 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

Date:	07-August-2008	

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

PC Code:  128975	DP Barcode:  349580

MRID No.:  None	Registration No.: None

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

Assessment Type:  None	Reregistration Case No.:  None

TXR No.:  None

	

FROM:	Myron S. Ottley, Pharmacologist

		Barry O’Keefe, Senior Biologist

		Amelia Acierto, Chemist

		Registration Action Branch 3

		Health Effects Division (7509P)

		Office of Pesticide Programs

THRU:	Paula Deschamp, Branch Chief

		Registration Action Branch 3

		Health Effects Division (7509P)

		Office of Pesticide Programs

TO:	Tom Myers / Jill Bloom (RM-52

		Reregistration Branch 2

		Special Review and Reregistration Division (7508P)

		Office of Pesticide Programs

Executive Summary

Flutolanil [N-[3-(1-methylethoxy)-phenyl]-2-(trifluoromethyl)-benzamide]
is a systemic benzanilide fungicide which has preventative and curative
actions against Rhizoctonia solani, which causes limb/pod rot in
peanuts, sheath blight in rice, and black scurf in potatoes.  Flutolanil
is also effective in controlling Southern stem rot (white mold)
Sclerotium rolfsii in peanuts and rust diseases of several crops.

Flutolanil is currently registered for food and non-food uses.  Food
uses include application to wheat, soybean, peanut, potato, and rice. 
Tolerances are also established for ruminant byproducts and other organ
meats.  Non-food uses of flutolanil include turf, greenhouse, and potted
ornamentals. 

The acute, subchronic and chronic toxicity of flutolanil is generally
low, producing low toxicity at moderate to high dose levels.  An acute
dietary endpoint was not identified for flutolanil.  A chronic dietary
endpoint was identified based on a chronic dog study, with the chronic
RfD set at 0.50 mg/kg/day based on an increased incidence of clinical
signs (NOAEL = 50 mg/kg/day) at the LOAEL of 250 mg/kg/day.  Uncertainty
factors (including FQPA) totaled 100. Endpoints were not identified for
incidental oral, dermal or inhalation exposure. Flutolanil is considered
to be non-carcinogenic.  The chronic dietary exposure estimates for food
and drinking water do not exceed the Agency’s level of concern for the
general U.S. population (<1% of the population adjusted dose (PAD) and
all population subgroups (< 1% PAD).

The HED Flutolanil Registration Review Team has evaluated the most
recent human health assessments and database for the fungicide
flutolanil, supporting several Section 3 registered products and Section
24C registrations by Nichino America, Inc. (formerly Nihon Nohyaku), to
determine the scope of work necessary to support the Registration Review
process. The most recent human health assessment (November 2007), which
addressed requests for inadvertent or indirect tolerances for use on
soybean, wheat, corn and cotton adequately reflects current
registrations and uses of flutolanil, current Food Quality Protection
Act (FQPA) policies, and adequately addresses susceptibility of infants
and children, and aggregate exposures.  For a complete listing of the
registrations, please see the Attachments section.

Introduction  

The HED Flutolanil Registration Review Team has evaluated the human
health assessments for the fungicide flutolanil to determine the scope
of work necessary to support the Registration Review.  A comprehensive
listing of the documents considered is presented in the reference
section of this document. The purpose of this screen is to determine
whether sufficient data are available and whether a new human health
risk assessment is needed to support continued registration. The HED
Risk Assessment team is Myron Ottley, Barry O’Keefe, and Amelia M.
Acierto.

The HED registration review team contacted the Pesticide Management
Regulatory Agency (PMRA) of Canada, and the California Department of
Pesticide Regulation (CalDPR) to determine if they are actively working
on the active ingredient flutolanil, or are planning on doing so in the
near future.  The team has learned that flutolanil has never been
registered in Canada and therefore not subject to re-evaluation.
Flutolanil has been placed in the low priority category for risk
assessment by CalDPR, and they do not expect to conduct any risk
assessment unless there are some significant changes in the established
use patterns.  Additionally, the HED registration review team accessed
the OECD monograph document repository.  An OECD Monograph was completed
for flutolanil in May 2006.  Flutolanil is authorized for use on various
crops in Belgium, Finland, France, Great Britain, Netherlands, and Spain

No new data germane to risk assessment of flutolanil were available from
the open literature.  The primary sources for the status update were the
risk assessments on the registered uses in peanut, potato and rice (F.
Fort, D334156, D335050, 11/26/07). The molecular structure, chemical
names, and other identifiers are found in the chemical identity table
attached to this document.

Flutolanil is currently registered for food and non-food uses.  Food
uses include broadcast foliar applications and/or in-furrow applications
to soybean, wheat, peanuts, potatoes, and rice.  Flutolanil is also used
as a tree bark dust application – Non-food uses include turf,
greenhouse, and potted ornamentals.  The currently registered uses of
flutolanil will result in exposures in food and drinking water. 
Residential uses of flutolanil can result in dermal, inhalation, and
incidental oral exposures.  Occupational uses will result in exposures
via the dermal and inhalation routes.

Hazard Identification/Toxicology

Overall, the quality of the toxicology data base for flutolanil is good
and confidence in the hazard and dose response assessments is high.  At
the time of the last human health risk assessment (11/26/07), the
toxicology data base was deemed to be complete, adequate to support
existing and proposed registrations, and there were no data gaps.  No
new data have been submitted since then; however, acute and subchronic
neurotoxicity studies and an immunotoxicity study are now required under
the revised 40 CFR §158.340.  For more detailed information about the
toxicology of flutolanil, please refer to the Hazard Identification
Assessment Review Committee Report (HIARC report dated 11/2/99; TXR No.
013851).

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. Acute
toxicity data show 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.

Subchronic and chronic toxicity studies showed that the primary effects
of flutolanil are increases in liver weight combined with decreases in
body weight.  The available data for flutolanil do not show neurotoxic,
carcinogenic, nor mutagenic effects.  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.

The FQPA Safety Factor for flutolanil was reduced to 1X because there
was no increased sensitivity to fetuses as compared to maternal animals
in the developmental rat and rabbit studies and no increased sensitivity
to pups as compared to adults in a multi-generation reproduction study
in rats.

Only a chronic dietary endpoint was identified for flutolanil (Table 4).
  HED selected a chronic RfD/PAD of 0.50 mg/kg/day (NOAEL = 50
mg/kg/day; Uncertainty Factor = 100).  This chronic RfD/PAD is based on
the chronic oral toxicity study in dogs in which increased incidences of
clinical signs (emesis, salivation, and soft stool) occurred at LOAEL =
250 mg/kg/day following 65 weeks of exposure.

Dietary Exposure

 conducted using the Dietary Exposure Evaluation Model, DEEM-FCID™,
Version 2.03, which uses food consumption data from the U.S. Department
of Agriculture’s Continuing Surveys of Food Intakes from 1994-1996 and
1998. An acute exposure assessment for flutolanil was not performed
since an appropriate endpoint attributable to a single oral dose was not
established. 

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) in the
memorandum: “Flutolanil Tier II Estimated Environmental Concentration
for Use in the Human Health Drinking Water Risk Assessment” (D260066,
S. Abel, 12/13/99).  The surface water and groundwater, estimated
drinking water concentrations (EDWCs) were generated from PRZM/EXAMS and
from Tier I SCI-GROW analysis, respectively. The inputs and assumptions
used to generate the EDWCs for flutolanil adequately cover the currently
registered use patterns. The water residues were incorporated directly
in the DEEM-FCID into the food categories “water, direct, all
sources” and “water, indirect, all sources.”

The chronic dietary assessments for food and drinking water demonstrated
that exposures for the general population and all population subgroups
were less than 1% of the population adjusted dose. These assessments are
considered conservative as they were conducted assuming tolerance level
residues and 100% crop treated.

Residential Exposure

There are non-occupational/residential uses associated with flutolanil. 
Registered products include several for use on turf grass and potted
ornamentals which, if not specifically prohibited through label
directions could be used in a residential/public site.  However,
although such potential residential handler and post-application
exposures exist, assessments were not conducted because no dermal, oral
(incidental), or inhalation toxicological endpoints attributable to
short- or intermediate-term exposures have been identified, and the
current use patterns do not indicate long-term exposure (6 or more
months of continuous exposure) potential.  Therefore, there is currently
adequate information to support non-occupational/residential uses of
flutolanil.  However, should HED identify new regulatory endpoints for
risk assessment purposes for flutolanil in the future, then
non-occupational/residential exposures may need to be assessed.

Aggregate Risk Assessment

Aggregate risk assessments for flutolanil were performed for chronic
aggregate exposure (food + drinking water) only.  Short- and
intermediate-term aggregate risk assessments were not performed because
toxicological endpoints from dermal, inhalation, and incidental oral
exposures were 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) 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
registered uses of flutolanil does not exceed HED’s level of concern
for the general U.S. population or any population subgroups. Should HED
identify new regulatory endpoints for risk assessment purposes, revise
the current safety factors for flutolanil, or update the dietary
assessment, a new aggregate risk assessment may need to be conducted.

Occupational Exposure

Occupational handlers may be exposed to flutolanil during mixing,
loading, and application of products containing flutolanil. 
Additionally, workers may be exposed to flutolanil residues during
postapplication activities.  Based on the proposed application rates and
use scenarios, short- and intermediate-term occupational exposures may
occur.  However, assessments of exposures and risks were not conducted
because no dermal or inhalation toxicological endpoints attributable to
short- or intermediate-term exposures have been identified, and the
current use patterns do not indicate long-term exposure potential. 
Therefore, there is currently adequate information to support
occupational uses of flutolanil.  However, should HED identify new
regulatory endpoints for risk assessment purposes for flutolanil in the
future, then occupational exposures may needed to be assessed.

Public Health and Pesticide Epidemiology Data

A summary report listing incidents reported to EPA for flutolanil will
be provided for the docket.  The reported incidents will be screened in
more detail during the development of the Final Work Plan for
flutolanil.

Tolerance Assessment

Tolerances have been established in 40 CFR§180.484 for residues of
flutolanil and its metabolites converted to 2-trifluoromethyl)benzoic
acid (calculated as flutolanil) in/on plant and livestock commodities.

International Harmonization

Codex Maximum Residue Limits (MRLs) for flutalonil and transformation
products containing the 2-trifluoromethyl-benzoic acid moiety, expressed
as flotolanil, are established in rice commodities at 1 to 10 ppm, and
in livestock commodities at 0.05 to 0.2 ppm.  

The US tolerances for both plant and livestock commodities are expressed
as flutolanil, N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethy)benzamide,
and its metabolites converted to 2-(trifluoromethyl) benzoic acid and
calculated as flutolanil.  These US tolerance, for rice, peanuts and
potatoes, are listed under 40 CFR §180.484(a) at 0.2 – 25.0 ppm, and
for soybean and wheat, are listed under 40 CFR §180.484(d) at 0.05 –
8.0 ppm.  US 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.  

The US and Codex residue definitions for livestock commodities both
include flutolanil and its metabolites converted to 2-(trifluoromethyl)
benzoic acid and calculated as flutolanil; however, there are
quantitative differences in the US tolerance levels and Codex MRLs.  In
the case of plant commodities, the US and Codex residue definitions as
well as US tolerance levels and Codes MRLs are different.  Future work
is needed to achieve harmonization in this area.    For a complete
listing of US Tolerances and Codex MRLs, please refer to Table 5 in the
Attachments section.

No Canadian or Mexican MRLs have been established.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pd
f" 
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf
.  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 may 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

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

Human Studies

Flutolanil risk assessments rely in part on data from studies in which
adult human subjects were intentionally exposed to a pesticide or other
chemical.  These studies have been determined to require a review of
their ethical conduct, and have received that review. 

Data Requirements

Toxicology  

The revised Toxicology Data Requirements for Conventional Pesticides [40
CFR §158.340] now include studies which are better able to detect
toxicities that are outside the scope of standard subchronic and chronic
assays.  These new studies are:

   Acute neurotoxicity  [OPPTS Guideline 870.6200a]

   Subchronic neurotoxicity  [OPPTS Guideline 870.6200b]

   Immunotoxicity  [OPPTS Guideline 870.7800]

For a more complete rationale on these data requirements, please see
Tables 6 and 7.

Chemistry

The availability of the analytical reference standards for flutolanil
and its metabolites has been verified and reported in 2007 to be either
“not in stock” or “have expired” (D335050, F. Fort, 11/26/2007).
 An updated inventory from the National Pesticide Standard Repository
(e-mail, Dallas Wright, EPA, Analytical Chemistry Laboratory,
08/14/2008) showed that the analytical standards for flutolanil [with
expiration date of 10/27/2011] and flutolanil metabolite,
2-trifluoromethyl benzoic acid metabolites [which expired 8/12/2008] are
available.  Standards for metabolites M-2 and M-4 are still not in
stock, and standards for metabolites M-3 and M-7 [which expired on
1/1/04 and 4/1/02, respectively] have not been replenished nor
recertified (updated Certificate of Analysis).  Therefore, the
requirements for standards have not been satisfied.

The Agency previously concluded that the following additional data are
required to support the enforcement method AU/95R/04:  (1) additional
radio validation 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.

References

Author	Barcode	Date	Title

M. Xue	D261391	12/10/1999	PP# 6F4693 & PP#4F4380. Flutolanil in/on
Potatoes and Rice. Memo to the Metabolism Assessment Review Committee
(MARC)

W. Wassell	D267571	7/21/2000	PP6F4693/PP6H5749.  Flutolanil in/on
Potatoes and Rice. Evaluation of Independent Laboratory Valiation Data.

M. Xue	D265019	7/24/2000	Reevaluation of Chronic Dietary Exposure
Analyses for Proposed Tolerances for Flutolanil in/on Rice, Potatoes and
Potato Processed Commodities. (PC Code 128975.

M. Xue	D267657	8/2/2000	PP# 6F4693 & PP#6H5749.. Flutolanil in/on
Potatoes and Rice.  Review of Storage Stability and Magnitude of Residue
Data for Rice. 

A. Lowit,

J. Arthur

M. Bonner

M. Xue	D268880	9/11/2000	Residential uses of flutolanil include turf,
greenhouse, and potted ornamentals 



M. Xue 	D226667, D226670,D247229	12/1/2000	PP# 6F4693 & PP#6H5749..
Flutolanil in/on Potatoes, Potato Processed Commodities, Rice Grain and
Rice Straw.  Evaluation of Analytical Methods and Residue Data. 

M. Xue	D278457	11/28/2001	ID#071711-00008, Flutolanil: Label Amendment
for Rotational Crop Plantback Intervals for Corn, Soybeans, Cotton and
Sorghum.

F. Fort	D346322	11/1/2007	Flutolanil Chronic Aggregate Dietary (Food and
Drinking Water) Exposure and Risk Assessment for the Section 3
Registration Action.

F. Fort	D335050	11/26/2007	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.  PRIA R17.  PP#0F6159 (Soybean and Wheat) and PP6F7070
(Corn and Cotton).

W.Wassell	D277210	11/7/2001	WA010016; Special Local Needs Registration
(24c) for the use of Flutolanil on Potatoes.  Review of residue Data for
Potatoes.

ATTACHMENTS

2-trifluoromethylbenzoic acid (2-TFBA)



Table 2.	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

	

Table  3.	Chemical Names and Structures of Flutolanil and Metabolites. 


Common name;





Table 4	Summary of Toxicological Doses and Endpoints for Flutolanil for
Use in Dietary and Non-Occupational Human Risk Assessments



Exposure

Scenario	

Point of Departure	

Uncer-tainty/

FQPA Factors 	

RfD, PAD, Level of Concern for Risk Assess-ment	

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 

Table 5.  Summary of US and International Tolerances and Maximum Residue
Limits 

US	Canada	Mexico	Codex

Residue Definition:

40CFR180.484 (a)

 flutolanil, N -(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide,
and its metabolites converted to 2-(trifluoromethyl) benzoic acid and
calculated as flutolanil .	None	None	For plant commodities, flutolanil.

For animal commodities, flutolanil and transformation products
containing the 2-trifluoromethyl-benzoic acid moiety, expressed as
flutolanil.

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

Commodity	US	Canada	Mexico	Codex

Cattle, fat	0.10	None	None

	Cattle, kidney	1.00

	0.1

Cattle, liver	2.00

	0.2

Cattle, meat byproducts	0.05



	Cattle, meat	0.05

	0.05 (*)

Egg	0.05

	0.05 (*)

Goat, fat	0.10



	Goat, kidney	1.00

	0.1

Goat, liver	2.00

	0.2

Goat, meat byproducts	0.05



	Goat, meat	0.05

	0.05 (*)

Hog, fat	0.10



	Hog, kidney	1.00

	0.1

Hog, liver	2.00

	0.2

Hog, meat byproducts	0.05



	Hog, meat	0.05

	0.05 (*)

Horse, fat	0.10



	Horse, kidney	1.00



	Horse, liver	2.00



	Horse, meat byproducts	0.05



	Horse, meat	0.05

	0.05 (*)

Milk	0.05

	0.05 (*)

Peanut	0.5



	Peanut, hay	15.0



	Peanut, meal	1.0



	Potato	0.20



	Potato, wet peel	0.30



	Poultry, fat	0.05



	Poultry, meat	0.05

	0.05 (*)

Poultry, meat byproducts	0.05

	0.05 (*)

Rice, bran	10.0

	10 (unprocessed)

Rice, grain	7.0

	2 husked

1 polished

Rice, hulls	25.0



	Rice, straw	10.0

	10

Sheep, fat	0.10



	Sheep, kidney	1.00

	0.1

Sheep, liver	2.00

	0.2

Sheep, meat	0.05

	0.05 (*)

Sheep, meat byproducts	0.05



	Residue Definition:

40CFR180.484 (d)

indirect or inadvertent residues of the fungicide flutolanil, N
-(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide, and its
metabolites converted to 2-(trifluoromethyl) benzoic acid and calculated
as flutolanil

None	None	None

Soybean, forage	8.0



	Soybean, hay	2.5



	Soybean, seed	0.20



	Wheat, bran	0.20



	Wheat, forage	2.5



	Wheat, grain	0.05



	Wheat, hay	1.2



	Wheat, straw	0.20



	

* = absent at the limit of quantitation.



				Data Call-In Tables

Table 6.

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  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 may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.  



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. Since 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 flutolanil poses either a greater
or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for flutolanil may need to be revised
to reflect the magnitude of potential risk derived from the new data.

 

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



Table 7.

Guideline Number:  870.6200

Study Title:  Neurotoxicity Screening Battery

Rationale for Requiring the Data

Acute and subchronic neurotoxicity studies with flutolanil were not
conducted, flutolanil showed no indication of neurotoxicity in the
provided studies and there was no evidence of neurotoxicity in open
literature searches, however, the submitted studies did not examine
neurotoxicity endpoints.  These data are now required under the revised
CFR 158.340.



Practical Utility of the Data

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

For many chemicals, the amount of toxicity data that is available for
flutolanil would be considered to be a complete toxicity database.  In
fact, the Agency was able to select doses and endpoints for conducting a
risk assessment from the available studies. However,the existing
toxicity database for flutolanil does not include any neurotoxicity
studies.  None of the submitted studies measured neurotoxicity
endpoints.  In the absence of any such data, there is uncertainty about
the neurotoxicity potential of flutolanil.

How will the data be used?

After the review and evaluation of the acute and subchronic
neurotoxicity studies, it is possible that the Agency could choose a
dose and endpoint from either the acute or subchronic neurotoxicity
study that is appropriate for the deriving the acute RfD.

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

If a dose can be selected for the acute RfD from the new data, then a
flutolanil acute dietary risk assessment would need to be conducted. At
present there were no effects observed in oral toxicity studies
including developmental toxicity studies in rats or rabbits that could
be attributable to a single dose (exposure).  The risk would then be
identified for the acute RfD. 

Existing Registrationsfor Flutolanil

Section 3 :

	EPA Reg Nos.: 

Bayer Environmental Science

432-1222	Prostar 50WP.  Contains 50.3% flutolanil.  Labeled for the
control of brown patch, fairy ring, red thread/pink patch,
yellow/patch/Southern blight, gray snow mold, and large brown patch on
turf.

432-1223	Prostar 70 WP. Contains70% flutolanil.  Labeled for control of
brown patch, fairy ring, red thread/pink patch, yellow/patch/Southern
blight, gray snow mold, and large brown patch on turf, various fungal
diseases of greenhouse, container, and nursery grown ornamentals. 

432-1403	Prostar 1.5G.  Contains 1.5% flutolanil, with fertilizer. 
Labeled for control of brown patch on turf.

432-1440	Sysstar WDG.  Contains 51.42% flutolanil and 28.6%
thiophanate-methyl.  Labeled for control of multiple fungal diseases of
turf and ornamentals.

432-1477	Prostar 70 WDG Fungicide.  Contains 70% flutolanil.  Labeled
for control of multiple fungal diseases of turf and ornamentals.  

Gowan Company

10163-247	Flutolanil Technical.  Contains 98.3% flutolanil.  For
formulation only.

Nichino America, Inc.

71711-1	Moncut® 70 WP (70% ai) registered for control of Southern stem
rot (white mold) caused by Sclerotium rolfsii and limb/pod rot complex
caused by Rhizoctonia solani in peanuts, and for control of sheath
blight caused by Rhizoctonia solani in rice.  The existing label for
rotational crops states that corn, soybean, or cotton may be planted 240
days or more following the last application of Moncut 70WP to peanuts;
soybean or grain sorghum may be planted 240 days or more following last
application to rice.  

	71711-2	Moncut CL Flowable fungicide.  Contains 38.6% chlorothalonil
and 10.3% flutolanil.   Designed for use on peanuts, under conditions
which favor the development of diseases caused by fungi which attack
both the crop canopy and structures beneath the soil surface (roots,
pegs, and pods).

71711-3	Moncut® 50WP (50% ai) registered for use on peanuts and rice. 
The same use as EPA Reg. No. 71711-1.  For control of Southern stem rot
(white mold) caused by Sclerotium rolfsii and limb/pod rot complex
caused by Rhizoctonia solani in peanuts; for control of sheath blight
caused by Rhizoctonia solani in rice; and for control of clack scurf
caused by Rhizoctonia solani in peanuts.

71711-5	Flutolanil Technical.  Contains 98.3% flutolanil.  For
formulation only.

	71711-8	Moncoat® MZ—a coformulation containing 1.5% flutolanil and
6% mancozeb in a tree bark based formulation.  MonCoat MZ is to be used
as an integral part of a potato disease management strategy for the
suppression of Black scurf and Rhizoctonia stem canker (Rhizoctonia
solani), Fusarium dry rot (Fusarium sambucinum, F. coeruleum), and
Silver scarf (Helminthosporium solani) on potato seed pieces.  Use for
potato seed treatment @ 0.75 – 1.0 lb product/100 lb seed. (<0.25 lb
ai/A). 

71711-14	Moncut®70-DF (70% DF formulation) used for on peanut, rice and
potato ( Not for use on peanuts and rice in California). as broadcast
foliar 2 lb ai/A in forrow application.  For control of Southern stem
rot (white mold) caused by Sclerotium rolfsii and limb/pod rot complex
caused by Rhizoctonia solani in peanuts; for control of sheath blight
caused by Rhizoctonia solani in rice; and for control of clack scurf
caused by Rhizoctonia solani in potatoes.

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containing 3 lb flutolanil and 0.6 lb propiconazole per gallon.  For use
on peanuts.

71711-24	NAI-301, 4SE fungicide (Alternate name fro Artisan Trifecrs)
containing 17.2% flutolanil, 1.8% propiconazole and 21.65%
chlorothalonil. Used for the control of early and late leaf spot disease
as well as control of whit mold (Southern blight) caused by Sclerotium
rolfsii and limb rot caused by Rizoctonia solani.

71711-28	Flutolanil 40SC Fungicide.  Contains 40% flutolanil. 
Registered 5/2/08; labeled for control of fungal diseases of peanut and
potato (in-furrow and seed-piece treatments).

Section 24(c) 

		ID040008

ID080003

NV020006

		WA010016	

		WA040032   

Page   PAGE  1  of   NUMPAGES  18 

