Document ID: EPA-HQ-OPP-2009-0032-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-05-12T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 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.:    SEQ CHAPTER \h \r 1 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)	  SEQ CHAPTER \h \r 1 

		

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)		  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h
\r 1 

	Table of Contents

  TOC \f  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

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

 

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. 

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
intermediate-term (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.

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
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 of the revised method.

Adequate FDA   SEQ CHAPTER \h \r 1 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.

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. 

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. 

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 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

(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.

  TC \l1 "1.0	Ex

ecutive Summary 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 flowable-suspension concentrate (FlC).  Copies of the proposed
labels were provided, and the proposed uses on the requested crops are
summarized in Table 2.1, below.

 

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.

2.2   Structure and Nomenclature

  SEQ CHAPTER \h \r 1 TABLE 2.2.   Test Compound Nomenclature

Compound	Chemical Structure

                              

Empirical Formula	

C13H4Cl2F6N4O4

Molecular Weight	465.1

Common Name	Fluazinam

Company Experimental Names	Fluazinam, IKF-1216

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

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

CAS Number	79622-59-6

End-use Product/(EP)	Omega® 500F (USA); Allegro® 500F (Canada)

2.3   Physical and Chemical Properties

  SEQ CHAPTER \h \r 1 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

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

λmax (nm)	Regulatory Note REG2003-12

	5

7

>10	238

239, 342

260, 343, 482

	  SEQ CHAPTER \h \r 1   

  TC \l2 "2.3	Physical and Chemical Properties 

3.0   Hazard Characterization/Assessment 

3.1   Hazard and Dose-Response Characterization

3.1.1   Database Summary  TC \l3 "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.

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 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

als 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)

  TC \l2 "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%).  

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  TC \l2 "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
treatment-related 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 treatment-related 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.

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 treatment-related 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.   

  TC \l3 "3.3.2	Evidence of Neurotoxicity 

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 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.

  TC \l3 "3.3.5	Additional Information from Literature Sources 3.3.5  
Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	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  TC \l4
"3.3.6.2	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 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.

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. 

  TC \l2 "3.4	Safety Factor for Infants and Children 

3.5   Hazard Identification and Toxicity Endpoint Selection  TC \l2 "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.

  = 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 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.

  = 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. 

   

1st 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.

2nd 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)

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.

  = 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  TC \l3 "3.5.5	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)

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.

  

t ≥ 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.

3.5.7   Level of Concern for Margin of Exposure  TC \l3 "3.5.8	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

  TC \l3 "3.5.9	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

  SEQ CHAPTER \h \r 1 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 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:  

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. 

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.

.

  TC \l3 "3.5.10	Classification of Carcinogenic Potential 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.  

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); Intermediate-Term (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 Intermediate-Term (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  TC \l2 "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 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:    HYPERLINK
"http://www.epa.gov/endo/"  http://www.epa.gov/endo/ .

  TC \l2 "3.6	Endocrine disruption 4.0   Public Health and Pesticide
Epidemiology Data

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

  TC \l2 "4.4	Other Pesticide Epidemiology Published Literature 5.0  
Dietary Exposure/Risk Characterization

5.1   Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

5.1.1   Metabolism in Primary Crops  TC \l3 "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.

5.1.2   Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

 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

  TC \l3 "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 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.

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	SOURCE

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

	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.

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). 

 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. 

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.

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   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
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.

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
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.

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.

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 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 TC \l3 "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-FCID™, 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

  TC \l3 "5.2.2  Chronic 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  TC \l3 "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.

5.2.3   Cancer Dietary Risk  TC \l3 "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 TC
\l2 "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.

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
off-target drift risks associated with pesticide application.

7.0   Aggregate Risk Assessments and Risk Characterization

7.1   Acute Aggregate Risk

 TC \l2 "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 TC \l2 "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 TC \l2 "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.   

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   HYPERLINK http://www.epa.gov/pesticides/cumulative/.
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: 

	Mixer/Loaders

Mixing/loading liquid concentrates to support aerial applications, 

Mixing/loading liquid concentrates to support chemigation applications,

Mixing/loading liquid concentrates to support groundboom applications,

Mixing/loading liquid concentrates to support airblast applications,

Applicators

Applying sprays with aircraft (enclosed cockpit),

Applying sprays with groundboom equipment,

Applying sprays with airblast equipment, and 

Flaggers

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;

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)

	

	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 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 

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 intermediate-term 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.

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 Inhalationµg/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

	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.

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

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”  SEQ CHAPTER \h \r 1 	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). 

The highest average DFR value occurred immediately after the first
application (1.56 μg/cm2).  The residues then declined to 0.0085
μg/cm2 by 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/cm2 by 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 ½LOQ. 

For both treatment plots, the highest average residue was observed 1
hour after application (0.071 μg/cm2 for 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/cm2 to 0.0059 μg/cm2 in the 3x plot. 

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/cm2 for 1x rate and 0.046 µg/cm2
for 3x rate) that were lower than the actual residue on day 0 (0.071
µg/cm2 for 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)

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 0d	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.  

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  TC \l1 "10.0	Data Needs and
Label Requirements 

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  TC \l2 "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.

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.

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.

  

  TC \l2 "10.1	Toxicology 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.

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

 



Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1   Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

 TC \l2 "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

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



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



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

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 post-partum 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/carcino-genicity

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

M: 0, 126, 377, 964 mg/kg/day

F: 0, 162, 453, 1185 mg/kg/day	

NOAEL =  Males:<126 mg/kg/day, Females: <162 mg/kg/day

LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased
liver weights and liver and brain histopathology in both sexes

Equivocal/some evidence of carcinogenicity (hepatocellular tumors) in
male mice, but not in females

870.5100

Bacterial reverse mutation assay (Ames test)	

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) 	



 

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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 inhibition in B. subtilis	

42270607 (1988)

Unacceptable/guideline

0.003 to 0.3 μg/disk (-S9)

0.3 to 30 μg/disk (+S9)	

Negative, however only one replicate plate/dose was used. 

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 TC \l2 "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).

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

	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-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluor
omethyl)-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).”

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