Document ID: EPA-HQ-OPP-2007-1021-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-11T04:00Z

MEMORANDUM

Date:		11/27/07

Subject:	Flutolanil.  Human Health Risk Assessment. Requests for
Inadvertent or Indirect Tolerances for Use on Soybean, Wheat, Corn and
Cotton.

PP#s	6F7070,  0F6159	40 CFR:	180.484

PC Code:	128975	Decision #s:	303953, 367541

DP Num:	335050, 334156	Trade Names	Moncut( 50WP 

Moncut( 70WP 

From:	Felecia Fort, Senior Chemist/Risk Assessor

	Byong-Han Chin, Toxicologist	

	Reregistration Branch 1

	Health Effects Division (HED) (7509P)	

Through:	Kit Farwell, Senior Scientist

		Reregistration Branch 1 (RRB1)

		Health Effects Division (HED) (7509P)

To:		Lisa Jones/Mary Waller, PM Team 21

		Fungicides Branch

		Registration Division (7505P)

 

The Health Effects Division (HED) has conducted a human health risk
assessment for the fungicide flutolanil to estimate the risk to human
health that will result from proposed and registered uses of flutolanil.
 Nichino America, Inc. (formerly Nihon Nohyaku) has submitted two
petitions proposing the establishment of permanent tolerances for
indirect or inadvertent residues in/on corn and cotton (PP#6F7070) and
soybean and wheat commodities (PP#0F6159).     

The risk assessment, the residue chemistry data review, and the dietary
risk assessment were provided by F. Fort and the hazard assessment was
provided by Byong-Han Chin.

  SEQ CHAPTER \h \r 1 1.0	EXECUTIVE SUMMARY

Flutolanil [N-[3-(1-methylethoxy)-phenyl]-2-(trifluoromethyl)-benzamide]
is a mildly systemic benzanilide fungicide.  Flutolanil has both
preventative and curative actions against economic pests such as
Rhizoctonia solani, which is the causal agent of limb/pod rot in
peanuts, sheath blight in rice, and black scurf in potatoes.  Flutolanil
is also effective in controlling white mold in peanuts and rust diseases
of several crops.  Flutolanil is currently registered for application to
peanuts, potatoes, and rice.

The proposed tolerances for corn and cotton commodities are for residues
of the fungicide flutolanil and the metabolite desisopropyl flutolanil
a.k.a. M-4 in/on the following raw agricultural commodities (RACs):

Corn, field, forage 	0.30 ppm

Corn, field, grain 	0.20 ppm

Corn, field, stover 	0.30 ppm

Cotton, undelinted seed	0.20 ppm

The proposed tolerances for soybean and wheat commodities are for
residues of flutolanil and its metabolites converted to
2-trifluoromethyl benzoic acid and calculated as flutolanil in or on the
following RACs and processed commodities:

Soybean forage 	8.0 ppm

Soybean hay 	2.0 ppm

Soybean seed 	0.20 ppm

Wheat forage 	2.0 ppm

Wheat grain 	0.05 ppm

Wheat hay 	0.5 ppm

Wheat straw 	0.2 ppm

Wheat bran 	0.3 ppm

The submitted toxicology data base for technical flutolanil is complete.
 No additional studies are required to support the proposed or
registered uses of flutolanil.  The database is considered sufficient to
clearly define the toxicity of flutolanil.  

In general, the toxicology studies conducted on flutolanil demonstrate
few or no biologically significant toxic effects at relatively low-dose
levels in animal studies and only mild or no toxic effects at high
doses.   The subchronic and chronic toxicity studies showed that the
primary effects of flutolanil are increases in liver weight combined
with decreases in body weight.   The toxicological database indicates
that technical grade flutolanil has relatively low acute toxicity
(Category III and IV).  Flutolanil is not a dermal sensitizer, primary
eye irritant, or primary skin irritant.  Flutolanil is also not
neurotoxic, carcinogenic, nor mutagenic.  Flutolanil is not a
developmental or reproductive toxicant.  There is no evidence of
increased susceptibility of rat or rabbit fetuses to in utero exposure
or rat pups to post-natal exposure to flutolanil.  No toxic effects were
observed in studies in which flutolanil was administered by the dermal
routes of exposure.

≤1% cPAD).   

In addition to food and drinking water, the use pattern for flutolanil
is expected to result in exposure to the general population through
residential settings from use on turf.  Exposures can also occur for
occupational handlers loading or applying flutolanil, as well as through
postapplication exposure.   However, as previously stated, no
appropriate toxicological endpoints of concern was identified in the
database based on the lack of adverse effects for these routes of
exposure. Consequently, neither a occupational nor residential exposure
assessment is required.  

Since toxicological endpoints have only been identified for chronic oral
exposures, aggregate exposure and risk assessments include only chronic
dietary food and water sources of exposure.  As discussed above, the
aggregate chronic risk estimates were below the Agency’s level of
concern for all population subgroups. 

	Recommendation

HED has examined the residue chemistry database for flutolanil.  Due to
major issues pertaining to the absence of storage stability to support
the lengthy sample storage durations, the submitted data are not
acceptable to support reduced PBIs or proposed tolerances for rotated
corn and cotton.  Pending submission of a revised section B (see
requirements under Directions for Use for soybean and wheat), a revised
Section F (see requirements under Proposed Tolerances for soybean and
wheat), and the submission of additional data concerning the proposed
enforcement method (see requirements under Residue Analytical Methods
for Method AU/95R/04), there are no residue chemistry issues that would
preclude granting unconditional registration for the requested amended
use of flutolanil or establishment of tolerances for indirect or
inadvertent residues of flutolanil as follow:  

Tolerances to be established under “(d) Indirect or inadvertent
residues”:

Soybean, forage	8.0 ppm

Soybean, hay	2.5 ppm

Soybean, seed	0.20 ppm

Wheat, forage	2.5 ppm 

Wheat, grain	0.05 ppm

Wheat, hay	1.2 ppm

Wheat, straw	0.20 ppm

Wheat, bran	0.20 ppm

Additionally, analytical standards for metabolites M-2 and M-4 are
currently not in stock, and the available standards for metabolites M-3
and M-7 have expired (expiration dates 1/1/04 and 4/1/02, respectively;
personal communication with Dallas Wright, ACB, 4/30/07).  Analytical
reference standards of flutolanil and its metabolites must be supplied
and supplies replenished as requested by the Repository.  For the
expired reference standards, the petitioner must either recertify the
lot in the repository and send in an updated certificate of analysis
(COA), or submit new standards (different lot #) if the previous lots
will not be recertified.  If new COAs are being submitted, they should
be faxed to the repository at 410-305-2999.

Data deficiencies pertaining to rotated corn and cotton need be
addressed only if the petitioner intends to pursue reduced plantback
intervals (PBI) for these commodities.

2.0	INGREDIENT PROFILE

	2.1	Summary of Registered/Proposed Uses 

Tolerances are currently established under 40 CFR §180.484(a)(1) for
residues of flutolanil and its metabolites converted to
2-(trifluoromethyl)benzoic acid and calculated as flutolanil in/on
peanut, potato, and rice commodities at levels ranging from 0.5 ppm for
peanut to 25.0 ppm for rice hulls.  Tolerances for livestock commodities
are also established under §180.484(a) at levels ranging from 0.05 ppm
for egg, milk, meat, and meat byproducts to 2.0 ppm for liver.  

Nichino America, Inc. (formerly Nihon Nohyaku) has submitted two
petitions proposing the establishment of permanent tolerances for
indirect or inadvertent residues in/on corn and cotton (PP#6F7070) and
soybean and wheat commodities (PP#0F6159).  The formulations registered
for use on peanuts and rice are Moncut® 50WP (EPA Reg. No. 45639-195)
and Moncut® 70WP (EPA Reg. No. 45639-206); these products contain 50%
and 70%, respectively, flutolanil as the active ingredient (ai). 
Moncut® is a systemic fungicide for control of Southern stem rot (white
mold) Sclerotium rolfsii, and limb/pod rot complex, Rhizoctonia solani,
in peanuts; and for the control of sheath blight and Rhizoctonia solani,
in rice.

rate ≤0.25 lb ai/A.  The 70% DF formulation is currently registered
for use on peanuts, rice, and potatoes as broadcast foliar applications
in peanuts at up to 2.0 lb ai/A, in-furrow applications in peanuts and
potatoes at up to 0.77 lb ai/A, and broadcast foliar applications in
rice at up to 1.0 lb ai/A.  The label for the 70% DF formulation
specifies PHIs of 40 days for broadcast applications to peanuts and 30
days for rice.  The registered use directions for flutolanil are
presented in Table 1; the proposed rotational crop restrictions follow.

Table 2.1.1  Summary of Directions for Use of Flutolanil.

Applic. Timing, Type, and Equip.	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 Limitations

Potato

Seed-piece treatment,

Dispensing equipment	1.5% D

[71711-8]	0.75-1.0 lb product/100 lb cut seed	1

made in ≥3 gal/A.  Use of an adjuvant is prohibited.  Use is
prohibited in Nassau and Suffolk Counties, NY.

Peanut

Broadcast foliar,

Ground, aerial or chemigation	70% DF

to be made in ≥3 gal/A.  Use of an adjuvant is prohibited.  Use is
prohibited in CA and in Nassau and Suffolk Counties, NY.

Rice

Broadcast foliar,

Aerial	70% DF

[71711-14]	0.35-0.70	2	1.00	302	Applications are to be made at first
internode elongation at retreatment intervals of 10- to 14-days. 
Applications may be made using aerial equipment in 5-10 gal/A.  Use of
an adjuvant is prohibited.  Flooded fields may be used for aquaculture
of crayfish only following rice harvest.  Use is prohibited in CA and in
Nassau and Suffolk Counties, NY.

1  NS = Not specified

2  The label specifies a 30-day PHI or beyond 75% heading development
stage, whichever occurs first.

The following rotational crop restrictions are specified for the 1.5% D
formulation:  Following total seasonal applications of ≤0.25 lb ai/A,
do not plant rotational crops other than labeled crops for 12 months
with the following exceptions:  (1) field corn, cotton, soybeans, or
wheat may be planted 30 days after last application; (2) leafy
vegetables (such as lettuce, spinach, or celery), or small grain crops
(such as barley, oats, rye) may be planted 150 days after the last
application; and (3) corn (such as sweet or popcorn) and sorghum may be
planted 240 days after the last application.  We note that the 150-day
PBI for leafy vegetables and small grain crops (including wheat) appears
on the accepted label, along with a 12-month restriction for rotational
crops other than potatoes, peanuts, or rice. 

The following rotational crop restrictions are specified for the 70% DF
formulation:  Do not plant rotational crops other than peanuts, rice, or
potatoes for 12 months with the following exceptions:  (1) corn, cotton,
soybeans, or wheat may be planted 30 days after last application; (2)
leafy vegetables (such as lettuce, spinach, or celery), small grain
crops (such as barley, rye, or oats), or crops grown for seed (such as
grass seed, alfalfa, or timothy) may be planted 150 days after the last
application; and (3) root crops (such as sugar beets, onions, carrots,
or garlic grown for seed); legume vegetables (such as peas or beans); or
sorghum may be planted 240 days after the last application.  We note
that the 150-day PBI for leafy vegetables and small grain crops
(including wheat) and a 240-day PBI for corn (including field, sweet,
and popcorn), sorghum, soybeans, and cotton appear on the accepted
label, along with a 12-month restriction for rotational crops other than
potatoes, peanuts, or rice. 

The 70% DF formulation also specifies the following feeding restrictions
for broadcast foliar application to peanuts:  Do not feed hay or
threshings from rotational crops of soybeans or cotton planted following
the harvest of treated peanuts (>1.00 lb ai/A), and do not allow cattle
to graze soybean or cotton forage in these previously treated peanut
fields. 

	2.2	Structure and Nomenclature 

The nomenclature of flutolanil is summarized in Table 2.2.1, and the
physicochemical properties are summarized in Table 2.3.1.  The chemical
names and structures of flutolanil and its transformation products are
presented in Appendix B.

Table 2.2.1 Flutolanil Nomenclature.

Chemical structure	

Common name	Flutolanil

Company experimental name	N/A

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

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

CAS registry number	66332-96-5

End-use product (EP)	MonCoat MZ® (1.5% tree bark based dust
formulation; EPA Reg. No. 71711-8; MAI formulation containing mancozeb)
and Moncut® 70-DF (70% DF formulation; EPA Reg. No. 71711-14)

Chemical structure of common moiety determined by enforcement method	

2-trifluoromethylbenzoic acid (2-TFBA)

	2.3	Physical and Chemical Properties  tc "2.3	Physical and Chemical
Properties " \l 2 

Table 2.3.1	Physicochemical Properties of Flutolanil.

Parameter	Value	Reference

Melting range	100.4-103.8 °C	DP#s 190584 and 190586, 3/24/94, J.
Garbus; MRID 42606601

Ph	5.69

	Density	1.325 @ 20-25

	Water solubility	6.53 mg/L at 20 °C

	Solvent solubility			at 20 °C 

Methanol	232 g/L

n-Hexane	  0.9 g/L

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

	Dissociation constant, pKa	Not applicable

	Octanol/water partition coefficient, Log(KOW)	log POW = 3.74

	UV/visible absorption spectrum	Not available

	

HAZARD CHARACTERIZATION/ASSESSMENT

	3.1	Hazard and Dose-Response Characterization

The hazard characterization for flutolanil is discussed in detail in the
document entitled Flutolanil on Rice and Potato: Human Health Risk
Assessment [DP barcode D268880, September 11, 2000]. The conclusions
from that assessment remain unchanged, with the exception that the
chronic reference dose (RfD) has been revised, as discussed below. 

All toxicological data requirements for a food-use chemical have been
satisfied, and the toxicology database for flutolanil is considered
complete for the purpose of assessing human health risks. No additional
studies are required to support rotational crop tolerances on wheat,
soybean, corn, and cotton.  

	

The toxicology studies conducted on flutolanil demonstrate few or no
biologically significant toxic effects. Liver effects in rats included
increases in absolute and relative liver weight in the absence of
clinical chemistry and/or histopathology findings. In dogs, there was an
elevation in alkaline phosphatase and cholesterol levels together with
dose-related increases in absolute and relative liver weights, slightly
enlarged livers, and an increase in severity of glycogen deposition. The
increased liver weights are considered to be an adaptive response to
flutolanil treatment and not an adverse effect. Based on the lack of
evidence of carcinogenicity and the lack of evidence of mutagenicity,
flutolanil is classified as “not likely to be carcinogenic to
humans”.

Flutolanil is not neurotoxic, and it is not a developmental or
reproductive toxicant. No maternal, reproductive, or developmental
toxicity was observed at the limit dose. There was no evidence for
increased susceptibility of rat or rabbit fetuses to in utero exposure
or rat pups to post-natal exposure to flutolanil.  No toxic effects were
observed in studies in which flutolanil was administered by the dermal
route of exposure at the limit dose.

Previously, the Health Effects Division (HED) Hazard Identification
Assessment Review Committee (HIARC report dated 11/2/99; TXR No. 013851)
determined that no appropriate toxicological endpoint attributable to a
single oral dose (exposure) was identified in the available data on
flutolanil. Therefore, no acute reference dose (RfD) was selected and an
acute dietary risk assessment was not required. The HIARC selected a
chronic RfD of 0.87 mg/kg/day for use in chronic dietary risk
assessment, based on the 2-year combined chronic
toxicity/carcinogenicity study in rats in which decreases in body
weight/gain and increases in absolute and relative liver weights were
observed at the lowest-observable-effect level (LOAEL) of 460 mg/kg/day.
The HED Food Quality Protection Act (FQPA) Safety Factor Committee
(November 9, 1999) concluded that the 10X FQPA safety factor should be
reduced to 1X.  

For the current rotational crop tolerances assessment, the flutolanil
risk assessment team reevaluated the database and concurred with the
HIARC regarding the lack of an appropriate endpoint for the acute RfD
and reduction of the FQPA safety factor to 1X. However, the team
identified an endpoint from the 2-year chronic dog study as providing a
more appropriate endpoint for the chronic RfD. This is based on the
conclusion that the liver effects, in the absence of clinical chemistry
or histopathological findings, in the chronic rat study used previously,
are considered to be an adaptive response and not adverse. In the
chronic dog study, the increased incidence of clinical signs (emesis,
salivation, and soft stool) at 250 mg/kg/day (LOAEL) occurred following
65 weeks of exposure.  The flutolanil risk assessment team selected a
chronic RfD of 0.5 mg/kg/day (NOAEL of 50 mg/kg/day; 10X interspecies
factor; 10X intraspecies factor; 1X FQPA SF). 

Previously, an assessment of incidental oral exposure was not performed.
For the current rotational crop tolerances assessment, the flutolanil
risk assessment team concluded that there is no appropriate endpoint for
either short-term or intermediate-term incidental oral assessment based
on the lack of adverse effects following these exposure durations. 

		3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

A summary of the hazard assessment of flutolanil is provided below.
Additional details may be found in the 2000 Human Health Risk Assessment
(DP Barcode D268880). The acute toxicity of flutolanil technical is
summarized in Appendix A: Table A.3 and the toxicity profile of
flutolanil is shown in Appendix A: Table A.4.

		3.1.1.1	 Studies considered 

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

Developmental:  rat and rabbit developmental toxicity studies

Reproduction: two-generation reproduction study (rat)

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

Other:  mutagenicity battery, metabolism

	3.2	Consideration of Toxicity to Children

There was no evidence of increased susceptibility of rat or rabbit
fetuses to in utero exposure or rat pups to post-natal exposure to
flutolanil.  Flutolanil is not neurotoxic, and it is not a developmental
or reproductive toxicant. No maternal, reproductive, or developmental
toxicity was observed at the limit dose. A developmental neurotoxicity
study is not required for flutolanil. Consistent with the previous
assessment (1999), the FQPA safety factor for the protection of infants
and children is reduced to 1X.

	3.3	Absorption, Distribution, Metabolism, Excretion (ADME) 

In a metabolism study in rats (MRID No. 42606602) disposition and
metabolism of 14C-flutolanil was investigated at a low oral dose of 20
mg/kg, repeated low oral doses of 20 mg/kg for 14 days, and a single
high dose of 1000 mg/kg.  Absorption of flutolanil was incomplete at the
single low and high doses but appeared to be increased after repeated
low oral dosing.  There were no appreciable tissue levels of flutolanil
at study termination (168 hours post-dose).  At the single low oral
dose, excretion in urine and feces was equivalent, with approximately
40% of an administered dose excreted via each route in male and female
rats.  Repeated low dosing resulted in an increased percentage of
radioactive flutolanil in urine (approximately 70%) with a corresponding
decrease in fecal excretion (10% of dose).  At the single high dose, the
majority of radioactivity (66-78%) was excreted via the feces, with less
than 10% found in urine.  Identification of urinary and fecal
metabolites by TLC showed the presence of a major metabolite (M-4) in
urine, N-(3'-hydroxyphenyl)-2-(trifluoromethyl)benzamide, in all dose
groups.  In feces, radioactivity was excreted mainly as parent chemical,
with limited conversion to M-4.

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

The toxicity endpoints and doses for risk assessment were selected based
upon the available toxicity data and the use exposure information on
flutolanil. The selected endpoints and doses are presented below.

		3.4.1	Acute Reference Dose (aRfD) - Females age 13-49

No appropriate endpoint attributable to a single exposure (dose) was
identified from oral toxicity studies for females 13+. This risk
assessment is not required.

		3.4.2	Acute Reference Dose (aRfD) - General Population

No appropriate endpoint attributable to a single exposure (dose) was
identified from oral toxicity studies for the general population. Since
repeat oral exposure at or greater than the limit dose does not result
in neurotoxicity, there is no need for an acute neurotoxicity study.  

		3.4.3	Chronic Reference Dose (cRfD)

HED selected a chronic PAD of 0.50 mg/kg/day (NOAEL = 50 mg/kg/day;
Uncertainty Factor = 100) based on a chronic oral toxicity study in
dogs.  In this study, the NOAEL of  50 mg/kg/day was based on an
increased incidence of clinical signs of toxicity (emesis, salivation,
and soft stool) observed from the 65th week at the systemic LOAEL of 250
mg/kg/day.  The Uncertainty Factor accounts for both interspecies
extrapolation (10X) and intraspecies variability (10X)(See Appendix A.,
Guideline §870.4100).

		3.4.4	Incidental Oral Exposure (Short -Term)

No appropriate endpoint attributable to a short duration of exposure was
identified from the database.

		3.4.5	Incidental Oral Exposure (Intermediate-Term)

No appropriate endpoint attributable to a 6-month duration of exposure
was identified from the database

		3.4.6	Dermal Absorption

There are no dermal absorption data on flutolanil.  A 21-day dermal
toxicity study in rats was performed at 1000 mg/kg/day (limit dose). No
dermal or systemic effects were observed.  Oral exposure at the limit
dose also shows no effects.  

		3.4.7	Dermal Exposure (Short-, Intermediate- and Long-Term)

In a 21 day dermal toxicity study in rats, no toxic effects were
observed in studies in which flutolanil was administered by the dermal
route of exposure at the limit dose (1000 mg/kg/day).  Further, there is
no developmental or reproductive concern at dose levels that do not
exceed the limit dose.  For these reasons, it is concluded that no
short-term, intermediate-term, or long-term dermal risk assessment is
required (see Appendix A.2, Guideline §870.320).

		3.4.8	Inhalation Exposure (Short- and Intermediate-Term)

No appropriate endpoint was identified in the database for these
durations of exposure. Although there is no route-specific study
available on flutolanil, the available data indicate that flutolanil is
not very toxic via either the oral or dermal routes of exposure; e. g.,
adverse effects observed only following dose levels at or close to the
limit dose and only following chronic exposure. A subchronic inhalation
toxicity study is not required at this time, based on the fact that
there is minimal inhalation exposure,  flutolanil is a Toxicity Category
IV (acute inhalation),  and the MOEs exceed 1000. 

		3.4.9	 Inhalation Exposure (Long-Term)

The current use pattern does not indicate long-term inhalation exposure
potential; therefore, this risk assessment is not required.

		3.4.10	Classification of Carcinogenic Potential 

Flutolanil is classified as “not likely to be carcinogenic to
humans”.  TC \l3 "3.5.10	Classification of Carcinogenic Potential 

		3.4.11	Summary of Toxicological Doses and Endpoints for Use in Human 

			Risk Assessments

The toxicological doses and endpoints selected for various exposure
scenarios are summarized in Table 3.4.11.



Table 3.4.11	Summary of Toxicological Doses and Endpoints for Flutolanil
for Use in Dietary and Non-Occupational Human Risk Assessments

Exposure

Scenario	

Point of Departure	

Uncertainty/

FPQA Factors 	

RfD, PAD, Level of Concern for Risk Assessment	

Study and Toxicological Effects

 Acute Dietary

(All populations)	No appropriate toxicological endpoint attributable to
a single exposure (dose) was identified from the oral toxicity studies
including developmental toxicity studies in rats and rabbits.  This risk
assessment is not required.                              

Chronic Dietary

(All populations)	

NOAEL= 50 mg/kg/day

 	UFA=10X

UFH=10X

FQPA SF = 1X

	cRfD = 

0.5 mg/kg/day

cPAD = 

0.5 mg/kg/day	2-year Chronic study in dogs.  

MRID no. 40342922

LOAEL = 250 mg/kg/day based on increased incidence  of clinical toxic
signs (emesis, salivation, and soft stool)

Incidental Oral Short- and intermediate-Terms 	No appropriate endpoint
was identified in the database for these durations of exposure.  

Dermal

 (all durations)	No appropriate endpoint was identified in the database
for this route of exposure.   

Inhalation 

 Short- and Intermediate-Terms	No appropriate endpoint was identified in
the database for these durations of exposure.   

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

Cancer (oral, dermal, inhalation)	

Classification:  “Not likely to be Carcinogenic to Humans” based on
the absence of significant tumor increases in two adequate rodent
carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  RfD = reference dose.  MOE = margin of exposure.  LOC =
level of concern.  PAD = Population adjusted dose 

	3.5	Endocrine Disruption  

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, flutolanil may
be subjected to further screening and/or testing to better characterize
effects related to endocrine disruption. 

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION tc "5.0	Dietary Exposure/Risk
Characterization" 

	4.1	Pesticide Metabolism and Environmental Degradation  tc "5.1 
Pesticide Metabolism and Environmental Degradation " \l 2 

		4.1.1	Metabolism in Primary Crops and Livestock tc "5.1.1	Metabolism
in Primary Crops " \l 3 

No plant or livestock metabolism data were submitted with the subject
petitions.  It has been previously concluded that the nature of the
residue in plants is adequately understood based on acceptable
metabolism studies in rice, cucumber leaves, and peanuts.  Flutolanil
and its metabolite M-4 (
N-(3'-hydroxyphenyl)-2-(trifluoromethyl)benzamide) were the major
residue components in plants.  The metabolites in the rotational crops
were similar to those in primary crops.  The major residue components
were flutolanil and metabolites M-4 and M-5
(N-[3',4'-(dihydroxy)phenyl]-2- (trifluoromethyl)benzamide).  The
residues of concern for tolerance expression and dietary risk assessment
for rotational crops are flutolanil and metabolites containing the
common moiety, 2-trifluoromethyl benzanilide.  

The nature of the residue in livestock is adequately understood based on
acceptable metabolism studies in goats and poultry.  HED previously
concluded that the residues of concern for tolerance expression and
dietary risk assessment in livestock commodities are flutolanil and
metabolites M-2
(N-[4'-hydroxy-3'-(1-methylethoxy)phenyl]-2-(trifluoromethyl)
benzamide), M-4, and M-7 (N-(4'-hydroxy-3'-methoxy)phenyl
-2-(trifluoromethyl)benzamide) in animal tissues, and the
glucuronide/sulfate conjugates of M-4 in milk.  As the petitioner has
proposed an enforcement analytical method that determines residues of
flutolanil and metabolites converted to 2-trifluoromethyl benzoic acid,
tolerances will be established in terms of parent plus metabolites
converted to the common moiety.

		4.1.2	Metabolism in Rotational Crops

The nature of the residue in rotational crop commodities is adequately
understood based on an acceptable confined rotational crops study with
lettuce, radish, and oat/sorghum conducted with
[U-14C-aminophenoxy]flutolanil.  The metabolites in the rotational crops
were similar to those in primary crops.  The major residue components
were flutolanil and metabolites M-4 and M-5.  

		4.1.3	Analytical Methodology  tc "5.1.4	Analytical Methodology " \l 3 

The proposed enforcement analytical method (Method AU/95R/04) is a
common moiety GC/MS method which determines residues of flutolanil and
metabolites as 2-trifluoromethyl benzoic acid (2-TFBA).  The method has
undergone a successful independent laboratory validation.  The Agency
previously concluded that the following additional data are required to
support the enforcement method AU/95R/04:  (1) additional
radiovalidation data from all previously submitted metabolism studies;
and (2) additional recovery data for potato.  In addition, because the
method is a common moiety method, a confirmatory method was required. 
These requirements do not appear to have been addressed, and the results
of the petition method validation were not available.  In addition, we
note that the method must be rewritten to include instructions for
analysis of additional crops including potatoes and rotational crops for
which tolerances are to be established.

Samples from the submitted corn and cotton rotational crop field trials
and processing study were analyzed for residues of flutolanil and its
metabolite M-4 using LC/MS/MS Method XAM-65.  The limit of quantitation
(LOQ) was 0.05 ppm for each analyte in/on all corn and cotton matrices. 
Under the current action, the petitioner has proposed Method XAM-65 as a
replacement enforcement method for Method AU/95R/04.  Method XAM-65 is
not acceptable as a data collection method and is not suitable as a
replacement for the current enforcement analytical method because it
does not determine the residues of concern in plant commodities,
flutolanil and metabolites containing the common moiety,
2-trifluoromethyl benzanilide.  Samples from the soybean and wheat
rotational crop field trials and processing study were analyzed by the
proposed enforcement method, Method AU/95R/04.  The method was adequate
for data collection based on acceptable concurrent recovery data.

Adequate multiresidue method testing data for flutolanil and metabolite
M-4 were submitted in conjunction with petitions for an experimental use
permit on rice (PP#3G4184/PP#3H5658).  Both analytes were tested through
Protocol I (corresponding to current Protocols C, E, and F) and Protocol
III (corresponding to Protocol D).  Because neither flutolanil nor M-4
was recovered through the Florisil column, no further testing was
conducted under Protocol I.  Under Protocol III (a.k.a. D), recoveries
of flutolanil were 90.2% and 90.9% at fortifications of 0.05 and 0.5
ppm, and recoveries of M-4 were 68.4% and 88.2% for M-4 at the same
fortification levels; neither analyte was recovered from spiked rice
samples at 0.05 ppm.  The multiresidue test results were forwarded to
FDA.  

		4.1.4	Drinking Water Residue Profile  tc "5.1.8	Drinking Water Residue
Profile " \l 3 

There are no established Maximum Contaminant Level for residues of
flutolanil in drinking water.  No health advisory levels for flutolanil
in drinking water have been established.  

EFED does not have monitoring data available to perform a quantitative
drinking water risk assessment for flutolanil at this time.  Ground and
surface water exposure estimates for use of flutolanil on rice were
provided by EFED (Memo from S. Abel, 12/13/1999).   Therefore, the
Agency is presently relying on computer-generated estimated
environmental concentrations (EECs).  For any given pesticide, the
SCI-GROW model generates a single EEC value of pesticide concentration
in ground water.  SCI-GROW is an empirical model based upon actual
monitoring data collected for a number of pesticides that serve as
benchmarks.  SCI-GROW is used to predict EECs in  ground water.  The
first approximation model generates a single mean concentration in
surface water for the rice paddy in the paddy water for an acute
assessment and pond water for the chronic assessment.  These models take
into account the use patterns and the environmental profile of a
pesticide, but do not consider processing of raw water for distribution
as drinking water.  The primary use of these models by the Agency at
this stage is to provide a coarse screen for assessing whether a
pesticide is likely to be present in drinking water at concentrations
which would exceed human health levels of concern.

For this risk assessment, the first approximation rice model was used to
estimate EECs in surface water.  The first approximation model is an
interim pesticide fate and transport model to account for the direct
application of pesticides to rice paddy water.  Fundamental
transformation processes (e.g., hydrolysis, metabolism, and photolysis)
are not incorporated into the model.  However, the partitioning between
the water and sediment/organic material fractions are accounted for
using a set of mathematical algorithms both in the paddy water for an
acute assessment and pond water for the chronic assessment.  Paddy water
depth is assumed to be 4 inches with a field size of 1 hectare and the
sediment-water interaction zone is 5 cm. Equilibrium is assumed to be
instantaneous between the water-sediment faction.  The release of the
paddy water is to the standard farm pond ( 1 hectare, 2 meters deep)
with subsequent partitioning between the water-sediment factions. 

Metabolism studies in water showed that flutolanil is resistant to all
modes of abiotic and biotic degradation. The residues in water are the
parent compound and M4; and the parent is the major residue. The MARC
concluded that only the parent needs be included in the drinking water
exposure assessment for flutolanil.   EFED conducted its Tier I
screening-level assessments using the simulation models SCI-GROW and
first approximation rice model to generate EECs for ground and surface
water, respectively.  The modeling was conducted based on the
environmental profile and the maximum seasonal application rate proposed
for flutolanil (0.5 lb ai/A x 2 applications/A/year on rice).  The first
approximation rice model was used to account for the direct application
of pesticides to rice paddy water.  The EECs are shown in Table 10.  

	Table 4.1.4.1:  EFED Estimated Environmental Concentrations (EECs)

	SCI-GROW1   (µg/L)2	

First Approximation Model 3   (µg/L) 2

	0.34   (acute & chronic)	

	3.75(Mean, Chronic)

1	SCI-GROW (Screening Concentration in Ground Water) is an empirical
model for predicting pesticide levels in ground water.  The value from
SCI-GROW is considered an upper bound concentration estimate.  

2	µg/L  = parts per billion.

3	First approximation model is an interim pesticide fate and transport
model to account for the direct application of pesticides to rice pond
water.  

		4.1.5	Food Residue Profile 

PP#0F6159.   The field rotational crop studies with soybeans and wheat
are adequate and are geographically representative of major production
regions of the primary crop peanuts.  Samples of treated soybean and
wheat RACs and processed commodities were stored frozen for
approximately 3 years from sampling until completion of the residue
analyses.  Supporting storage stability data are available indicating
that flutolanil residues are stable for (3 years in/on peanut
commodities

Soybean.  For soybeans planted 30 days following a soil application of
flutolanil (70% WP) at 2.0 lb ai/A (the 1x rate for peanuts),
flutolanil-derived residues were <0.05-7.4 ppm in/on soybean forage,
<0.05-1.5 ppm in/on soybean hay, and 0.10 ppm in soybean seed.  These
data support the proposed tolerances.  The soybean processing study was
conducted using seed from the NC test (1x).  Residues were <0.05 ppm in
soybean seed and hulls, meal, and refined oil, indicating that
tolerances for inadvertent residues of flutolanil are not required for
soybean processed commodities.  

Wheat.  For wheat planted 30 days following a soil application of
flutolanil (70% WP) at 2.0 lb ai/A (the 1x rate for peanuts),
flutolanil-derived residues were <0.05-1.6 ppm in/on wheat forage,
<0.05-0.47 ppm in/on wheat hay, <0.05 ppm in wheat grain, and <0.05-0.16
ppm in wheat straw.  These data support the proposed tolerances.  The
wheat processing study was conducted using grain from the OK test (1x). 
Residues were <0.05 ppm in wheat grain, germ, middlings, shorts, and
flour, and averaged 0.16 ppm in bran.  These data indicate that a
tolerance of 0.2 ppm would be appropriate for inadvertent residues in
wheat bran.

PP#6F7070.  Data depicting residues in corn ad cotton rotational crops
are classified as scientifically unacceptable.  Samples of corn and
cotton matrices were stored frozen for 7.5-8 years from harvest to
analysis.  Storage stability data are not available to support the
storage durations of the samples from the rotational crop field study.

Corn.  Residues of flutolanil and M-4 were each below the LOQ (<0.05
ppm) in/on all samples of rotated corn forage and grain. Maximum
residues of flutolanil and M-4 were 0.051 and 0.084 ppm, respectively,
for maximum combined residues of 0.134 ppm in corn fodder. In the corn
processing study, residues of flutolanil and M-4 were each below the
method LOQ (<0.05 ppm) in corn grain (RAC), processed corn starch, crude
oil, refined oil, grits (small, medium & large), coarse meal, meal, and
flour.   Because residues were below the LOQ in both the RAC and
processed commodities, processing factors could not be calculated.  No
conclusions concerning the concentration of residues in the processed
commodities of rotated corn can be made.  

Cotton.  Residues of flutolanil and M-4 were each below the LOQ (<0.05
ppm) in/on all samples of rotated cotton seed, seed lint, ginned seed,
and gin byproducts.  Residues of flutolanil and M-4 were each below the
method LOQ (<0.05 ppm) in cotton seed (RAC) and processed cotton hulls,
meal, crude oil, and refined oil.  Because residues were below the LOQ
in both the RAC and processed commodities, processing factors could not
be calculated.  No conclusions concerning the concentration of residues
in the processed commodities of rotated cotton can be made.  

		4.1.6	International Residue Limits  tc "5.2.10	International Residue
Limits " \l 3 

Codex maximum residue limits (MRLs) are established for residues of
flutolanil per se in rice commodities at 1-10 ppm, and in livestock
commodities at 0.05-0.2 ppm.  No Canadian or Mexican MRLs have been
established.

	4.2	Dietary Exposure and Risk  tc "5.2  Dietary Exposure and Risk " \l
2 

A chronic dietary exposure assessment (using tolerance-level residues
and assuming all crops are treated (100 %CT)) , and was conducted for
the general U.S. population and various population subgroups.  Exposure
to drinking water was incorporated directly into the dietary assessment
using the chronic (annual average) concentration for surface water
generated by the first approximation rice model.  This assessment
concludes that the chronic dietary exposure estimates are below HED’s
level of concern (<100% cPAD) for the general U.S. population and all
population subgroups.  The chronic dietary exposure is estimated for the
U.S. population at <1% of the cPAD and the most highly exposed
population subgroup, infants (<1 year old), at 1% of the cPAD.

Table 4.2.1:  Results of the Chronic Dietary Risk Analysis 

Population Subgroup	Chronic Dietary

	Dietary Exposure

(mg/kg/day)	% cPAD*

General U.S. Population	0.002607	<1

All Infants (< 1 year old)	0.005965	1.2

Children 1-2 years old	0.005369	1.1

Children 3-5 years old	0.004834	1.0

Children 6-12 years old	0.003358	<1

Youth 13-19 years old	0.002420	<1

Adults 20-49 years old	0.002490	<1

Adults 50+ years old	0.001640	<1

Females 13-49 years old	0.002083	<1

5.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE AND RISK 

There are non-occupational uses associated with flutolanil. 
Non-occupational handlers may mix, load and apply flutolanil products to
turf grass.  Although residential (non-occupational) exposure exists, an
assessment was not conducted since no toxicological endpoint
attributable to short- or intermediate-term route of exposure have been
identified and the current use pattern does not indicate long-term
exposure (6 or more months of continuous exposure) potential. 

6  SEQ CHAPTER \h \r 1 .0	Aggregate Risk Assessments and Risk
Characterization

In accordance with the FQPA, the Agency must consider aggregate
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, the Agency considers both the route and duration of exposure. 
In the case of flutolanil, aggregate risk assessments were performed for
chronic aggregate exposure (food + drinking water) only.  Short-, and
intermediate-term aggregate risk assessments were not performed because
toxicity form dermal and inhalation exposure was not identified. 
Additionally, the Agency does not expect residential exposure durations
that would result in long term exposures.  A cancer aggregate risk
assessment was also not performed because flutolanil is not
carcinogenic.  

The chronic aggregate risk assessment takes into account average
exposure estimates from dietary consumption of flutolanil (food and
drinking water) and residential uses.  However, due to the use patterns,
no hazard from chronic residential exposures is expected.  Therefore,
the chronic aggregate risk assessment will consider exposure from food
and drinking water only.  The chronic dietary exposure estimates for
food and drinking water are below HED’s level of concern (<100% cPAD)
for the general U.S. population (1% of the cPAD) and all population
subgroups (≤ 1).  Therefore, the chronic aggregate risk associated
with the proposed and registered uses of flutolanil does not exceed
HED’s level of concern for the general U.S. population or any
population subgroups.

7  SEQ CHAPTER \h \r 1 .0	Cumulative Risk Characterization/Assessment 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to flutolanil and any other
substances and flutolanil does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that flutolanil has a common mechanism of
toxicity with other substances. For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK "http://www.epa.gov/pesticides/cumulative/._" 
http://www.epa.gov/pesticides/cumulative/. 

8.0	Occupational Exposure/Risk Pathway

Workers may be exposed to flutolanil during mixing, loading,
application, and postapplication activities.   Based on the proposed
application rates and use scenarios, short- and intermediate-term
occupational exposures may occur.  However, since short-and
intermediate-term endpoints have not been established, an occupational
exposure assessment is not required. 

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

9.0	DATA NEEDS/LABEL REQUIREMENTS

Analytical reference standards of flutolanil and its metabolites must be
supplied and supplies replenished as requested by the Repository.  For
the expired reference standards, the petitioner must either recertify
the lot in the repository and send in an updated certificate of analysis
(COA), or submit new standards (different lot #) if the previous lots
will not be recertified.  If new COAs are being submitted, they should
be faxed to the repository at 410-305-2999.

The Agency previously concluded that the following additional data are
required to support the enforcement method AU/95R/04:  (1) additional
radiovalidation data from all previously submitted metabolism studies;
and (2) additional recovery data for potato.  In addition, because the
method is a common moiety method, a confirmatory method was required
that is able to confirm the identity and amount of all residues of
concern. These requirements do not appear to have been addressed, and
the results of the petition method validation were not available.  In
addition, we note that the method must be rewritten to include
instructions for analysis of additional crops including potatoes and
rotational crops for which tolerances are to be established.

Data deficiencies pertaining to rotated corn and cotton need be
addressed only if the petitioner intends to pursue reduced PBIs for
these commodities.

10.0 	REFERENCES

DP#:	None

Subject:	Flutolanil.  HED Metabolism Assessment Review Committee (MARC)
Meeting Held on 12-16-99.  PC Code 128975

From:	M. Xue

To:	G. Kramer

Date:	1/6/00

MRIDs:			None

DP#:	267571

Subject:	PP#6F04693/PP#6H05749, Flutolanil in/on Potatoes and Rice. 
Evaluation of Independent Laboratory Validation Data.

From:	W. Wassell

To:	M. Waller

Date:	7/21/00 

MRIDs:			44537601

DP#:	267801

Subject:	Flutolanil.  PP#0F06159:  Evaluation of Residue Chemistry Data
to Support Permanent Tolerances for Indirect or Inadvertent Residues in
Rotated Crops

From:	M. Xue

To:	L. Jones/M. Waller

Date:	11/28/01 

MRIDs:	45104001

DP#:	334156 & 335050

Subject:	Flutolanil.:  Petitions for Establishment of Tolerances for
Indirect or Inadvertent Residues in/on Corn, Cotton, Soybean, and Wheat
Commodities.  Summary of Analytical Chemistry and Residue Data

From:	F. Fort

To:	L. Jones/M. Waller

Date:	11/19/07

MRIDs:	46790801-4670803

DP#:	268880

Subject:	PP#6F4693 and PP#4F04380  Flutolanil on Rice and Potato: Human
Health Risk Assessment 

From:	A. Lowit

To:	L. Jones

Date:	09/11/00

MRIDs:			None

 

Appendix A:  Executive Summaries

A.1     Chronic oral toxicity study– dog

In a chronic oral toxicity study (MRID 40342922), flutolanil (97.5-99.8%
a.i., Lot No. NNF-136) was administered orally, by gelatin capsule, to 6
male and female beagle dogs/group at dose levels of 0, 50, 250, and 1250
mg/kg/day for 2-years.  

All dogs survived until study termination.  No treatment-related changes
in ophthalmoscopic, hematological, clinical chemistry, organ weights,
gross pathology, or histopathology parameters were observed in either
sex.  Following 65 weeks of exposure, there was a dose-related increase
in the incidence of clinical signs (emesis, salivation, and soft stool)
in both sexes at 250 and 1250 mg/kg/day, which continued until study
termination.  In addition, at 1250 mg/kg/day, decreased body weight
gains (from the 82nd week in males and from the 81st week in females)
and decreased food consumption (from the 79th week in males and from the
74th week in females) were observed.  The LOAEL was 250 mg/kg/day based
on increased incidence of clinical toxic signs (emesis, salivation, and
soft stool).  The NOAEL was 50 mg/kg/day.

This chronic study in dogs is classified acceptable (guideline), and it
satisfies the guideline requirement (870.4100b) for a chronic oral
toxicity study in a nonrodent.

A.2       21-Day dermal toxicity study – rat

In a 21-day dermal toxicity study (MRID 41841205), flutolanil (97.6 %
a.i., Lot No. 543251) in distilled water was administered dermally to 5
male and 5 female CD rats/group in 15 applications (6 hours/day, 5
days/week) over a 21-day interval at doses of 0 (vehicle control) or
1000 mg/kg/day (limit dose). No treatment-related changes in clinical
observations, dermal effects, body weights, food consumption,
hematology, clinical chemistry, organ weights, gross pathology or
histopathology parameters were observed.  The NOAEL for systemic
toxicity or dermal irritation was 1000 mg/kg/day (limit dose) and a
LOAEL was not established for systemic toxicity or dermal irritation.

This dermal study is classified acceptable (guideline), and it satisfies
the guideline requirement (870.3200) for the repeat dose dermal toxicity
study.



Table A.3.  Acute Toxicity of Flutolanil Technical1

GDLN	

Study Type	

MRID nos.	

Results	

Tox Category

§81-1	

Acute Oral	

40342905	

LD50 > 10,000 mg/kg	

IV

§81-2	

Acute Dermal	

40342906	

LD50 > 2,000 mg/kg	

III

§81-3	

Acute Inhalation	

40342910	

LC50 > 5.98 mg/L (4 hours)	

IV

§81-4	

Primary Eye  Irritation	

40342912	

Minimal irritation	

IV

§81-5 	

Primary Skin Irritation	

40342915	

Not a dermal irritant	

IV

§81-6	

Dermal Sensitization	

40342917	

Not a dermal sensitizer	

N/A

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

Table A.4. Toxicity Profile of Flutolanil Technical

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100 (82-1)

90-day Oral Toxicity Rat - diet	

40342919 (1986)/

Acceptable-Guideline/

0, 500, 4000, 20000 ppm (M: 0, 37, 299, 1512 mg/kg/d; F: 0, 44, 339,
1743 mg/kg/d)	

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

LOAEL =  not established 

At 1512  mg/kg/day (HDT): increased absolute liver weights (males), 
increased relative liver weights (males and females), slight decrease in
body weights (males) and slight increases in absolute and relative
thyroid/parathyroid weights were observed.  No treatment-related changes
in ophthalmoscopic, hematological, clinical chemistry, gross pathology,
or histopathology parameters were observed.  Therefore, the increased
liver weights are considered to be an adaptive response to flutolanil
treatment.

870.3150 (82-1)

90-day Oral Toxicity In Nonrodents (Dog) - gelatin capsule	

40342920 (1986)/ Acceptable-Guideline/ 0, 80, 400, 2000 mg/kg/d	

NOAEL = 80 mg/kg/day,

LOAEL = 400 mg/kg/day based on enlarged livers and increased severity of
hepatic glycogen deposition in both males and females.

At 2000 mg/kg/day (HDT), an elevation in alkaline phosphatase and
cholesterol levels and slight increases in absolute and relative
thyroid/parathyroid weights were observed

870.3200 (82-2)

21-day Dermal Toxicity - Rat	

41841205 (1991)/ Acceptable-Guideline/ 0, 1000 mg/kg/d	

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

Systemic LOAEL > 1000 mg/kg/day.

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

Dermal irritation > 1000 mg/kg/day.

870.3250

90-day Dermal Toxicity	

Not available	

Not available

870.3465

90-day Inhalation Toxicity	

Not available	

Not available

870.3700a(83-3a)

Prenatal Developmental In Rat - oral gavage	

41850804(1987)/ Acceptable-Guideline/0, 40, 200, 1000 mg/kg/d	

Maternal NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day, 

Developmental NOAEL= 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

870.3700b(83-3b)

Prenatal Developmental In Rabbit - oral gavage 	

40342924(1987)/ Acceptable-Guideline/ 0,40,200,1000 mg/kg/d	

Maternal NOAEL= 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day, 

Developmental NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

870.3800(83-4)

Reproduction And Fertility Effects In Rat - 2 Generation - diet	

41850805(1992)/ Acceptable-Guideline/ 0,200,2000,20000 ppm

(M: 0,16,159,1625 mg/kg/d;

F: 0,19,190,1936 mg/kg/d)	

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

LOAEL > 1000 mg/kg/day, 

Reproductive NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

Offspring NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

870.3800(83-4)

Reproduction And Fertility Effects In Rat - 3 Generation - diet	

40342923(1982)/ Unacceptable/ 0, 1000, 10000 ppm (M: 0, 63, 661 mg/kg/d;
F: 0, 86, 880 mg/kg/d)	

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

LOAEL > 661 mg/kg/day, 

Reproductive NOAEL = 661 mg/kg/day,

LOAEL > 661 mg/kg/day.

870.4100a

Chronic Toxicity Rodents	

See combined chronic / carcinogenicity study available (see below)	

 

870.4100b (83-1)

Chronic Toxicity Dogs- gelatin capsule	

40342922(1982)/ Acceptable-Guideline/ 0, 50, 250, 1250 mg/kg/d	

NOAEL = 50 mg/kg/day,

LOAEL = 250 mg/kg/day based on increased incidence of clinical toxic
signs (emesis, salivation, and soft stool) observed from the 65th week. 

At 1250 mg/kg/day (HDT), increased incidence of clinical toxic signs
(from the 65th week), decreased body weight gains (from 82nd week in
males and from 81st week in females) and decreased food consumption
(from 79th week in males and from 74th week in females) were observed.  

No treatment-related changes in ophthalmoscopic, hematological, clinical
chemistry, organ weights, gross pathology, or histopathology parameters
were observed.  

870.4100a & 870.4200

 (83-1 & 83-5)

Chronic/ Oncogenicity Rats - diet	

40342921 (1982)/ Acceptable-Guideline/ 

0, 40, 200, 2000, 10000 ppm 

(M: 0, 2, 9, 87, 460 mg/kg/d F: 0, 2, 10, 103, 536 mg/kg/d) 	

NOAEL = 460 mg/kg/day,

LOAEL = not established 

At 460 mg/kg/day (HDT), increased absolute and relative liver weights
(males and females) were observed in the absence of clinical chemistry
or histopathology findings.  Therefore, the increased liver weights are
considered to be an adaptive response to flutolanil treatment.

870.4300(83-2)

Carcinogenicity Mice - diet	

41850803(1990)/ Acceptable-Guideline/ 0, 300, 1500, 7000, 30000 ppm (M:
0,32,162,735,3333 mg/kg/d; F: 0, 34, 168, 839, 3676 mg/kg/d)	

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

LOAEL = 3333 (M) and 839 (F) mg/kg/day based on decreased body weight
gains.

Gene Mutation

870.5375 (84-2), In vitro Chromosomal Aberration Assay in Cultured
Mammalian Cell 	

40342925(1986)/ Acceptable-Guideline/0, 37, 75, 150 uM/plate 	

Positive finding, flutolanil induced chromosomal aberrations in cultured
Chinese hamster lung cells in the presence of metabolic activation (S9).

Gene Mutation  870.5100 (84-2), Reverse Mutation Assay	

40342926(1981)/  Acceptable-Guideline/0, 10, 50, 100, 500, 1000, 5000,
10000, 25000 ug/plate.	

Negative (with and without S-9 metabolic activator) at doses up to 25
mg/plate in the increase in revertant colonies using Salmonella strains
TA98, TA10, TA1535, TA1537, and TA1538 and in the E. Coli WP2 uvrA
strain.

Gene Mutation  870.5375 (84-2), Gene Mutation in Cultured Mammalian
Cells (Mouse Lymphoma Cells) 	

41841207(1989)/ Acceptable-Guideline/0,  6, 15, 30, 60, 80, 100 ug/mL.	

Negative (either in the presence or absence of S9 activation) for the
induction of forward mutations at the TK+/- locus in L5178Y mouse
lymphoma cells.

Cytogenetics 

870.5395 (84-2), Mouse Micronucleus	

40342927(1983)/ Acceptable-Guideline/0, 6400, 8000, 10000 mg/kg either
in a single dose or 10 gm/kg/day over 4 days by gastric intubation to
BDF1 mice (6/sex/group).	

Negative up to a dose of 10000 mg/kg in the induction of micronuclei in
the bone marrow erythrocytes of male and female mice.

Cytogenetics  870.5385 (84-2), Mammalian Cells in Culture Cytogenetics
Assay in Human Lymphocytes	

42606628(1990)/ Acceptable-Guideline/0, 120, 250, 500, 1000 ug/mL.	

Negative in the structural chromosome assay.  There was no significant
increase in the frequency of aberrations with any treatment levels,
either with or without activation. 

Other Genotoxicity Effects  84-2,  In Vitro Unscheduled DNA Synthesis
Assays in Primary Rat Hepatocytes	

41841206(1989)/ Acceptable- Nonguideline/0,  2.67, 27, 53, 80 ug/mL.  	

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870.6200a

Acute Neurotoxicity Screening Battery	

Not available

	

Not available

870.6200b

Subchronic Neurotoxicity Screening Battery	

Not available	

Not available

870.6300

Developmental Neurotoxicity	

Not available	

Not available

870.7485

Metabolism And Pharmacokinetics -Rat	

42606602(1992)/ Acceptable-Guideline/ single oral dose of 20 and 1000
mg/kg and

repeated oral doses of 20 mg/kg for 14 days 	

No appreciable tissue levels of flutolanil at study termination (168
hours post-dose). 

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

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

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

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

Fecal metabolite by TLC:  Mainly parent chemical with limited conversion
to M-4.

870.7600

Dermal penetration - Rat	

Not available	

Not available

Special Studies	

Not available	

Not available

Appendix B:  Chemical Structures  

 

APPENDIX B.	Chemical Names and Structures of Flutolanil and
Metabolites.  

Common name;

Company code	Chemical name	Chemical structure

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

M-2 	N-[4'-hydroxy-3'-(1-methylethoxy)phenyl]-2-(trifluoromethyl)
benzamide	

M-3 	N-[3'-(2-hydroxy-1-methylethoxy)
phenyl]-2-(trifluoromethyl)benzamide	

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

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

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

M-7 	N-(4'-hydroxy-3'-methoxy)phenyl -2-(trifluoromethyl)benzamide	

M-11 	2-[[3-[2-(trifluoromethyl)benzoyl]-amino]phenoxy]propanoic acid	

2-TFBA: 	2-trifluoromethyl benzoate	

Tolerances to be established under “(d) Indirect or inadvertent
residues”:

Soybean, forage	8.0 ppm

Soybean, hay	2.5 ppm

Soybean, seed	0.20 ppm

Wheat, forage	2.5 ppm 

Wheat, grain	0.05 ppm

Wheat, hay	1.2 ppm

Wheat, straw	0.20 ppm

Wheat, bran	0.20 ppm

	  PAGE  6  of   NUMPAGES  28