UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDES

                                                                        
                   AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:		9/2/2009

SUBJECT:	Fluazinam.  Human Health Assessment Scoping Document in Support
of Registration 			Review  

PC Code:  129098	DP Barcode:  D362190

Decision No.:  406437	Registration No.:  None

Petition No.:  None 	Regulatory Action: Registration Review             
Scoping Document

Risk Assessment Type:  None	Case No.: None

TXR No.:  None	CAS No.:  79622-59-6

MRID No.:  None	40 CFR:  180.574



FROM:		Douglas Dotson, Ph.D., Chemist

		Karlyn Middleton, Toxicologist 

		Suku Oonnithan, Ph.D., Biologist

		Risk Assessment Branch II

		Health Effects Division (7509P)

		Office of Pesticide Programs

THROUGH:	Richard Loranger, Senior Scientist

		Christina Swartz, Branch Chief

		Risk Assessment Branch II

		Health Effects Division (7509P)

		Office of Pesticide Programs

TO:		Molly Clayton, CRM

		Special Review and Reregistration Division (7508P)

		Office of Pesticide Programs

Attached is the Health Effects Division’s (HED) human health risk
assessment scoping document for fluazinam to support registration
review.

Executive Summary

The Health Effects Division Fluazinam Risk Assessment team has evaluated
the database and the most recent human health risk assessments for the
fungicide fluazinam,
3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoro
methyl)-2-pyridinamine.  HED performed this evaluation in order to
determine the scope of work necessary to support the established
tolerances and existing registrations.  The primary source of
information for this evaluation was the most recent human health risk
assessment written for the chemical.  Fluazinam is a contact fungicide
of the pyridinamine class, registered for agricultural use on a variety
of crops.  Fluazinam is formulated as a flowable suspension concentrate
end use product and is applied using common agricultural equipment
(e.g., groundboom).

 

Fluazinam (technical) has mostly low or mild acute toxicity (Categories
III and IV), except for acute eye irritation (I) and acute inhalation
toxicity (II).  The liver appeared to be a primary target organ, with
numerous effects being observed in rats, mice, and dogs. 
Treatment-related effects were also noted in other organs.  However,
these effects were not regularly noted in all three species or in all
studies in a given species.  

No signs of neurotoxicity were observed in an acute neurotoxicity study
or in two subchronic neurotoxicity studies.  However, a neurotoxic
lesion described as vacuolation of the white matter of the central
nervous system (CNS) was observed in long-term (1-2 year) chronic
studies in mice and dogs.  The presence of this lesion in this long term
study led to re-examination of the short-term studies (4-week to 90-day)
in mice and dogs.  Similar lesions were seen in the short-term studies. 
The cause of the lesion is attributed to an impurity referred to as
impurity-5.

 

There was no evidence of increased quantitative or qualitative
susceptibility in a developmental toxicity study in rabbits or in a
2-generation reproduction study in rats.  In a developmental toxicity
study in rats, there was no evidence of increased quantitative
susceptibility; however, there was evidence of increased qualitative
susceptibility.  Developmental effects were seen in the presence of
maternal toxicity.

A developmental neurotoxicity study in rats and a series of special
studies were submitted to address the issues of increased susceptibility
and the presence of neurotoxic lesions observed in the toxicological
database.  In the developmental neurotoxicity study, there was evidence
of increased susceptibility:  offspring effects were seen in the absence
of maternal toxicity. 

The concern was low for the increased susceptibilities seen in the
developmental toxicity and the developmental neurotoxicity studies
because clear NOAELs were established, dose-responses were well defined,
and sensitive endpoints were used for overall risk assessments. 
Consequently, the FQPA Safety Factor was reduced to 1x because of the
completeness of the toxicology database and lack of residual uncertainty
for pre-and post natal toxicity. 

 

HED’s Cancer Assessment Review Committee (CARC) classified fluazinam
as having “Suggestive evidence of carcinogenicity, but not sufficient
to assess human carcinogenic potential.”  The CARC also determined
that the quantification of human cancer risk was not required.

An immunotoxicity study is required as a part of new data requirements
in the 40 CFR Part 158 for conventional pesticide registration.  Because
the immune system is highly complex, studies not specifically conducted
to assess immunotoxic endpoints are inadequate to characterize a
pesticide’s potential immunotoxicity.  While data from hematology,
lymphoid organ weights, and histopathology in routine chronic or
subchronic toxicity studies might offer useful information on potential
immunotoxic effects, these endpoints alone are insufficient to predict
immunotoxicity.  In the absence of required studies, EPA may use a
database uncertainty factor of up to 10X.  An immunotoxicity study on
fluazinam should be conducted (see Attachment 3).  The fluazinam
Registration Review Team recommends that, once all data have been
received and reviewed, the points of departure and safety factors used
for risk assessment purposes be reexamined and a new risk assessment
done, if necessary.

A PoD from a 7-day inhalation study is currently used for assessing
inhalation risks.  As the study duration is short-term, a subchronic
(28-day) inhalation toxicity study is needed in order to characterize
hazard and assess risk following subchronic exposures.  

The endpoints and safety factors used for risk assessment purposes from
the most recent human health risk assessment are considered to be
appropriate.  However, after evaluation of the new studies, the current
endpoints might need to be revised.

The dietary exposure database is adequate to support the registration
review of fluazinam.  No additional data are required.  A new drinking
water assessment will be conducted during registration review.  The
dietary risk assessment will be revised to include the new estimated
drinking water concentrations.  If the outstanding immunotoxicity study
shows a more sensitive point of departure than that used in the current
risk assessment, the revised point of departure will be incorporated
into the dietary risk assessment.  Acute and chronic dietary (food and
drinking water) risks are not of concern for the existing uses of
fluazinam.

There are no residential uses associated with fluazinam; therefore, a
residential exposure assessment is not required.  During registration
review, and updated aggregate risk assessment will be conducted to
include the updated estimated drinking water concentrations and any
changes in toxicological endpoints. 

≤100 (i.e., the risks are of concern).   Use of REIs greater than the
48-hour REI specified in accordance with the WPS have been placed on the
product label and found to provide adequate mitigation for the high
exposure post-application activities, such as hand harvesting, pruning,
training, etc.  During registration review, inhalation exposures and
risks will be re-evaluated using the endpoints from the required 28-day
inhalation toxicity study.

Introduction

HED evaluated the most recent human health risk assessment for fluazinam
to determine if sufficient data are available and if updates are needed
to support registration review.  To perform this evaluation, HED
considered the most recent human health risk assessment (Memo, D334949,
K. Bailey, 8/22/2007) for this chemical in association with the updates
to its toxicity, exposure, and usage databases.  In addition, HED
considered the latest Agency science policies and risk assessment
methodologies.  The structure of fluazinam, as well as its chemical
names and other identifiers can be found in the chemical identity table
attached to this document (Attachment 1).

Fluazinam is a contact fungicide of the pyridinamine class and is
registered for agricultural use on a variety of crops.  The chemical is
formulated as a flowable suspension concentrate end use product and is
applied using common agricultural equipment (e.g., groundboom, airblast,
sprinkler irrigation).  On the various crops, up to seven applications
may be made per year.  

Applications may be made preplant, at planting, postplant, and
postemergence.

Tolerances are established for residues of fluazinam in or on food and
feed commodities under 40 CFR §180.574.  For all commodities except
wine grapes, tolerances are established in terms of parent fluazinam
only.  For wine grapes, the tolerance is established in terms of parent
fluazinam and the 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). 

Hazard Identification/Toxicology

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.  When it
is applied to plants, it remains primarily on the plant surface and
kills any fungal spores that come into contact with it.  It is not taken
up to any extent by the plant, and is not translocated within the plant
like systemic fungicides.

In subchronic and chronic oral and dermal studies in rats, dogs, and
mice, the liver was a primary target organ.  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 or basophilic hepatocytes, rarefied or vacuolated
hepatocytes, altered hepatocytic foci, hepatocytic single cell necrosis,
hepatocytic hypertrophy, hepatocellular fatty changes, increased brown
pigmented macrophages, sinusoidal chronic inflammation, pericholangitis
(inflammation of the tissues surrounding the bile ducts), 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, decreased food consumption, mild
anemia, increased serum cholesterol, increased serum phospholipid,
increased serum aspartate aminotransferase, testicular atrophy,
increased testes weights (inhalation study), pancreatic exocrine
atrophy, increased lung weights, 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, increased 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 serum glucose, increased kidney
weights, cystic thyroid follicules, and an increased incidence of both
benign and malignant hepatocellular liver tumors (males) were seen.  The
available toxicology database does not indicate potential
immunotoxicity.  Fluazinam does not belong to a class of compounds that
would be expected to be toxic to the immune system (e.g., the
organotins, heavy metals, or halogenated aromatic hydrocarbons).

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.  When
dams were exposed to 250 mg/kg/day, there were decreases in body
weights, decreases in placental weights, and increases in the 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
increased urogenital staining.  

There was no evidence of increased quantitative or qualitative
susceptibility in a developmental toxicity study in rabbits or in a
2-generation reproduction study in rats.  In the developmental rabbit
study, there were decreases in food consumption and increased liver
histopathology in maternal animals.  At higher doses, fetal toxicity was
observed in the form of increased incidences of total litter resorptions
and a slight increased incidence of fetal skeletal abnormalities (e.g.,
kinked tail tip, fused or incompletely ossified sternebrae, and
abnormalities of head bones).  In the rat reproduction study, liver
pathology (hepatocytic fatty changes) was observed in parental F1 males.
 At higher doses, reproductive toxicity was manifested as a decreased
number of implantation sites and decreased litter sizes to day 4 post
partum for F1 females (F2 litters).  In addition, offspring effects
observed were limited to decreased body weight gain during lactation for
both F1 and F2 pups.

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 strictly a result of neurotoxicity.  In two subchronic
neurotoxicity studies (evaluated together) in rats, no signs of
neurotoxicity were observed at doses up to 280 mg/kg/day.  A reversible
neurotoxic lesion observed in chronic studies was attributed to an
impurity referred to as impurity-5.  A developmental neurotoxicity study
in rats and a series of special studies were submitted to address the
issues of increased susceptibility and the presence of neurotoxic
lesions observed in the toxicological database.  In the developmental
neurotoxicity study, there was evidence of increased susceptibility. 
Offspring effects (decreased body weight and body weight gain and delay
in completion of balano-preputial separation) were seen in the absence
of maternal toxicity.  HED reduced the FQPA Safety Factor to 1x because:
 (1) the toxicology database is complete, (2) there are no residual
uncertainties for pre-and post natal toxicity, 3) the dietary food
exposure assessment is based on HED-recommended tolerance-level residues
and assumes 100% crop treated for all commodities, resulting in upper
bound estimates of dietary exposure, (4) the drinking water assessment
is based on values generated by a computer model and associated modeling
parameters which are designed to provide conservative, health protective
upper bound estimates of water concentrations, and (5) there are no
registered or proposed residential uses.  

   

In a combined chronic/carcinogenicity study in rats, increased
incidences of thyroid gland follicular cell tumors were observed in male
rats.  There were no treatment-related increases in female rats.  The
CARC concluded that there was some evidence that the thyroid tumors
observed in the male rats were treatment-related.  In two
carcinogenicity studies in mice, increased incidences of hepatocellular
tumors were observed in males with no treatment-related tumors being
observed in the females.  The CARC concluded that, in one study, there
was clear evidence of treatment-related increases in both benign and
malignant liver tumors in the male mice.  From the other study, it was
concluded that there was equivocal/some evidence for hepatocellular
tumors in the male mice.  There is no evidence of mutagenicity after
exposure to fluazinam.  In accordance with the EPA Draft Guidelines for
Carcinogen Risk Assessment (July 2, 1999), the CARC classified fluazinam
as having “Suggestive evidence of carcinogenicity, but not sufficient
to assess human carcinogenic potential.”  The CARC also determined
that the quantification of human cancer risk was not required. 

The summary tables of toxicity endpoints from the most recent human
health risk assessment (Memo, D334949, K. Bailey, 8/22/2007) are
provided in Attachment 2.

Conclusions for Hazard Identification/Toxicology

An immunotoxicity study is required as a part of new data requirements
in the 40 CFR Part 158 for conventional pesticide registration.  Because
the immune system is highly complex, studies not specifically conducted
to assess immunotoxic endpoints are inadequate to characterize a
pesticide’s potential immunotoxicity.  While data from hematology,
lymphoid organ weights, and histopathology in routine chronic or
subchronic toxicity studies might offer useful information on potential
immunotoxic effects, these endpoints alone are insufficient to predict
immunotoxicity.  In the absence of required studies, EPA may use a
database uncertainty factor of up to 10X.  An immunotoxicity study on
fluazinam should be conducted (see Attachment 3).  The fluazinam
Registration Review Team recommends that, once all data have been
received and reviewed, the points of departure and safety factors used
for risk assessment purposes be reexamined and a new risk assessment
done, if necessary.

Additionally, a subchronic (28-day) inhalation toxicity study is
required in order to be able to perform a more accurate inhalation risk
assessment.  A 10x safety factor was retained to account for the lack of
histopathology evaluation and because the short-term study was used for
intermediate-term inhalation exposure risk assessment.  The required
subchronic study can potentially result in the removal of the database
uncertainty factor that was applied for the lack of this study.

The endpoints and safety factors used for risk assessment purposes from
the most recent human health risk assessment are still appropriate;
however, after evaluation of the new studies, the current endpoints
might need to be revised.

Dietary Exposure

Fluazinam is a contact fungicide of the pyridinamine class registered
for agricultural use on a variety of crops.  Fluazinam is formulated as
a flowable suspension concentrate end use product and is applied using
common agricultural equipment (e.g., groundboom).  Tolerances for
fluazinam range up to 7.0 ppm for the members of the Bushberry subgroup
(13-07B).  The tolerances for Brassica leafy vegetables (Crop Group 5)
and turnip greens are set at the LOQ of the analytical method (0.01ppm).
 No separate tolerances are established for processed commodities.  HED
has concluded that there is no reasonable expectation of finite residues
in animal commodities.  None of the commodities with fluazinam
tolerances have significant animal feed items associated with them.

HED used the Dietary Exposure Evaluation Model (DEEM-FCID™ Version
2.03) to conduct the most recent acute and chronic aggregate dietary
(food and drinking water) risk assessments for fluazinam.  This model
incorporates consumption data from the USDA’s Continuing Survey of
Food Intakes by Individuals taken between 1994 and 1996 along with a
supplemental children’s survey taken in 1998.  Tolerance level
residues and 100 percent crop treated assumptions were made for all
commodities in both the acute and chronic dietary risk assessments. 
DEEM default processing factors were used for peanut butter and dried
potatoes, the only processed commodities associated with the registered
uses of fluazinam.  Fluazinam was classified as having “suggestive
evidence of carcinogenicity, but not sufficient to assess human
carcinogenic potential.”  As a result, a cancer dietary risk
assessment was not conducted.   

The estimated acute dietary exposure to fluazinam resulted in an
estimated risk equivalent to 1.2% of the aPAD (acute population adjusted
dose) for the general U.S. population at the 95th percentile of
exposure.  The most highly exposed population subgroup was Females
13-49, which utilized 8.3% of the aPAD at the 95th percentile of
exposure.  The estimated chronic dietary exposure to fluazinam resulted
in an estimated risk equivalent to 9% of the cPAD (chronic population
adjusted dose) for the general U.S. population.  The most highly exposed
population subgroup was All Infants, which utilized 16% of the cPAD    

EFED recommended that modeled estimates of residues in drinking water be
used in the most recent dietary risk assessment.  A new drinking water
assessment will be conducted during registration review.

Conclusions for Dietary Exposure

The dietary exposure database is adequate to support the existing
registrations and tolerances.  No new residue chemistry data are
required.  A new drinking water assessment will be conducted during
registration review.  Further, a revised dietary risk assessment will be
conducted to include the revised estimated drinking water concentrations
and any changes in toxicological endpoints.

Residential Exposure

There are no registrations of fluazinam for use in residential or public
recreational settings.  Therefore, adults and children are not directly
exposed to fluazinam by either direct application or post-application.

Aggregate Risk Assessment

As residential exposures are not expected based on the registered uses,
the existing aggregate risk assessment includes food and drinking water
only.  As discussed in the dietary section above, food and drinking
water exposures are below HED’s level of concern.  A new drinking
water assessment will be conducted during registration review.  An
updated aggregate assessment will be conducted to include updated
estimated drinking water concentrations and any changes in toxicological
endpoints.

Occupational Exposure 

Handler Exposure and Risk

Omega 500F (EPA Reg. No. 71512-1) and its Special Local Need (SLN) are
the only current end-use product (EP) registrations of fluazinam (Table
1).  The labeled application methods include foliar applications
(groundboom, airblast, and sprinkler irrigation) and soil-directed
treatments (band, bed, drench, drip irrigation, and in-furrow).  The
maximum single application rate ranges up to 1.56 lb a.i./A in potato
which has a maximum application rate of 1.82 lb a.i./A per crop cycle. 
Exposures associated with the registered use patterns are expected to be
of short- and intermediate-term durations for occupational handlers.  On
the various crops, the total seasonal application rate ranges up to 3.9
lb ai/acre/season.

≥ 100.  

The Omega 500F label gives the signal word as “WARNING.”  Although
the acute toxicity of fluazinam technical material is classified as
mostly low or mild (Categories III and IV), it also includes Categories
I and II, respectively, for eye irritation and acute inhalation.  In
accordance with 40CFR §156.64, any pesticide product that meets the
criteria of Toxicity Category I for any route of exposure must bear on
the front panel the signal word “Danger.”  In addition, if the
product is assigned to Toxicity Category I on the basis of its oral,
inhalation, or dermal toxicity (as distinct from skin and eye
irritation), the word “Poison” must appear in red on a background of
distinctly contrasting color, and the skull and crossbones symbol must
appear in immediate proximity to the word “Poison.”  HED recommends
that the proper regulatory division ensure that the appropriate signal
word is placed on the product label.  

Absence of histopathological examination in the 7-day rat inhalation
study resulted in the retention of a 10x factor which was applied to the
conventional uncertainty factor of 100x.  The resulting level of concern
(LOC) for inhalation exposure is equal to, or greater than, a margin of
exposure (MOE) of 1,000.  The level of concern for dermal exposures is
an MOE of 100.  As the dermal and inhalation endpoints are based on
different toxicological effects, the MOEs for the two routes of exposure
were not combined.

All potential occupational exposure scenarios applicable to mixers,
loaders, and applicators resulting from all the registered uses have
been addressed (Table 1), with the exception of the at-plant in-furrow
use on potatoes, (Table 2, D340845, Z. Figueroa, 8/22/2007, D346976, M.
Collantes,  2/27/2008, and D349315, M. Collantes, 3/18/2008).   The MOEs
for all assessed scenarios are not of concern with baseline PPE plus
gloves, a dust/mist respirator, and/or engineering controls for some
scenarios.

Table 1.  Fluazinam:  Occupational Exposure Scenarios Assessed for
Mixer, Loader, and Applicator Risks.

EP Reg. No	Crop	Application method	Max. rate/appl.

(lb AI/A)	No. appl./season  (Re-Treatment Interval)	Assessed  (Y/N)     
                                                           and Comments 

71512-1

Omega 500F

4.17 lb a.i./gal	beans (dry/  succulent)	foliar (chemigation)	0.44	2 (7
days)	Yes

	Brassica vegetables	post-transplant soil drench	0.007 lb AI        
/seedling	--	Yes2



pre-transplant soil spray (band or bed)	1.36	1-2 (none)	Yes3

	bush berry	foliar (airblast)	0.65	6 (7 days)1	Yes

	ginseng	at-transplant soil spray and foliar	0.78	4 (7 days)	Yes3

	peanut	foliar (chemigation)	1.0	2 (21 days)1	Yes

	potato	aerial and foliar (chemigation)	0.26	7 (7 days)1	Yes

CO 070003

Omega 500F	potato

seed pieces	at-plant in-furrow over seed piece	1.8	1	No 

1  For bushberries, peanuts, and potatoes, the scenarios involve
intermediate-term handler exposures.

2  Although the soil drench use was not assessed previously, such
applications are done mechanically and handler exposure is expected to
be negligible. 

3  The soil sprays were assessed as a foliar groundboom application,
which is the closest to the soil-directed scenarios.  The foliar
groundboom scenario is expected to be protective of the soil application
because of the reduced spray drift and there is less bounce-back from
the soil surface.

Table 2 gives the soil-directed application method of fluazinam that has
not been assessed for mixer, loader, and applicator exposures.  Handler
exposure associated with this scenario should be assessed during
registration review.

Table 2.  Fluazinam:  Occupational Exposure Scenarios Requiring
Assessment for Mixer, Mixer/Loader, and Applicator Risks.

EPA Reg. No	Crop	Application method	Application scenario 1

CO 070003

Omega 500F	potato

seed pieces	at-plant in-furrow over seed piece followed by covering the
seed 	groundboom scenario is applicable 

  

Post-application Exposures and Risks

The registrant submitted two chemical-specific dislodgeable foliar
residue (DFR) studies on peanut and potato (MRID 45584201and MRID
45584202).  The results of these studies were used to estimate
post-application exposure to agricultural workers when they enter fields
treated with fluazinam.  Using these chemical-specific data in
combination with HED’s ExpoSAC’s default/surrogate values,
post-application risks to workers were evaluated.  The MOEs for workers
entering fluazinam-treated fields ranged from 100 to 2,200, depending
upon the crop, nature of activity, and days after treatment.  In
instances where the estimated post-application risks (margins of
exposure, or MOEs) were found to be less than that of HED’s LOC (100
for dermal) at the 48-hour REI set by the WPS, HED made recommendations
to set adequate REIs for high exposure activities such as weeding,
harvesting, and other crop-specific activities.  These longer REIs now
appear on the Omega 500F label.

Conclusions for Occupational Exposure and Risk 

Most of the occupational exposure scenarios identified for the
registered uses of fluazinam have been addressed, and none of the
scenarios are of concern with a combination of baseline clothing and the
addition of PPE such as gloves and a dust-mist respirator.  During
registration review, agricultural handler risks must be addressed for
in-furrow spray application on potato seed pieces.  There are some
post-application exposure scenarios where the MOEs for agricultural
workers are ≤100 (i.e., the risks are of concern) at 48 hours after
application.  Use of REIs greater than the 48-hour REI specified in
accordance with the WPS have been found to provide adequate mitigation
for the high exposure post-application activities, such as hand
harvesting, pruning, training, etc.  During registration review,
inhalation risks may be re-evaluated depending on the results of the
required 28-day inhalation toxicity study.

Public Health and Pesticide Epidemiology Data 

The OPP Incident Data System (IDS) was consulted for poisoning incident
data on the active ingredient fluazinam.  The purpose of the database
search is to identify potential patterns on the extent and severity of
the health effects attributed to fluazinam exposure.  The IDS includes
reports of incidents from various sources, including mandatory Federal
Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2)
reports from registrants, other federal and state health and
environmental agencies and individual consumers.

The evaluation of incident data for fluazinam has revealed that a
relatively low volume of incidents has occurred, and no moderate or
severe health effects that are plausibly related to fluazinam have
occurred.  Only one incident has been reported.  The symptoms appear to
be generic and have not been confirmed to be related to exposure.  There
is no clear evidence of a trend or exposure pattern.  Therefore, at this
time, there are no remarkable case reports that suggest a plausible
association between a moderate or severe health outcome and exposure to
fluazinam, nor can HED discern any suggestion of a trend or pattern
regarding the health effects resulting from the alleged exposure to
fluazinam.  The current review of the incident data indicates that no
further investigation is warranted at this time.  

Tolerance Assessment and International Harmonization

Tolerances are established for residues of fluazinam in or on food and
feed commodities under 40CFR §180.574.  For all commodities except wine
grapes, tolerances are established in terms of parent fluazinam only. 
For wine grapes, the tolerance is established in terms of parent
fluazinam and the metabolite AMGT.  The international residue limit
status sheet is appended to this scoping document and is contained in
Attachment 5.  

No Codex MRLs are established for fluazinam.  Canada has an MRL for
potato at the same level as the U.S. tolerance, 0.02 ppm.  Mexico has an
MRL for potato at 0.05 ppm, which is higher than both the U.S. tolerance
and the Canadian MRL.  Mexico has an MRL for beans at 0.1 ppm, which is
the same as the U.S. tolerance for Crop Subgroup 6-A, Vegetable, legume,
edible podded, except pea.  However, the U.S. also has tolerances for
Crop Subgroup 6-B (Pea and bean, succulent shelled, except pea) at 0.04
ppm and 6-C (Pea and bean, dried shelled, except soybean, except pea) at
0.02 ppm.  As a result, with respect to beans, the U.S. is harmonized
with Mexico for Crop Subgroup 6-A only, and not for subgroups 6-B and
6-C.

In registration review, no effort will need to be made to harmonize with
Codex, unless Codex establishes MRLs for commodities with U.S.
tolerances.  For potatoes, the U.S. is harmonized with Canada.  It will
not be possible to harmonize with both Canada and Mexico because those
two countries have differing MRLs for that commodity.  The U.S. might
consider harmonizing the Subgroup 6-B and 6-C tolerances with Mexico’s
MRL for beans.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in the 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,"   HYPERLINK
"http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustic
e.pdf" 
http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice
.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.

The Office of Pesticide Programs (OPP) typically considers the highest
potential exposures from the legal use of a pesticide when conducting
human health risk assessments, including, but not limited to, people who
obtain drinking water from sources near agricultural areas, the
variability of diets within the U.S., and people who might be exposed
when harvesting crops.  Should these highest exposures indicate
potential risks of concern, OPP further refines the risk assessments to
ensure that the risk estimates are based on the best available
information.

Cumulative Risk Assessments 

The Food Quality Protection Act (FQPA) requires the Agency to consider
the cumulative risks of chemicals sharing a common mechanism of
toxicity.  The Agency has determined that there was insufficient
evidence to suggest fluazinam shares a common mechanism of toxicity with
other chemical substances (e.g., other pyridinamines).

Human Studies

The fluazinam risk assessments have relied 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), were determined to require a review of their
ethical conduct, and received that review.  The studies in PHED were
considered to be appropriate (or ethically conducted) for use in risk
assessments.

Data Requirements

An immunotoxicity study, which is a new requirement under 40 CFR Part
158 as a part of the data requirements for registration of a pesticide
(food and non-food uses), should be submitted for fluazinam to support
registration review.  

Also, a subchronic (28-day) inhalation toxicity study is required in
order to perform a more accurate inhalation risk assessment for
potential occupational inhalation hazard, and to be able to remove the
extra uncertainty factor.  No new residue chemistry or residential
exposure data requirements have been identified for fluazinam to support
registration review.

References 

Author	Barcode/TXR No.	Date	Title

Karlyn Bailey	D334949	8/22/2008	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

	TXR 0051576	2/19/2003	Fluazinam-2nd Report of the Hazard Identification
Committee. TXR 0051576. Data Package Submitted by E. Budd.  

	HED Doc No.

014512	3/29/2001	Evaluation of the Carcinogenic Potential of Fluazinam.
Data Package Submitted by E. Budd.

Michael Doherty	D340854	8/1/2007	Fluazinam Acute and Chronic Aggregate
Dietary (Food and Drinking Water) Exposure and Risk Assessments for the
Section 3 Registration Action on Ginseng, Brassica Vegetables, Legume
Vegetables, and Bushberries

Margarita Collantes	D346976	2/27/2008	Fluazinam: Occupational Handler
Exposure/Risk Assessment for the Use on Potatoes.

Margarita Collantes	D349315	3/18/2008	Fluazinam:  Addendum to
Occupational Post-application Exposure/Risk Assessment for the Use on
Edible-Podded Beans, Shelled Succulent and Dried Beans, Brassica
Vegetables, Bush berries, Ginseng, and Potatoes.

William Drew	D347333	3/5/2008	Fluazinam:  Human Health Risk Assessment
to Address Requests for Label Amendments Adding Aerial Application of
the Fungicide on Potatoes and Reducing the Plant-back Interval for all
Non-Label Crops from 70 to 30 Days Following Use of the Fungicide.

Zaida Figueroa	D340845	8/22/2007	Fluazinam:  Occupational Exposure/Risk
Assessment for the Proposed Use on Edible-Podded Beans, Brassica Leafy
Vegetables, Bush berries, and  Ginseng. 



Monica Hawkins and Jesse

Cordova	N/A	5/7/2009	Updated Review of Fluazinam Incident Reports



Attachments

Attachment 1.  Chemical Identity Table

Attachment 2.  Fluazinam Endpoint Selection Tables

Attachment 3.  DCI Justification for Immunotoxicity Study

Attachment 4.  Justification for Inhalation Toxicity Study

Attachment 5.  International Residue Limit Status

Attachment 1.  Chemical Identity Table

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

PC Code	129098

Chemical Abstracts Number	79622-59-6

Registration Review Case No.	7013-1

Chemical Class	Pyridinamine

Vapor Pressure	8.25 x 10-6 torr

Chemical Structure	

                              



Attachment 2.  Fluazinam Endpoint Selection Tables

Table 1.  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”



  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 2.  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 testes 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 testes weights.

Cancer (oral, dermal, inhalation)	Classification: “Suggestive evidence
of carcinogenicity, but not sufficient to assess human 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). 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.

       Attachment 3.  DCI Justification for Immunotoxicity Study

Table D. 2       Guideline Number:  870.7800

Study Title:  Immunotoxicity 

Rationale for Requiring the Data



An immunotoxicity study is required as a part of new data requirements
in the 40 CFR Part 158 for conventional pesticide registration.  Because
the immune system is highly complex, studies not specifically conducted
to assess immunotoxic endpoints are inadequate to characterize a
pesticide’s potential immunotoxicity.  While data from hematology,
lymphoid organ weights, and histopathology in routine chronic or
subchronic toxicity studies might offer useful information on potential
immunotoxic effects, these endpoints alone are insufficient to predict
immunotoxicity.  In the absence of required studies, EPA may use a
database uncertainty factor of up to 10X.  An immunotoxicity study on
fluazinam should be conducted (see Attachment 3).  The fluazinam
Registration Review Team recommends that, once all data have been
received and reviewed, the points of departure and safety factors used
for risk assessment purposes be reexamined and a new risk assessment
done, if necessary.

  

Practical Utility of the Data



How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure.  As epidemiologic data on the effects of
chemical exposures on immune parameters are limited and are inadequate
to characterize a pesticide’s potential immunotoxicity in humans,
animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation.  For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

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

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material might need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have these data, a 10X database uncertainty
factor might be applied for conducting a risk assessment from the
available studies.







Attachment  4.  Justification for Inhalation Toxicity Study

Guideline Number: 870.3465

Study Title:   90-Day Inhalation Toxicity 

Rationale for Requiring the Data



Instead of conducting the inhalation study for 90-days, the Agency only
needs a 28-day inhalation study because only short- and
intermediate-term (but not long-term) exposure to workers is expected
based on fluazinam's use pattern.  A longer-term inhalation study is
required in situations in which a specific concern exists for increased
hazard related to exposure via the inhalation route.  The 28-day
inhalation toxicity study evaluates the potential hazard of a pesticide
chemical following repeated inhalation exposures.  This study is
critical for pesticides with use patterns in which there is potential
for repeated human exposures (e.g., professional applicators, green
house use, etc.).  The study design simulates the route of human
exposure (inhalation).  In this study, animals are exposed (nose/whole
body) to aerosol concentrations of the test material for 6 hours/day, 5
days/week for 28 days.  A detailed toxicological examination including
the histopathology of the respiratory system is conducted.  This
route-specific study would provide data for hazard characterization,
dose response assessment, and a dose and endpoint for assessing
potential risks via the inhalation route.  



Practical Utility of the Data



How did the Agency make its re-registration decision without these data?
 

A subchronic inhalation study provides critical scientific information
needed to characterize potential hazard to the human respiratory system
from pesticide exposure.  In the case of fluazinam, the available
inhalation study is judged to be inadequate because of the short
duration of exposure (i.e., rats were exposed for only 7 days) and lack
of evaluation of the target organ (i.e., no histopathology of the
respiratory system).  Although this study is currently used in
occupational risk assessments, the Agency has applied an additional 10X
Uncertainty Factor because of the limitations of the study.  A 28-day
repeated exposure study that follows the Test Guidelines (870.3465) will
characterize hazard and provide data for a much more accurate inhalation
risk assessment.

How will the data be used?  

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This study will identify hazard (i.e., provide a dose and endpoint)
following longer repeated exposures.  The data will be used in risk
assessments and will result in the removal of the database uncertainty
factor.







Attachment 5.  International Residue Limit Status

Summary of US and International Tolerances and Maximum Residue Limits
for Fluazinam

US	Canada	Mexico	Codex

Residue Definition:

40CFR180.574 

Fluazinam1	

Fluazinam	

Fluazinam

	

None

Commodity Tolerance (ppm)/Maximum Residue Limit (mg/kg)

Commodity	US	Canada	Mexico	Codex

Brassica Leafy Vegs, Group 5	0.01	-	-	-

Turnip Greens	0.01	-	-	-

Bushberry subgroup 13-07B	7.0	-	-	-

Ginseng	4.5	-	-	-

Grape, wine	0.02	-	-	-

Peanut	0.02	-	-	-

Potato	0.02	0.02	0.05	-

Subgroup 6-A, Vegetable, legume, edible podded, except pea	0.10	-	0.1	-

Subgroup 6-B, Pea and bean, succulent shelled, except pea	0.04	-	0.1	-

Subgroup 6-C, Pea and bean, dried shelled, except soybean, except pea 
0.02	-	0.1	-

 

1The residue definition for all commodities, except for grape, wine is
parent fluazinam,
3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoro
methyl)-2-pyridinamine.  The residue definition for grape, wine is
parent fluazinam and the 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).   

Fluazinam Registration Review Human Health Assessment Scoping Document

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