no

yes

yes

yes

---

---

yes

yes

yes

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

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

yes

no

yes

---

870.7800 Immunotoxicity................................................ yes no
Page 60 of 67

A.2 Toxicity Profiles

Table A.2.a. 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
Page 61 of 67

Table A.2.b. Acute Toxicity Data on Fluazinam (Formulation)

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 (1)

(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 

sensitization

guinea pigs

Omega 500F

(40% fluazinam)

42974912 Positive NA

(1) Study satisfies requirement for testing on Omega 500F
Page 62 of 67

Table A.2.c. Subchronic, Chronic, and Other Toxicity Studies

Guideline No.

Study Type

MRID No./ (year) 

Classification /Doses

Results

870.3100

90-Day oral toxicity 

rats

42248610 (1984); 

44807214 (1998)

Acceptable/guideline

M : 0, 0.15, 0.77, 3.8, 38 

mg/kg/day;

F: 0, 0.17, 0.86, 4.3, 44 

mg/kg/day

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

42248611 (1991); 

44807215 (1998)

Acceptable/guideline

M & F: 0, 1, 10, 100 

mg/kg/day

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 vacuolation of the cerebral white 

matter (equivocal)

870.3200

21-Day dermal 

toxicity

rats

42270602 (1985)

Acceptable/guideline

M & F: 0, 10, 100, 1000 

mg/kg/day

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

870.3250

90-Day dermal 

toxicity

NA NA

870.3465

90-Day inhalation 

toxicity

NA NA

870.3700a

Prenatal 

developmental 

toxicity 

rats

42248613 (1985)

Acceptable/guideline

F: 0,10, 50, 250 mg/kg/day

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 types, greenish amniotic fluid and possible 

increased late resorptions and postimplantation loss

870.3700b

Prenatal 

developmental 

toxicity

rabbits

42248616 (1988)

Acceptable/guideline

F: 0, 2, 4, 7, 12 mg/kg/day

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
Page 63 of 67

Table A.2.c. Subchronic, Chronic, and Other Toxicity Studies

Guideline No.

Study Type

MRID No./ (year) 

Classification /Doses

Results

870.3700b

Prenatal 

developmental 

toxicity 

rabbits

42248615 (1985); 

42248614 (1984); 

42248617 (1984)

Unacceptable/guideline

F: 0, 0.3, 1, 3 mg/kg/day

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

42248619 (1987); 

42208406 (1985); 

42248618 (1986)

Acceptable/guideline

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

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

44839901 (1993)

Acceptable/guideline

M: 0, 1.0, 1.9, 3.9 

mg/kg/day

F: 0, 1.2, 2.4, 4.9 mg/kg/day

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

42270603 (1987); 

44807219 (1998)

Acceptable/guideline

M & F: 0, 1, 10, 50 

mg/kg/day

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

42248620 (1988); 

44807223 (1999); 

45150201 (2000)

Acceptable/guideline

M: 0, 0.04, 0.38, 3.8, 40 

mg/kg/day

F: 0, 0.05, 0.47, 4.9, 53 

mg/kg/day

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 (thyroid gland 

follicular cell tumors) in male rats, but not in females.

870.4200b

Carcinogenicity 

mice

42208405 (1988); 4807220 

(1996)

Acceptable/guideline

M: 0, 0.12, 1.1, 10.7, 107 

mg/kg/day

F: 0, 0.11, 1.2, 11.7, 117 

mg/kg/day

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

44807222 (1996); 

44807221 (1998);

45201301 (2000)

Acceptable/guideline

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 
Page 64 of 67

Table A.2.c. Subchronic, Chronic, and Other Toxicity Studies

Guideline No.

Study Type

MRID No./ (year) 

Classification /Doses

Results

M: 0, 126, 377, 964 

mg/kg/day

F: 0, 162, 453, 1185 

mg/kg/day

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)

42270605 (1988)

Acceptable/Guideline

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)

Negative with and without S9 up to cytotoxic 

concentrations. 

870.5100

Bacterial reverse 

mutation assay 

(Ames test)

42270604 (1989)

Acceptable/Guideline

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)

Negative with and without S9 up to cytotoxic 

concentrations. 

870.5300

In vitro mammalian 

gene mutation assay 

45261801 (2000)

Acceptable/guideline

Up to 9 μg/ml (+S9), up to 

0.3 μg/ml (-S9) 

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 

gene mutation assay 

45156902 (1986)

Acceptable/guideline

Up to 5 μg/ml (+/-S9)

Negative with and without S9 activation up to 5 μg/ml. 

Compound tested to cytotoxic concentrations.

870.5375

In vitro mammalian 

chromosome 

aberration (CHL 

cells)

42270606 (1988)

Acceptable/guideline

Up to 9.5 μg/ml (+S9) up to 

4 μg/ml (-S9)

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

44807224 (1999)

Acceptable/guideline

500, 1000, 2000 mg/kg 

(oral gavage)

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

45156901 (1984)

Unacceptable/guideline

0.05 to 6.25 μg/ml

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 

42270607 (1988)

Unacceptable/guideline

0.003 to 0.3 μg/disk (-S9)

Negative, however only one replicate plate/dose was used. 
Page 65 of 67

Table A.2.c. Subchronic, Chronic, and Other Toxicity Studies

Guideline No.

Study Type

MRID No./ (year) 

Classification /Doses

Results

inhibition in B. 

subtilis

0.3 to 30 μg/disk (+S9)

870.6200a

Acute neurotoxicity 

screening battery 

rats

44807210 (1995)

Acceptable/guideline

M & F: 0, 50, 1000, 2000 

mg/kg

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

44807217 (1998); 

44807218 (1998)

Acceptable/guideline

M :0, 21, 69, 74, 149, 233 

mg/kg/day;

F: 0, 23, 81, 89, 175, 280 

mg/kg/day

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

46534401, 47018301 and 

47037001. 

Acceptable/Non-Guideline

0, 2, 10 or 50 mg/kg/day

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

44807233 (1995); 

43521004 thru 43521008, 

43553001 (1993-1995)

Acceptable/guideline

0.5, 50 mg/kg

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. 

A.3 Executive Summaries

For the executive summaries of the toxicology studies submitted for fluazinam, refer to the 

previous risk assessment that HED prepared for fluazinam (Memo, D334949, K. Bailey, 

8/22/2007).
Page 66 of 67

Appendix B: Tolerance Summary Table

Table B.1. Tolerance Summary for Fluazinam

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity Definition

PP#8E7506

Bushberry, subgroup 13-07B 4.5 7.0 Adequate blueberry residue data are available. 

The recommended tolerance for Subgroup 13-07B 

is the same as that for Subgroup 13B (i.e., 7.0 

ppm)

The established individual tolerances for aronia 

berry, buffalo currant, Chilean guava, European 

barberry, highbush cranberry, edible honeysuckle, 

edible jostaberry, Juneberry, lingonberry, native 

currant, salal, and sea buckthorn should be deleted 

because they are included under the revised 

Bushberry subgroup, 13-07B.

Onion, bulb, subgroup 3-07A 0.15 0.20 Adequate bulb onion residue data are available.

Lettuce, head 0.02 0.02 Adequate head lettuce residue data are available.

Lettuce, leaf 2.0 2.0 Adequate leaf lettuce residue data are available.

PP#9E7570

Carrot, roots 0.8 None* Adequate carrot residue data are available. 

HED’s tolerance generator directs that the 

tolerance for this data set should be 0.70 ppm. 

PP#9F7571

Apples 1.7 None* Adequate apple residue data are available. HED’s 

tolerance generator directs that the tolerance for 

this data set should be 1.50 ppm. The USEPA and 

Canada’s PMRA agreed to establish the tolerance 

at 2.0 ppm at such time as the data deficiencies 

are resolved.

Apple, pomace, wet 5.0 None* Adequate apple processing data are not available.

Cattle, fat 0.03 None An adequate cattle feeding study is not available. 

Based on the results of the inadequate study, the 

maximum expected residues in meat byproducts 

and fat is 0.05 ppm. This value can be used as a 

very conservative residue value for the dietary 

exposure assessment.

Based on the results of the inadequate feeding 

study, tolerances will probably not be needed for 

milk and meat of cattle, goat, horse, and sheep.

Cattle, kidney 0.03 Not required

Cattle, liver 0.03 Not required

Cattle, meat 0.03 Not required

Cattle, meat byproducts 0.03 None

Goat, fat 0.03 None

Goat, kidney 0.03 Not required

Goat, liver 0.03 Not required

Goat, meat 0.03 Not required

Goat, meat byproducts 0.03 None

Horse, fat 0.03 None

Horse, kidney 0.03 Not required

Horse, liver 0.03 Not required

Horse, meat 0.03 Not required

Horse, meat byproducts 0.03 None

Milk 0.03 Not required
Page 67 of 67

Table B.1. Tolerance Summary for Fluazinam

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity Definition

Sheep, fat 0.03 None

Sheep, kidney 0.03 Not required

Sheep, liver 0.03 Not required

Sheep, meat 0.03 Not required

Sheep, meat byproducts 0.03 None

* HED is recommending against the establishment of tolerances on apples and carrots because 

of deficiencies in the livestock residue analytical method, the cattle feeding study, and the apple 

processing study.

HED recommends that 40CFR §180.574(a)(1) be amended by replacing the tolerance expression 

with the following: “Tolerances are established for residues of fluazinam (3-chloro-N-[3-chloro2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2-pyridinamine), including its 

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

tolerance levels specified below is to be determined by measuring only fluazinam.” HED further 

recommends that 40CFR §180.610(a)(2) be amended by replacing the tolerance expression with 

the following: “Tolerances are established for residues of fluazinam, including its metabolites 

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

levels specified below is to be determined by measuring only 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).”