Document ID: EPA-HQ-OPP-2009-0184-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-03-19T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		16-DEC-2009

SUBJECT:	Flutriafol.  REVISED Human-Health Risk Assessment for Proposed
Uses on Apple and Soybean.

PC Code:  128940	DP Barcode:  D372347

Decision No.:  377412	Registration No.:  67760-TL, 4787-LL

Petition No.:  7F7197	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical/Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  76674-21-0

MRID No.:  NA	40 CFR:  §180.629

FROM:	Kelly M. Lowe, Environmental Scientist

Thomas Bloem, Chemist

William Greear, M.P.H., D.A.B.T., Toxicologist

Robert Mitkus, Ph.D., D.A.B.T., Toxicologist

Risk Assessment Branch 1 (RAB1) 

Health Effects Division (HED) (7509P)

Gregory Akerman, Ph.D., Toxicologist 

Elizabeth Mendez, Ph.D., Toxicologist

Toxicology and Epidemiology Branch (TEB), HED (7509P)

		

THRU:	Dana M. Vogel, Branch Chief

		George F. Kramer, Ph.D., Senior Chemist

RAB1, HED (7509P)

Jess Rowland, Toxicologist

Dennis McNeilly, Chemist

Risk Assessment Review Committee (RARC) Secondary Review

TO:		Mary Waller, Risk Manager 21

		Registration Division (RD; 7505P)

Note:  This document supersedes the previous flutriafol human-health
risk assessment (Memo, 01-JUN-2009, K. Lowe, et al., D353078).

Under Section 3 of the Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA), as amended, Cheminova has requested registration of the
fungicide flutriafol.  The HED of the Office of Pesticide Programs (OPP)
is charged with estimating the risk to human health from exposure to
pesticides.  The RD of OPP has requested that HED evaluate hazard and
exposure data and conduct dietary, occupational, residential, and
aggregate exposure assessments, as needed, to estimate the risk to human
health that will result from the proposed uses of flutriafol in/on apple
and soybean. 

A summary of the findings and an assessment of human-health risk
resulting from the proposed and registered uses of flutriafol are
provided in this document.  The residue chemistry review and
dietary-exposure assessment was provided by Thomas Bloem (RAB1); the
hazard and dose-response assessment was provided by William Greear
(RAB1), Gregory Akerman (TEB), Elizabeth Mendez (TEB) and Robert Mitkus
(RAB1); the occupational/residential exposure assessment and the risk
assessment were provided by Kelly Lowe (RAB1); and the drinking water
assessment was provided by Lucy Shanaman of the Environmental Fate and
Effects Division (EFED).

Table of Contents

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc248563584"  1.0	Executive
Summary	  PAGEREF _Toc248563584 \h  5  

  HYPERLINK \l "_Toc248563585"  2.0	Ingredient Profile	  PAGEREF
_Toc248563585 \h  10  

  HYPERLINK \l "_Toc248563586"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc248563586 \h  10  

  HYPERLINK \l "_Toc248563587"  2.2	Structure and Nomenclature	  PAGEREF
_Toc248563587 \h  12  

  HYPERLINK \l "_Toc248563588"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc248563588 \h  12  

  HYPERLINK \l "_Toc248563589"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc248563589 \h  12  

  HYPERLINK \l "_Toc248563590"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc248563590 \h  12  

  HYPERLINK \l "_Toc248563591"  3.1.1	Database Summary	  PAGEREF
_Toc248563591 \h  12  

  HYPERLINK \l "_Toc248563592"  3.1.1.1	Studies Available and Considered
(Animal, Human, General Literature)	  PAGEREF _Toc248563592 \h  12  

  HYPERLINK \l "_Toc248563593"  3.1.1.2	Mode of Pesticidal Action	 
PAGEREF _Toc248563593 \h  13  

  HYPERLINK \l "_Toc248563594"  3.1.1.3	Sufficiency of Studies/Data	 
PAGEREF _Toc248563594 \h  13  

  HYPERLINK \l "_Toc248563595"  3.1.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc248563595 \h  13  

  HYPERLINK \l "_Toc248563596"  3.1.3	Hazard and Dose-Response
Characterization	  PAGEREF _Toc248563596 \h  13  

  HYPERLINK \l "_Toc248563597"  3.1.4	Developmental and Reproductive
Toxicity	  PAGEREF _Toc248563597 \h  14  

  HYPERLINK \l "_Toc248563598"  3.1.5	Evidence of Neurotoxicity	 
PAGEREF _Toc248563598 \h  14  

  HYPERLINK \l "_Toc248563599"  3.1.6	Immunotoxicity	  PAGEREF
_Toc248563599 \h  15  

  HYPERLINK \l "_Toc248563600"  3.1.7	Additional Information from
Literature Sources	  PAGEREF _Toc248563600 \h  15  

  HYPERLINK \l "_Toc248563601"  3.2	Dose-Response	  PAGEREF
_Toc248563601 \h  15  

  HYPERLINK \l "_Toc248563602"  3.3	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc248563602 \h  15  

  HYPERLINK \l "_Toc248563603"  3.3.1	Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc248563603 \h  15  

  HYPERLINK \l "_Toc248563604"  3.3.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc248563604 \h  16  

  HYPERLINK \l "_Toc248563605"  3.3.3	Chronic Reference Dose (cRfD) –
General Population	  PAGEREF _Toc248563605 \h  16  

  HYPERLINK \l "_Toc248563606"  3.3.4	Dermal Absorption	  PAGEREF
_Toc248563606 \h  17  

  HYPERLINK \l "_Toc248563607"  3.3.5	Dermal Exposure (Short-,
Intermediate-Term)	  PAGEREF _Toc248563607 \h  17  

  HYPERLINK \l "_Toc248563608"  3.3.6	Inhalation Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc248563608 \h  17  

  HYPERLINK \l "_Toc248563609"  3.3.7	Long-term (>6 Months) Dermal and
Inhalation	  PAGEREF _Toc248563609 \h  18  

  HYPERLINK \l "_Toc248563610"  3.3.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc248563610 \h  18  

  HYPERLINK \l "_Toc248563611"  3.4	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc248563611 \h  18  

  HYPERLINK \l "_Toc248563612"  3.5	Determination of Susceptibility	 
PAGEREF _Toc248563612 \h  18  

  HYPERLINK \l "_Toc248563613"  3.5.1	Degree-of-Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility	 
PAGEREF _Toc248563613 \h  19  

  HYPERLINK \l "_Toc248563614"  3.5.2	Recommendation for a DNT Study	 
PAGEREF _Toc248563614 \h  19  

  HYPERLINK \l "_Toc248563615"  3.6	FQPA Considerations	  PAGEREF
_Toc248563615 \h  19  

  HYPERLINK \l "_Toc248563616"  3.7	Classification of Carcinogenic
Potential	  PAGEREF _Toc248563616 \h  20  

  HYPERLINK \l "_Toc248563617"  3.8	Summary of Toxicological Doses and
Endpoints for Flutriafol for Use in Human Risk Assessments	  PAGEREF
_Toc248563617 \h  20  

  HYPERLINK \l "_Toc248563618"  3.9	Endocrine Disruption	  PAGEREF
_Toc248563618 \h  21  

  HYPERLINK \l "_Toc248563619"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc248563619 \h  22  

  HYPERLINK \l "_Toc248563620"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc248563620 \h  22  

  HYPERLINK \l "_Toc248563621"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc248563621 \h  22  

  HYPERLINK \l "_Toc248563622"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc248563622 \h  22  

  HYPERLINK \l "_Toc248563623"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc248563623 \h  22  

  HYPERLINK \l "_Toc248563624"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc248563624 \h  23  

  HYPERLINK \l "_Toc248563625"  5.1.4	Analytical Methodology	  PAGEREF
_Toc248563625 \h  23  

  HYPERLINK \l "_Toc248563626"  5.1.5	Environmental Degradation	 
PAGEREF _Toc248563626 \h  24  

  HYPERLINK \l "_Toc248563627"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc248563627 \h  25  

  HYPERLINK \l "_Toc248563628"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc248563628 \h  25  

  HYPERLINK \l "_Toc248563629"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc248563629 \h  25  

  HYPERLINK \l "_Toc248563630"  5.1.9	Drinking Water Residue Profile	 
PAGEREF _Toc248563630 \h  27  

  HYPERLINK \l "_Toc248563631"  5.1.10	Food Residue Profile	  PAGEREF
_Toc248563631 \h  28  

  HYPERLINK \l "_Toc248563632"  5.1.11	International Residue Limits	 
PAGEREF _Toc248563632 \h  31  

  HYPERLINK \l "_Toc248563633"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc248563633 \h  31  

  HYPERLINK \l "_Toc248563634"  5.2.1	Acute Dietary Risk
Characterization	  PAGEREF _Toc248563634 \h  32  

  HYPERLINK \l "_Toc248563635"  5.2.2	Chronic Dietary Risk
Characterization	  PAGEREF _Toc248563635 \h  32  

  HYPERLINK \l "_Toc248563636"  6.0	Residential (Non-Occupational) Risk	
 PAGEREF _Toc248563636 \h  33  

  HYPERLINK \l "_Toc248563637"  7.0	Aggregate Risk Assessments	  PAGEREF
_Toc248563637 \h  33  

  HYPERLINK \l "_Toc248563638"  7.1	Acute and Chronic Aggregate Risk	 
PAGEREF _Toc248563638 \h  34  

  HYPERLINK \l "_Toc248563639"  8.0	Cumulative Risk Characterization	 
PAGEREF _Toc248563639 \h  34  

  HYPERLINK \l "_Toc248563640"  9.0	Occupational Risk Assessment	 
PAGEREF _Toc248563640 \h  34  

  HYPERLINK \l "_Toc248563641"  9.1	Occupational Handler Risk Assessment
  PAGEREF _Toc248563641 \h  35  

  HYPERLINK \l "_Toc248563642"  9.2	Occupational Post-application
Exposure	  PAGEREF _Toc248563642 \h  38  

  HYPERLINK \l "_Toc248563643"  9.3	REI	  PAGEREF _Toc248563643 \h  40  

  HYPERLINK \l "_Toc248563644"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc248563644 \h  40  

  HYPERLINK \l "_Toc248563645"  Appendix A:	Toxicology Assessment	 
PAGEREF _Toc248563645 \h  42  

  HYPERLINK \l "_Toc248563646"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc248563646 \h  42  

  HYPERLINK \l "_Toc248563647"  A.2.	Toxicity Profiles	  PAGEREF
_Toc248563647 \h  43  

  HYPERLINK \l "_Toc248563648"  A.3.	Executive Summaries	  PAGEREF
_Toc248563648 \h  51  

  HYPERLINK \l "_Toc248563649"  Appendix B.	Metabolism Assessment	 
PAGEREF _Toc248563649 \h  72  

  HYPERLINK \l "_Toc248563650"  Appendix C.	Tolerance Summary Table	 
PAGEREF _Toc248563650 \h  86  

  HYPERLINK \l "_Toc248563651"  Appendix D:	Chemical Name and Structure
Table	  PAGEREF _Toc248563651 \h  87  

 1.0	Executive Summary

Flutriafol
((±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethano
l) is a systemic, triazole fungicide that can be used as a systemic
eradicant and a protectant.  It has a post-infection activity that can
stop pathogen establishment in the early phases of disease development. 
There are no Section 3 uses or permanent tolerances currently
established for flutriafol.  Furthermore, there are no registered or
proposed uses of flutriafol that would result in residential exposure. 
The last HED risk assessment for flutriafol was performed in 2006 (Memo,
J. Tyler, D319153, 3/30/2006) for a Section 18 Emergency Exemption for
use on soybean (time-limited tolerance of 0.1 ppm; 40 CFR 180.629).  

Proposed Uses

For the current action, Cheminova proposes new food/feed uses of
flutriafol on apples and soybeans.  The application rate is 0.11 pounds
(lb) active ingredient (ai)/acre (A) for both apples and soybeans.  The
maximum seasonal use rate is 0.63 lb ai/A for apples and 0.23 lb ai/A
for soybeans.  The specified minimum retreatment interval (RTI) for
apples is 7-14 days and for soybeans is 14-35 days.  The pre-harvest
interval (PHI) for apples is 14 days and for soybeans is 21 days.  Based
on the proposed uses, dietary and occupational exposures are expected.  

Hazard Characterization

Flutriafol has low acute oral toxicity and low acute inhalation
toxicity.  There is no acceptable acute dermal toxicity study in the
database; however, a 28-day dermal toxicity study did not reveal any
signs of toxicity at the limit dose (1000 mg/kg/day).  Therefore, based
on this study, flutriafol is classified in Category II for acute
toxicity.  Flutriafol is minimally irritating to the eyes (Toxicity
Category III) and is not a dermal irritant (Toxicity Category IV). 
Flutriafol was not shown to be a skin sensitizer when tested in guinea
pigs.

Flutriafol appears to be generally equally toxic to rats, mice, and dogs
with all three species having similar (within one order of magnitude)
no-observed adverse-effect levels (NOAELs)/lowest-observed
adverse-effect levels (LOAELs).  The target organ is the liver in dogs,
rats, and mice.  Hepatotoxicity occurred at similar dose levels across
several species and durations of exposure.  Flutriafol is considered to
be “Not likely to be Carcinogenic to Humans” based on the results of
the carcinogenicity studies in rats and mice.  The results of the rat
chronic toxicity/carcinogenicity study and the mouse carcinogenicity
study are negative for carcinogenicity.  All genotoxicity studies on
flutriafol showed no evidence of clastogenicity or mutagenicity.  

The potential impact of in utero and perinatal flutriafol exposure was
investigated in three developmental toxicity studies (two in rats, one
in rabbits) and a multigeneration reproduction toxicity study in rats. 
Only one of the rat developmental toxicity studies was acceptable.  In
the acceptable rat developmental study, a qualitative susceptibility was
noted.  Although developmental toxicity occurred at the same dose level
that elicited maternal toxicity, the developmental effects were more
severe than those observed in the dams.  For rabbits, intrauterine
deaths occurred at a dose level that also caused adverse effects in
maternal animals.  Similar to what was seen in the developmental study
in rats, offspring effects occurred at the same dose level as parental
effects in the multi-generation toxicity study in rats.  However, the
nature of the effects in the offspring was more severe than in the dams.
 Clear NOAELs were observed in all of these studies.  Signs of
neurotoxicity were reported in the acute and subchronic neurotoxicity
studies at the highest dose only; however, these effects were primarily
seen in animals that were agonal (at the point of death) and, thus are
not indicative of neurotoxicity.  In addition, there was no evidence of
neurotoxicity in any additional short-term studies in rats, mice, and
dogs, or in the long-term toxicity studies in rats, mice, and dogs.  A
developmental-neurotoxicity (DNT) study is not required.

An in vivo rat dermal-absorption study is available for flutriafol that
is acceptable and indicates that the absorption is 17%, 21%, and 11%,
respectively, at 2, 20, and 200 µg/cm2, following a 10-hour exposure. 
A conservative dermal-absorption value of 21% absorption is considered
appropriate for dermal risk assessments.  There is an absence of
systemic toxicity at 1000 mg/kg/day in the 28-day dermal toxicity study
in the rat.

  

Food Quality Protection Act (FQPA)

The flutriafol risk assessment team recommends that the 10X FQPA Safety
Factor (SF) be reduced to 1X since the toxicology database is complete,
there are no residual uncertainties for pre and/or post natal toxicity,
and the conservative nature of the dietary exposure analysis (i.e.,
tolerance-level residues and 100% crop treated; no residential uses).  

Dose-Response Assessment

The acute dietary points of departure for child-bearing females (13+
years old) was based on the prenatal developmental toxicity study in
rabbits, where the LOAEL was 15 mg/kg/day [based on decreased number of
live fetuses, complete litter resorptions and increased
post-implantation loss] and the NOAEL was 7.5 mg/kg/day.  An uncertainty
factor (UF) of 100X (10-fold for interspecies extrapolation and 10-fold
for intra-species variability) was applied to the NOAEL of 7.5 mg/kg/day
to derive the acute reference (aRfD) dose for child-bearing females (13+
years old).  The FQPA SF of 1X is applicable for acute dietary risk
assessment for females 13+ years old.  Therefore, the acute
population-adjusted dose (aPAD) for females 13+ years old is 0.075
mg/kg/day.  

The acute dietary point of departure for the general population was
based on the acute neurotoxicity screening battery in the rat, where the
LOAEL was 750 mg/kg/day (based on decreased body weight, body-weight
gain, absolute and relative food consumption, and clinical signs of
toxicity in both sexes: dehydration, urine-stained abdominal fur,
ungroomed coat, ptosis, decreased motor activity, prostration, limp
muscle tone, muscle flaccidity, hypothermia, hunched posture, impaired
or lost righting reflex, scant feces; in males: red or tan perioral
substance, chromodacryorrhea, chromorhinorrhea and labored breathing,
and in females:  piloerection and bradypnea) and the NOAEL was 250
mg/kg/day.  An UF of 100X (10-fold for interspecies extrapolation and
10-fold for intra-species variability) was applied to the NOAEL of 250
mg/kg/day to derive the aRfD.  The FQPA SF of 1X is applicable for acute
dietary risk assessment.  Therefore, the aPAD for the general population
is 2.5 mg/kg/day.  

The chronic dietary point of departure for the general population was
based on the chronic toxicity study in dogs, where the LOAEL was 20
mg/kg/day (based on adverse liver findings (increased liver weights,
increased centrilobular hepatocyte lipid in the liver, and increases in
alkaline phosphatase, albumin, and triglycerides), increased adrenal
cortical vacuolation of the zona fasciculata, and marked hemosiderin
pigmentation in the liver and spleen in both sexes; mild anemia
(characterized by decreased hemoglobin, hematocrit, and red blood cell
count) in the males; and initial body weight losses, decreased
cumulative body-weight gains, and increased adrenal weights in the
females) and the NOAEL was 5 mg/kg/day.  An UF of 100X (10-fold for
interspecies extrapolation and 10-fold for intraspecies variability) was
applied to the NOAEL of 5 mg/kg/day to derive the chronic reference dose
(cRfD).  The FQPA SF of 1X is applicable for chronic dietary risk
assessment.  Therefore, the chronic population-adjusted dose (cPAD) for
the general population is 0.05 mg/kg/day.

Points of departure for short- and intermediate-term dermal and
inhalation risk assessments were based on the prenatal developmental
toxicity study in rabbits, where the LOAEL was 15 mg/kg/day and the
NOAEL was 7.5 mg/kg/day.  Points of departure for long-term dermal and
inhalation risk assessments were not selected since exposures of these
durations are not expected based on the use pattern.  Since oral studies
were selected for the dermal exposure assessment, a dermal-absorption
factor of 21% (based on an in vivo rat dermal-absorption study) was
used.  Inhalation toxicity is assumed to be equivalent to oral toxicity.
 HED’s level of concern (LOC) for flutriafol occupational and
residential dermal and inhalation exposures is 100 (i.e., a margin of
exposure (MOE) greater than 100 is not of concern to HED).  The LOC is
based on a 10X UF to account for inter-species extrapolation to humans
from the animal test species and 10X UF to account for intra-species
sensitivity.

Environmental Fate and Drinking Water Assessment

Flutriafol is a triazole fungicide and 1,2,4-triazole (T), which forms
as a minor degradate of flutriafol, is a common degradate of conazole
pesticides.  T is not included in this assessment, but has been
addressed in a separate assessment (EFED memo; D320682, I. Maher,
28-Feb-2006).  The drinking water assessment for the parent is a Tier I,
screening-level drinking water assessment using the Screening
Concentration in Ground Water (SCI-GROW) and FQPA Index Reservoir
Screening Tool (FIRST) models with the maximum application rate for
apples.  Flutriafol is expected to be persistent and moderately mobile
in the environment, with its major routes of dissipation through biotic
degradation in aquatic environmental compartments.  Flutriafol is
expected to degrade with a half-life of more than one year in
terrestrial biotic environments.  This persistence indicates that
flutriafol does have the potential to build up in the soil as a result
of application over multiple consecutive years.  Maximum aquatic
concentrations expected from the proposed new uses are acute exposure of
48.8 ppb in surface water, chronic exposure of 5.7 ppb in surface water,
and 4.8 ppb for both acute and chronic exposure to groundwater.  The
surface water estimates were used in the dietary risk analysis.

Dietary Risk

, version 2.03) model, and assumed tolerance-level residues, 100%
crop treated (CT), and DEEM version 7.81 default processing factors. 
Drinking water was included in the dietary assessments.  

The acute (food + water) exposure risk estimate for females 13-49 years
old was 3.7% aPAD at the 95th percentile of the exposure distribution,
and is not of concern to HED.  The acute (food + water) exposure
estimates were <100% aPAD for the U.S. general population (<1.0% aPAD)
and all population sub-groups; the most highly exposed population
subgroup was infants (<1 year old) with <1.0% aPAD.  Therefore, acute
dietary exposure to flutriafol is not of concern to HED. 

The chronic (food + water) exposure estimates were <100% cPAD for the
U.S. general population (1.0% cPAD) and all population sub-groups; the
most highly exposed population subgroup was children 1-2 years old with
4.6% cPAD.  Therefore, chronic dietary exposure to flutriafol is not of
concern to HED. 

Since the annual application rate for flutriafol is ≤0.63 lb ai/acre
and since all environmental degradates were identified at <10% total
radioactive residue (TRR), a revised drinking water assessment is
unnecessary.  

Residential Risk

As there are no registered or proposed uses of flutriafol that would
result in residential exposure, a residential exposure assessment was
not conducted.

Aggregate Risk

Acute and chronic aggregate risks are assessed based on dietary exposure
from food and drinking water sources and are the same as reported for
acute and chronic dietary exposure.  Therefore, acute and chronic
aggregate risks to flutriafol are not of concern to HED.  As there are
no registered or proposed uses of flutriafol that would result in
residential exposure, short- and intermediate-term aggregate risks were
not assessed.

Occupational Handler Risk

Based on the proposed uses on soybeans and apples, handlers may be
potentially exposed to flutriafol.  Handlers include mixer/loaders who
handle concentrated liquid flutriafol and applicators using aerial or
groundboom equipment, and flaggers for aerial applications.  Short- and
intermediate-term dermal and inhalation risks were assessed with a
baseline layer of clothing, and with additional personal-protective
equipment (PPE).  Chemical-specific data were not available; therefore,
surrogate data from the Pesticide Handlers Exposure Database (PHED) were
used.  The combined dermal and inhalation exposure risks for
mixer/loaders are not of concern [i.e., MOEs>100], provided the
mixer/loaders wear protective gloves as directed on the label.  For
aerial applicators, risks were assessed using engineering controls
(enclosed cockpits) and baseline attire (long-sleeve shirt, long pants,
shoes, and socks); pilots are not required to wear protective gloves. 
With this level of protection, there are no risks of concern for aerial
applicators.  With baseline attire, there are also no risks of concern
for groundboom applicators and for flaggers.

 

Occupational Post-application Risk

Following flutriafol application to soybean and apples, occupational
post-application exposure is possible.  Post-application activities may
include scouting, maneuvering irrigation equipment, hand weeding, and
hand harvesting.  Risks are not of concern (i.e., MOE>100) on day 0
(restricted-entry interval (REI) = 12 hours) for all of the exposure
activities.  Based on the acute toxicity of flutriafol, the REI should
be set at 24 hours (i.e., Category II for acute dermal).   

Environmental Justice Considerations  

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human-health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"
(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pd
f).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under Continuing Surveys
of Food Intakes by Individuals (CSFII) and are used in pesticide risk
assessments for all registered food uses of a pesticide.  These data are
analyzed and categorized by subgroups based on age, season of the year,
ethnic group, and region of the country.  Additionally, OPP is able to
assess dietary exposure to smaller, specialized subgroups and exposure
assessments are performed when conditions or circumstances warrant. 
Whenever appropriate, non-dietary exposures based on home use of
pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
post-application are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  The database listed below has been determined to require a
review of its ethical conduct.  It has received the appropriate review. 
It was concluded it does not violate current ethical standards.

Studies reviewed for ethical conduct:  The PHED Task Force, 1995.  The
Pesticide Handlers Exposure Database, Version 1.1.  Task Force members
Health Canada, U.S. Environmental Protection Agency, and the National
Agricultural Chemicals Association, released February, 1995.

Regulatory Recommendations 

Provided Revised Sections B and F are submitted and the petitioner
submits flutriafol per se analytical standards to the Analytical
Chemistry Laboratory (ACL), HED concludes that the toxicological,
residue chemistry, and occupational/residential databases are sufficient
to support a conditional registration for application of flutriafol to
apple and soybean.  

(±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethanol
]:  apple - 0.20 ppm, soybean, seed - 0.35 ppm; grain, aspirated
fractions - 2.2 ppm; cattle, liver - 0.02 ppm; goat, liver - 0.02 ppm;
hog, liver - 0.02 ppm; horse, liver - 0.02 ppm; and sheep, liver - 0.02
ppm.  

Data Gaps

Toxicology:  

As part of the new 40 CFR revised Part 158 requirement, an
immunotoxicity study is required.  

Chemistry:

Information concerning the storage conditions/interval for the samples
collected from the ruminant metabolism study; if the storage intervals
were >6 months, then data demonstrating the stability of the metabolic
profile in the various matrices will be required.  

Submission of storage stability data demonstrating the stability of T,
TA, and TAA in the soybean matrices for the employed intervals (soybean
seed - 16 months; soybean meal, hull, and oil - 12 months).

Storage stability data for flutriafol, T, TA, and TAA in ruminant liver
(139 days).

Occupational and Residential Exposure

Change the REI on the proposed label from 12 hours to 24 hours.

2.0	Ingredient Profile

Flutriafol is a contact and systemic Group 3 triazole fungicide which
acts primarily as an inhibitor of ergosterol biosynthesis, thereby
interfering with synthesis of fungal cell membranes.  In the U.S., there
is currently only a soybean Section 18 Emergency Exemption and a
corresponding time-limited soybean tolerance (set to expire December
2010) for residues of flutriafol per se at 0.10 ppm (40 CFR 180.629; 2 x
0.057 lb ai/acre; RTI = 18-20 days; PHI = 21 days).  Flutriafol is sold
in about 40 countries for use on such crops as grapes, stone fruit, pome
fruit, cereals, oilseed rape, table and sugar beets, bananas, and
soybeans.  

Aside from a Section 18 Emergency Exemption for use on soybeans, there
are currently no food/feed uses for flutriafol in the U.S.  

2.1	Summary of Proposed Uses

.04 lb ai/gal suspension-concentrate (SC) formulation (Topguard™
Fungicide, EPA File Symbol No. 67760-###; 12-hour REI; equivalent to a
flowable-concentrate (FlC)).  The label recommends application of
flutriafol to apple for control of scab (Venturia inaequalis) and
powdery mildew (Podosphaera leucotricha) and to soybean for control of
rust (Phakospora pachyrizi), Frogeye Leaf Spot (Cercospora sojina),
Cercospora Blight and Leaf Spot (Cercospora kikuchii), Brown Spot
(Septoria glycines), and Powdery Mildew (Microsphaera diffusa).  For
apple scab resistance management, the label recommends that flutriafol
be tank-mixed with a protectant fungicide and notes that soybean spray
solutions may be tank mixed with other approved fungicides, herbicides,
or insecticides (no tank mix partners are specified).  The label does
not include any rotational crop restrictions and prohibits application
through irrigation equipment.  

The submitted use directions are sufficient to allow evaluation of the
residue data relative to the proposed use.  The petitioner should
resolve the discrepancy between the use pattern listed for soybeans in
Section B (proposed maximum seasonal rate is stated to be 0.18 lb
ai/acre in the text and 0.21 lb ai/acre in the table) and the use
pattern listed on the draft label (proposed maximum seasonal rate of
0.23 lb ai/acre); the submitted soybean field trial data will support a
maximum seasonal rate of 0.23 lb ai/acre.  A revised Section B with the
following changes is requested:  (1) the proposed minimum apple RTI of 7
days for apples is not supported by the crop field trial data; the use
directions should be revised to specify a minimum apple RTI of 14 days;
(2) the apple use directions should be amended to specify a minimum
spray volume of >20 GPA (gallons per acre); (3) since the soybean and
apple field trials did not include an adjuvant, the label should be
revised prohibiting the addition of adjuvants to the spray solutions;
(4) the soybean use directions should be limited to the application to
soybeans harvested for the dried seed; and (5) the label should indicate
that only soybean may be rotated to a treated field.  A revised Section
B should be submitted.

Table 2.1 summarizes the proposed use pattern and formulation specified
in the end-use product containing flutriafol.

Table 2.1.  Summary of Directions for Use of Flutriafol.

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

Apple

Foliar, Broadcast, Equipment not specified	1.04 lb/gal  FlC

[67760-###]	0.07-0.11	6	0.63	14	Applications are to be initiated at
green tip or when environmental conditions are favorable for primary
scab development.  RTI = 7-14 days.

Soybean

Foliar, Broadcast, Ground or aerial	1.04 lb/gal FlC

e using ground (≥10 gal/acre) or aerial (≥5 gal/acre) equipment. 
Feeding/grazing soybean forage/hay is prohibited.

2.2	Structure and Nomenclature

Common name	Flutriafol

Company experimental name	PP450 (ICI/Syngenta until 2001)

IUPAC name
(RS)-2,4’-difluoro-α-(1H-1,2,4-triazol-1-ylmethyl)benzhydryl alcohol

CAS name
(±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethanol

CAS registry number	76674-21-0

End-use product (EP)	1.04 lb ai/gal FlC formulation (Topguard™
Fungicide, EPA File Symbol No. 67760-XXX)

Physical and Chemical Properties 

Table 2.3.  Physicochemical Properties of Flutriafol.

Melting point/range	--	Not available

pH	6.1 in a 1% aqueous dilution	CSF for Flutriafol Technical dated
3/23/07

Density	0.99 g/cm3

	Water solubility	95 mg/L at 20 ºC	PP#7F7197 administrative materials

Solvent solubility	At 21 ºC	g/L

1,2-Dichloroethane	19-20

Acetone	116-135

Ethyl acetate	29-34

Methanol	115-134

n-Heptane	<10

Xylene	<10

	Vapor pressure	4 x 10-7 Pa at 20 ºC

	Dissociation constant, pKa	2.3 at 25 ºC

	Octanol/water partition coefficient, Log(KOW)	log POW = 2.3 at 20 ºC

	UV/visible absorption spectrum	--	Not available

3.0	Hazard Characterization/Assessment

3.1	Hazard and Dose-Response Characterization 

3.1.1	Database Summary

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

Acute toxicity – one each of oral, dermal, eye irritation, dermal
irritation, skin sensitization studies on the technical (80% a.i.)

Subchronic toxicity – one 28-day dermal toxicity in rat, one oral
90-day rat, one oral 90-day dog

Chronic toxicity - one chronic oral dog, one chronic
toxicity/carcinogenicity rat, one carcinogenicity mouse

Reproductive/developmental toxicity – two oral developmental rat, one
oral developmental rabbit, one rat fertility/reproduction

Neurotoxicity – one acute neurotoxicity rat, one subchronic
neurotoxicity rat

Mutagenicity- in vitro bacterial gene mutation, in vitro mouse lymphoma
gene mutation, in vitro mammalian cytogenetics (chromosomal aberration
assay human lymphocytes), in vitro mammalian cytogenetics (chromosomal
aberration assay in rat bone marrow), erythrocyte micronucleus assay in
mice, dominant lethal study, unscheduled DNA synthesis (UDS)

3.1.1.2	Mode of Pesticidal Action

Flutriafol is a member of the conazole triazole class of pesticides. 
The triazole fungicides inhibit one specific enzyme, C14-demethylase,
which plays a role in sterol production.  Sterols, such as ergosterol,
are needed for fungal membrane structure and function, making them
essential for the development of functional cell walls.  

3.1.1.3	Sufficiency of Studies/Data

The toxicity database is complete for flutriafol for risk assessment
evaluations and determination of the FQPA SFs.  The acute dermal study
was unacceptable; however, since there is an acceptable 28-day dermal
study with no systemic effects seen up to the limit dose, there is no
acute concern.  Therefore, a new acute dermal study is not needed.  

Note that while the new 40 CFR revised Part 158 requirement for an
immunotoxicity study has not yet been fulfilled, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under FQPA.

3.1.2	Absorption, Distribution, Metabolism, Excretion (ADME)

Flutriafol is quickly absorbed, extensively metabolized, and quickly
eliminated (within 48 hours) regardless of sex, dose, or whether
exposure was to single or multiple dosing regimens.  More than 78% of
the dose was recovered in the bile and urine.  In the blood,
radioactivity partitioned into the red blood cells.  In both sexes and
all groups, concentrations of radioactivity were relatively high in
whole blood, liver, and kidneys.  Other organs with high concentrations
included the adrenal glands, spleen, and pituitary.  The total amount of
radioactivity isolated in the tissues and carcass was <1-3%. 
Bioaccumulation was considered unlikely.  The parent was isolated in
only trace amounts in the urine and feces and more than 19 metabolites
were isolated, indicating extensive metabolism.  The primary site for
metabolism was the 2-fluorophenyl ring.  The initial metabolic step was
epoxidation followed by rearrangement to form either the dihydrodiol
isomers or the hydroxy or dihydroxy metabolites.  The hydroxyl groups on
these primary metabolites may then be either conjugated with glucuronic
acid or methylated.  A second, minor route for metabolism of flutriafol
was via the removal of the triazole ring to form 1-(2
fluorophenyl)-1-(4-fluorophenyl)-ethandiol, which is then conjugated
with glucuronic acid. 

3.1.3	Hazard and Dose-Response Characterization

Flutriafol appears to be generally equally toxic to rats, mice, and dogs
with all three species having similar (within one order of magnitude)
NOAELs/LOAELs.  The target organ is the liver in dogs, rats, and mice. 
Hepatotoxicity occurred at similar dose levels across several species
and durations of exposure.  Flutriafol has low acute toxicity via the
oral and inhalation routes (Toxicity Category III and IV, respectively)
in rats.  There is no acceptable acute dermal toxicity study in the
database.  However, a 28-day dermal-toxicity study did not reveal any
signs of toxicity at the limit dose (1000 mg/kg/day).  Thus, flutriafol
is not considered to be acutely toxic via the dermal route.  Flutriafol
is minimally irritating to the eyes (Toxicity Category III) and is not a
dermal irritant (Toxicity Category IV).  Flutriafol was not shown to be
a skin sensitizer when tested in guinea pigs (Buehler method).  

The pattern of toxicity attributed to flutriafol exposure via the oral
route includes hepatotoxicity, developmental toxicity (manifested as
increased intrauterine death) and generalized toxicity (body
weight/body-weight gains and food consumption decrements as well as
slight anemia). 

Short-term, subchronic, and chronic toxicity studies in rats, mice, and
dogs identified the liver as the primary target organ of flutriafol. 
Hepatotoxicity was first evident in the subchronic studies (rats and
dogs) in the form of increases in liver enzymes (alkaline phosphatase),
liver weights, and histopathology findings ranging from hepatocyte
vacuolation to centrilobular hypertrophy and slight increases in
hemosiderin-laden Kupffer cells.  It is noteworthy that with chronic
exposures, there are no indications of progression of liver toxicity in
either species.  After over one year of exposure, hepatotoxicity in
rats, dogs, and mice took the form of (1) minimal to severe fatty
change; (2) bile duct proliferation/cholangiolarfibrosis; (3)
hemosiderin accumulation in Kupffer cells; (4) centrilobular
hypertrophy, and (5) increases in alkaline phosphatase.  Neither the
chronic/carcinogenicity study in rats or the carcinogenicity study in
mice revealed treatment-related increases in tumor incidences.

Slight indications of effects in the hematopoietic system are
sporadically seen in the database.  These effects are manifested in the
form of slight anemia (rats and dogs) and increased platelet, white
blood cell, neutrophil, and lymphocyte counts (mice).  These effects,
however, were minimal in severity.

3.1.4	Developmental and Reproductive Toxicity

The potential impact of in utero and perinatal flutriafol exposure was
investigated in three developmental toxicity studies (two in rats, one
in rabbits) and a multigeneration reproduction toxicity study in rats. 
Only one of the rat developmental toxicity studies was acceptable.  In
the acceptable rat developmental study, a qualitative susceptibility was
noted.  Although developmental toxicity occurred at the same dose level
that elicited maternal toxicity, the developmental effects (external,
visceral, and skeletal malformations; embryo lethality, skeletal
variations, a generalized delay in fetal development and fewer live
fetuses) were more severe than the decreased food consumption and
body-weight gains observed in the dams.  For rabbits, intrauterine
deaths occurred at a dose level that also caused adverse effects in
maternal animals. In the two-generation reproduction study, a
qualitative susceptibility was seen. Effects in the offspring (decreased
litter size and percentage of live births and liver toxicity) can be
attributed to the systemic toxicity of the parental animals (decreased
body weight and food consumption and liver toxicity).

3.1.5	Evidence of Neurotoxicity

Effects that may be considered signs of neurotoxicity (decreased motor
activity and hindlimb grip strength, ptosis, lost righting reflex,
hunched posture, ataxia) were reported in the acute and subchronic
neurotoxicity studies at the highest dose only.  These effects, however,
were primarily seen in animals that were agonal (at the point of death)
and, thus are not indicative of neurotoxicity.  This conclusion is
further reinforced by the observation that there was no evidence of
neurotoxicity in any additional short-term studies in rats, mice, and
dogs, or in the long-term toxicity studies in rats, mice, and dogs.  It
is important to note that in the acute neurotoxicity study, for animals
that did not die in the study or were sacrificed in extremis, all
effects resolved by Day 8.

3.1.6	Immunotoxicity

There was no evidence of toxicity to the immune organs at the LOAEL in
any study in the database.  In addition, flutriafol does not belong to a
class of chemicals (e.g., the organotins, heavy metals, or halogenated
aromatic hydrocarbons) that would be expected to be immunotoxic.  Based
on the above considerations, HED does not believe that conducting a
special series 870.7800 immunotoxicity study will result in a point of
departure less than the cRfD NOAEL of 5 mg/kg/day for flutriafol;
therefore, an additional UF for database uncertainties (UFDB) does not
need to be applied.  Note that while the new 40 CFR revised Part 158
requirement for an immunotoxicity study has not yet been fulfilled, the
existing data are sufficient for endpoint selection for exposure/risk
assessment scenarios and for evaluation of the requirements under FQPA. 
Further, the data requirements pertaining to immunotoxicity (see Section
10.1) should be fulfilled as a condition of registration.

3.1.7	Additional Information from Literature Sources

A literature search, conducted on TOXLINE, did not reveal any other
additional relevant information beyond what was included in the studies
that were submitted by the registrant.  

3.2	Dose-Response

The critical effects for flutriafol exposure via the oral route are
hepatotoxicity, developmental toxicity (manifested as increased
intrauterine death) in the presence of maternal toxicity, and
generalized toxicity (body weight/body-weight gains and food consumption
decrements as well as slight anemia).  Hepatotoxicity, the primary toxic
effect for this compound, was seen in all species tested with the first
indications occurring after subchronic exposure, with LOAELs for this
toxicity ranging from 15-20 mg/kg/day in dogs (subchronic and chronic
exposures, respectively) to 200 mg/kg/day in rats.  In general, duration
of exposure does not seem to exacerbate toxicity as evidenced by the
fact that the NOAELs/LOAELs for subchronic and chronic exposure are very
similar and the nature and severity of effects does not appear to worsen
with time.

3.3	Hazard Identification and Toxicity Endpoint Selection

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
3.8.  See text below for rationales.

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

Study Selected:  Prenatal Developmental Toxicity Study - Rabbit 
870.3700b

Dose/Endpoint for Establishing the aRfD:  The aRfD for females, age
13-49, was established based on the LOAEL from the developmental
toxicity study in rabbits.  The LOAEL of 15 mg/kg is based on decreased
number of live fetuses, complete litter resorptions and increased
post-implantation loss.  The NOAEL was 7.5 mg/kg.

aRfD   =   7.5 mg/kg (NOAEL)   =   0.075 mg/kg

                                                   100 (UF) 

Comments:  The NOAEL selected provides the lowest NOAEL from any
toxicity study in the flutriafol database in which a toxic response
could be the outcome of 1-2 days of dosing.  UFs for inter-species
extrapolation (10X) and intra-species variation (10X) were retained for
a total UF of 100. 

3.3.2	Acute Reference Dose (aRfD) - General Population

Study Selected:  Acute Neurotoxicity Study			870.6200a

Dose/Endpoint for Establishing the aRfD:  The aRfD for the general
population was established based on the LOAEL from the acute
neurotoxicity screening battery in the rat.  The LOAEL of 750 mg/kg is
based on decreased body weight, body-weight gain, absolute and relative
food consumption, agonal effects in both sexes (dehydration,
urine-stained abdominal fur, ungroomed coat, ptosis, decreased motor
activity, prostration, limp muscle tone, muscle flaccidity, hypothermia,
hunched posture, impaired or lost righting reflex, scant feces), in
males (red or tan perioral substance, chromodacryorrhea,
chromorhinorrhea, labored breathing, and slight ataxia), and in females
(piloerection and bradypnea).  The NOAEL is 250 mg/kg.  

aRfD   =   250 mg/kg/ (NOAEL)   =   2.5 mg/kg

                                                   100 (UF) 

Comments:  The NOAEL selected provides the lowest NOAEL from any
toxicity study in the flutriafol database in which a toxic response
occurred after a single exposure.  Though these effects are not
considered to be indicative of effects in the nervous system per se
(they were considered agonal since they were primarily observed in
animals that were moribund), they are nonetheless toxic effects and are,
therefore, appropriate for risk assessment purposes.  UFs for
inter-species extrapolation (10X) and intra-species variation (10X) were
retained for a total UF of 100. 

3.3.3	Chronic Reference Dose (cRfD) – General Population

Study Selected:  Chronic Toxicity Study - Dog			870.4200

Dose/Endpoint for Establishing the cRfD:  The cRfD for the general
population was established based on the NOAEL derived from the chronic
oral toxicity study in dogs.  The LOAEL of 20 mg/kg/day is based on
adverse liver findings (increased liver weights, increased centrilobular
hepatocyte lipid in the liver, and increases in alkaline phosphatase,
albumin, and triglycerides), increased adrenal cortical vacuolation of
the zona fasciculata, and marked hemosiderin pigmentation in the liver
and spleen in both sexes, mild anemia (characterized by decreased
hemoglobin, hematocrit, and red blood cell count) in the males, and
initial body-weight losses, decreased cumulative body-weight gains, and
increased adrenal weights in the females.  The NOAEL is 5 mg/kg/day.   

cRfD   =   5 mg/kg/day (NOAEL)   =   0.05 mg/kg/day

                                                     100 (UF) 

Comments:  This NOAEL is lower than any NOAEL in the database for
chronic effects.  In addition, the study duration is appropriate for the
duration of exposure.  Both the 28-day dog and 90-day dog oral toxicity
studies provide NOAEL/LOAELs and toxic effects of the same kind (adverse
liver effects) and orders of magnitude as the chronic dog study.  UFs
for inter-species extrapolation (10X) and intra-species variation (10X)
were retained for a total UF of 100.

3.3.4	Dermal Absorption

An in vivo rat dermal-absorption study is available for flutriafol that
is acceptable and indicates that the absorption is 17%, 21%, and 11%,
respectively, at 2, 20, and 200 µg/cm2, following a 10-hour exposure. 
A value of 21% is appropriate (most protective) for dermal risk
assessments.

3.3.5	Dermal Exposure (Short-, Intermediate-Term) 

Study Selected:  Prenatal Developmental Toxicity Study - Rabbit 
870.3700b

Dose/Endpoint for Risk Assessment:  The effects of concern that are
relevant to the selection of the short- and intermediate-term dermal
exposure are based on the LOAEL from the developmental toxicity study in
rabbits.  The LOAEL of 15 mg/kg is based on decreased number of live
fetuses, complete litter resorptions and increased post-implantation
loss.  The NOAEL was 7.5 mg/kg.

Comments:  The developmental toxicity study in rabbits is considered
appropriate for this risk assessment.  No effects were reported in the
28-day dermal toxicity study in rats at doses up to 1000 mg/kg/day
(limit dose); however, that study did not evaluate the potential impact
of flutriafol exposure on the developing organism or in pregnant
females.   A relatively steep dose-response was observed in the rabbit
developmental study with a developmental NOAEL of 7.5 mg/kg/day and a
developmental LOAEL of 15 mg/kg/day, based on decreased number of live
fetuses, complete litter resorptions and increased post-implantation
loss.  Although maternal toxicity was also observed at 15 mg/kg/day, the
effects were restricted to moderate decreases in bodyweight and food
consumption, and were less severe than the effects observed in the
offspring at the developmental LOAEL (15 mg/kg/day).  In addition,
although decreased body weight was an adverse effect observed in
non-pregnant animals with flutriafol, results of this study indicate
that pregnant animals were more sensitive to this effect.

Using a dermal-absorption factor of 21%, the dermal-equivalent dose is
~35.7 mg/kg/day (NOAEL of 7.5 mg/kg/day / 21% dermal absorption = 35.7
mg/kg/day).

3.3.6	Inhalation Exposure (Short- and Intermediate-Term) 

Study Selected:  Prenatal Developmental Toxicity Study - Rabbit 
870.3700b

Dose/Endpoint for Risk Assessment:  The effects of concern that are
relevant to the selection of the short- and intermediate-term inhalation
exposure are based on the LOAEL from the developmental toxicity study in
rabbits.  The LOAEL of 15 mg/kg is based on decreased number of live
fetuses, complete litter resorptions and increased post-implantation
loss.  The NOAEL was 7.5 mg/kg.

Comments:  With the exception of an acute inhalation toxicity study
(intended to establish the LC50), there are no inhalation toxicity
studies in the flutriafol database.  Developmental toxicity was observed
in the rabbit oral developmental study.  The developmental rabbit study
had a developmental NOAEL of 7.5 mg/kg/day and a developmental LOAEL of
15 mg/kg/day, based on decreased number of live fetuses, complete litter
resorptions and increased post-implantation loss.

Inhalation toxicity is assumed to be equivalent to oral toxicity.

3.3.7	Long-term (>6 Months) Dermal and Inhalation  

Based on the use pattern, long-term dermal and inhalation exposure for
workers and homeowners is not expected to occur; therefore, a long-term
risk assessment is not required.

3.3.8	Level of Concern for Margin of Exposure

Table 3.3.9.  Summary of LOC for Risk Assessment1.

Route	Short-Term MOE

(1-30 Days)	Intermediate-Term MOE

(1-6 Months)	Long-Term MOE

(>6 Months)2

Occupational (Worker) Exposure1

Dermal	<100	<100	-

Inhalation	<100	<100	-

Residential Exposure1

Dermal	100	<100	-

Inhalation	<100	<100	-

1	LOC based on UFA = 10X [(extrapolation from animal to human
(intra-species); UFH = 10X [potential variation in sensitivity among
members of the human population (inter-species)].  FQPA SF = 1X.

2	Long-term exposures are not expected for the exposure scenarios
listed.

3.4	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, an aggregate risk assessment must consider exposures from
three major sources: oral, dermal and inhalation exposures.  As there
are no registered or proposed uses of flutriafol that would result in
residential exposure, short- and intermediate-term aggregate risks were
not assessed.

3.5	Determination of Susceptibility

There is some evidence of increased qualitative, but not quantitative,
susceptibility following in utero exposure to flutriafol.  In an
acceptable/guideline rabbit developmental toxicity study, developmental
effects were observed at a dose level that also induced maternal
toxicity.  In an acceptable/guideline rat developmental toxicity study,
flutriafol exposure resulted in decreased body weight and food
consumption in dams and increased late resorptions, malformations and
variations in several bones in offspring at the same dose.  In the
two-generation reproduction study in rats, offspring toxicity occurred
at the same dose level at which parental toxicity occurred for the
parameters measured.  

3.5.1	Degree-of-Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility

There is no evidence for quantitative susceptibility following in utero
exposures to rats or rabbits and following pre-and post-natal exposures
to rats for two generations.  There is evidence for increased
qualitative susceptibility in a prenatal study in rats and rabbits and
the two generation reproductions study in rats, however, there is no
concern for these observations since: 1) the effects were seen in the
presence of maternal/parental/systemic toxicity; 2) clear NOAELs and
LOAELs were established in the fetuses/offspring; 3) the dose-response
for these effects are  well defined and characterized; and 4)
developmental endpoints are used for assessing acute dietary risks to
the most sensitive population (females 13-49) as well as all other
short- and intermediate-term exposure scenarios.  Additionally, there
are no residential uses and thus no potential exposure for infants and
children.

3.5.2	Recommendation for a DNT Study

A DNT study is not required.  This decision is based on the following
observations:

The clinical signs reported in the acute and subchronic neurotoxicity
studies are not considered to be indicative of neurotoxicity, but rather
were determined to be agonal (i.e., at the point of death).

There are no indications of structural or functional neurological
deficits in any of the other studies in the database.

3.6	FQPA Considerations

The flutriafol risk assessment team recommends that the 10X FQPA SF be
reduced to 1X.  This recommendation is based on the following
considerations:  

Except for an immunotoxicity study, the toxicological database is
complete.

In accordance with the revised Part 158 an immunotoxicity study in
required.  In the case of flutriafol there was no evidence of toxicity
to the immune organs in any study in the database.  In addition,
flutriafol does not belong to a class of chemicals (e.g., the
organotins, heavy metals, or halogenated aromatic hydrocarbons) that
would be expected to be immunotoxic.  Based on the above considerations,
HED does not believe that conducting a special series 870.7800
immunotoxicity study will result in a point of departure lower than that
used for overall risk assessment.  Therefore an additional UFDB does not
need to be applied.  

There are no concerns or residual uncertainties for pre- and/or
post-natal toxicity. As noted above, although there is evidence for
increased qualitative susceptibility in a prenatal study in rats and
rabbits and the two generation reproductions study in rats, there is no
concern for these observations since: 1) the effects were seen in the
presence of maternal/parental/systemic toxicity; 2) clear NOAELs and
LOAELs were established in the fetuses/offspring; 3) the dose-response
for these effects are  well defined and characterized; and 4)
developmental endpoints are used for assessing acute dietary risks to
the most sensitive population (females 13-49) as well as all other
short- and intermediate-term exposure scenarios.

There is no concern for neurotoxicity with flutriafol. Signs of
neurotoxicity were reported in the acute and subchronic neurotoxicity
studies at the highest dose only; however, these effects were primarily
seen in animals that were agonal (at the point of death) and, thus are
not indicative of neurotoxicity.  In addition, there was no evidence of
neurotoxicity in any additional short-term studies in rats, mice, and
dogs, or in the long-term toxicity studies in rats, mice, and dogs. 

A developmental neurotoxicity study is not required.

The dietary exposure assessment is conservative in nature (utilize
tolerance level residues and 100% CT).

There are no proposed residential uses.

3.7	Classification of Carcinogenic Potential

Flutriafol is considered to be “Not likely to be Carcinogenic to
Humans” based on the results of the carcinogenicity studies in rats
and mice.  The results of the rat chronic toxicity/carcinogenicity study
and the mouse carcinogenicity study are negative for carcinogenicity. 
All genotoxicity studies on flutriafol showed no evidence of
clastogenicity or mutagenicity.  Although several triazoles are
carcinogenic, many are not and flutriafol has been adequately tested and
found not to be carcinogenic in long-term studies in rats and mice.

Structure-activity-relationship (SAR) analysis indicates that flutriafol
may have the potential to produce thyroid and/or liver tumors in
rodents.  However, in the rat and mouse carcinogenicity studies, there
were no treatment-related increases in tumor incidence when comparing
treated animals to controls.  

3.8	Summary of Toxicological Doses and Endpoints for Flutriafol for Use
in Human Risk Assessments

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment are found in Table
3.8.

Table 3.8.  Summary of Toxicological Doses and Endpoints for Flutriafol
for Use in Dietary and Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA SFs	RfD, PAD, Level of
Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary

(Females, 13-49 years of age)

	NOAEL = 7.5 mg/kg

	UFA = 10X

UFH  = 10X

FQPA SF = 1X

	Acute RfD = 0.075 mg/kg/day

aPAD = 0.075 mg/kg	Developmental study – rabbit 

LOAEL = 15 mg/kg, based on decreased number of live fetuses, complete
litter resorptions and increased post-implantation loss.  

Acute Dietary 

(General Population, Including Infants and Children)

	NOAEL = 250 mg/kg

	UFA = 10X

UFH = 10X

FQPA SF = 1X

	Acute RfD = 2.5 mg/kg/day

aPAD = 2.5 mg/kg/day

	Neurotoxicity screening battery – rat

LOAEL = 750 mg/kg, based on decreased body weight, body-weight gain,
absolute and relative food consumption, and clinical signs of toxicity
in both sexes: dehydration, urine-stained abdominal fur, ungroomed coat,
ptosis, decreased motor activity, prostration, limp muscle tone, muscle
flaccidity, hypothermia, hunched posture, impaired or lost righting
reflex, scant feces; in males: red or tan perioral substance,
chromodacryorrhea, chromorhinorrhea and labored breathing, and in
females:  piloerection and bradypnea.

Chronic Dietary (All Populations)

	NOAEL = 5 mg/kg/day

	UFA  = 10X

UFH = 10X

FQPA SF = 1X

 

	Chronic RfD = 0.05

mg/kg/day

cPAD = 0.05 mg/kg/day

	Chronic toxicity – dog

LOAEL = 20 mg/kg/day, based on adverse liver findings (increased liver
weights, increased centrilobular hepatocyte lipid in the liver, and
increases in alkaline phosphatase, albumin, and triglycerides),
increased adrenal cortical vacuolation of the zona fasciculata, and
marked hemosiderin pigmentation in the liver and spleen in both sexes;
mild anemia (characterized by decreased hemoglobin, hematocrit, and red
blood cell count) in the males; and initial body weight losses,
decreased cumulative body-weight gains, and increased adrenal weights in
the females.

Dermal

Short (1-30 days)- and Intermediate (1-6 months) -Term 	NOAEL= 7.5

mg/kg/day 

Dermal-absorption factor = 21%	UFA = 10X

UFH = 10X

FQPA SF =  1X

	Residential/

Occupational LOC for MOE = 100	Developmental toxicity – rabbit

LOAEL = 15mg/kg, based on decreased number of live fetuses, complete
litter resorptions and increased post-implantation loss.  

Dermal Long-Term (>6 months)

	-	-	-	Based on the use pattern, long-term dermal and intermediate
exposure for workers is not expected to occur, therefore, a long-term
risk assessment is not required.

Inhalation Short (1-30 days)- and   Intermediate (1-6 months) -Term 

	NOAEL = 7.5 mg/kg/day

Inhalation toxicity assumed to be equivalent to oral toxicity	UFA = 10X

UFH = 10X

FQPA SF =  1X

	Residential/

Occupational LOC for MOE = 100

	Developmental toxicity – rabbit

LOAEL = 15 mg/kg, based on decreased number of live fetuses, complete
litter resorptions and increased post-implantation loss.  

Inhalation Long-Term (>6 months)

	-	-	-	Based on the use pattern, long-term dermal and intermediate
exposure for workers is not expected to occur; therefore, a long-term
risk assessment is not required.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the carcinogenicity studies in rats
and mice. 

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 (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  FQPA SF = FQPA Safety Factor.  PAD =
population-adjusted dose (a = acute, c = chronic).  RfD = reference
dose.  MOE = margin of exposure.  LOC = level of concern. 

3.9	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 the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there were
scientific bases for including, as part of the program, 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.  When the appropriate
screening and/or testing protocols being considered under the Agency’s
Endocrine Disrupter Screening Program (EDSP) have been developed and
vetted, flutriafol may be subjected to additional screening and/or
testing to better characterize effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data 

Literature searches were not performed by the registrant.  A cursory
review of human exposure to flutriafol on the internet yielded no
additional information.

5.0	Dietary Exposure/Risk Characterization

References: 

D355605, R. Daiss, 3-Sep-2008 (Residue of Concern Knowledge-Base
Subcommittee (ROCKS) decision memorandum)

D360863, L. Shanaman, 1-Jan-2009 (flutriafol drinking water assessment)

D340513, T. Bloem, 11-Mar-2009 (flutriafol residue chemistry summary)

D355939, T. Bloem, 11-Mar-2009 (flutriafol dietary exposure analysis)

D359490, M. Doherty, 09-Dec-2008 (T, TA/TAA risk assessment)

D350664, M. Doherty, 06-Oct-2008 (T, TA/TAA dietary exposure analysis)

D320682, I. Maher, 28-Feb-2006 (T, TA/TAA drinking water assessment)

5.1	Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops 

The petitioner submitted adequate apple, sugar beet, and rapeseed
metabolism studies conducted with [triazole-3,5-14C]flutriafol and
[carbinol-14C]flutriafol (1 x 0.010-0.12 lb ai/acre).  The radiolabel
position did not affect TRRs or the metabolic profile for rapeseed
(forage, pod, and mature seed; PHI = 0-21 days) or sugar beet tops (TRRs
in root were too low for a comparison; PHI = 0-21 days); for apple (PHI
= 64 days), TRRs were slightly higher following treatment with
[triazole-3,5-14C]flutriafol, but the resulting metabolic profiles did
not vary with radiolabel position.  Flutriafol (50-96% TRR) was the
major residue identified in the apple, rapeseed (foliage, pod, and
seed), and sugar beet tops (TRR in roots too low for identification). 
Defluorinated flutriafol (12-14% TRR) and conjugated flutriafol (27-28%
TRR) were identified at significant concentrations in rapeseed pod.  All
other identified/unknowns were ≤8% TRR (T, TA, and TAA were not
identified).  Wheat and barley metabolism studies (foliar and seed
treatment) were also submitted, but were deemed unacceptable due to
numerous deficiencies.

5.1.2	Metabolism in Rotational Crops 

The petitioner submitted a confined rotational crop study; however, this
study was determined to be inadequate for the following reasons:  (1)
the study did not include a leafy vegetable crop; (2) residues in wheat
forage were not investigated; (3) sandy loam soil was not used and no
data were provided concerning the soil characteristics; (4) insufficient
information was provided concerning analytical methodology and a
confirmatory method was not used for the identification of metabolites;
(5) insufficient information was provided to determine whether
identification/characterization of residues met Agency requirements
(e.g., five unknowns designated “others” accounted for up to >50% of
TRR in carbinol-label sugar beet tops and were not further investigated;
reference standards used were not identified); (6) insufficient attempts
were made to characterize nonextractable residues of 120-day wheat straw
and grain and 365-day wheat straw samples; (7) insufficient storage
stability data/information are available to support the storage interval
of at least 4 years; and (8) insufficient information/data in general
were provided to support the study, including details of sample handling
at the field site and analytical laboratory; the distribution of
radioactivity into sample extracts and fractions; representative
chromatograms, raw data, or example calculations; and storage conditions
and durations.  Based on these deficiencies, HED does not believe the
study is upgradeable and a new confined rotational crop study conducted
with [triazole-3,5-14C]flutriafol and [carbinol-14C]flutriafol as
specified in OPPTS 860.1850 should be submitted.  

5.1.3	Metabolism in Livestock 

Poultry:  The petitioner submitted a hen metabolism study conducted with
[triazole-3,5-14C]flutriafol and [carbinol-14C]flutriafol at a dietary
rate of 13.9 ppm (160x) and 11.6 ppm (130x), respectively.  TRRs were
consistently higher following dosing with [triazole-3,5-14C]flutriafol
and significant differences were noted in the metabolic profiles
depending on radiolabel position.  Flutriafol was identified as a
significant residue in [triazole-3,5-14C]flutriafol and
[carbinol-14C]flutriafol samples (non-detect - 80% TRR).  T (11-75% TRR)
was identified as a significant residue in [triazole-3,5-14C]flutriafol
samples.  An unknown, M3, was identified at significant concentrations
following dosing with [carbinol-14C]flutriafol (6-46% TRR); M3 was also
identified at similar concentrations following dosing with
[triazole-3,5-14C]flutriafol, but at lower %TRR (3-11% TRR) due to the
higher TRRs in these samples.  All other identified/unknown residues
were found at <10% TRR.  

C]flutriafol study was not submitted.  TRRs were ≤0.01 ppm in all
commodities, excluding kidney (0.061 ppm) and liver (0.291 ppm).  The
major residues identified in kidney and liver were flutriafol (7-29%
TRR) and M1B (4-hydroxy flutriafol; 1-23% TRR); TRRs in milk appeared to
plateau by day 4.  The following deficiencies were identified in the
dairy cow metabolism study:  (1) a confirmatory method was not used for
the identification of metabolites; (2) no information concerning storage
duration was provided; (3) reference standards for the triazole
metabolites (T, TA, and TAA) were not included; and (4) the GLP
statement indicated that since Cheminova (the petitioner) did not
conduct the study and was not the sponsor, they could not be certain
that the study was conducted in accordance with GLP practices (40 CFR
160).  In addition, supporting information and data were extremely
limited for this study.  

5.1.4	Analytical Methodology 

Residue Analytical Methods - Primary Crops:  For tolerance enforcement,
the petitioner is proposing the following methods:  apple - the Food and
Drug Administration (FDA) Multiresidue Method (MRM) Protocol D [Section
302 E1 (acetone extraction); analysis using module DG5)] and soybean -
the GC/nitrogen/phosphorus detector (NPD) method employed in the field
trials [acetonitrile (ACN):water extraction (70:30, v:v)].  As part of
the MRM testing for flutriafol, the petitioner demonstrated that
Protocol D [Section 302 E1 (acetone extraction); analysis using module
DG5 (GC/NPD)] adequately recovered flutriafol residues from apples
fortified at 0.1 ppm and 0.5 ppm (see FDA MRM section below).  The
proposed soybean enforcement method was validated in conjunction with
the soybean magnitude of the residue studies and an adequate independent
laboratory validation (ILV) was also submitted.  The petitioner did not
submit radiovalidation data for the proposed apple enforcement method;
since the extraction procedures for the proposed apple enforcement
method are similar to those used in the apple metabolism study [ACN and
ACN:water (1:1, v:v), and/or water; flutriafol identified only in the
extracts], HED concludes that radiovalidation is unnecessary for apple. 
The petitioner did submit adequate radiovalidation for the proposed
soybean method using rapeseed seed samples from the metabolism study. 
Therefore, HED concludes that the proposed soybean seed and apple
tolerance enforcement methods are adequate and forwarded these methods
to the FDA for inclusion in the Pesticide Analytical manual (PAM;
D362421, T. Bloem, 11-Mar-2009).  

Residue Analytical Method - Livestock:  For enforcement of the ruminant
liver tolerance, the petitioner is proposing method ICIA AM00306
(revisions of 13-Aug-2007 and 8-Oct-2007).  This method was validated in
conjunction with the ruminant feeding study and an adequate ILV was also
submitted.  The petitioner did not include radiovalidation data for this
method.  Based on the extraction solvent used for liver (ACN) and that
used in the livestock metabolism studies [ACN:water (1:1 (v:v))] ,
radiovalidation data are unnecessary.  Therefore, HED concludes that the
proposed ruminant liver tolerance enforcement method is adequate and
forwarded this method to the FDA for inclusion in PAM (D362421, T.
Bloem, 11-Mar-2009).  

FDA MRM:  Based on the decision tree provided in Appendix II of the FDA
PAM I, flutriafol was tested through Protocols A, C (modules DG1 and DG
5 only), D, E, and F.  Protocols A, E, and F were determined to be
unacceptable for determination of flutriafol due to unacceptable
recoveries from the clean-up column and/or unacceptable analytical
response using the specified conditions.  Flutriafol yielded acceptable
instrument response using the Protocol C gas-liquid chromatograph (GLC)
conditions specified in modules DG1 [electron-capture detector (ECD)]
and DG5 (NPD).  Flutriafol yielded acceptable recoveries through
protocol D (Section 302 E1; acetone extraction) using a non-fatty matrix
(apple) fortified at 0.1 ppm [116% (n=2)] and 0.5 ppm (112% and 155%)
and quantified using module DG5 (NPD); HED notes that matrix blanks were
not analyzed.  These data were forwarded to FDA (D355835, T. Bloem,
3-Sep-2008).

5.1.5	Environmental Degradation

Flutriafol is expected to be persistent and moderately mobile in the
environment, with its major routes of dissipation through biotic
degradation.  Flutriafol is expected to degrade with a half-life of more
than one year in the environment.  Batch equilibrium data on flutriafol
suggest that the compound will sorb to soil with moderate affinity, and
display moderate mobility (Kd values range from 2.0 to 13.6).  The
compound does not volatilize significantly, with a partial vapor
pressure of 4 x 10-7 Pa at 20 °C.  Therefore, dissipation in the
environment is expected to occur via runoff of dissolved residues, and
sorption to eroding sediments.  Flutriafol leachate is expected to
persist in both aerobic and anaerobic soil compartments.

Flutriafol biodegrades with half-lives of more than a year in both
aerobic and anaerobic terrestrial and aquatic environments, and is
expected to persist for years in both aerobic and anaerobic
environments.  Additionally, flutriafol is stable to both hydrolysis and
aquatic photolysis.  Dissipation occurred with half-lives of 106 to
13,566 days in terrestrial field studies, which is consistent with the
submitted, laboratory-derived data.  Due to the length of the studies,
and the persistence of flutriafol, major degradates were not detected in
either laboratory or field studies.  Minor degradates of flutriafol
(which were only reported in two studies: a soil photolysis study and an
anaerobic aquatic metabolism study) include:  T, TAA, TA,
2,4’-difluorobenzophenone, and CO2.  

5.1.6	Comparative Metabolic Profile

In rat metabolism studies, parent was isolated in only trace amounts in
the urine and feces (<0.5% of the administered dose) and more than 19
metabolites were isolated (<0.1-16% of the administered dose).  In rats,
the primary site for metabolism was the 2-fluorophenyl ring.  The
initial metabolic step was probably epoxidation followed by either
rearrangement to form the dihydrodiol isomers or to form hydroxy or
dihydroxy metabolites.  The hydroxyl groups on these primary metabolites
may then be either conjugated with glucuronic acid or methylated.  A
second, minor route for metabolism of flutriafol was via the removal of
the triazole ring to form 1-(2
fluorophenyl)-1-(4-fluorophenyl)-ethandiol, which is then conjugated
with glucuronic acid.

 metabolism study resulted in TRRs ≤0.01 ppm in all samples, except
for liver and kidney.  The major residues identified in liver and kidney
were flutriafol and M1B (4-hydroxyflutriafol), with minor amounts of M1D
(4-hydroxy-5-methoxyflutriafol) also identified.  The poultry metabolism
study yielded sufficient radioactivity in all matrices for residue
identification, with flutriafol and T being the major identified
residues.  An unknown, M3, was identified at significant concentrations
following dosing with [carbinol-14C]flutriafol; M5 (hydroxylated
flutriafols) was also identified, but at an insignificant concentration.
 The submitted confined rotational crop study has been determined to be
unacceptable.  

5.1.7	Toxicity Profile of Major Metabolites and Degradates

Based on structural similarity, HED concludes that the defluorinated and
hydroxylated flutriafols identified in the plant and livestock
metabolism studies are not likely to be more toxic than flutriafol.  HED
has previously reviewed toxicological data for T, TA, and TAA and
concluded that the toxicological effects of T and TA/TAA are different
from each other (D322215, M. Doherty et al., 07-Feb-2006).  Based on
these data and the flutriafol toxicological data, HED concludes that the
toxicological effects of T and TA/TAA are different from that of
flutriafol.  

5.1.8	Pesticide Metabolites and Degradates of Concern

The HED ROCKS met on 12-August-2008 to discuss the residues of concern
in apple, dried soybean seed, and livestock (D355605, R. Daiss,
03-Sep-2008).  Table 5.1.8.1 and the following paragraphs are summaries
of the ROCKS conclusions (see Appendix D for chemical names and
structures).  Since flutriafol contains fluorine, HED evaluated the
potential for increased exposure to fluoride as a result of the proposed
application scenarios; based on the plant, livestock, and environmental
metabolism/degradation studies, HED concludes that exposure to fluoride
from flutriafol is negligible (see below).  

Table 5.1.8.1  Summary of Metabolites and Degradates of Concern for
Risk Assessment and Tolerance Enforcement.

Matrix	Residues of Concern

	Risk Assessment1	Tolerance Enforcement

soybean seed	flutriafol, T, TA, and TAA	flutriafol

apple

poultry2

ruminant3	flutriafol, M1B, T, TA, and TAA

	water	flutriafol and T	not applicable

1	The ROCKS concluded that based on the toxicity of the residues of
concern, three risk assessments are necessary when evaluating the
exposure resulting from application of flutriafol [flutriafol and M1B; T
(1,2,4-triazole); and TA (triazolylalanine) and TAA (triazolylacetic
acid)].

2	HED notes that if the poultry dietary burdens increase, these
conclusions will be revisited and poultry metabolism studies conducted
as specified in OPPTS 860.1300 with [carbinol-14C]flutriafol and
[triazole-3,5-14C]flutriafol may be required.

3	HED notes that if the ruminant dietary burden increases, these
conclusions will be revisited and ruminant metabolism studies conducted
as specified in OPPTS 860.1300 with [carbinol-14C]flutriafol and
[triazole-3,5-14C]flutriafol may be required.

Apple and Dried Soybean Seed:  Based on the apple, sugar beet and
rapeseed metabolism data, the ROCKS concluded that the residues of
concern in apple and dried soybean seed are flutriafol, T, TA, and TAA
and the residue of concern for tolerance enforcement is flutriafol per
se.  Defluorinated flutriafol and conjugated flutriafol were not
included as residues of concern since apple and dried soybean seed do
not possess a commodity similar to rapeseed pod (label prohibits
feeding/foraging soybean forage/hay and use will be restricted to only
soybean harvested for the dried seed).  For future uses on legumes other
than dried seeds, defluorinated flutriafol and conjugated flutriafol
should be included for risk assessment.  T, TA, and TAA were included as
residues of concern as they were identified in the apple and soybean
field trial studies and/or to be consistent with the other triazole
fungicides.  

Poultry:  Based on the poultry metabolism study, the ROCKS concluded
that the residues of concern in poultry for risk assessment are
flutriafol, T, TA, and TAA and the residue of concern for tolerance
enforcement is flutriafol per se.  Residues of TA and TAA were included
as residues of concern due to their presence in feed commodities.  M3
was excluded as a residue of concern since residues are expected to be
negligible when normalized to the current dietary burden.  HED notes
that if the poultry dietary burdens increases, these conclusions will be
revisited and poultry metabolism studies conducted as specified in OPPTS
860.1300 with [carbinol-14C]flutriafol and [triazole-3,5-14C]flutriafol
may be required.

Ruminants:  Based on the results of the dairy cow metabolism study and
for the reasons listed below, the ROCKS concluded that the residues of
concern for risk assessment in ruminants are flutriafol, M1B, T, TA, and
TAA and the residue of concern for tolerance enforcement is flutriafol
per se.  The reasons include:  (1) based on (a) the DEREK analysis,
which did not result in alerts for potential flutriafol metabolites
without the triazole ring; (b) the rat metabolism study, which resulted
in the identification of a metabolite without the triazole ring in urine
and feces (M18; <1-8% of the administered dose); and (c) the fact that
developmental toxicity demonstrated for many of the triazole fungicides,
including flutriafol, is likely a result of the triazole ring, HED
concludes that flutriafol metabolites without the triazole ring are not
likely to be more toxic than parent (a [carbinol-14C]flutriafol ruminant
metabolism study has not been submitted); (2) based on the TRRs from the
[triazole-3,5-14C]flutriafol dairy cow metabolism study (10x) and
because the hen metabolism study resulted in higher TRRs following
dosing with [triazole-3,5-14C]flutriafol as compared to
[carbinol-14C]flutriafol, residues in all ruminant commodities,
excluding liver and kidney, are expected to be insignificant [liver -
0.291 ppm; kidney - 0.061 ppm; all other tissues ≤0.01 ppm; and milk -
≤0.008 ppm (TRRs in milk appeared to plateau by day 4)]; and (3) the
ruminant feeding studies resulted in low flutriafol per se residues when
normalized to 1x the current maximum reasonable dietary burden (MRDB;
liver ≤0.013 ppm; kidney ≤0.002 ppm; fat ≤0.002 ppm; muscle
≤0.0008 ppm; and milk <0.001 ppm).  Residues of TA and TAA were
included as residues of concern due to their presence in feed
commodities.  HED notes that if the ruminant dietary burden increases,
these conclusions will be revisited and ruminant metabolism studies
conducted as specified in OPPTS 860.1300 with [carbinol-14C]flutriafol
and [triazole-3,5-14C]flutriafol may be required.

Water:  Based on the environmental fate data, the ROCKS concluded that
the residues of concern in water are flutriafol and T.  

Fluoride:  Defluorinated flutriafol was not identified in the apple,
sugar beet, wheat, livestock, or environmental metabolism/degradation
studies (acceptable confined rotational crop study has not been
submitted).  Defluorinated flutriafol was identified in the canola
metabolism study [pod without the seed - 12-15% TRR (≤0.12 ppm); seed
- 4% TRR (≤0.05 ppm)].  Using the canola metabolism data as a
surrogate for soybean and accounting for application rate, a fluoride
residue of 0.006 ppm in soybean seed resulting from application of
flutriafol was calculated.  

HED has previously conducted separate dietary exposure analyses for
fluoride resides from the insecticides cryolite and sulfuryl fluoride as
well as from naturally occurring fluoride residues in food and water. 
It was noted that many pesticides contain the fluorine atom, but it was
assumed that only cryolite and sulfuryl fluoride would result in
meaningful increases in fluoride residues as compared to background
levels (presumably due to the lack of carbon-fluorine bonds in these two
compounds).  Table 5.1.8.2. is a summary of the fluoride residue
estimate in soybean from flutriafol and the fluoride residue estimates
incorporated into the sulfuryl fluoride and background dietary exposure
analyses (cryolite not registered for use on soybean).  Based on this
comparison, flutriafol is not a significant contributor to fluoride
residues in soybean.  

Fluoride residues from flutriafol in apple, livestock, and water were
considered negligible for the following reasons:  apple - the apple
metabolism study did not result in the identification of defluorinated
flutriafol; livestock - fluoride concentrations in plant leaves usually
range from 0.1 to 15 ppm (  HYPERLINK
"http://www.inchem.org/documents/ehc/ehc/ehc227.htm#5.1" 
http://www.inchem.org/documents/ehc/ehc/ehc227.htm#5.1 ); concentrations
which are several orders of magnitude greater than that estimated for
soybean; and water - the environmental fate/degradation studies did not
result in the identification of defluorinated flutriafol.  

Table 5.1.8.2  Summary of Fluoride Residues in Soybean from Flutriafol,
Sulfuryl Fluoride, and Background.

Source	Commodity	Fluoride Residue*	Comments

flutriafol	soybean seed	0.006 ppm	assumes 100% crop treated; based on
the canola metabolism data and accounting for application rate

background	soybean seed, flour, milk, and oil	0.494 ppm	D309014;
residues in bean cooked in fluoridated water

sulfuryl fluoride	soybean flour	0.081 ppm	D362183; residue from
structural fumigation; percent treated estimates incorporated into the
residue estimate

sulfuryl fluoride	soy milk	2.4 ppm

(0.0096 ppm)	D362183; residue from structural fumigation; only 0.4% of
soy milk is expected to be treated

sulfuryl fluoride	soy oil	1.5 ppm

(0.006 ppm)	D362183; residue from structural fumigation; only 0.4% of
soy oil is expected to be treated

*  Residue in parenthesis accounts for percent crop treated.

5.1.9	Drinking Water Residue Profile

Hydrolysis and aqueous photolysis of flutriafol are very slow.  In soil,
flutriafol is persistent, with a biotic half-life value greater than one
year.  Flutriafol degrades more rapidly under aerobic aquatic
environments, with a half-life value of approximately 6 weeks in an
aerobic water/sediment test system.  No major degradation products
(i.e., >10% of applied) were identified in any water or soil studies.  

Flutriafol is moderately mobile in laboratory tested soils.  This
moderate potential for mobility, combined with the persistence
demonstrated by laboratory metabolism half-lives greater than one year,
indicate that under some environmental conditions, flutriafol does
possess the potential to reach groundwater.  Flutriafol residues have
been detected in surface samples taken from the Svalbard archipelago ice
cap in arctic Norway indicating a potential for long range transport. 
Six terrestrial field dissipation studies with applications made over
several consecutive years, most with applications over multiple years,
indicate that flutriafol residues will remain undegraded, allowing
residues to carry-over from year to year under actual use conditions.  

Due to the length of the studies, and the persistence of flutriafol,
major degradates were not detected in either laboratory or field
studies.  Minor degradates of flutriafol, which were only reported in
two studies, a soil photolysis study and an anaerobic aquatic metabolism
study, include T, TAA, TA, 2,4’-difluorobenzophenone, and CO2.  With
the exception of T, none of the degradates above were considered a
residue of concern by the ROCKS.  T was a minor degradate in the
submitted studies, but is a common degradate to other fungicides.  T is
not included in this assessment, but has been addressed in a separate
assessment (EFED memo; D320682, I. Maher, 28-Feb-2006).

The drinking water assessment is a Tier 1, screening-level drinking
water assessment using the SCIGROW and FIRST models with the maximum
application rate for apples.  Maximum aquatic concentrations expected
from the proposed new uses are an acute exposure of 48.8 ppb in surface
water, a chronic exposure of 5.7 ppb in surface water, and 4.8 ppb for
both acute and chronic exposure to ground water, all resulting from use
of flutriafol at the proposed maximum labeled application rate to
apples.  Proposed maximum use rates for soybeans produced lower
estimated drinking-water concentrations (EDWCs).  

Table 5.1.9.  Summary of EDWCs for Flutriafol.

	Flutriafol

	Surface Water Conc., ppb1	Groundwater Conc., ppb2

Acute	48.8	4.8

Chronic (non-cancer)	5.7	4.8

1	From the FIRST (Version 1.1, 12/12/05) model.  Input parameters are
based on 0.11 lbs a.i./acre per application with a 7-day minimum
interval between applications and six applications per season (apples). 
The percent cropped area (PCA) factor was 0.87.

2	From the SCI-GROW model assuming a maximum seasonal use rate of 0.11
lbs ai/A, a Koc of 140 mL/g, and a half-life of 588 days.

5.1.10	Food Residue Profile 

Magnitude of the Residue - Apple and Soybean Raw Agricultural
Commodities (RACs):  Pending submission of supporting storage stability
data for T, TA, and TAA in/on soybean seed, the submitted apple and
soybean field trial data are acceptable.  The number and locations of
the field trials are in accordance with OPPTS Guideline 860.1500
requirements.  The field trials employed the requested formulation and,
provided the petitioner submits a revised Section B, the application
scenarios were appropriate.  The harvested samples were analyzed for
residues of flutriafol, T, TA, and TAA using acceptable methods. 
Residues of flutriafol, T, TA, and/or TAA in/on apple were as follows: 
flutriafol - 0.029-0.138 ppm (controls <0.01 ppm), T - <0.01 ppm
(controls <0.01 ppm), TA - <0.01-0.052 ppm (controls <0.01-0.060 ppm),
and TAA - <0.01 – 0.012 ppm (controls <0.01 ppm).  Residues of
flutriafol, T, TA, and/or TAA in/on dried soybean seed were as follows: 
flutriafol - <0.01-0.306 ppm (controls <0.01 ppm), T - <0.01 ppm
(controls <0.01 ppm), TA - 0.038-0.670 ppm (controls 0.028-1.34 ppm),
and TAA - <0.01 – 0.028 ppm (controls <0.01-0.037 ppm).  The
petitioner stated that the source of the TA (apple and soybean) and TAA
(soybean) residues in/on the control samples was unknown, but was likely
to be of natural origin and unrelated to the triazole-class pesticides. 
Based on the soybean TA and TAA treated to control residue ratios of
0.11-6.44 (average = 2.29) and 0.58-12.4 (average = 1.36), flutriafol
may degrade to these compounds in soybean; however, for apple, there was
not a significant difference between TA residue in treated and control
samples (residue ratios of 0.38-2.51; average = 1.21).  HED notes that
samples of forage and hay were not collected from the soybean field
trials and that these data are not required because the petitioner is
proposing a feeding/grazing restriction for soybean.  Based on the apple
and soybean field trial data and the maximum residue limit (MRL)
tolerance calculator, the following tolerances for residues of
flutriafol per se are appropriate:  apple - 0.20 ppm and soybean seed -
0.35 ppm.  A revised Section F is requested.  

Magnitude of the Residue - Apple and Soybean Processed Commodities: 
Pending submission of supporting storage stability data for T, TA, and
TAA in/on aspirated grain fractions (AGF) and soybean processed
commodities, the submitted apple and soybean processing studies are
acceptable.  The studies reflect application of flutriafol at 1.5x and
5.2x the proposed seasonal rate for apple and soybean (note that the
soybean AGF residue data were generated using a 1.0x rate).  Samples
were analyzed for flutriafol, T, TA, and TAA using acceptable methods
(flutriafol residues were >LOQ in/on the RAC).  The processing data
resulted in the following flutriafol processing factors (see residue
chemistry summary memo (D340513) for T, TA, and TAA processing factors):
 apple juice - 0.5x; wet apple pomace - 1.8x; soybean meal - 1.4x;
soybean hull - 1.0x; soybean oil - 1.3x; and soybean AGF - <7.4x.  Based
on the highest-average field trial (HAFT) flutriafol per se residues in
apple (0.123 ppm) and soybean seed (0.303 ppm) and the processing
factors, expected residues in wet apple pomace, soybean meal, soybean
hull, soybean oil, and soybean AGF would be 0.22 ppm, 0.42 ppm, 0.30
ppm, 0.39 ppm, and 2.24 ppm, respectively.  Based on the HED-recommended
apple (0.20 ppm) and soybean seed (0.35 ppm) tolerances, HED concludes
that tolerances in/on wet apple pomace, soybean meal, soybean hull, and
soybean oil are unnecessary.  However, HED concludes that a tolerance
for residues of flutriafol per se of 2.2 ppm in/on AGF is appropriate. 
A revised Section F is requested.  

Magnitude of the Residue - Rotational Crops:  The petitioner submitted a
confined rotational crop study, but this study was determined to be
inadequate (see Section 5.1.2).  The petitioner submitted two field
rotational crops studies, which monitored for residues of flutriafol,
TA, and TAA following a single bare soil incorporated application at 16x
the proposed soybean application rate (studies conducted in the UK). 
Wheat (same year as application) or sugar beet (24 months after
application) were planted and grown to maturity (residue data were not
presented for these crops); the sites were planted 34-36 months after
application with the rotational crops corn, potato, sunflower, sugar
beet, barley, cabbage, carrot, pea, rapeseed, and wheat (sugar beet was
planted 24-30 months after application).  Residues of TA and TAA were
found in/on many of the crops (TA:  <0.05-17.0 ppm; TAA:  <0.05-0.84
ppm; see residue chemistry summary memo (D340513) for details). 
Residues of flutriafol were also found in/on many of the samples. 
Normalizing the residues to 1x the soybean rate and assuming a LOQ of
0.01 ppm, quantifiable residues in/on cabbage (≤0.008 ppm), carrot
root (≤0.008 ppm), sugar beet tops (≤0.026 ppm), corn straw (i.e.,
stover; ≤0.020 ppm), barley straw (≤0.097 ppm), wheat straw
(≤0.161 ppm), and pea hay (≤0.245 ppm) may be expected.  

Excluding instances where phytotoxicity is an issue, HED considers a
maximum 12-month plant back interval (PBI) to be practical.  If the
limited field rotational crop study demonstrates quantifiable residues
at 12 months, then extended field trial data are required for each
desired rotational crop/PBI and tolerances are established based on
these data.  Note that the limited rotational crop data are conducted on
root, leafy vegetable, and cereal grain crop as these are the
HED-accepted surrogates for all rotational crops.  In the current
instance, the limited field rotational crop study indicates that
quantifiable residues of flutriafol may be present in a root crop, leafy
vegetable, and cereal grain planted 34-36 months following application
at 1x the proposed soybean application rate.  Therefore, a PBI where
residues in rotational crops are <LOQ has not been demonstrated and HED
does not have sufficient data to estimate residues or establish
tolerance in rotational crops at any PBI.  HED notes that although the
nature of the residue in rotational crops has not been defined, it is
convention for HED to include parent as a residue of concern in all
matrices.  

The petitioner has indicated that they have conducted new confined and
field (limited and extended; 1x) rotational crop studies and that these
data will be submitted to HED in the summer of 2009.  Since these data
are forthcoming and based on the currently available data, the label
should indicate that only soybean may be rotated to a treated field; a
revised Section B is requested.  If the petitioner would like to rotate
to crops other than soybean, then confined and field rotational crop
studies should be submitted as specified in OPPTS 860.1850 and OPPTS
860.1900.

p.  Normalizing the average residues to 1x the MRDB results in residues
of ≤0.0013 ppm.  Residues of T, TA, and TAA were <LOQ in/on all
matrices.  The cattle study resulted in flutriafol per se residues of
<LOQ in all commodities except for liver samples collected from the 2.4x
(<0.01-0.040 ppm; avg = 0.0249 ppm), 7.2x (0.0896-0.0973 ppm; avg =
0.0934 ppm), and 24x (0.225-0.386 ppm; avg = 0.279 ppm) dosing groups. 
Normalizing the average residues to 1x the MRDB results in residues of
0.010-0.013 ppm.  Residues of T, TA, and TAA were <LOQ in/on all
matrices.

Based on the acceptable dairy cattle and hen feeding studies, HED
concludes that a tolerance for residues of flutriafol per se in/on liver
(cattle, goat, horse, and sheep) of 0.02 ppm is appropriate.  HED notes
that the results of the unacceptable livestock feeding study do not
indicate that a ruminant liver tolerance >0.02 ppm is required or that
tolerances on the remaining livestock commodities are required.  

Proposed and HED-Recommended Tolerances:  Tolerances are established for
residues of flutriafol, including its metabolites and degradates, in or
on the commodities listed below.  Compliance with these tolerance levels
is to be determined by measuring only flutriafol.  A revised Section F
is requested which indicates the Chemical Abstracts Service (CAS)
chemical name for flutriafol and reflects the correct commodity
definition and/or numerical tolerance specified in Table 5.1.10.1.  A
revised Section F is requested.

Table 5.1.10.1.  Tolerance Summary for Flutriafol.

Commodity	Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Comments

Apple	0.2	0.20	Numerical tolerance should be 0.20.

Soybean	0.3	0.35	Based on the field trial data and the tolerance
calculator, the numerical tolerance should be 0.35 ppm and the correct
commodity definition is "Soybean, seed."

Soybean, aspirated grain fractions	0.5	2.2	Based on the field trial and
processing data, the numerical tolerance should be 2.2 ppm and the
correct commodity definition is "Grain, aspirated fractions."

Liver (cattle, goat, hog, horse, sheep)	0.01	--	Incorrect commodity
definition.

Cattle, liver	--	0.02	--

Goat, liver	--	0.02	--

Hog, liver	--	0.02	--

Horse, liver	--	0.02	--

Sheep, liver	--	0.02	--

Eggs	0.01	--	Tolerance not required.

5.1.11	International Residue Limits

No Codex, Canadian, or Mexican MRLs have been established for
flutriafol; therefore, harmonization is not an issue for this petition. 

5.2	Dietary Exposure and Risk

The ROCKS concluded that based on the toxicity of the residues of
concern, three risk assessments are necessary when evaluating the
exposure resulting from application of flutriafol (flutriafol and M1B;
T; and TA/TAA).  

 is ≤0.63 lb ai/acre and since all environmental degradates were
identified at <10% TRR, a revised drinking water assessment is
unnecessary.  

Flutriafol and M1B:  Acute and chronic aggregate dietary (food and
drinking water) exposure and risk assessments were conducted for
flutriafol using DEEM-FCID™ (ver 2.03), which incorporates food
consumption data from the USDA CSFII (1994-1996 and 1998).  The residue
of concern in apple and soybean seed for tolerance enforcement and risk
assessment is flutriafol per se; the residue of concern in ruminants for
tolerance enforcement is flutriafol per se and for risk assessment is
flutriafol and M1B.  

The acute and chronic analyses assumed tolerance level apple and soybean
residues and modeled drinking water estimates.  Since the apple
processing study did not indicate a concentration of flutriafol residues
in apple juice, the DEEM (ver 7.81) apple juice default processing
factor was reduced to 1; the DEEM (ver 7.81) default dried apple
processing factor was retained since processing data for dried apple
were not provided.  As indicated above, the residues of concern in
ruminants for risk assessment are flutriafol and M1B (feeding study did
not monitor for residues of M1B).  Residues of M1B were found at 1% TRR
in liver collected from the ruminant liver metabolism study
(47090443.der.doc); therefore, adjustment of the ruminant liver
tolerance to include residues of M1B is unnecessary.  M1B was included
as a residue of concern in ruminants as it was the major residue in
kidney (M1B - ~23% TRR; flutriafol - 7% TRR; M1B <4% TRR in the
remaining analyzed matrices).  The ruminant feeding study resulted in
flutriafol per se residues of <0.01 ppm (<LOQ) in kidney following
dosing at 24x.  Based on this, a ruminant kidney flutriafol per se
tolerance was not established.  Combined flutriafol and M1B kidney
residues of 0.002 ppm were calculated ((0.01 ÷ 24) + (0.01 x 3.3 ÷ 24)
= 0.002 ppm), assuming LOQ flutriafol residues and the flutriafol to M1B
kidney residue ratio from the metabolism study.  This kidney residue
estimate was incorporated into the acute and chronic analyses.  

5.2.1	Acute Dietary Risk Characterization 

The acute (food + water) exposure risk estimate for females 13-49 years
old was 3.7% aPAD at the 95th percentile of the exposure distribution. 
The acute (food + water) exposure estimates were <100% aPAD for the U.S.
general population (<1.0% aPAD) and all population sub-groups; the most
highly exposed population subgroup was infants (<1 year old) with <1.0%
aPAD.  Therefore, acute dietary exposure to flutriafol is not of concern
to HED. 

5.2.2	Chronic Dietary Risk Characterization

The chronic (food + water) exposure estimates were <100% cPAD for the
U.S. general population (1.0% cPAD) and all population sub-groups; the
most highly exposed population subgroup was children 1-2 years old with
4.6% cPAD.  Therefore, chronic dietary exposure to flutriafol is not of
concern to HED. 

Table 5.2.1.  Summary of the Acute and Chronic Dietary Exposure and
Risk.

Population	aPAD (mg/kg/day)	Exposure (mg/kg/day)1	%aPAD	cPAD (mg/kg/day)
Exposure (mg/kg/day)	%cPAD

General U.S. Population	2.5	0.003661	<1.0	0.05	0.000514	1.0

All Infants (<1 year old)

0.012649	<1.0

0.002138	4.3

Children 1-2 years old

0.009584	<1.0

0.002280	4.6

Children 3-5 years old

0.006915	<1.0

0.001574	3.1

Children 6-12 years old

0.003834	<1.0

0.000715	1.4

Youth 13-19 years old

0.002635	<1.0

0.000372	<1.0

Adults 20-49 years old

0.002724	<1.0

0.000326	<1.0

Adults 50+ years old

0.002410	<1.0

0.000313	<1.0

Females 13-49 years old	0.075	0.002773	3.7

0.000333	<1.0

1	95th percentile (tier 1 analysis)

5.2.3 Leaching of Flutriafol to Groundwater

; however, based on a commodity analysis, water contributed ≤0.8% to
the cPAD; and (4) the acute and chronic exposure estimates were all <5%
the PAD. 

6.0	Residential (Non-Occupational) Risk

There are no existing or proposed residential uses for flutriafol. 
Therefore, a residential assessment was not necessary.

7.0	Aggregate Risk Assessments

Acute and chronic aggregate risks were assessed based on dietary
exposure from food and drinking water sources.  As there are no
registered or proposed uses of flutriafol that would result in
residential exposure, short- and intermediate-term aggregate risks were
not assessed.

A quantitative cancer aggregate risk was not needed since there was no
evidence of carcinogenicity. 

T and TA/TAA:  As noted above, the previous T and TA/TAA dietary
analyses (D350664, M. Doherty, 6-Oct-2008), which resulted in exposures
less than HED's level of concern, are sufficient to account for exposure
to T and TA/TAA as a result of the proposed flutriafol application. 
Based on this, and since the proposed use is for agricultural purposes
only, HED concludes that previously calculated T and TA/TAA aggregate
assessments (D359490, M. Doherty, 09-Dec-2008), which resulted in
exposures less than HED's level of concern, are sufficient to account
for exposure to T and TA/TAA as a result of the proposed flutriafol
application.  

7.1	Acute and Chronic Aggregate Risk

Since the acute and chronic dietary assessments included food and water
only, the exposures in Table 5.2.2 represent aggregate exposures. 
Therefore, acute and chronic aggregate risks to flutriafol are not of
concern to HED. 

 

8.0	Cumulative Risk Characterization

Flutriafol is a member of the triazole-containing class of pesticides. 
Although conazoles act similarly in plants (fungi) by inhibiting
ergosterol biosynthesis, there is not necessarily a relationship between
their pesticidal activity and their mechanism of toxicity in mammals. 
Structural similarities do not constitute a common mechanism of
toxicity.  Evidence is needed to establish that the chemicals operate by
the same, or essentially the same, sequence of major biochemical events
(EPA, 2002).  In conazoles, however, a variable pattern of toxicological
responses is found; some are hepatotoxic and hepatocarcinogenic in mice.
Some induce thyroid tumors in rats.  Some induce developmental,
reproductive, and neurological effects in rodents.  Furthermore, the
conazoles produce a diverse range of biochemical events including
altered cholesterol levels, stress responses, and altered DNA
methylation.  It is not clearly understood whether these biochemical
events are directly connected to their toxicological outcomes.  Thus,
there is currently no evidence to indicate that conazoles share common
mechanisms of toxicity and EPA is not following a cumulative risk
approach based on a common mechanism of toxicity for the conazoles.  For
information regarding EPA’s procedures for cumulating effects from
substances found to have a common mechanism of toxicity, see EPA’s
website at http://www.epa.gov/pesticides/cumulative.

Flutriafol is a triazole-derived pesticide.  This class of compounds can
form the common metabolite T and two triazole conjugates (TA and TAA). 
To support existing tolerances and to establish new tolerances for
triazole-derivative pesticides, including flutriafol, U.S. EPA conducted
a human-health risk assessment for exposure to T, TA, and TAA resulting
from the use of all current and pending uses of any triazole-derived
fungicide.  The risk assessment is a highly conservative,
screening-level evaluation in terms of hazards associated with common
metabolites (e.g., use of a maximum combination of uncertainty factors)
and potential dietary and non-dietary exposures (i.e., high-end
estimates of both dietary and non-dietary exposures).  In addition, the
Agency retained the additional 10X FQPA SF for the protection of infants
and children.  The assessment includes evaluations of risks for various
subgroups, including those comprised of infants and children.  The
Agency’s complete risk assessment is found in the propiconazole
reregistration docket at http://www.regulations.gov, Docket
Identification (ID) Number EPA-HQ-OPP-2005-0497.

9.0	Occupational Risk Assessment

Reference: Memo, K. Lowe, D353076, 01-JUN-2009.

Based on the proposed uses on soybeans and apples, occupational handler
and post-application exposure is expected.  

9.1	Occupational Handler Risk Assessment

There is potential for occupational handler exposure from the proposed
uses on agricultural crops.  It is anticipated that the following
scenarios could result in handler exposure:  

Mixing/loading liquid concentrate to support aerial applications;

Mixing/loading liquid concentrate to support groundboom applications;

Mixing/loading liquid concentrate to support airblast application;

Applying sprays with aircraft (enclosed cockpit);

Applying sprays with groundboom equipment;

Applying sprays with airblast equipment; and

Flagging to support aerial spray applications.

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED
(August, 1998).  For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline,” that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves, as well as for “baseline” and the use of protective gloves
or other PPE as might be necessary.  The flutriafol product labels
direct applicators and other handlers to wear long-sleeved shirt and
long pants, chemical-resistant gloves, and shoes plus socks.

Exposure Duration

Handler exposure is expected to be short- or intermediate-term based on
information provided on proposed labels.  In addition, the short- and
intermediate-term toxicological endpoints are the same; therefore, the
estimates of risk for short-term duration exposures are protective of
those for intermediate-term duration exposures.  Long-term exposures are
not expected; therefore, a long-term assessment was not conducted.  

Risk Calculations

A dermal-absorption factor of 21% based on an in vivo rat
dermal-absorption study was identified and an inhalation absorption
factor of 100% for extrapolation from an oral exposure to an inhalation
exposure will be assumed.  A body weight of 60 kg was used since the
endpoints were from developmental toxicity studies.  The dermal and
inhalation MOEs were combined for the occupational handler risk
assessments because the toxicity PODs for the dermal and inhalation
routes of exposure are based on the same toxicological effects.  

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task using the following formula:

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x
Application Rate (lbs ai/gallon) x Amount Handled (gal/day)

Where:  

Daily Exposure		=	Amount (mg ai/day) deposited on the surface of the
skin that is available for 

dermal absorption or amount inhaled that is available for inhalation
absorption;

Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August
1998 PHED data or from 

ORETF data;

Application Rate		=	Normalized application rate (lb ai/gal); and

Daily Area Treated 	=	Normalized amount handled (gal/day). 

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate dermal or inhalation absorption factor using the following
formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100) / Body Weight (kg)

Where:

Average Daily Dose 	= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg 

ai/kg bw/day);

Daily Exposure 		=	Amount (mg ai/day) deposited on the surface of the
skin that is available for 

				dermal absorption or amount inhaled that is available for inhalation
absorption;

Absorption Factor 	= 	A measure of the amount of chemical that crosses a
biological boundary such as 

				the skin or lungs (% of the total available absorbed); and

Body Weight 		= 	Body weight determined to represent the population of
interest in a risk 

				assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler
scenario are calculated using a MOE, which is a ratio of the POD to the
daily dose.  All MOE values were calculated using the formula below:

MOE= POD (mg/kg/day) / Average Daily Dose (mg/kg/day)

A total MOE was calculated because the dermal and inhalation
toxicological PODs are based on the same adverse effects.  The total MOE
values were calculated using the formula below:

Total MOE = 1 / [(1/dermal MOE) + (1/inhalation MOE)]

Table 9.1 presents the exposure/risks for short and intermediate-term
dermal and inhalation exposures at baseline, and with additional PPE. 
The combined dermal and inhalation exposure risks for mixer/loaders are
not of concern (i.e., MOEs >100), provided the mixer/loaders wear
protective gloves as directed on the label.

 

HED has no data to assess exposures to pilots using open cockpits.  The
only data available is for exposure to pilots in enclosed cockpits. 
Therefore, risks to pilots are assessed using the engineering control
(enclosed cockpits) and baseline attire (long-sleeve shirt, long pants,
shoes, and socks); pilots are not required to wear protective gloves. 
With this level of protection, there are no risks of concern for
applicators.

	Application Rates based on proposed uses on label for flutriafol
product TOPGUARD™ (EPA 67760-xxx).

2.	Science Advisory Council for Exposure (ExpoSAC) Policy # 9.1.

3.	Unit Exposures based on PHED Version 1.1.  Baseline Dermal: 
Long-sleeve shirt, long pants, and no gloves.  Baseline Inhalation:  no
respirator.  PPE-G:  Baseline plus chemical-resistant gloves.  Eng
control: engineering control for applying sprays via aerial equipment =
enclosed cockpit.  

4.	Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate
(lb ai/acre) x acres treated x absorption factor (dermal:  21%;
inhalation: 100%) / body weight (60 kg adult female).

5.	Combined dose (mg/kg/day) = Dermal dose (mg/kg/day) + Inhalation dose
(mg/kg/day).

6.	MOE = POD (NOAEL, 7.5 mg/kg/day) / Dose (mg/kg/day) and Combined MOE
= POD (NOAEL, 7.5 mg/kg/day) / combined dose (mg/kg/day).9.2
Occupational Post-application Exposure

HED assumes that inhalation exposures are minimal following outdoor
applications of an active ingredient with low vapor pressure.  Since
flutriafol is applied only in outdoor settings and has a low vapor
pressure, post-application inhalation exposures and risks were not
assessed. 

There is a potential for post-application exposure to field workers
following foliar application of flutriafol to agricultural crops. 
Post-application exposure is expected to be short- or intermediate-term
based on information provided on proposed labels.  In addition, the
short- and intermediate-term toxicological endpoints are the same;
therefore, the estimates of risk for short-term duration exposures are
protective of those for intermediate-term duration exposures.  Since no
post-application data were submitted in support of this registration
action, dermal exposures during post-application activities were
estimated using dermal transfer coefficients (TCs) from the ExpoSAC
Policy Number 3.1: Agricultural TCs, August 2000, summarized in Table
9.2.1 below and the following assumptions:

					

Application Rate	= 	0.11 lb ai/A 

Exposure Duration	=	8 hours per day

Body Weight		=	60 kg for adult female		

Dermal Absorption	= 	21%

Fraction of a.i. retained on foliage is assumed to be 20% (0.2) on the
day of application (= % dislodgeable foliar residue, DFR, after initial
treatment) for agricultural crops.  This fraction is assumed to further
dissipate at the rate of 10% (0.1) per day on following days.  These are
default values established by HED’s ExpoSAC.

Table 9.2.1.  Anticipated Post-application Activities and Dermal TCs.

Proposed Crops	Policy Crop Group Category	Transfer Coefficients (cm2/hr)
Activities

Apples	Tree, fruit, deciduous	3,000	Thinning

1,500	Hand harvesting, propping, hand pruning, training

1,000	Scouting and hand weeding and irrigating

Soybeans	Field row crop, low/medium	1,500	Scouting and irrigating

100	Scouting and hand weeding

The following equations were used to calculate risks for workers
performing post-application activities:

DFRt = AR x F x (1-D)t x CF1 x CF2

Where:	

	DFRt 	=	dislodgeable foliage residue on day "t" (µg/cm2)

	AR	=	application rate (lb ai/acre)

	F	=	fraction of ai retained on foliage (unitless)

	D	=	fraction of residue that dissipates daily (unitless)

	CF1	=	conversion factor, 4.54E8 µg/lb

	CF2	=	conversion factor, 2.47E-8 acre/cm2

and

Daily dermal dose t = (DFRt x CF1 x TC x DA x ET) / BW 

Where:

Daily dermal dose	=	Absorbed dose received from exposure to a pesticide
in a given scenario on day “t” (mg/kg/day)

DFRt 			=	dislodgeable foliage residue on day "t" (µg/cm2)

	CF1			=	conversion factor, 1E-3 mg/µg

	TC			=	transfer coefficient (cm2/hr)

     	DA			=     	dermal-absorption factor (unitless)

	ET			=	exposure time (hr/day)

	BW			=	body weight (kg)

and

		MOE = POD (mg/kg/day) / Daily Dermal Dose (mg/kg/day)

The post-application exposures associated with the proposed uses are
summarized in Table 9.2.2.  The resulting MOEs are greater than 100 on
day 0 (12 hours after application) and, therefore, do not exceed HED’s
LOC.

Table 9.2.2.  Post-application Exposure and Risk for Flutriafol.

Crop Grouping/Crop	Activity	Transfer

Coefficient	Days after Treatment	DFR1 (µg/cm2)	Daily Dermal Dose2
(mg/kg/day)	MOE3

Tree Fruit,

Apples	Thinning	3,000	0

(12 hours)	0.25	0.021	360

	Hand harvesting, hand pruning, training, propping	1,500

	0.010	720

	Scouting, hand weeding, irrigating	1,000

	0.007	1100

Field and row crops, soybeans	Scouting and irrigating	1,500

	0.010	720

	Scouting and hand weeding	100

	0.0007	11,000

1		DFR = application rate (0.11 lb ai/A) x (1- daily dissipation rate) t
x 4.54E8 µg/lb x  24.7E-9 A/cm2  x  20% DFR after initial treatment.

2	Daily Dermal Dose = [DFR (µg/cm2) x TC x 0.001 mg/µg x 8 hrs/day x
21% dermal absorption] ( body weight (60 kg adult female).

3	MOE = POD (NOAEL, 7.5 mg/kg/day) / Daily Dose.   

9.3	REI

Since post-application risks were not a concern on day 0 (12 hours
following application), the REI is based on the acute toxicity of
flutriafol technical material which is classified as Category III for
eye irritation potential and Category IV for skin irritation potential. 
Flutriafol is classified as Category II for acute dermal toxicity based
on an absence of systemic toxicity at 1000 mg/kg/day in the 28-day
dermal toxicity study in the rat.  Flutriafol is not a dermal
sensitizer.  Under the Worker Protection Standard for Agricultural
Pesticides, active ingredients classified as acute Toxicity Category II
are assigned a 24-hour REI.  Therefore, the 12-hour REI that appears on
the proposed label needs to be corrected to 24 hours.

10.0	Data Needs and Label Recommendations

Toxicology

Immunotoxicity Study.  An immunotoxicity study is now a data requirement
in the 40 CFR revised Part 158.

Residue Chemistry 

Submission of flutriafol analytical standard to ACL.

A revised Section B with the following changes is requested:  (1) the
proposed minimum apple RTI of 7 days for apples is not supported by the
crop field trial data; the use directions should be revised to specify a
minimum apple RTI of 14 days; (2) the apple use directions should be
amended to specify a minimum spray volume of >20 GPA; (3) since the
soybean and apple field trials did not include an adjuvant, the label
should be revised prohibiting the addition of adjuvants to the spray
solutions; (4) the soybean use directions should be limited to the
application to soybeans harvested for the dried seed; and (5) the label
should indicate that only soybean may be rotated to a treated field.  

flutriafol
[(±)-α-(2-fluorophenyl)-α-(4-fluorophenyl)-1H-1,2,4-triazole-1-ethano
l]: 

Commodity	Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Comments

Apple	0.2	0.20	Numerical tolerance should be 0.20.

Soybean	0.3	0.35	Based on the field trial data and the tolerance
calculator, the numerical tolerance should be 0.35 ppm and the correct
commodity definition is "Soybean, seed."

Soybean, aspirated grain fractions	0.5	2.2	Based on the field trial and
processing data, the numerical tolerance should be 2.2 ppm and the
correct commodity definition is "Grain, aspirated fractions."

Liver (cattle, goat, hog, horse, sheep)	0.01	--	Incorrect commodity
definition.

Cattle, liver	--	0.02	--

Goat, liver	--	0.02	--

Hog, liver	--	0.02	--

Horse, liver	--	0.02	--

Sheep, liver	--	0.02	--

Eggs	0.01	--	Tolerance not required.

Information concerning the storage conditions/interval for the samples
collected from the ruminant metabolism study; if the storage intervals
were >6 months, then data demonstrating the stability of the metabolic
profile in the various matrices will be required.  

Submission of storage stability data demonstrating the stability of T,
TA, and TAA in the soybean matrices for the employed intervals (soybean
seed - 16 months; soybean meal, hull, and oil - 12 months).

Storage stability data for flutriafol, T, TA, and TAA in ruminant liver
(139 days).  

Occupational and Residential Exposure

Change the REI on the proposed label from 12 hours to 24 hours.

Appendix A:	Toxicology Assessment

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.500) for food use for flutriafol are in
Table 1.  Use of the new guideline numbers does not imply that the new
(post-1998) guideline protocols were used.

Table 1.  Toxicology Data Requirements for Flutriafol

Test	Technical

	Required	Satisfied

870.1100	Acute Oral Toxicity

870.1200	Acute Dermal Toxicity

870.1300	Acute Inhalation Toxicity

870.2400	Primary Eye Irritation

870.2500	Primary Dermal Irritation

870.2600	Dermal Sensitization	yes

yes

yes

yes

yes

yes	yes

no

yes

yes

yes

                yes

870.3100	Oral Subchronic (rodent)

870.3150	Oral Subchronic (nonrodent)

870.3200	21-Day Dermal

870.3250	90-Day Dermal

870.3465	90-Day Inhalation	yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a	Developmental Toxicity (rodent)

870.3700b	Developmental Toxicity (nonrodent)

870.3800	Reproduction	yes

yes

yes	yes

yes

yes

870.4100a	Chronic Toxicity (rodent)

870.4100b	Chronic Toxicity (nonrodent)

870.4200a	Oncogenicity (rat)

870.4200b	Oncogenicity (mouse)

870.4300	Chronic/Oncogenicity	yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5400	Mutagenicity—Structural Chromosomal Aberrations

870.5500	Mutagenicity—Other Genotoxic Effects	yes

yes

yes

yes	yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)

870.6100b	90-Day Neurotoxicity (hen)

870.6200a	Acute Neurotox. Screening Battery (rat)

870.6200b	90-Day Neuro. Screening Battery (rat)

870.6300	Develop. Neurotoxicity	no

no

yes

yes

no	-

-

yes

yes

-

870.7485	General Metabolism

870.7600	Dermal Penetration

870.7800       Immunotoxicity	yes

yes

yes	yes

yes

no

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

A.2.	Toxicity Profiles

Table A.2.1.  Acute Toxicity Profile – Flutriafol.

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral (rat)	47090336	LD50 = 1140 mg/kg (M); 1480 mg/kg (F)
III

870.1200	Acute dermal (rat)	47090337	-	II

870.1300	Acute inhalation (rat)	47090338	LC50 > 5.20 mg/L	IV

870.2400	Primary eye irritation (rabbit)	47090339	Minimally irritating
III

870.2500	Primary dermal irritation (rabbit)	47090341	Not a dermal
irritant	IV

870.2600	Dermal sensitization (mouse)	47090343	Not a sensitizer	-

Table A.2.2.  Subchronic and Chronic Toxicity and Genotoxicity Profile
– Flutriafol.

Guideline No.	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3050

	28-Day oral toxicity (rat)	47090344 (1982)

Acceptable/non-guideline

0, 100, 300, 800, 2000, or 5000 ppm (0, 10, 30, 80, 200, and 500
mg/kg/day)	NOAEL = 800 ppm (80 mg/kg/day)

LOAEL = 2000 ppm (200 mg/kg/day), based on liver toxicity (increased
weight, centrilobular hepatocellular hypertrophy, fatty change, hydropic
degeneration, smooth endoplasmic reticulum proliferation, and increased
aminopyrine-N-demethylase activity) in both sexes and decreased
body-weight gain and food consumption in males.

870.3100	90-Day oral toxicity (rat)	47090345 (1982) 

Acceptable/guideline

0, 20, 200, or 2000 ppm 

M: 0, 1.5, 14, and 158 mg/kg/day)

F: 0, 1.6, 22, and 145 mg/kg/day	NOAEL = 200 ppm (14/22 mg/kg/day in
M/F)

LOAEL = 2000 ppm (158/145 mg/kg/day in M/F), based on decreased
body-weight gain, decreased food consumption and liver toxicity
(increased absolute and adjusted liver weights, increased endoplasmic
reticulum proliferation in the males, and increased APDM activity).

870.3150

	90-Day oral toxicity (dog)	47090346 (1982) 

Acceptable/guideline

0, 1, 5, or 15 mg/kg bw/day	NOAEL = 5 mg/kg/day

LOAEL = 15 mg/kg/day, based on adverse liver findings (increases in
organ weight, alkaline phosphatase, aminopyrine N-demethylase activity,
and incidence of hemosiderin-laden Kupffer cells) in both sexes, spleens
with hemosiderin content slightly higher than controls in the males, and
decreased cumulative body-weight gains and increased triglycerides in
the females.

870.3200

	28-Day dermal toxicity (rat)	47090347 (2007)

Acceptable/guideline

0, 250, 500, or 1000 mg/kg/day	NOAEL = 1000 mg/kg/day

LOAEL was not established

870.3700a

	Prenatal developmental (rat)	47090349 (1982)

Unacceptable/guideline

0, 10, 50, or 125 mg/kg/day	Maternal NOAEL = 50 mg/kg/day

LOAEL = 125 mg/kg/day, based on increased incidence of ventral/genital
staining of the fur and decreased maternal body-weight gains and food
consumption.

Developmental NOAEL = 10 mg/kg/day

LOAEL = 50 mg/kg/day, based on delayed ossification or non-ossification
of the skeleton in the fetuses.

870.3700a

	Prenatal developmental (rat)	47521303 (2008)

Acceptable/guideline

0, 2, 5, 10, or 755 mg/kg/day	Maternal NOAEL = 10 mg/kg/day

LOAEL = 75 mg/kg/day, based on decreased body-weight gains and food
consumption.

Developmental NOAEL = 10 mg/kg/day

LOAEL = 75 mg/kg/day, based on increased late resorptions; malformations
(cleft palate and multiple hyoid malformations) and variations in the
hyoid; variations in the maxilla/mandible, rudimentary and long cervical
ribs, pelvic girdle, and radius/ulna; numerous skeletal retardations
detailed above and corresponding decrease in fetal weights.

870.3700b

	Prenatal developmental (rabbit)	47090350 (1982)

Acceptable/guideline

0, 2.5, 7.5, or 15 mg/kg/day	Maternal NOAEL = 7.5 mg/kg/day

LOAEL = 15 mg/kg/day, based on decreased corrected and uncorrected
body-weight gains and food consumption.

Developmental NOAEL = 7.5 mg/kg/day

LOAEL = 15 mg/kg/day, based on decreased number of live fetuses,
complete litter resorptions and increased post-implantation loss.  

870.3800

	2-gen. reproduction and fertility effects

(rat)	47090351 (1986)

Acceptable/guideline

0, 60, 240 or 1,000 ppm M: 0, 4.8, 20.6 and 88.7 mg/kg/day)

F: 0, 5.5, 21.9, and 103 mg/kg/day	Parental/Systemic NOAEL = 240 ppm
(20.6/21.9 mg/kg/day [M/F])

LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on decreased
body-weight gains and food consumption and on effects on the liver
(increased liver weights, centrilobular hypertrophy, and fatty change).

Reproductive NOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F])

LOAEL was not determined.

Offspring NOAEL = 240 ppm (20.6/21.9 mg/kg/day [M/F])

LOAEL = 1000 ppm (88.7/103 mg/kg/day [M/F]) based on decreased live
birth index and litter size and on effects on the liver (fatty
change/vacuolation).

870.4100

	Chronic toxicity (1 year; dog)	47090353 (1988)

Acceptable/guideline

0, 1, 5, or 20 mg/kg/day	NOAEL = 5 mg/kg/day

LOAEL = 20 mg/kg/day, based on: adverse liver findings (increased liver
weights, increased centrilobular hepatocyte lipid in the liver, and
increases in alkaline phosphatase, albumin and triglycerides), increased
adrenal cortical vacuolation of the zona fasciculata, and marked
hemosiderin pigmentation in the liver and spleen in both sexes; mild
anemia (characterized by decreased hemoglobin, hematocrit, and red blood
cell count) in the males; and initial body weight losses, decreased
cumulative body-weight gains, and increased adrenal weights in the
females.

870.4200

	Carcinogenicity

(mouse)	47090354 (1988)

Acceptable/guideline

0 (two control groups), 10, 50, or 200 ppm

M: 0, (0, 1.1, 5.9, and 24 mg/kg/day)

F: 0, 1.4, 7.4, and 31 mg/kg/day	NOAEL = 50 ppm (5.9/7.4 mg/kg/day in
M/F)

LOAEL = 200 ppm (24/31 mg/kg/day in M/F), based on hepatotoxicity
(increased fatty change) in both sexes.

No evidence of carcinogenicity.

870.4300

	Combined Chronic Toxicity/

Carcinogenicity

(rat)	47090352 (1986)

Acceptable/guideline

0, 20, 200, or 2000 ppm M: 0, 1.02, 10.0, and 102 mg/kg/day)

F: 0, 1.27,12.2, and 122 mg/kg/day	NOAEL = 200 ppm (10.0/12.2 mg/kg/day
in males/females)

LOAEL = 2000 ppm (102/122 mg/kg/day in males/females), based on adverse
liver effects (increased liver weights, fatty change, bile duct
proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer
cells and centrilobular hypertrophy), and clinical chemistry findings.

No evidence of carcinogenicity.

870.5100	In vitro Bacterial Gene Mutation (Salmonella typhimurium)/
mammalian activation gene mutation assay	47090401 (1988)

Acceptable/guideline

0, 1.6, 8, 40, 200, 1000, or 5000 µg/plate ( Trial 1) or 0, 8, 40, 200,
1000, 2500, or 5000 µg/plate (Trial 2); Both trials were  performed
w/wo S9-activation	There were no marked increases in the mean number of
revertants/plate in any strain.  There was no evidence of induced mutant
colonies over background.

870.5300	In Vitro Gene Mutation assay in mouse lymphoma cells	47090402
(1986)

Acceptable/guideline

0, 10, 33, 100, 333, or 1000 µg/mL (+S9, Trial 1); 0, 150, 300, 450,
600, or 750 µg/mL (-S9, Trial 1); 0, 150, 300, 450, 600, 750, 900,
1050, or 1200 µg/mL (+S9, Trial 2); or 0, 200, 300, 400, 500, 600, 700,
or 800 µg/mL

(-S9, Trial 2)	There was a dose-related increase in mutant frequency
(7.0-9.0x10-5 treated vs. 3.0x10-5 controls) and absolute mutant numbers
(70-148 colonies/plate vs. 63 controls) at 100 µg/mL and above in Trial
1 and a marked increase in mutant frequency at 750 µg/mL (6.5x10-5
treated vs. 1.2x10-5 controls) in Trial 2 attributable to severe
cytoxicity (2% relative survival).  However, the increases in mutant
frequency did not achieve the threshold value for a positive response
(>10x10-5) in either trial and there was no marked increase in absolute
mutant numbers at 750 µg/mL in Trial 2.  In the absence of S9, there
were no marked increases in mutant frequency or absolute mutant numbers
compared to controls in either trial.  There was no convincing evidence
of induced mutant colonies over background in the presence or absence of
S9-activation.

870.5375	In vitro Mammalian Cytogenetics (Chromosomal Aberration Assay
in Human Peripheral Blood Lymphocytes)	47090403 (1989)

Acceptable/guideline

0, 25, 125, or 250 µg/mL (+/-S9)	No significant increases in the
numbers of cells with aberrations (excluding gaps) were observed in
either donor in the presence or absence of S9. There was no evidence of
chromosome aberrations induced over background in the presence or
absence of S9-activation.

870.5385	In vivo Mammalian Cytogenetics – [Bone Marrow Chromosomal
Aberration Test	47090404 (1982)

Acceptable/guideline

0, 15, 70, or 150 mg/kg	There was no evidence of chromosome aberration
induced over background.

870.5395	In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay
in Mice	47090405 (1986)

Acceptable/guideline

0, 93.8, or 150 mg/kg	Decreased (p<0.01) polychromatic erythrocyte to
normochromatic erythrocyte ratios (PCE:NCE) were observed in both doses
at all time points, indicating that the test material was toxic to the
bone marrow.  There was no significant increase in the frequency of
micronucleated polychromatic erythrocytes in bone marrow after any
treatment time.

870.5450	Dominant Lethal Assay - Mice

	47090406 (1982)

Acceptable/guideline

0, 25, 50, or 100 mg/kg/day (total doses of 0, 125, 250, or 500 mg/kg)
Mortality (3/15 males) was noted at 100 mg/kg/day during dosing.  Slight
decreases (p<0.05) in body weight were observed at 50 mg/kg/day and
above during dosing.  There were no treatment-related effects on
fertility, mean number of implantations, or the number of early or late
deaths.  There was no time-related positive response of increased pre-
or post-implantation loss compared to controls.

870.5550	Unscheduled DNA Synthesis in Primary Rat Hepatocytes/Mammalian
Cell	47090407 (2003)

Acceptable/guideline

0, 250, 500, or 1000 mg/kg	The net nuclear grain (NNG) counts in the
treated animals (–3.42 to –2.64) were well below the threshold of
≥5 NNG needed for a positive response, and no increase in the mean
percent of cells in repair was observed.  There was no evidence that
unscheduled DNA synthesis, as determined by radioactive tracer
procedures [nuclear silver grain counts] was induced.

870.6200a

	Acute neurotoxicity screening battery	47090408 (2005)

Acceptable/guideline

0, 125, 250, or 750 mg/kg	NOAEL = 250 mg/kg

LOAEL = 750 mg/kg, based on decreased body weight, body-weight gain,
absolute and relative food consumption, and clinical signs of toxicity,
indicative of a moribund condition, in both sexes: dehydration,
urine-stained abdominal fur, ungroomed coat, ptosis, decreased motor
activity, prostration, limp muscle tone, muscle flaccidity, hypothermia,
hunched posture, impaired or lost righting reflex, scant feces; in
males: red or tan perioral substance, chromodacryorrhea,
chromorhinorrhea and labored breathing, and in females:  piloerection
and bradypnea, and signs of neurotoxicity:  hunched posture in females
and ataxia in males.

870.6200b	Subchronic Neurotoxicity – Feeding Study in Rats	47090410
(2007)

Acceptable/guideline

0, 500, 1500, or 3000 ppm (0/0, 28.9/32.6, 84.3/97.6, and 172.1/185.0
mg/kg/day [M/F])	NOAEL = 1500 ppm (84.3/97.6 mg/kg/day [M/F]).

LOAEL = 3000 ppm (172.1/185.0 mg/kg/day [M/F]) based on decreased
body-weight gain, absolute and relative food consumption; and decreased
hindlimb grip strength in males.

870.7485

	Metabolism and pharmacokinetics

(rat)	47090412 (2006)

Acceptable/guideline

5 or 250 mg/kg	More than 78% of the dose was recovered in the bile and
urine.  Absorption was similar between sexes and between single and
multiple dose regimes.  Absorption is extensive.  The dose was mostly
eliminated within 48 hours. Only 0.04-0.05% of the dose was found in the
expired carbon dioxide.  Most of the radioactivity was excreted in the
bile (47-79% of the dose).  The excretion profile was similar between
sexes.  In the blood, radioactivity partitioned into the red blood
cells.  In both sexes and all groups, concentrations of radioactivity
were relatively high in whole blood, liver and kidneys.  Other organs
with high concentrations included the adrenal glands, spleen, and
pituitary.  The distribution profiles were similar between species, dose
level, and single vs multiple dose regime.  In the whole blood, the
concentrations were proportional to the dose.  The total amount of
radioactivity isolated in the tissues and carcass was <1-3%. 
Bioaccumulation was considered unlikely.  The parent was isolated in
only trace amounts in the urine and feces and more than 19 metabolites
were isolated, indicating extensive metabolism.  Metabolism profiles
were similar between sexes.  The metabolic profiles were similar
regardless of the matrix (feces, urine, or bile), the dose, and the sex.
 The primary site for metabolism was the 2-fluorophenyl ring.  The
initial metabolic step was epoxidation followed by either rearrangement
to form the dihydrodiol isomers or to form hydroxy or dihydroxy
metabolites.  The hydroxyl groups on these primary metabolites may then
be either conjugated with glucuronic acid or methylated.  A second,
minor route for metabolism of flutriafol was via the removal of the
triazole ring to form 1-(2 fluorophenyl)-1-(4-fluorophenyl)-ethandiol,
which is then conjugated with glucuronic acid.

870.7600	In vivo dermal penetration

(rat)	47090415 (2006)

Acceptable/guideline

0.02, 0.2 or 2 mg/cm2 skin were tested (10 µl/cm2 skin), and actual
doses were 0.0208, 0.201, and 2.154 mg/cm2 skin	Dermal ranged up to
15.8% of the applied dose.  Absorption was minimal with only 4 h of
exposure.  Absorbable radioactivity (radioactivity in the skin at the
application site and the adjacent skin) was minimal in groups that were
exposed for 10 h and evaluated for an additional 158 h post-exposure. 
Thus, almost all of the dose isolated in the skin will be absorbed. 
Considering the sum of absorbable and absorbed doses, 4-37% of the
applied dose was recovered in the treatment groups (11%).  Absorption
rate constants were calculated as 0.236, 0.190, and 0.072 h-1 for the 2,
20, and 200 µg/cm2 dose groups.  Absorption mechanisms were saturated
at the high dose.  The elimination half-lives were calculated to be 31,
30, and 37 h for the 2, 20, and 200 µg/cm2 dose groups.  A maximum of
36.56% of the applied dose was noted as absorbed/absorbable (observed
after 24 h exposure to 2 µg/cm2). The dose that is absorbed/absorbable
following a 10 h exposure is 16.54%, 21.31% and 11.39%, respectively, at
2, 20 and 200 µg/cm2.

A.3.	Executive Summaries

A.3.1	Subchronic Toxicity

	870.3100	90-Day Oral Toxicity – Rat

In a subchronic oral toxicity study (MRID 47090345), PP450 (93% a.i.;
Batch No. P10) was administered to 20 Wistar rats/sex/dose in the diet
at dose levels of 0, 20, 200, or 2000 ppm (calculated to be 0, 1.5, 14
and 158 mg/kg bw/day in males, and, 0, 1.6, 22 and 145 mg/kg/day in
females) for 90 days.

No treatment-related effects were noted on mortality, clinical signs of
toxicity, ophthalmoscopic examinations, urinalysis, or gross pathology
at any dose in either sex.

At 2000 ppm, body-weight gains were decreased (p<0.01) throughout the
study by 15-62% in both sexes.  Food consumption was decreased (p<0.05)
by 7-21% in the males (Weeks 1, 3, 5, 8, 10, and 12) and 9-35% in the
females (throughout the study).  Total (Weeks 1-13) food consumption was
decreased (p<0.01) by 7-19% in both sexes.  At 200 ppm, sporadic
decreases (p<0.05) of 5-12% were noted in food consumption and overall
food consumption was decreased by 6-7% in both sexes. At 20 ppm,
sporadic decreases (p<0.05) in food consumption of 4-12% in was observed
in both sexes. 

Slight anemia was noted at 2000 ppm as indicated by decreases (p<0.01)
in the following parameters: (i) hemoglobin (↓4-7%) at Weeks 4 and 13;
(ii) hematocrit (↓5%) at Week 13; (iii) mean corpuscular volume
(↓3%) at Week 13; (iv) mean corpuscular hemoglobin (↓3-4%) at Weeks
4 and 13 and (v) mean corpuscular hemoglobin concentration at Weeks 4
and 13 (↓1-3%). The kaolin-cephalin time was decreased (↓13%) at
terminal sacrifice.  APDM activity was increased (p<0.05) by 22-27% in
both sexes, triglycerides were decreased (p<0.01), and cholesterol was
increased (p<0.01) at Weeks 4 and 13 in both sexes.

The target organ was the liver.  At 200 ppm, the absolute and adjusted
liver weights were increased (p<0.05) in females by 5-8% at this dose. 
At 2000 ppm, increases (p<0.01) in absolute and adjusted for body weight
liver weights were observed in both sexes.  Increased incidence (#
affected/40) of hepatocyte vacuolation (fatty change) was noted in 25
treated animals vs. 5 controls. Centrilobular hypertrophy (25 treated
vs. 0 controls) with associated proliferation of smooth endoplasmic
reticulum and elevated aminopyridine-N-demethylase (APDM) activity was
also observed in both sexes at this dose.   Smooth endoplasmic reticulum
proliferation in the liver was increased (p<0.01) in the males.   

The LOAEL is 2000 ppm (158/145 mg/kg bw/day in males/females) based on
decreased body-weight gain; decreased food consumption and liver
toxicity (increased absolute and adjusted liver weights, increased
endoplasmic reticulum proliferation in the males, and increased APDM
activity).  The NOAEL is 200 ppm (14/22 mg/kg bw/day in males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3100a; OECD 408) for a subchronic oral
toxicity study in the rat.

	

870.3150	90-Day Oral Toxicity - Dog

In a subchronic toxicity study in dogs (MRID 47090346), Flutriafol
technical (PP450; 93.0% a.i.; batch # P10) was administered to four
beagle dogs/sex/dose group daily by capsule for 90 days at doses of 0,
1, 5, or 15 mg/kg/day.

No adverse, treatment-related effects were observed on mortality,
clinical signs of toxicity, food consumption, ophthalmoscopic
examinations, hematology, urinalysis, or gross pathology.

Mild focal alveolitis/bronchiolitis of the lungs was observed in the
females at 1 (3/4 dogs), 5 (1/4 dogs), and 15 (3/4 dogs) mg/kg/day
compared to (0/4) controls.  However, the Sponsor stated that this
finding was common in Alderley Park beagles, and was probably partly
associated with migration of Ascarid larvae and partly with respiratory
viruses.  Additionally, there was no strong dose relationship, and this
finding was observed in (2/4) control males.  Therefore, this finding
was considered equivocal.

≤0.05) in both sexes during Weeks 4, 8, and 13 by 42-82%, and the
increases became greater in magnitude with time of exposure. 
Triglycerides were increased (p≤0.01) by 65% in the 15 mg/kg/day
females during Week 13.  Hepatic aminopyrine N-demethylase activity was
increased (p≤0.01) in both sexes by 149-156%.

Additionally at 15 mg/kg/day, cumulative body-weight gains in the
females were decreased (p≤0.05; except NS during Weeks 2, 5, and 6)
throughout treatment by 39-75%, with body weight losses of 0.3-0.5 kg
occurring during Weeks 1 and 2.  Additionally, males were also noted to
have spleens with hemosiderin content slightly higher than controls in
3/4 dogs compared to 0 controls.

The LOAEL is 15 mg/kg/day, based on adverse liver findings (increases in
organ weight, alkaline phosphatase, aminopyrine N-demethylase activity,
and incidence of hemosiderin-laden Kupffer cells) in both sexes, spleens
with hemosiderin content slightly higher than controls in the males, and
decreased cumulative body-weight gains and increased triglycerides in
the females.  The NOAEL is 5 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3150) for a subchronic oral toxicity
study in dogs.

	870.3200	21/28-Day Dermal Toxicity – Rat

In a 28-day dermal toxicity study (MRIDs 47090347 and 47090348),
Flutriafol Technical (Batch # UPL Bx 1; purity 95.1% a.i.) was applied
to the clipped skin of ten Sprague Dawley (Crl:CD[SD]) rats/sex at dose
levels of 0, 250, 500, or 1000 mg/kg bw/day (corrected for purity) in a
dose volume of 1.0 mL/kg for six hours/day on at least 28 consecutive
days.  Rats were sacrificed on Day 29.

No effects of treatment were observed on mortality, clinical signs of
toxicity, neurobehavioral examinations, body weights, body-weight gains,
food consumption, ophthalmology, hematology, clinical chemistry, or
gross or microscopic pathology.

In the 500 mg/kg/day females, increased incidence (total #
observations/# of rats with observation) of erythema grade 1 (24/5; not
significant [NS]) and flaking grade 1 (12/5; p≤0.05) were observed at
the treatment site.  Additionally at 1000 mg/kg/day, increased
(p≤0.01) incidences of erythema grade 1 (52/7 males; 73/10 females),
flaking grade 1 (11/6 males; 49/7 females), and scab(s) (35/5 males
[NS]; 17/4 females) were noted at the treatment site.

The systemic LOAEL was not observed.  The NOAEL is 1000 mg/kg bw/day
(limit dose).

This 28-day dermal toxicity study is classified acceptable/guideline and
satisfies the guideline requirement (OPPTS 870.3200) for a dermal
toxicity study in the rat.

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 47090349), Flutriafol (PP450;
93%; Batch # P10) in corn oil was administered via daily oral gavage in
a dose volume of 10 mL/kg to 24 presumed pregnant Wistar rats at doses
of 0, 10, 50, or 125 mg/kg/day from gestation days (GD) 6-15.  On GD 21,
all dams were euthanized; each dam’s uterus was removed via cesarean
section and its contents examined.  Fetuses were examined for external,
visceral, and skeletal malformations and variations.

All dams survived until scheduled termination.  There were no
treatment-related macroscopic findings.

Increased incidence of staining of the genital/ventral fur was observed
primarily during the dosing period in 16 dams at 125 mg/kg/day compared
to 7 dams in the control group.  Additionally at 125 mg/kg/day, maternal
body-weight gains were decreased (p≤0.01) during the treatment (decr.
26%) and post-treatment (decr. 33%) intervals, and for the overall study
(decr. 23%).  Overall net weight gain, corrected for gravid uterine
weight, was decreased by 19% compared to controls.  Food consumption was
decreased by 14-17% at this dose compared to controls during the
treatment and post-treatment intervals.

 

The maternal LOAEL is 125 mg/kg bw/day based on increased incidence of
ventral/genital staining of the fur and decreased maternal body-weight
gains and food consumption.  The maternal NOAEL is 50 mg/kg bw/day.

The number and percent of early intrauterine deaths were increased at
125 mg/kg/day (40 deaths; 14.8%) compared to controls (15 deaths; 6.3%),
with a significantly higher (p≤0.05) proportion of dams affected at
125 mg/kg/day (14/21 dams) compared to controls (6/20 dams).  Similarly,
the number and percent of late intrauterine deaths were increased at 125
mg/kg/day (46 deaths; 18.7%) compared to controls (0 deaths; 0%), with a
significantly higher (p≤0.05) proportion of dams affected at 125
mg/kg/day (14/21 dams) compared to controls (0/20 dams).  The increases
in early and late intrauterine deaths were reflected by an increased
post-implantation loss at this dose (33.5% affecting 17/21 dams)
compared to controls (6.3% affecting 6/20 dams).

≤0.01) by 16-27%.

Incidences of the following skeletal variations, indicating skeletal
retardation, were increased (p≤0.05) over concurrent controls and/or
the provided historical control data:  (i) in all treated groups -
incompletely ossified unilateral and/or bilateral calcanea, partially
ossified occipital, and not ossified odontoid; (ii) in the 50 and 125
mg/kg/day fetuses - unilateral and/or bilateral cervical rib and
unilateral and/or bilateral extra (14) ribs; (iii) at 125 mg/kg/day -
partially ossified parietals, increased fontanelle, partially ossified
cervical arches between and including #3 and #6, partially ossified 1st
sternebra, partially ossified 2nd sternebra, not ossified 5th sternebra,
partially ossified, not ossified 6th sternebra, and partially ossified
frontals.  Mean scores for ossification of the manus were increased in
all treated groups (2.66-3.13) compared to concurrent (2.42) and
historical (1.88-2.59) controls.  Similarly, mean scores for
ossification of the pes were increased in all treated groups (3.06-3.63)
compared to concurrent (2.72) and historical (2.53-3.05) controls. 
Aside from the variations listed above indicating skeletal retardation,
there were no treatment-related external, visceral, or skeletal
variations.

There were no treatment-related external, visceral, or skeletal
malformations.

The developmental LOAEL is 50 mg/kg bw/day based on delayed ossification
or non-ossification of the skeleton in the fetuses.  The developmental
NOAEL is 10 mg/kg bw/day.

This study is classified unacceptable/guideline and does not satisfy the
guideline requirement for a developmental toxicity study (OPPTS
870.3700; OECD 414) in rats.

	870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 47521303), Flutriafol (95.1%;
Batch # UPL Bx 1 (2001)) in corn oil was administered via daily oral
gavage in a dose volume of 4 mL/kg to 22 presumed pregnant Wistar rats
per dose group at doses of 0, 2, 5, 10, or 75 mg/kg bw/day from
gestation days (GD) 6-20.  On GD 21, all dams were euthanized; each
dam’s uterus was removed via cesarean section and its contents
examined.  Fetuses were examined for external, visceral, and skeletal
malformations and variations.

All dams survived until scheduled termination.  There were no clinical
signs of toxicity throughout the study, and no gross abnormalities were
observed at necropsy.  At 75 mg/kg/day, absolute maternal body-weight
gains were decreased by 33% compared to controls during GD 6-9 and by
20% during GD 9-12.  Body-weight gains for the overall (GD 6-21)
treatment period were decreased by 8% compared to controls; when
corrected for gravid uterine weight, body-weight gains were 28% lower
than controls.  When expressed as a percent of body weight on GD 6,
body-weight gains were significantly decreased (p≤0.01) beginning the
first day after dosing (GD 6-7) and continuing through GD 17.  The
decrease was most pronounced for GD 6-7 (decr 100%) and diminished to
13% lower than controls on GD 14.  Although not statistically
significant, relative body-weight gains at 75 mg/kg/day were also
decreased (decr 11-12%) on GD 18 and 19.  Additionally at this dose,
mean body-weight gain for the overall (GD 6-20) treatment period was
decreased by 9% (p≤0.05) compared to controls.  Food consumption at
this dose was decreased by 11-15% compared to controls throughout the
treatment interval.

The maternal LOAEL is 75 mg/kg bw/day based on decreased body-weight
gains and food consumption.  The maternal NOAEL is 10 mg/kg bw/day.

There were no abortions, premature deliveries, dead fetuses, or complete
litter resorptions and no effects of treatment on the number of litters
or sex ratio.  The number of late resorptions at 75 mg/kg/day was higher
than controls (21 treated vs 1 control), with the number of late
resorptions per dam significantly increased (p≤0.05) at this dose
(1.0/dam treated vs 0.0/dam controls).  The number of early resorptions
was also increased at 75 mg/kg/day (17 treated vs 12 controls), with the
number of early resorptions per dam increased at this dose (0.8/dam
treated vs 0.5/dam controls), although this increase was not
significant.  The increases in early and late resorptions, particularly
late resorptions, resulted in a significantly decreased (p≤0.05)
number of live fetuses/dam (11.7 treated vs 13.1 controls).  Although
numerically minor, there was a reduction in fetal weights at 75
mg/kg/day that was statistically significant and would correspond to the
delay in development (non-ossified, incompletely ossified bones) at this
dose level.

Treatment-related malformations were observed in the hyoid at 75
mg/kg/day compared to 0 concurrent and historical controls, including
incidences of:  misshapen arch (1% fetuses; 5% litters); absent body (1%
fetuses; 5% litters); interrupted body (7% fetuses; 18% litters); and
bent body (2% fetuses; 9% litters).  Short intestine was noted in a
single 75 mg/kg/day fetus and was not observed in the historical
controls.  Cleft palate was noted in a single fetus at 75 mg/kg/day. 
This uncommon malformation was also observed in a single fetus at 100
mg/kg/day in the supplementary range-finding study (MRID 47521302).  It
should also be noted that cleft palate occurred in a single historical
control fetus.  There were no other treatment-related external,
visceral, or skeletal malformations.

Treatment-related visceral variations included misshapen nasopharynx
lumen and displaced common carotid artery origin, which were observed at
75 mg/kg/day, but were not found in any concurrent or historical
controls.

The following skeletal variations at 75 mg/kg/day were considered to be
due to the test material because the fetal and litter incidences were
dose-related and exceeded concurrent and historical controls:  (i)
additional ossification of the squamosal or zygomatic process of the
maxilla; (ii) zygomatic arch fusion; (iii) blue-stained focus on the
maxilla or mandible; (iv) accentuated curvature of the hyoid body; (v)
long cervical rib; (vi) rudimentary cervical rib; (vii) caudal
displacement of the pelvic girdle; (viii) bilateral radius and ulna
bent; and (ix) cervical rib cartilage fused with thoracic rib 1
cartilage.

≤0.05) at 75 mg/kg/day over concurrent controls and exceeded the range
of historical controls:  (i) incompletely ossified sternebra 6; (ii)
unilateral left supernumerary rib; (iii) unilateral left rudimentary
rib; (iv) unilateral right supernumerary rib; 

(v) unilateral right rudimentary rib; (vi) supernumerary unilateral left
costal cartilage; 

≤0.05) at 75 mg/kg/day (0%) compared to concurrent controls and fell
below the range of historical controls. 

≤0.05); however, both the fetal and litter incidences fell within the
range of historical controls.  The incidence of cervical vertebral body
2 was lower at this dose compared to concurrent and historical controls,
with the litter incidence attaining statistical significance (p≤0.05);
however, incidences of this finding fell within the historical control
range.  Although the incidences of several of these findings were not
significantly increased and/or fell within the range of historical
controls, they were considered treatment-related because of their
increase over concurrent controls and their corroboration of the
generalized skeletal retardation.

≤0.05) at 75 mg/kg/day compared to concurrent controls.  Although the
incidences of these findings fell within the range of historical
controls, they were considered to be due to treatment due to the
substantial and statistically significant increases over concurrent
controls and the fact that this developmental delay is consistent with
the other indications of skeletal retardation.  Furthermore, the fact
that these incidences fall within the range of historical controls is
attributed to a single study (No. 857932). 

In summarizing, administration of flutriafol to dams at 75 mg/kg/day
results in teratogenicity (external, visceral and skeletal
malformations), embryo-lethality, skeletal variations, a generalized
delay in fetal development and fewer live fetuses.

The developmental LOAEL is 75 mg/kg bw/day based on:  increased late
resorptions; malformations (cleft palate and multiple hyoid
malformations) and variations in the hyoid; variations in the
maxilla/mandible, rudimentary and long cervical ribs, pelvic girdle, and
radius/ulna; numerous skeletal retardations detailed above and
corresponding decrease in fetal weights. The developmental NOAEL is 10
mg/kg bw/day.

This study is classified acceptable/guideline and satisfies the
guideline requirement for a developmental toxicity study (OPPTS
870.3700a; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study (MRID 47090350), Flutriafol (PP450;
93%; Batch # P10) was administered daily in gelatin capsules to 24
presumed pregnant Dutch rabbits at doses of 0, 2.5, 7.5, or 15 mg/kg/day
from gestation days (GD) 6-18.  On GD 29, each surviving female was
euthanized, and the uterus was removed via cesarean section and its
contents examined.  Fetuses were examined for external, visceral, and
skeletal malformations and variations.

At 7.5 mg/kg/day, one doe (#52) aborted part of its litter on GD 20.  At
15 mg/kg/day, one doe (#70) was killed in extremis after observations
that the animal had not been eating or drinking and that it had lost
weight and was in poor condition.  No other maternal deaths could be
attributed to treatment.  Loose feces on the cage floor and/or fur of
the animals was observed in 2/15 rabbits at 7.5 mg/kg/day and 4/15
rabbits at 15 mg/kg/day.  These findings were observed only once per
female, except for one doe at 7.5 mg/kg/day for which the observation
was made on 2 days and one doe at 15 mg/kg/day for which loose feces was
noted on three days.

At 15 mg/kg/day, maternal body weight gains were decreased during the
treatment interval (-79 g treated vs 48 g controls) and for the overall
(GD 0-29) study, both when uncorrected for (149 g treated vs 230 g
controls) and when corrected for (-158 g treated vs -55 g controls)
gravid uterine weights.  Additionally at this dose, maternal food
consumption was increased by 24% (p≤0.01) over controls during the
pre-treatment interval, but was decreased by 22% (not significant)
during treatment.

In two of the females examined at 15 mg/kg/day, the stomach was found to
contain a fur ball and was otherwise empty or contained little food. 
Only a single female at 7.5 mg/kg/day had little to no food in the
stomach.  Additionally at 15 mg/kg/day, one of the aforementioned does
had dark pitted areas on the mucosal surface of the glandular portion of
the stomach.

The maternal LOAEL is 15 mg/kg/day based on decreased corrected and
uncorrected maternal body weight gains and food consumption.

The number of early intrauterine deaths was higher at 15 mg/kg/day than
controls (36 deaths; 31.0%) compared to controls (11 deaths; 10.4%). 
Similarly, the number of late intrauterine deaths was increased at this
dose (19 deaths; 16.4%) compared to controls (1 death; 1.0%).  Complete
litter resorptions were significantly higher (p<=0.05) at 15 mg/kg/day,
occurring in 5/14 does compared to 0/15 controls.  These findings
resulted in a significantly increased (p<=0.01) post-implantation loss
at 15 mg/kg/day (45.5% vs 13.1% controls); a decreased number of litters
(9 vs 15); and a decreased total (61 vs 94) and mean (4.0 vs 6.5;
p<=0.05) number of live fetuses.

There were no treatment-related effects on growth or development of the
fetuses.  Fetal body weights and litter weights of the treated groups
were comparable to controls.  Reduced/delayed ossification was observed
in several bones in the skeleton (skull, vertebrae, and sternebrae) at
an increased incidence over controls.  However, these findings were
minor in incidence and were not significantly different from the
controls.  Furthermore, mean scores for ossification of the manus and
pes in all treated groups were comparable to controls.

There were no treatment-related external, visceral, or skeletal
malformations or variations.  Two fetuses, one at 7.5 mg/kg/day and
another at 15 mg/kg/day, had multiple abnormalities; however, historical
control data showed that similar findings were previously noted in
individual fetuses (e.g., cleft palate, gastroschisis, malformed eyes,
and shortened/flexed limbs with reduced number of digits).  Furthermore,
the findings in the fetus at 7.5 mg/kg/day were more severe than those
in the 15 mg/kg/day fetus.  All other findings were unrelated to dose,
minor in incidence, and/or not significantly different from the
controls.

The developmental LOAEL is 15 mg/kg/day based on decreased number of
live fetuses, complete litter resorptions and increased
post-implantation loss.   The developmental NOAEL is 7.5 mg/kg/day.

This study is classified acceptable/guideline and satisfies the
guideline requirement for a developmental toxicity study (OPPTS
870.3700; OECD 414) in rabbits.

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction toxicity study (MRID 47090351),
Flutriafol (93%; Batch # P10) was administered in the diet to 15 male
and 30 female Wistar rats/sex/dose group at dietary levels of 0, 60,
240, or 1000 ppm (0, 4.8, 20.6 and 88.7 mg/kg bw/day in P  males; and,
0, 5.5, 21.9 and 103 mg/kg bw/day in  P females)  The P generation
animals were fed the test diets for 12 weeks prior to mating to produce
the F1a litters. After weaning of the F1a litter, the females were mated
with a different male to produce the F1b litters.  On post-natal day
(PND) 36, offspring from the F1b litters were selected to be parents and
were fed the same test diet concentration as their dam for 11 weeks
prior to mating to produce the F2a litters.  This procedure continued
through weaning of the F2b litters which was produced by mating of the
F1b.

There were no treatment-related deaths or clinical signs of toxicity.

Treatment-related effects on body-weight gain, food consumption, and
food utilization during the pre-mating period were observed at 1000 ppm.

Body-weight gains were decreased (p≤0.05, unless otherwise noted) at
1000 ppm compared to controls:  throughout the pre-mating period in the
P males (decr. 6-8%); beginning at Week 7 in the P females (decr. 4-6%,
not significant [NS] at Week 8); and throughout pre-mating in the F1
females (decr. 6-18%; NS at Week 6).

≤0.05) at 1000 ppm compared to controls:  generally throughout
pre-mating in the P males (decr. 4-7%), resulting in a decrease in total
food consumption (Weeks 1-12) of 2% (p≤0.01) compared to controls;
beginning at Week 6 in the P females (decr. 6-8%), resulting in a
decrease of 5% (p≤0.01) in total food consumption; and at Week 8 in
the F1 females (decr. 6%; p≤0.01).

Food utilization was increased by 3% (p≤0.01) compared to controls in
the 1000 ppm P males for Weeks 1-4.  Food utilization was increased by
10% (p≤0.05) over controls in the F1 females at this dose for Weeks
1-4, resulting in an increase of 8% (p≤0.01) for the overall (Weeks
1-11) pre-mating period.

Throughout gestation, cumulative body-weight gains were decreased by
3-25% at 1000 ppm in the P dams during both litters and in the F1 dams
during the F2b litter.  With the exception of the P females on GD 8 and
22 during the F1a litter and the F1 females on GD 22 during the F2b
litter, these decreases were significantly (p≤0.05) different from
controls.

Absolute and adjusted (for body weight) liver weights were increased
(p≤0.01) by 11-29% over controls in both sexes in both generations,
with the exception of the absolute liver weight in the P females, which
was increased by 6% over controls (NS).

Treatment-related microscopic findings were found in the liver. 
Centrilobular hypertrophy was observed in 1000 ppm males in the P
generation (2/15 treated vs. 0/15 controls) and F1 generation (4/15
treated vs. 0/15 controls).  Increased incidences of fatty change in the
liver were observed at this dose in the P generation males (8/15 treated
vs. 0/15 controls) and females (5/30 treated vs. 1/30 controls) and in
the F1 generation males (13/15 treated vs. 0/15 controls) and females
(3/30 treated vs. 0/30 controls).  Fatty change was also observed in the
240 ppm F1 males (5/15 treated vs. 0/15 controls).

The LOAEL for parental toxicity is 1000 ppm (88.7/103 mg/kg bw/day in
males/females) based on decreased body-weight gains and food consumption
and on effects on the liver (increased liver weights, centrilobular
hypertrophy, and fatty change). The NOAEL is 240 ppm (20.6 mg/kg bw/day
in P males and 21.9 mg/kg bw/day in P females).

Although no data were provided, it was stated that the offspring
generally remained in good clinical condition and that there were no
clinical abnormalities which could be related to treatment.  There were
no effects of treatment on the offspring survival indices (percent pups
surviving to PND 22 and proportion of litters with all pups surviving to
PND 22) or cumulative pup body-weight gains throughout the post-natal
period.  At necropsy, no macroscopic findings could be attributed to
treatment.

≤0.05) throughout the post-natal period in the F1b litter (decr.
17-18%) and in the F2a litter (decr. 22-23%).  The percent of pups born
alive was decreased (p≤0.05) in the F2a litter (94.9% treated vs. 100%
controls) and F2b litter (90.1% treated vs. 99.3% controls).  The
proportion of litters with all pups born alive was decreased at this
dose in the F2a litter (15/20 treated vs. 18/18 controls) and F2b litter
(19/29 treated vs. 24/26 controls).  In the liver, fatty change was
observed at 1000 ppm in the F1b male pups (1/7 treated vs. 0/6 controls)
and F1b female pups (1/6 treated vs. 0/8 controls).  Fine vacuolar
hepatocyte vacuolation/fatty change was observed in the F2b males (5/10
treated vs. 0/10 controls) and F2b females (1/10 treated vs. 0/10
controls).

The LOAEL for offspring toxicity is 1000 ppm (88.7/103 mg/kg bw/day in
males/females) based on decreased live birth index and litter size and
on effects on the liver (fatty change/vacuolation).  The NOAEL is 240
ppm (approximately equivalent to 20.6 mg/kg bw/day in males and 21.9
mg/kg b w/day in females). 

There was no apparent effect of treatment on estrous cycle duration or
periodicity in the P generation.  There were no effects of treatment on
precoital interval, gestation duration, or fertility in either litter in
either generation.

The LOAEL for reproductive toxicity was not observed.  The NOAEL is 1000
ppm (approximately equivalent to 88.7/103 mg/kg bw/day in
males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3800; OECD 416) for a two-generation
reproduction study in the rat.

A.3.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity – Rat

In a combined chronic toxicity/carcinogenicity study (MRID 47090352), 52
Alpk:AP rats/sex/dose were exposed to flutriafol (93% a.i.; Batch No.:
P10) for up to 24 months in the diet at concentrations of 0, 20, 200, or
2000 ppm (calculated to be, 0, 1.02, 10.0, and 102 mg/kg bw/day in
males; and 0, 1.27, 12.2 and 122 mg/kg bw/day in females). 
Additionally, 12 rats/sex/dose were treated similarly for up to 12
months.   

No treatment-related effects were observed on mortality, ophthalmology,
clinical chemistry, or urinalysis. 

Grossly,  small discolored foci were commonly observed after 2 years of
treatment.  After 1 year of treatment, an increased incidence of fatty
change in the liver was observed in the 200 and 2000 ppm males (21-93%
of treated rats vs 7% controls).  The severity was minimal in the
controls and 200 ppm males, but was minimal to marked in the 2000 ppm
males.  After 2 years of treatment of the 200 and 2000 ppm males,
increased incidences of minimal to severe hepatic fatty change (54-96%
treated vs 24% controls) and clear cell foci of hepatocytes (40-50%
treated vs 18% controls) were observed.

At 2000 ppm, systemic toxicity was noted in both sexes as follows.  More
rats appeared thin and fewer rats had distended abdomens.  Final body
weights were decreased by 12-22%, and cumulative body-weight gains were
decreased by 12-48% throughout the study.  Weekly food consumption was
frequently decreased by 4-24% throughout treatment, and total food
consumption was decreased by 8-12% for the Weeks 1-13 interval.  Food
utilization (g food/g growth) was increased by 8-11% for the Weeks 1-4
interval, and by 7% (each sex) for the Weeks 1-12 interval.  

A slight treatment-related anemia was noted in the 2000 ppm group as
indicated by the following decreases (p≤0.05) in hematological
parameters: (i) hemoglobin in males (↓4-7%) during Weeks 4-65 and
females (↓4-9%) during Weeks 13-52, 78, and 92; (ii) hematocrit in
males (↓3-8%) during Weeks 26-65 and females (↓5-11%) during Weeks
13-52, 78, and 104; (iii) mean cell volume in males (↓3-8%) during
Weeks 4-104 and females (↓2-10%) during Weeks 4-104; and (iv) mean
cell hemoglobin in males (↓4-7%) during Weeks 4, 26, 39, and 78-104
and females (↓4-10%) during Weeks 4-52 and 78-104.  The total iron
binding capacity of the 2000 ppm females was increased (p≤0.01) by
40%.  Increased (p≤0.05) lymphocytes were observed in the 2000 ppm
females (↑22-61%) during Weeks 26-78 and 104, and increased (p≤0.05)
total leukocytes were noted at Weeks 26, 39, and 78 (↑20-38%).  The
hematological changes were not considered to be an adverse effect due to
the minor decreases in magnitude without corroborating clinical signs.  

At 2000 ppm, the following toxicologically significant differences
(p≤0.05) were observed: (i) increased plasma cholesterol in the
females throughout the study (↑24-49%; NS at Week 91); (ii) decreased
plasma triglycerides in the males during Weeks 4-65 (↓40-68%); (iii)
decreased alkaline phosphatase in the males during Weeks 13-91
(↓12-33%); (iv) increased plasma total protein in the females
throughout treatment (↑4-9%); and (v) increased plasma alanine
transaminase during Weeks 4 and 13 (↑54-82%).  

At 2000 ppm, hepatoxicity was noted in both sexes.  In both sexes,
increased liver weights, both absolute and adjusted for body weight,
were observed after 1 year of treatment (incr 11-37%) and after 2 years
(incr 27-34%, except similar to control for absolute liver weight of the
females).  There was hepatic enlargement, often coupled with the
presence of numerous discolored foci, commonly observed in both sexes. 
These liver findings were observed after 2 years of treatment, but not
after 1 year of treatment.  After 2 years of treatment, the following
histological hepatic lesions were increased in incidence in the females:
 (i) minimal to severe fatty change (65% treated vs 23% controls); (ii)
bile duct proliferation/ cholangiolarfibrosis (67% treated vs 44%
controls); (iii) hemosiderin accumulation in Kupffer cells (55% treated
vs 0% controls); and (iv) centrilobular hypertrophy (8% treated vs 0%
controls).  Hepatic centrilobular hypertrophy was increased in incidence
at the interim sacrifice in males (71%) and females (31%), but only
minor increases were noted at terminal sacrifice in both sexes (6-8%)
with 0% in the controls.  An increased incidence of foci of cortical
macrophages in adrenal glands was observed in the 2000 ppm females (80%
treated vs 25% controls); however, there was no corroborating evidence
of toxicity in the adrenal gland, and this lesion alone was not
considered adverse.  

The LOAEL is 2000 ppm (102/122mg/kg bw/day in males/females), based on
adverse liver effects (increased liver weights, fatty change, bile duct
proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer
cells and centrilobular hypertrophy), and clinical chemistry findings. 
The NOAEL is 200 ppm (10.0/12.2 mg/kg bw/day in males/females).  

At the doses tested, there was not a treatment related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on decreased body-weight gain and food consumption, increased food
utilization, and hepatotoxicity observed in both sexes. 

This study is classified as Acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.4300; OECD 453) for a combined chronic
toxicity/carcinogenicity study in rats.

	870.4100b Chronic Toxicity – Dog

In a chronic toxicity study in dogs (MRID 47090353), flutriafol (PP450;
93.0% a.i.; batch # P10) was administered to four beagle dogs/sex/dose
group daily by capsule for at least 52 weeks at doses of 0, 1, 5, or 20
mg/kg bw/day.

No adverse, treatment-related effects were observed on mortality,
clinical signs of toxicity, food consumption, ophthalmoscopic
examinations, or gross pathology.

One 20 mg/kg/day female was observed to be subdued and not eating during
Week 15.  This dog was dehydrated and thin, had pale mucus membranes,
loud intestinal sounds and a tense abdomen, with marked reduction in
muscle mass.  Mucus containing blood was present in the feces, and vomit
was present on the pen floor on three days.  This animal was killed for
humane reasons during Week 16.  In view of the limited toxicity noted in
the other dogs receiving 20 mg/kg/day, it was unclear if the poor
condition of this dog was due to administration of the test compound.

The liver was a target organ.  At 20 mg/kg/day, liver weights were
increased (p≤0.01) by 27-39% in both sexes.  The following
treatment-related alterations in clinical chemistry parameters were
observed:  (i) alkaline phosphatase was increased (p≤0.01, except not
significant [NS] for Week 13 males) by 60-268% in both sexes during
Weeks 4, 13, 26, and 52, and the increases became greater in magnitude
with time of exposure; (ii) albumin was decreased (p≤0.05) by 15-19%
during Weeks 4, 13, 26, and 52 in the males, and by 9-10% during Weeks
13 and 26 in the females; and (iii) triglycerides were increased
(p≤0.05) by 31% during Week 52 in the males, and by 62-71% during
Weeks 4 and 13 in the females.  Additionally, minimal to slight
increased centrilobular hepatocyte lipid in the liver was noted in 3/4
females vs. 0/4 controls.

Body weight losses (p≤0.05) of 0.02-0.17 kg were observed in the
females during Weeks 1 and 2.  These animals did not recover over the
course of the study, and demonstrated decreased (not significant [NS])
cumulative body-weight gains for the study period (Weeks 0-52; decr.
28%).  Adrenal weights were increased (p≤0.01) by 38% in the females,
and increased cortical vacuolation of the zona fasciculata was observed
in the adrenal in 4/4 males (slight severity) and 4/4 females (minimal
to slight severity) vs. 0/4 controls of both sexes.  Additionally in the
males, during Weeks 26 and 52, hemoglobin was decreased (p≤0.05) by
7-9%, hematocrit was decreased (p≤0.05 for Week 52; NS for Week 26) by
8-11%, and red blood cell counts were decreased (NS). Marked liver
sinusoidal cell hemosiderin pigmentation was observed in 4/4 males and
4/4 females vs. minimal to moderate in 4/4 controls of both sexes, and
marked hemosiderin pigmentation in the spleen was noted in 4/4 males and
4/4 females vs. minimal to moderate in 4/4 controls of both sexes.

At 5 mg/kg/day, a minimal severity of cortical vacuolation of the zona
fasciculata was present in one female and one male out of a total of 8
animals.  RAB1 toxicologists concluded that this minimal effect in the
adrenal gland was not an adverse effect.

The LOAEL is 20 mg/kg/day, based on:  adverse liver findings (increased
liver weights, increased centrilobular hepatocyte lipid in the liver,
and increases in alkaline phosphatase, albumin and triglycerides),
increased adrenal cortical vacuolation of the zona fasciculata, and
marked hemosiderin pigmentation in the liver and spleen in both sexes;
mild anemia (characterized by decreased hemoglobin, hematocrit, and red
blood cell count) in the males; and initial body weight losses,
decreased cumulative body-weight gains, and increased adrenal weights in
the females.  The NOAEL is 5 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.4100) for a chronic oral toxicity
study in dogs.  

A.3.5	Carcinogenicity

	870.4200a Carcinogenicity Study – Rat

(see A.3.4 870.4100a Chronic Toxicity- rat) 

	870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study (MRID 47090354), Flutriafol (93% a.i.; Batch
No. P10) was administered in the diet to C57BL/10JfCD-1/Alpk mice
(50/sex/dose) for up to 2 years at doses of 0 (two control groups), 10,
50, or 200 ppm (calculated to be 0, 1.1, 5.9, and 24 mg/kg bw/day in
males; and 0, 1.4, 7.4 and 31 mg/kg bw/day in females).  

No adverse treatment-related effects were observed on mortality or food
consumption.

≤0.05) generally throughout the study in both sexes (decr. 2-8%). 
Overall (Weeks 1-104) body-weight gains were decreased in the males
(decr. 18%; p≤0.01) and females (decr. 8%; not statistically
significant [NS]); and decreased (p≤0.01) food efficiency was observed
in the males during Weeks 1-4 (decr. 38%) and 1-12 (decr. 21%). 
Additionally, increased (p≤0.05) platelet (incr 42%), white blood cell
(incr 62%), neutrophil (incr. 81%), and lymphocyte (incr 58%) counts
were noted in the males.  Hepatotoxicity was also noted.  Increased
(p<0.01) liver weights (absolute and adjusted for body weight) were
observed in males (incr. 32-37%) and females (incr. 17-26%). 
Furthermore, increased incidences (# affected/50 in treated vs controls)
of minimal to marked hepatic centrilobular fatty change were noted in
the males (23 vs. 1) and females (17 vs. 0); and minimal to moderate
hepatic centrilobular hypertrophy were noted in the males (14 vs 0-1)
and females (3 vs 0).

At 50 ppm, a slight effect was observed on body weights and body-weight
gains in males.  Body weights were decreased by 5% (p≤0.05) on Week
104, and overall (Weeks 1-104) body-weight gains were decreased by 8%
(NS).  Furthermore, a treatment-related increased incidence of hepatic
centrilobular fatty change was noted in 6/50 males (1 minimal, 4 slight,
and 1 marked severity).  

The LOAEL is 200 ppm (24/31 mg/kg bw/day in males/females), based on
hepatotoxicity (increased fatty change) in both sexes.  The NOAEL is 50
ppm (5.9/7.4 mg/kg bw/day in males/females).

At the doses tested, there was not a treatment related increase in tumor
incidence when compared to controls.  There was an apparent increase in
the incidence of generalized composite lymphomas in the 200 ppm female
decedents (100% treated vs 62% controls).  Although this finding was
statistically significant (p≤0.05), the difference was no longer
evident when all animals were considered (92% treated vs 81-91%
controls).  Furthermore, the effect was not clearly dose-dependent. 
Dosing was considered adequate based on decreases in body weights and
body-weight gain in both sexes, decreased food efficiency in males,
hematological findings in males, and hepatoxicity in both sexes. 

This study is classified as acceptable/guideline and satisfies the
guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD
451] in mice.

A.3.6	Mutagenicity

	

Gene Mutation

870.5100, In vitro Bacterial Gene Mutation (Salmonella typhimurium)/
mammalian activation gene mutation assay

MRID 47090401 Acceptable/guideline	0, 1.6, 8, 40, 200, 1000, or 5000
µg/plate ( Trial 1) or 0, 8, 40, 200, 1000, 2500, or 5000 µg/plate
(Trial 2); Both trials were performed w/wo S9-activation. There were no
marked increases in the mean number of revertants/plate in any strain. 
There was no evidence of induced mutant colonies over background.

870.5300, In Vitro Gene Mutation assay in mouse lymphoma cells 

MRID 47090402

Acceptable/guideline	0, 10, 33, 100, 333, or 1000 µg/mL (+S9, Trial 1);
0, 150, 300, 450, 600, or 750 µg/mL (-S9, Trial 1); 0, 150, 300, 450,
600, 750, 900, 1050, or 1200 µg/mL (+S9, Trial 2); or 0, 200, 300, 400,
500, 600, 700, or 800 µg/mL (-S9, Trial 2).  There was a dose-related
increase in mutant frequency (7.0-9.0x10-5 treated vs. 3.0x10-5
controls) and absolute mutant numbers (70-148 colonies/plate vs. 63
controls) at 100 µg/mL and above in Trial 1 and a marked increase in
mutant frequency at 750 µg/mL (6.5x10-5 treated vs. 1.2x10-5 controls)
in Trial 2 attributable to severe cytoxicity (2% relative survival). 
However, the increases in mutant frequency did not achieve the threshold
value for a positive response (>10x10-5) in either trial and there was
no marked increase in absolute mutant numbers at 750 µg/mL in Trial 2. 
In the absence of S9, there were no marked increases in mutant frequency
or absolute mutant numbers compared to controls in either trial.  There
was no convincing evidence of induced mutant colonies over background in
the presence or absence of S9-activation.  

	

Cytogenetics

870.5375, In vitro Mammalian Cytogenetics (Chromosomal Aberration Assay
in Human Peripheral Blood Lymphocytes)

MRID 47090403

Acceptable/guideline	No significant increases in the numbers of cells
with aberrations (excluding gaps) were observed in either donor in the
presence or absence of S9. There was no evidence of chromosome
aberrations induced over background in the presence or absence of
S9-activation.

870.5385, In vivo Mammalian Cytogenetics – [Bone Marrow Chromosomal
Aberration Test

MRID 47090404 Acceptable/guideline	0, 15, 70, or 150 mg/kg. There was no
evidence of chromosome aberration induced over background.  

870.5395, In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus
Assay in Mice

MRID47090405 

Acceptable/guideline	0, 93.8, or 150 mg/kg. Decreased (p<0.01)
polychromatic erythrocyte to normochromatic erythrocyte ratios (PCE:NCE)
were observed in both doses at all time points, indicating that the test
material was toxic to the bone marrow. There was no significant increase
in the frequency of micronucleated polychromatic erythrocytes in bone
marrow after any treatment time.

	Other Genotoxicity

870.5450, Dominant Lethal Assay – Mice

MRID 47090406

Acceptable/guideline	0, 25, 50, or 100 mg/kg/day (total doses of 0, 125,
250, or 500 mg/kg). Mortality (3/15 males) was noted at 100 mg/kg/day
during dosing.  Slight decreases (p<0.05) in body weight were observed
at 50 mg/kg/day and above during dosing.  There were no
treatment-related effects on fertility, mean number of implantations, or
the number of early or late deaths. There was no time-related positive
response of increased pre- or post-implantation loss compared to
controls.

870.5550, Unscheduled DNA Synthesis in Primary Rat Hepatocytes/Mammalian
Cell

MRID 47090407 (2003)

≥ 5 NNG needed for a positive response, and no increase in the mean
percent of cells in repair was observed. There was no evidence that
unscheduled DNA synthesis, as determined by radioactive tracer
procedures [nuclear silver grain counts] was induced.

A.3.7	Neurotoxicity

		870.6200 Acute Neurotoxicity Screening Battery - Rat

In an acute neurotoxicity study (MRID 47090408), Flutriafol (95.1% a.i.;
Lot # UPL Bx 1 [2001]) was administered once via gavage (10 mL/kg) to 10
Sprague-Dawley rats/sex/group at dose levels of 0, 125, 250, or 750
mg/kg.  Neurobehavioral assessment (functional observational battery
[FOB] and motor activity testing) was performed on 10 rats/sex/group at
pre-dosing and Days 1 (approximately 8 hours post-dosing; estimated time
of peak effect), 8, and 15.  At study termination, 5 rats/sex/group were
anesthetized and perfused in situ for neuropathological examination. 
The tissues from the perfused animals in the control and 750 mg/kg
groups were subjected to histopathological evaluation of brain and
peripheral nervous system tissues.  Acceptable positive control data
were provided.

No compound-related effects were observed in brain weights or gross or
neuropathology.

At 125 mg/kg, males exhibited a dose-dependent body weight loss of -4.2%
on Days 1-2.  At 250 mg/kg and above, dose-dependent losses (-4.2-28.5
g) (p<0.01) in body weight were observed in both sexes on Days 1-2.  On
Days 2-3, body-weight gains were increased (52-74%) (p<0.05) in both
sexes at 250 mg/kg but remained decreased in both sexes at 750 mg/kg. 
The increase in the 250 mg/kg females was sufficient to compensate for
the initial body weight loss and allowed the body weights in this group
to remain similar to controls for the remainder of the study.  Despite
the increase at 250 mg/kg, the body-weight gain remained decreased in
the 250 mg/kg males during the interval, 1-3 days (-76%).  At 750 mg/kg,
overall (Days 1-16) body-weight gain was decreased in the males (-20%)
(p<0.01) and females (-17%) (NS).  In the males, dose-dependent
decreases (p<0.01) were noted in both absolute and relative food
consumption on Days 1-2 in the 250 mg/kg group (64% and 63%,
respectively) and the 750 mg/kg group (89% and 88%, respectively).  This
initial decrease resulted in a continued reduction in both absolute and
relative food consumption in males on Days 1-3.  In the 750 mg/kg males,
overall (Days 1-16) absolute food consumption was decreased (-15%)
(p<0.01) compared to controls while no statistically significant
decrease in relative food consumption was observed.  In the 750 mg/kg
females, no statistically significant decreases in absolute or relative
food consumption were observed during the remainder of the study or in
the overall (Days 1-16) values.

 

Additionally at 750 mg/kg, 4/10 males and 2/10 females were sacrificed
in moribund condition on Days 2 or 3.  Increases (p<0.01) were noted in
the incidence of the following clinical signs in the males (unless
otherwise stated):  dehydration (both sexes), chromorhinorrhea,
urine-stained abdominal fur (both sexes), ungroomed coat (both sexes),
decreased motor activity, chromodacryorrhea, ptosis, lost righting
reflex, scant feces, and red or tan perioral substance.  The following
additional clinical signs of toxicity were noted in the animals
sacrificed in a moribund condition:  males (prostration, limp muscle
tone, muscle flaccidity, hypothermia, hunched posture, and labored
breathing) and females (ptosis, prostration, piloerection, bradypnea,
decreased motor activity, impaired righting reflex, lost righting
reflex, limp muscle tone, scant feces, and hypothermia). 

At 125 mg/kg, effects were limited to minor decreases (p<0.01) in
body-weight gain and absolute and relative food consumption in the
males.

At 750 mg/kg, increased (p<0.01) incidence (# affected/10 vs. 0
controls) of the following neurological effects were noted at 8 hours
post-dosing during the FOB: (i) hunched posture in 6 males and 4 females
and (ii) slight ataxia in 3 males.  All findings were resolved by Day 8.
 No statistically significant differences were observed on either the
interval or total session motor activity (number of movements or time
spent in movement).  However, at 8 hours post-dosing, total session
number of movements and time spent in movement were slightly decreased
in both sexes.  These parameters remained decreased in the males on Day
8.  These changes in motor activity were observed at a dose that
resulted in moribundity and are considered related indirectly to the
overall toxicity of the test material.  No treatment-related microscopic
lesions were observed.  

The LOAEL is 750 mg/kg, based on decreased body weight, body-weight
gain, absolute and relative food consumption, and clinical signs of
toxicity, indicative of a moribund condition, in both sexes:
dehydration, urine-stained abdominal fur, ungroomed coat, ptosis,
decreased motor activity, prostration, limp muscle tone, muscle
flaccidity, hypothermia, hunched posture, impaired or lost righting
reflex, scant feces; in males: red or tan perioral substance,
chromodacryorrhea, chromorhinorrhea and labored breathing, and in
females: piloerection and bradypnea, and signs of neurotoxicity: hunched
posture in females and ataxia in males.  The NOAEL is 250 mg/kg.

The study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.6200a) for a neurotoxicity screening
battery in rats.

870.6200 Subchronic Neurotoxicity - Rat

In a subchronic neurotoxicity study (MRID 47090410), Flutriafol (95.1%
a.i.; Lot # UPL Bx 1 [2001]) was administered in the diet to 10
Sprague-Dawley rats/sex/group at dose levels of 0, 500, 1500, or 3000
ppm (equivalent to 0/0, 28.9/32.6, 84.3/97.6, and 172.1/185.0 mg/kg/day
[M/F], respectively) for 92 days.  Neurobehavioral assessment
(functional observational battery [FOB] and motor activity testing) were
performed in 10 rats/sex/group at pre-dosing and Weeks 2, 4, 8, and 13. 
At study termination, 5 rats/sex/group were anesthetized and perfused in
situ for neuropathological examination.  The tissues from the perfused
animals in the control and 3000 ppm groups were subjected to
histopathological evaluation of brain and peripheral nervous system
tissues.  Acceptable positive control data were provided.

No compound-related effects were observed in mortality, clinical signs
of toxicity, ocular effects, motor activity, brain weights, or gross or
neuropathology.  

At 1500 ppm, body-weight gains were decreased (p≤0.05) in the males by
28% compared to controls during the first week of dosing and overall
(Days 1-92) body-weight gain was decreased (p≤0.05) by 19% in the
females.  Likewise, absolute and relative food consumption were
decreased (p≤0.01) by 15-16% in both sexes during Week 1.

At 3000 ppm, body weights were decreased throughout the study in the
males (decr. 5-14%) and females (decr 5-10%) and attained statistical
significance (p≤0.05) at Days 8 and 57 through 92 in the males and
Days 50, 64, and 85 through 92 in the females.  During the first week of
dosing, body-weight gains were decreased (p≤0.05) by 108% in both
sexes at this dose compared to controls.  During Week 2, body-weight
gain was increased (p≤0.01) by 36% in the males.  Overall (Days 1-92)
body-weight gain was decreased (p≤0.05) by 23-34% in the males and
females compared to controls.  Similarly, absolute and relative food
consumption were decreased (p≤0.01) by 35-40% in both sexes during the
first week of dosing. Additionally in the females, absolute food
consumption was decreased (p≤0.05) by 9-14% at most intervals
throughout the exposure period.  Overall absolute food consumption was
decreased (p≤0.01) by 10-13% in both sexes.  During Week 2, relative
food consumption was increased (p≤0.01) by 10% in the males.  In the
females, relative food consumption was slightly lower throughout the
rest of the exposure period, but only attained statistical significance
(decr 8%; p≤0.01) on Days 29-36.  Overall relative food consumption
was only slightly decreased (decr 5%; not statistically significant) in
the females.  

Additionally at 3000 ppm, hindlimb grip strength was decreased
(p≤0.05) in the males by 17% compared to controls during Week 2.  The
decreased hindlimb grip strength was considered to be a
treatment-related neurotoxic effect.

No treatment-related effects were observed at 500 ppm in either sex.

The LOAEL was 3000 ppm (equivalent to 172.1/185.0 mg/kg/day [M/F]) based
on decreased body-weight gain, and absolute and relative food
consumption and decreased hindlimb grip strength.  The NOAEL is 1500 ppm
(equivalent to 84.3/97.6 mg/kg/day [M/F]).

The study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.6200b) for a subchronic neurotoxicity
study in rats.

A.3.8	Special

	870.7485	Metabolism – Rat

In rat metabolism studies (MRIDs 47090412, 47090413, and 47090414),
14C-flutriafol (>97% radiochemical purity) in polyethylene glycol 600
was administered to rats as a single oral gavage dose at 5 or 250 mg/kg
body weight.  Group sizes were 1 rat/sex in a preliminary study at 5
mg/kg, 2 rats/sex/dose in bile duct-cannulation studies, one group of 6
females at 250 mg/kg, and 4-5 rats/sex/dose in other dose groups.  One
group of 4 rats/sex received 14 consecutive daily doses at 5 mg/kg/day. 
14C-carbinol-flutriafol was administered to all groups, except one group
of 2 rats/sex was treated with 5 mg/kg 14C-triazole-flutriafol.  Excreta
(urine, feces, and bile [in some groups]) were collected, and analyzed
for radioactivity concentration.  Additionally, pools of selected
excreta were analyzed to identify and quantify metabolites.  Animals
were sacrificed at 48 hours in the preliminary experiment and at 72 or
168 hours post-dose or post final dose in the other studies.  Tissues
were collected and analyzed for radioactivity concentration.

More than 78% of the administered dose was recovered in the bile and
urine of the single 5 mg/kg (both radiolabels) and 250 mg/kg dose
groups.  Absorption was generally similar between sexes, radiolabels,
and between single and multiple dose regimes.  Comparing absorption in 5
mg/kg groups to the 250 mg/kg groups, absorption remains extensive;
however, a longer time is required for absorption to complete. 

Total recoveries at 168 hours post-dose were 97-99% of the administered
single dose and 115-125% daily dose in the multiple dose study.  The
administered dose was mostly eliminated within 48 hours at 5 mg/kg
(86-97% of the single dose or 104% daily dose of the multiple dose
groups) and at 250 mg/kg (68-85% dose, except bile duct-cannulated
females which was 38% dose).  

Only 0.04-0.05% of the dose was found in the expired carbon dioxide in a
preliminary study.  In the bile duct-cannulation study, most of the
radioactivity was excreted in the bile (47-79% of the dose).  In the
single dose 5 mg/kg group (not bile duct-cannulated), similar amounts of
radioactivity were excreted in the feces as in the urine, but only
approximately half as much was excreted in the feces as in the urine at
250 mg/kg.  Slightly more radioactivity was found in the urine of the
multiple dosed animals compared to the single dosed animals.  The
excretion profile was generally similar between the sexes, and was also
similar following 1, 5, 10, and 14 doses.  

Tissue distribution was examined in animals sacrificed 168 hours
post-dose.  In the blood, radioactivity partitioned into the red blood
cells.  In animals receiving multiple daily 5 mg/kg doses,
concentrations of radioactivity were higher in the blood cells than
plasma of males (218-fold) and females (129-fold).  Excluding blood
cells and GI tract measurements, the highest concentrations were found
in whole blood in males (190 ng equivalents flutriafol/g tissue in the
single 5 mg/kg dose group, 8040 ng equiv/g in the 250 mg/kg dose group,
and 1450 ng equiv/g in the multiple 5 mg/kg/day dose group) and in
females (140 ng equivalents flutriafol/g tissue in the single 5 mg/kg
dose group, 6740 ng equiv/g in the 250 mg/kg dose group, and 519 ng
equiv/g in the multiple 5 mg/kg/day dose group).  In both sexes and all
groups, concentrations of radioactivity were relatively high in both
liver and kidneys.  Other organs with high concentrations in one or more
groups included the adrenal glands, spleen, and pituitary.  The
distribution profiles were generally similar between species, dose
level, and single vs multiple dose regime.  A 50-fold increase in dose
resulted in an approximately 42-48-fold increase in radioactivity
concentrations in the whole blood; thus, the concentrations were roughly
proportional to the dose.

The total amount of radioactivity isolated in the tissues and carcass
was miniscule: <1% of the administered dose (single dose groups) or 3%
of the daily administered dose (multiple dose group).  Also, the amount
of the dose remaining in the body (GI tract and contents, tissues, and
remaining carcass) after 168 hours was <1.1% of the administered dose
regardless of sex, radiolabel position, or dose.  For these reasons,
bioaccumulation in all dose groups was considered unlikely.

The parent was isolated in only trace amounts in the urine and feces
(<0.5% of the administered dose) and more than 19 metabolites were
isolated, indicating extensive metabolism of flutriafol.  In general,
metabolism profiles were similar between sexes.  The metabolism profile
in urine was similar between the 250 mg/kg dose group and the multiple 5
mg/kg dose group, but the metabolism profiles in feces resulted in the
isolation of greater amounts of identified compounds in the high dose
group.  Summarizing the Sponsor’s stated results in MRID 47090413
(data not provided); the metabolic profiles were similar regardless of
the matrix (feces, urine, or bile), the dose, the sex, or the
radiolabel.  

The primary site for metabolism was the 2-fluorophenyl ring.  The
initial metabolic step was probably epoxidation followed by either
rearrangement to form the dihydrodiol isomers or to form hydroxy or
dihydroxy metabolites.  The hydroxyl groups on these primary metabolites
may then be either conjugated with glucuronic acid or methylated.  A
second, minor route for metabolism of flutriafol was via the removal of
the triazole ring to form 1-(2
fluorophenyl)-1-(4-fluorophenyl)-ethandiol, which is then conjugated
with glucuronic acid.

This metabolism study in the rat is classified acceptable/guideline and
satisfies the guideline requirement for a metabolism study [OPPTS
870.7485, OECD 417] in rats.

	870.7600	Dermal Absorption - Rat

In a dermal penetration study (MRID 47090415), 14C-carbinol-flutriafol
(98-99% radiochemical purity as applied; Batch No. Rad164) was applied
to the skin (10 cm2) of Sprague Dawley rats (4 males for each time point
at each dose level).  Nominal doses of 0.02, 0.2 or 2 mg/cm2 skin were
tested (10 µl/cm2 skin), and actual doses were 0.0208, 0.201, and 2.154
mg/cm2 skin.  The exposure durations were 0.5, 1, 2, 4, 10, and 24 h,
and the animals were terminated at the end of the exposure period.  An
additional group was exposed for 10 h and maintained for another 158 h
in the metabolism unit prior to termination.

 

Recovery of the applied dose (mass balance) was 96-103%.  The majority
of the dose was not absorbed (sum of soap and water wash of the
application site with the dose site appliance wash; generally 75-97% of
the applied dose), with the greatest amount of radioactivity being
recovered from the soap wash of the application site (generally 51-87%
of the applied dose).   Dermal absorption (based on the sum of residues
in urine, feces, cage wash, blood, and carcass) ranging up to 15.8% of
the applied dose was noted.  Absorption was minimal with only 4 h of
exposure (<1.5% of the applied dose), and was saturated in the high dose
(maximum absorption of only 3.7% dose).  Absorbable radioactivity
(radioactivity in the skin at the application site and the adjacent
skin) was minimal (<0.75% of the applied dose) in groups that were
exposed for 10 h and evaluated for an additional 158 h post-exposure. 
Thus, the data suggests that almost all of the dose isolated in the skin
will be absorbed.  Considering the sum of absorbable and absorbed doses,
4-37% of the applied dose was recovered in the treatment groups (mean of
11% and median of 9%).  Absorption rate constants were calculated as
0.236, 0.190, and 0.072 h-1 for the 2, 20, and 200 µg/cm2 dose groups,
respectively; thus, absorption mechanisms were saturated at the high
dose.  The elimination half-lives were calculated to be 31, 30, and 37 h
for the 2, 20, and 200 µg/cm2 dose groups, respectively.

As almost all of the absorbable dose (radioactivity in the skin at the
application site and the adjacent skin) will be absorbed, the most
conservative estimation of absorption would consider both the absorbed
dose and the absorbable dose.  In this study, a maximum of 36.56% of the
applied dose was noted as absorbed/absorbable (observed after 24 h
exposure to 2 µg/cm2).  This value is most conservative.  However, it
is likely that any area exposed to the chemical will be washed within 10
h.  The applied dose that is absorbed/absorbable following a 10 h
exposure  is 16.54%, 21.31% and 11.39% ,, respectively, at 2,  20 and
200 µg/cm2.  

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.7600; OECD none) for a dermal
penetration study in rats.

A.4.	References

MRID 47090344 Doe, J.E. (1982) PP450 (Flutriafol technical):  28-Day
feeding study in rats. Imperial Chemical Industries PLC, Central
Toxicology Laboratory, Alderley Park, Cheshire, UK.  Laboratory Study
No.: PR0429, September 23, 1982.  Unpublished.

MRID 47090345 Pigott, G.H. (1982) PP450 (Flutriafol technical):  90-Day
feeding study in rats. Imperial Chemical Industries PLC, Central
Toxicology Laboratory, Alderley Park, Cheshire, UK.  Laboratory Study
No.: PR0432, Laboratory Report No. CTL/P/744, October 21, 1982.
Unpublished.

                         MRID 47090346 Doe, J. E. (1982) PP450
(flutriafol technical):  90-day oral dosing study in dogs. Imperial
Chemical Industries, PLC, Central Toxicology Laboratory, Alderley Park,
Macclesfield, Cheshire, UK.  Laboratory Report No.:  CTL/P/733; Study
No.:  PD0433, November 2, 1982.  Unpublished.

MRID 47090347 Barnett, Jr., J. F. (2007) Percutaneous repeated dose
28-day toxicity study of flutriafol in rats.  Charles River Laboratories
Preclinical Services, Horsham, PA.  Laboratory Project ID.:  TQC00010,
January 31, 2007. Unpublished.

MRID 47090348 Barnett, Jr., J. F. (2006) Percutaneous repeated dose
14-day toxicity dosage range-finding study of flutriafol in rats. 
Charles River Laboratories Preclinical Services, Worcester, MA. 
Laboratory Project ID.:  TQC00009, June 30, 2006.  .  Unpublished.

			MRID 47090349 PP450 (Flutriafol):  Teratogenicity study in the rat. 
Imperial Chemical Industries PLC, Cheshire, UK.  Laboratory Study No.
RR0211, Report No. CTL/P/756, October 27, 1982.  Unpublished.

	MRID 47090350 PP450 (Flutriafol):  Teratogenicity study in the rabbit. 
Imperial Chemical Industries PLC, Cheshire, UK.  Laboratory Study No.
RR0211; Report No. CTL/P/756, October 20, 1982.  Unpublished.

MRID 47090351 Flutriafol:  Two generation reproduction study in the rat.
 Imperial Chemical Industries PLC, Cheshire, UK.  Laboratory Study No.
RR0229, Report No. CTL/P/1368, April 17, 1986.  Unpublished.

MRID 47090352 Pigott, G.H. (1986) Flutriafol:  2 year feeding study in
rats.  Imperial Chemical Industries PLC, Central Toxicology Laboratory,
Macclesfield, Cheshire, UK.  Laboratory Study No.: PR0542.  Laboratory
Report No.:  CTL/P/1220, May 22, 1986.  Unpublished.

MRID 47090353 Stonard, M. D. (1988) Flutriafol:  one year oral dosing
study in dogs.  Imperial Chemical Industries, PLC, Central Toxicology
Laboratory, Alderley Park, Macclesfield, Cheshire, UK.  Laboratory Study
No.:  PD0667; Report No.:  CTL/P/2019, May 18, 1988.  Unpublished.

MRID 47090354 Hext, P.M. (1988) Flutriafol:  two year feeding study in
mice.  Imperial Chemical Industries PLC, Cheshire, UK.  Laboratory
Study:  PM0637, Report No. CTL/P/1930, June 3, 1988.  Unpublished.

MRID 47090401 Longstaff, E. (1988) PP450 (Flutriafol) - An evaluation in
the Salmonella/ microsome mutagenicity assay.  Imperial Chemical
Industries PLC, Central Toxicology Laboratory, Alderley Park, Cheshire,
UK.  Laboratory Study No.:  CTL Study Nos. YV0603 and YV0625, February
8, 1988.  Unpublished.

MRID 47090402 McGregor, D.B. (1986) PP450 (Flutriafol) - Assessment of
mutagenic potential in the mouse lymphoma mutation assay.  Inveresk
Research International, Musselburgh, Scotland.  Laboratory Study No.: 
730420, May 15, 1986.  Unpublished.

MRID 47090403 Howard, C.A.. (1989) Flutriafol: An evaluation in the In
Vitro cytogenetic assay in human lymphocytes.  Imperial Chemical
Industries PLC, Central Toxicology Laboratory, Alderley Park, Cheshire,
UK.  Laboratory Study No.:  SV0343, June 21, 1989.  Unpublished.

MRID 47090404 Styles, J.A. (1982) PP450 (Flutriafol) – A cytogenetic
study in the rat.  Imperial Chemical Industries PLC, Central Toxicology
Laboratory, Alderley Park, Cheshire, UK.  Laboratory Study No.: 
CTL/P/725, September 9, 1982.  Unpublished.

MRID 47090405 Richardson, C.R. (1986) Flutriafol - An evaluation in the
mouse micronucleus test.  Imperial Chemical Industries PLC, Central
Toxicology Laboratory, Alderley Park, Cheshire, UK.  Laboratory Study
No.:  CTL Study No. SM0216, April 2, 1986.  Unpublished.

MRID 47090406 Longstaff, E. (1982) PP450 (Flutriafol) - Dominant lethal
study in the mouse.  Imperial Chemical Industries PLC, Central
Toxicology Laboratory, Alderley Park, Cheshire, UK.  Laboratory Study
No.:  CTL Study No. RM0206, September 28, 1982.  Unpublished.

MRID 47090407 Trueman, R.W. (1987) Flutriafol – Assessment for the
induction of unscheduled DNA synthesis in rat hepatocytes in vivo. 
Imperial Chemical Industries PLC, Central Toxicology Laboratory,
Alderley Park, Cheshire, UK.  Laboratory Study No.:  SR0259, June 16,
1987.  Unpublished.

MRID 47090408 Barnett Jr., J.F. (2006) Oral acute neurotoxicity study of
Flutriafol in rats.  Charles River Laboratories Preclinical Services,
Horsham, PA.  Laboratory Project ID: TQC00006, December 1, 2006. 
Unpublished.

MRID 47090409 Barnett Jr., J.F. (2006) Acute oral (gavage) dosage
range-finding study of Flutriafol in rats.  Charles River Laboratories
Preclinical Services, Horsham, PA.  Laboratory Project ID: TQC00005,
June 26, 2006.  Unpublished.

MRID 47090410 Barnett Jr., J.F. (2007) Oral (diet) subchronic
neurotoxicity study of Flutriafol in rats.  Charles River Laboratories,
Preclinical Services, Horsham, PA.  Laboratory Project ID: TQC00008,
February 1, 2007.  Unpublished.

MRID 47090411 Barnett Jr., J.F. (2006) Oral (diet) dosage range-finding
subchronic neurotoxicity study of Flutriafol in rats.  Charles River
Laboratories, Preclinical Services, Horsham, PA.  Laboratory Project ID:
TQC00007, Experimental Completion Date: October 6, 2005; Final Pilot
Report Date June 30, 2006.  Unpublished.

MRID 47090412 Jones, B.K. (1982) PP450 (Flutriafol): Excretion and
tissue retention of a single oral dose (5 mg/kg) in the rat.  Imperial
Chemical Industries PLC, Macclesfield, Cheshire, UK.  Laboratory Report
No.:  CTL/P/751, October 7, 1982.  Unpublished.

MRID 47090413 Jones, B.K. (1986) Flutriafol: Biotransformation in the
Rat.  Imperial Chemical Industries PLC, Macclesfield, Cheshire, UK. 
Laboratory Study-Report No.:  UR0149-CTL/P/856, June 12, 1986. 
Unpublished.

MRID 47090414 Millais, A.J. (2004) [14C]-Flutriafol metabolism in rats
after single and repeated doses.  Huntingdon Life Sciences Ltd.,
Huntingdon, Cambridgeshire, England.  Laboratory Project No.:  CHV
081/024050, August 16, 2004.  Unpublished.

MRID 47090415 Sved, D.W. (2006) A dermal-absorption study with
[14C]-labeled flutriafol in the rat. WIL Research Laboratories, LLC,
1407 George Rd, Ashland, OH.  Study No.: WIL-206008.  June 7, 2006. 
Unpublished.

Appendix B.	Metabolism Assessment

Plant Metabolism Studies:  The petitioner submitted apple, sugar beet,
rapeseed, and wheat/barley (foliar and seed treatment) metabolism
studies conducted with [triazole-3,5-14C]flutriafol and
[carbinol-14C]flutriafol.  HED notes that the wheat/barley metabolism
studies were deemed unacceptable due to numerous deficiencies but are
presented to supplement the acceptable studies.  

Apple (47248901.der.doc):  Apple trees were treated with a single foliar
application of [carbinol-14C]flutriafol or [triazole-3,5-14C]flutriafol
during early fruit development at 0.11 lb ai/acre (1x/0.2x the proposed
single/seasonal application rates).  Samples of apple fruit (both
labels) and foliage (triazole label only) were harvested at maturity, 64
days following application.  Table B.1 is a summary of the total TRRs;
TRRs were slightly higher in the triazole labeled samples.  

The majority of the radioactivity (72-84% TRR) in apple fruit and
foliage was solvent extracted with acetonitrile (ACN) and ACN/water.  An
additional ~5% TRR was released from apple fruit via mild acid (MA; 0.1
M HCl) and mild base (MB; 0.1 M NaOH) hydrolysis.  Nonextractable
residues were 18-23% TRR (≤0.012 ppm) in apple fruit and 16% TRR
(0.685 ppm) in triazole-label foliage.  

Residues were identified by high-performance liquid chromatography
(HPLC) and thin-layer chromatography (TLC) co-elution with reference
standards (flutriafol, TA, TAA, and T).  Total identified residues
accounted for 50-56% of the TRR in apple fruit (Tables B.2 and B.3). 
Unknowns represented <5% TRR in fruit.  Similar metabolic profiles were
observed for the two labels.  

Sugar beet (47090439.der.doc):  Sugar beets were treated with a single
foliar application of [carbinol-14C]flutriafol or
[triazole-3,5-14C]flutriafol at ~0.12 lb ai/acre (BBCH 49; harvestable
size root).  Samples of sugar beet root and tops were collected 0, 6,
11, 16, and 21 days after treatment (DAT; 6- and 11-DAT samples were not
analyzed).  Table B.1 is a summary of the TRRs; TRRs did not vary with
radiolabel position in sugar beet tops and TRRs in roots were to low to
draw a conclusion (≤0.009 ppm; not analyzed further)

The majority of the radioactivity in sugar beet tops was solvent
extracted with ACN and/or ACN/water (89-97% TRR).  An additional ~3-4%
TRR was released from 21-DAT tops via mild acid and base hydrolysis. 
Nonextractable residues were 5-11% TRR (0.029-0.078 ppm) in
carbinol-label tops and 3-9% TRR (0.030-0.040 ppm) in triazole-label
tops.  

Residues were identified by HPLC and TLC co-elution with reference
standards (flutriafol, TA, and TAA).  HED notes that although TA and TAA
were listed as reference standards, the behavior of these compounds
under the employed analytical systems were not provided.  A hexose
conjugate of flutriafol was identified based on comparison of the study
results with those of the rapeseed metabolism study.  Total identified
residues accounted for 73-95% TRR in sugar beet tops (Tables B.2 and
B.3).  Unknowns represented <8% TRR in tops.  Similar metabolite
profiles were observed for the two labels.  

Rapeseed (47090438.der.doc):  Rapeseed plants were treated with a single
foliar application of [carbinol-14C]flutriafol or
[triazole-3,5-14C]flutriafol at ~0.10 lb ai/acre (BBCH71; early pod
set).  Forage samples were harvested immediately following application;
samples of pod and foliage were harvested 7 and 14 days after treatment
(DAT); samples of whole plant were collected 21 DAT; and samples of
foliage and seed were collected at maturity, 42 DAT.  Samples harvested
7 and 21 DAT were not analyzed.  Table B.1 is a summary of the TRRs;
TRRs did not vary with radiolabel position.  

The majority of the radioactivity (60-98% TRR) in forage/foliage was
extracted by sequential extraction with ACN, ACN/water, and/or water;
40-41% TRR was extracted from 14-DAT pods with ACN/water.  Mature seed
was extracted with hexane (27-32% TRR) followed by ACN/water extraction
(42% TRR).  The following additional radioactivity was released via
hydrolysis with enzyme (E; cellulase and hemicellulase), MA, MB, strong
acid (SA; 6 M HCl), and strong base (SB; 2 M NaOH):  14- and 42-DAT
foliage - combined 7-20% TRR; 14-DAT pods -combined 53% TRR; and 42-DAT
seed - combined 14-22% TRR.  Nonextractable residues were as follows: 
14-DAT pods - 6-7% TRR in; 42-DAT seed - 4-7% TRR in; and forage/foliage
- 1-11% TRR (≤0.034 ppm) except in 42-DAT carbinol-label foliage which
had nonextractable residues of 20% TRR (0.071 ppm).  

n the hydrolysates of 14-DAT pods (27-28% TRR) and 42-DAT foliage (3-11%
TRR).  Flutriafol was identified in the remaining hydrolysates at ≤7%
TRR and defluorinated flutriafol was also identified in the hydrolysates
at ≤15% TRR.  

Barley/Wheat (foliar treatment; 47090440.der.doc): 
[Carbinol-14C]flutriafol or [triazole-3,5-14C]flutriafol were applied as
a single foliar broadcast application to spring barley and spring wheat
grown in pots maintained outdoors or in a greenhouse, at a rate of ~0.08
lb ai/acre.  The applications were made 4-26 days prior to ear
emergence, except for field-grown carbinol-label wheat and field-grown
triazole-label barley in which applications were made after ear
emergence.  Samples of mature grain and straw were harvested 56-94 days
after application for those samples treated pre-ear emergence and 44-45
days after application for those samples treated post-ear emergence. 
TRRs are summarized in Table B.1; TRRs did not vary significantly with
label position for straw but varied with label position in grain with
the triazole labeled yielding higher residues (chaff not analyzed
further).  

The majority of the radioactivity from the grain and straw samples
(60-95% TRR; 47% TRR for field-grown triazole-label barley grain) was
solvent extracted with ACN and ACN/water.  Nonextractable residues
accounted for 5-35% TRR (≤0.035 ppm) in the grain samples (both
labels) and 16-40% TRR (0.150-0.336 ppm) in the straw samples (both
labels).  Nonextractable residues in triazole-label wheat straw (23%
TRR) were subjected to limited sequential extraction procedures with
cold and boiling water and cold 1 M ammonia (released an additional 7%
TRR).  

Residues were identified using TLC by co-elution or reference standards
(flutriafol, TA, TAA, and triazole lactic acid).  Total identified
residues represented 36-38 % TRR in carbinol labeled grain and straw
samples and 56-84% TRR in all triazole labeled grain and straw samples
excluding the  triazole-label field-grown barley grain sample treated
post-ear emergence (32% TRR; Table B.4).  Unknowns were ≤4% TRR in the
carbinol labeled grain and straw samples, 5-14% TRR in the triazole
straw samples, and 8-34% TRR in the triazole grain samples (sufficient
characterization of these residues were performed).  The metabolic
profile did not vary significantly with label position in straw. 
However, the metabolic profile varied significantly with label position
in grain samples due to the identification of TA and TAA in the
triazole-label samples.  

The following deficiencies were identified in the barley/wheat foliar
metabolism study:  (1) residues in forage were not investigated; (2)
insufficient attempts were made to characterize nonextractable residues
of barley and wheat straw; (3) a confirmatory method was not used for
the identification of metabolites; (4) the ACN/water barley straw
extract (carbinol label) was not analyzed (20% TRR; 0.142 ppm), (5) no
information concerning storage conditions or durations was provided, and
(6) the GLP statement indicated that since Cheminova (the petitioner)
did not conduct the study and was not the sponsor, they could not be
certain that the study was conducted in accordance with GLP practices
(40 CFR 160).  In addition, supporting information and data were
extremely limited for this study.  

arley straw (both labels) and triazole-label barley/wheat grain
(carbinol grain samples were not analyzed due to low TRR (≤0.005
ppm)).

The majority of the radioactivity (84-88% TRR) in barley straw was
solvent extracted with ACN and ACN/water.  ACN released ≤1% TRR from
triazole-label barley/wheat grain while ACN/water released 89-94% TRR. 
Nonextractable residues were 6-10% TRR (0.008-0.016 ppm) for
triazole-label barley/wheat grain and 12-16% TRR (0.030-0.041 ppm) for
triazole- and carbinol-label barley straw.  

 and 59% TRR in the carbinol labeled straw sample (Table B.5).  Unknowns
were ≤5% TRR in the triazole labeled grain and straw samples and a
combined 19% TRR (0.047 ppm) in the carbinol labeled straw sample. 
Significant differences in the metabolic profile were found in carbinol
and triazole labeled grain and straw samples due to the identification
of TA and TAA in the triazole-label samples.  

The following deficiencies were identified in the barley and wheat seed
treatment metabolism study:  (1) residues in forage were not
investigated, (2) a confirmatory method was not used for the
identification of metabolites, (3) no information concerning storage
durations was provided; and (4) the GLP statement indicated that since
Cheminova (the petitioner) did not conduct the study and was not the
sponsor, they could not be certain that the study was conducted in
accordance with GLP practices (40 CFR 160).  In addition, supporting
information and data were extremely limited for this study.  



Table B.1:  TRRs

Crop	Timing and Applic. No.	PHI

(days)	Matrix	TRR (ppm parent equivalents)1

Carbinol label	Triazole label

Foliar Plant metabolism Studies

Apple	One foliar application made at early fruit development at 0.105 lb
ai/acre	64	fruit	0.041	0.065

	foliage	not analyzed	4.182

Rapeseed	One foliar application made at early pod set at 0.105 lb
ai/acre (carbinol label) or 0.103 lb ai/acre (triazole label)	0	Forage
1.497	0.782

14	Pod	0.779	0.751

	Foliage	1.601	1.165

42	Seed	0.729	1.316

	Mature Foliage	0.355	0.246

Sugar Beet	One foliar application made at the harvestable size root
stage at 0.115 lb ai/acre (carbinol label) or 0.119 lb ai/acre (triazole
label)	0	Root 	<0.001	0.001

	Tops 	1.273	1.368

16	Root	0.005	0.003

	Tops 	0.381	0.342

21	Root	0.005	0.009

	Tops 	0.596	0.747

Barley 

(field grown)	One foliar application made 13 days before ear emergence
at 0.080 lb ai/acre.	62	grain	0.007	--

	straw	0.72	--

	One foliar application made after ear emergence at 0.075 lb ai/acre.	44
grain	--	0.10

	straw	--	0.12

Barley 

(greenhouse grown)	One foliar application made 26 days before ear
emergence at ~0.080 lb ai/acre.	94	grain	0.02	0.41

	straw	not analyzed	2.10

Wheat

(field grown)	One foliar application made after ear emergence at 0.079
lb ai/acre. 	45	grain	0.006	--

	straw	0.53	--

	One foliar application made 20 days before ear emergence at 0.094 lb
ai/acre.	74	grain	--	0.05

	straw	--	0.65

Wheat

(greenhouse grown)	One foliar application made 4 days before ear
emergence at ~0.080 lb ai/acre.	56	grain	0.01	0.18

	straw	not analyzed	not analyzed

Seed Treatment Metabolism Study

Barley	Seed treatment at 114 ppm (carbinol label) or 121 ppm (triazole
label).	154	grain	0.005	0.17

	straw	0.25	0.24

	chaff	0.06	0.21

Wheat	Seed treatment at 104 ppm (carbinol label) or 73 ppm (triazole
label).	112	grain	0.003	0.14

	straw	0.17	0.23

	chaff	0.08	0.14

1	Samples in bold were analyzed further.



Table B.2:  Summary of Characterization and Identification of TRRs in
Apple, Rapeseed, and Sugar Beet Following Foliar Application of
[Carbinol-14C]Flutriafol.

Compound	Apple	Rapeseed	Sugar Beet

	64-DAT fruit	0-DAT forage	14-DAT Foliage	42-DAT Foliage	14-DAT Pod
42-DAT Seed	0-DAT Tops	16-DAT Tops	21-DAT Tops

	TRR = 

0.041 ppm	TRR =

1.497 ppm	TRR =

1.601 ppm	TRR =

0.355 ppm	TRR =

0.779 ppm	TRR =

0.729 ppm	TRR =

1.273 ppm	TRR =

0.381 ppm	TRR =

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	0.063	16.7	0.131	14.3	0.106	2.4	0.028	16.2	0.061	22.0	0.133

Total extractable	76.9	0.032	97.9	1.466	98.6	1.579	79.9	0.283	92.9	0.723
83.3	0.607	93.9	1.195	88.8	0.338	95.1	0.567

Unextractable	23.0	0.009	2.1	0.031	1.4	0.022	20.1	0.071	7.1	0.055	16.8
0.122	6.1	0.078	11.2	0.043	4.8	0.029

Accountability4	100	100	100	100	100	100	100	100	100

1	Includes flutriafol identified in the E, WA, WB, SA, and/or SB
hydrolysates for 14-DAT rapeseed forage (E-2.8% TRR, SA-0.4% TRR,SB-0.7%
TRR; total of 3.9% TRR; ), 42-DAT rapeseed foliage (E-2.8% TRR and
SA-8.2% TRR; total of 11.0% TRR), 14-DAT rapeseed pod (E-15.3% TRR,
WB-3.3% TRR, SA-3.0% TRR, and SB-6.2% TRR; total of 28% TRR), 42-DAT
rapeseed seed (E-0.4% TRR, WB-0.5% TRR, SA-4.9% TRR, and SB-1.5% TRR;
total of 7% TRR), and 21-DAT sugar beet tops (combined WA and WB-1.9%
TRR).

2	Hydrolysates in bold were not analyzed.	

3	Largest unknown of 2.8% TRR.

4	Accountability = (Total extractable + Total unextractable)/(TRR from
combustion analysis) * 100.



Table B.3:  Summary of Characterization and Identification of TRRs in
Apple, Rapeseed, and Sugar Beet Following foliar Application of
[Triazole-14C]Flutriafol.

Compound	Apple1	Rapeseed1	Sugar Beet

	64-DAT Fruit	14-DAT Foliage	42-DAT Foliage	14-DAT Pod	42-DAT Seed	0-DAT
Tops	16-DAT Tops	21-DAT Tops

	TRR = 

0.065 ppm	TRR = 

1.165 ppm	TRR = 

0.246 ppm	TRR = 

0.751 ppm	TRR = 

1.316 ppm	TRR = 

1.368 ppm	TRR = 

0.342 ppm	TRR = 

0.747 ppm

	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	%
TRR	ppm

Flutriafol2	49.9	0.032	82.7	0.963	55.6	0.137	59.4	0.446	67.6	0.889	95.4
1.304	77.7	0.266	70.8	0.529

FHC (R5a)3	--	--	2.7	0.031	5.7	0.014	1.5	0.011	3.8	0.050	--	--	1.1	0.004
5.0	0.038

DF (C6 )	--	--	1.5	0.018	0.8	0.002	12.1	0.091	3.0	0.039	--	--	--	--	--
--

TA	<2	<0.001	--	--	--	--	--	--	--	--	--	--	--	--	--	--

TAA	--	--	--	--	--	--	--	--	--	--	--	--	--	--	--	--

Unknown R1	--	--	0.3	0.003	4.9	0.012	1.6	0.012	3.5	0.046	0.2	0.003	8.1
0.028	3.1	0.023

Unknown R2	--	--	0.6	0.007	1.6	0.004	1.1	0.008	1.7	0.023	--	--	0.7	0.002
4.6	0.034

Unknown R3	--	--	1.2	0.014	1.2	0.003	0.8	0.006	--	--	--	--	0.9	0.003	2.1
0.016

Unknown R4	--	--	1.0	0.012	2.0	0.005	1.2	0.009	--	--	0.1	0.001	0.5	0.002
4.4	0.033

Unknown R5b	--	--	2.6	0.030	6.1	0.015	1.5	0.011	3.6	0.048	0.9	0.012	2.6
0.009	2.4	0.018

Unknown R6	--	--	0.3	0.003	--	--	--	--	--	--	0.2	0.003	--	--	1.0	0.008

Unknown C1	--	--	1.5	0.018	0.4	0.001	6.3	0.047	3.3	0.044	--	--	--	--	--
--

Unknown C2	--	--	0.1	0.001	--	--	0.5	0.004	--	--	--	--	--	--	--	--

Unknown C3	--	--	--	--	--	--	0.3	0.002	--	--	--	--	--	--	--	--

Unknown C4	--	--	0.1	0.001	--	--	0.5	0.004	--	--	--	--	--	--	--	--

Others (unknown)	21.63	0.013	1.9	0.022	2.4	0.006	6.5	0.048	7.8	0.102	0.4
0.005	--	--	2.4	0.018

Unretained	2.0	0.001	--	--	--	--	--	--	--	--	--	--	--	--	--	--

E4	not performed	5.0	0.058	2.6	0.006	17.1	0.128	1.4	0.018	not performed
not performed	not performed

WA4	2.1	0.001	0.2	0.002	0.4	0.001	0.3	0.002	0.4	0.005

	3.8	0.023

WB4	2.4	0.002	0.6	0.007	1.2	0.003	2.8	0.021	3.0	0.039

SA4	not performed	2.8	0.033	5.5	0.014	16.9	0.127	7.9	0.104

	not performed

SB4

2.8	0.033	3.0	0.007	15.8	0.119	9.1	0.120

	Total identified	49.9	0.032	86.9	1.012	62.1	0.153	73.0	0.548	74.4	0.978
95.4	1.304	78.8	0.270	75.8	0.567

Total characterized	28.1	0.017	10.4	0.120	25.8	0.063	21.0	0.156	21.4
0.282	1.8	0.024	12.8	0.044	20.0	0.150

Total extractable	82.2	0.054	97.0	1.130	88.9	0.218	94.1	0.706	95.8	1.26
97.1	1.328	91.1	0.312	95.8	0.716

Unextractable	17.8	0.012	2.9	0.034	11.1	0.027	5.8	0.044	4.3	0.057	2.9
0.040	8.9	0.030	4.2	0.031

Accountability5	100	100	100	100	100	100	100	100

1	Apple foliage and 0-DAT rapeseed forage were also analyzed but these
data are not presented here (64-DAT apple foliage - 64-DAT; 4.182 ppm;
48% TRR flutrifol; 29% TRR unknowns; 16% TRR unextracted; 0-DAT rapeseed
forage – 0.782 ppm; 97% TRR flutriafol).

2	Includes flutriafol identified in the E, WA, WB, SA, and/or SB
hydrolysates for 14-DAT rapeseed forage (E-4.5% TRR, SA-0.7% TRR, and
SB-1.4% TRR; total of 6.6% TRR; ), 42-DAT rapeseed foliage (SA-3.2% TRR;
total of 3.2% TRR), 14-DAT rapeseed pod (E-15.8% TRR, WB-1.9% TRR,
SA-3.2% TRR, and SB-6.1% TRR; total of 27% TRR), 42-DAT rapeseed seed
(E-0.5% TRR, WB-0.8% TRR, SA-2.0% TRR, and SB-3.0% TRR; total of 6.3%
TRR), and 21-DAT sugar beet tops (combined WA and WB-1.9% TRR).

3	Largest unknown of 4.2% TRR.

4	Hydrolysates in bold were not analyzed.

5	Accountability = (Total extractable + Total unextractable)/(TRR from
combustion analysis) * 100.



Table B.4:  Summary of Characterization and Identification of TRRs in
Barley and Wheat Following Foliar Application of [Carbinol-14C]- or
[Triazole-14C]-Flutriafol.

Compound	[Carbinol-14C]-Flutriafol treated	[Triazole-14C]-Flutriafol
treated

	Barley grain (62-DAT; field grown; treated pre-ear emergence)	Barley
Straw (62-DAT; field grown; treated pre-ear emergence)	Wheat straw
(74-DAT; field grown; treated pre-ear emergence)	Barley straw (94-DAT;
greenhouse grown; treated pre-ear emergence)	Barley grain (44-DAT; field
grown; treated after ear emergence)	Barley grain (94-DAT; greenhouse
grown; treated pre-ear emergence)	Wheat grain (74-DAT; field grown;
treated pre-ear emergence)	Wheat grain (56-DAT; greenhouse grown;
treated pre-ear emergence)

	TRR = 0.007 ppm	TRR = 0.72 ppm	TRR = 0.65 ppm	TRR = 2.10 ppm	TRR = 0.10
TRR = 0.41 ppm	TRR = 0.05 ppm	TRR = 0.18 ppm

	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	%
TRR	ppm

Flutriafol	36.3	0.003	37.5	0.270	56.6	0.368	63	1.323	24.0	0.024	--	--	--
--	--	--

TA	--	--	--	--

	--	--	7.6	0.008	40	0.164	57.9	0.029	48	0.086

TAA	--	--	--	--

	--	--	--	--	26	0.107	26.4	0.013	8	0.014

Others (unknowns)	3.6	<0.001	2.9	0.021	13.6	0.088	5	0.105	7.9	0.008	21
0.086	9.9	0.005	34	0.061

Total identified	36.3	0.003	37.5	0.270	56.6	0.368	63	1.323	31.6	0.032	66
0.271	84.3	0.042	56	0.10

Total characterized	38.6	0.002	22.6	0.163	20.2	0.131	15	0.315	32.7	0.034
23.2	0.095	10.6	0.005	34	0.061

Total extractable	60.26	0.005	60.2	0.434	73.8	0.480	81.0	1.701	47.4
0.048	89.2	0.366	94.9	0.047	90.0	0.162

Unextractable	25.7	0.002	39.8	0.287	23.1	0.150	16.0	0.336	35.1	0.035	6.5
0.027	5.1	0.003	5.0	0.009

Accountability1	86	100	97	97	83	96	100	95

1	Accountability = (Total extractable + Total unextractable)/(TRR from
combustion analysis) * 100.

Table B.5:  Summary of Characterization and Identification of TRRs in
Barley and Wheat Matrices Following Seed Treatment with
[Carbinol-14C]Flutriafol or [Triazole-14C]Flutriafol at ~100 ppm.

Compound	Triazole label	Carbinol label

	Barley grain	Wheat grain	Barley straw	Barley straw

	TRR = 0.17 ppm	TRR = 0.14 ppm	TRR = 0.24 ppm	TRR = 0.25 ppm

	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm

Flutriafol	--	--	--	--	35.8	0.086	59.2	0.148

TA	36.4	0.062	55.2	0.077	--	--	--	--

TAA	35.2	0.060	27.8	0.039	28.0	0.067	--	--

Others (unknowns)	4.6	0.008	4.9	0.007	4.7	0.011	18.8	0.047

Total identified	71.6	0.122	83.0	0.116	63.8	0.153	59.2	0.148

Total characterized	12.3	0.021	5.3	0.008	4.7	0.011	18.8	0.047

Total extractable	90.3	0.154	94.4	0.133	87.7	0.211	83.7	0.209

Unextractable	9.7	0.016	5.7	0.008	12.3	0.030	16.4	0.041

Accountability1	100	100	100	100

1	Accountability = (Total extractable + Total unextractable)/(TRR from
combustion analysis) * 100.

Livestock Metabolism Studies:  The petitioner submitted diary cow
([triazole-3,5-14C]flutriafol) and hen ([triazole-3,5-14C]flutriafol and
[carbinol-14C]flutriafol) metabolism studies.  The following is a
summary of these data.  

Dairy Cow (47090443.der.doc):  A single dairy cow was orally
administered [triazole-3,5-14C]flutriafol twice a day for seven
consecutive days at a dietary rate of 2 ppm (10x).  Milk was collected
twice daily throughout the study and muscle, fat (subcutaneous, omental,
and peritoneal), liver, and kidney were collected at sacrifice (4 hours
after the final dose).  Table B.6 is a summary of the TRRs. 
Radioactivity was highest in liver, and lowest in muscle and fat. 
Residues in milk were low (<0.01 ppm).  The majority of the administered
dose was excreted, with urine and feces accounting for ~78% of the
administered dose.  

); muscle and fat were not extracted due to low TRRs (≤0.008 ppm). 
Bacterial protease hydrolysis of the unextracted liver residues released
and additional 42% TRR.  This hydrolysate was characterized further by
partitioning with ether (ether – 0% TRR; water - 42% TRR) followed by
hydrolysis of the aqueous phase with β-glucuronidase and 6M HCl with
partitioning of the resulting hydrolysates with ether (ether phases –
0% TRR; aqueous phases - 42% TRR).  The aqueous phase was then
hydrolyzed with 0.1M NaOH and partitioned with ether (ether - 15% TRR
(analyzed); aqueous phase - 18% TRR (not analyzed)).  Nonextractable
residues were 3-11% TRR (<0.03 ppm) in milk, kidney, and liver.  

Residues were identified by TLC using co-elution with reference
standards including flutriafol, four metabolites isolated from the rat
metabolism study (M1B, M1D, M2B, and M2C), and a methoxyphenyl
metabolite of flutriafol (Compound X).  Reference standards for T, TA,
and TAA were not included.  Total identified residues accounted for
<5-32% TRR in milk, kidney, and liver (Table B.7).  

The following deficiencies were identified in the dairy cow metabolism
study:  (1) a confirmatory method was not used for the identification of
metabolites; (2) no information concerning storage durations was
provided; (3) reference standards for the triazole metabolites, T, TA,
and TAA, were not included; and (4) the GLP statement indicated that
since Cheminova (the petitioner) did not conduct the study and was not
the sponsor, they could not be certain that the study was conducted in
accordance with GLP practices (40 CFR 160).  In addition, supporting
information and data were extremely limited for this study.  

Hen (47090442.der.doc):  Laying hens were orally administered
[triazole-3,5-14C]flutriafol or [carbinol-14C]flutriafol once a day for
seven consecutive days at a dietary rate of 13.9 ppm (160x) or 11.6 ppm
(130x), respectively.  Eggs were collected twice daily throughout the
study and muscle (composite of breast and thigh), abdominal fat, and
liver were collected at sacrifice (20-24 hours after the final dose). 
Table B.6 is a summary of the TRRs.  TRR were consistently higher in the
triazole-label matrices.  Radioactivity for both labels was highest in
liver and lowest in muscle and fat.  The majority (90-91%) of the
administered dose was excreted.

The majority of the radioactivity was extracted from egg and muscle
using ACN/water (64-98% TRR; both labels) and from fat using
acetone/hexane (94-97% TRR; both labels).  ACN/water extraction released
lower levels of TRR from liver (33-41% TRR; both labels).  Additional
residues were released from liver (both labels) via sequential
hydrolysis with pepsin and pancreatin (21-25% TRR; analyzed), 1 N HCl
(4-6% TRR; not analyzed), 1 M NH4OH (8-9% TRR; not analyzed), and 6 N
HCl at reflux (30% TRR carbinol label; 12% TRR triazole label; not
analyzed).  Nonextractable residues (both labels) accounted for 2.4-6.0%
TRR (0.004-0.008 ppm) in eggs, 6.3-36.4% TRR (0.004 ppm) in muscle,
2.9-6.3% TRR in fat (0.001 ppm), and 1.4-8.5% TRR (0.005-0.035 ppm) in
liver.  

d as “other unknowns” accounted for ≤5% TRR in eggs, ≤9% TRR in
muscle, 3% TRR in triazole-label fat, and 10-12% TRR (0.043-0.045 ppm)
in liver.  Significantly different metabolic profiles were observed in
the triazole and carbinol labeled samples due to the identification of T
in all of the triazole samples or M3 in the carbinol muscle sample. 

Table B.6:  TRRs in Milk, Tissue and Excreta Following Dosing with
[Triazole-3,5-14C]Flutriafol or [Carbinol-14C]Flutriafol.

Matrix	Collection Timing	[Triazole-3,5-14C]Flutriafol (ppm)
[Carbinol-14C]Flutriafol (ppm)

Diary Cow	Hen1	Dairy Cow	Hen1

Milk/Egg	Day 1 am	--	--	Dosing with [Carbinol-14C]Flutriafol was not
performed.	--

	Day 1 pm	0.002	0.001

No sample

	Day 2 pm	0.004	0.041

0.032

	Day 2 am	0.005	0.089

0.016

	Day 3 pm	0.006	0.088

0.051

	Day 3 am	0.006	0.135

No sample

	Day 4 pm	0.007	0.129

0.079

	Day 4 am	0.007	No sample

0.116

	Day 5 pm	0.007	0.145

0.101

	Day 5 am	0.007	0.184

No sample

	Day 6 pm	0.008	0.167

0.117

	Day 6 am	0.007	0.206 (0.205)

0.160 (0.159)

	Day 7 pm	0.008	0.190

0.126

	Day 7 am	0.007	0.204

0.121

	Day 8 am	--	0.184 (0.204)

0.133 (0.134)

Muscle	At sacrifice	0.008	0.060 (0.064)

0.011 (0.011)

Fat	At sacrifice	--	0.038 (0.035)

0.018 (0.016)

Fat, subcutaneous	At sacrifice	0.002	--

--

Fat, omental	At sacrifice	<0.001	--

--

Fat, perirenal	At sacrifice	0.003	--

--

Kidney	At sacrifice	0.061	--

--

Liver	At sacrifice	0.291	0.360 (0.411)

0.343 (0.359)

Heart	At sacrifice	0.011	--

--

1	TRR reported in parentheses were calculated by summing extractable and
nonextractable radioactivity.

Table B.7:  Summary of Characterization and Identification of
Radioactive Residues in Cow Matrices when Dosed with
[Triazole-3,5-14C]Flutriafol at 2 ppm in the Diet.

Compound	Milk	Kidney	Liver

	TRR = 0.008 ppm	TRR= 0.061 ppm	TRR= 0.291 ppm

	% TRR	ppm	% TRR	ppm	%TRR	ppm

Flutriafol	1	<0.001	7	0.004	29	0.084

4-Hydroxyflutriafol (M1B)	<4	<0.001	<23	<0.014	1	0.003

4-Hydroxy-5-methoxyflutriafol (M1D)	--	--	--	--	2	0.006

Enzyme solubilzed	--	--	--	--	421	0.122

Total identified	<5	<0.001	<30	<0.018	32	0.093

Total characterized	38	0.003	34	0.021	51	0.148

Total extractable	97	0.008	89	0.054	92	0.268

Unextractable	3	<0.001	11	0.007	9	0.026

Accountability2	100	100	101

1	The hydrolysate was further characterized via sequential hydrolysis
followed with ß-glucuronidase, 6M HCl, and 0.1 M NaOH with ether
partitioning between each hydrolysis.  The TLC of the ether fractions
detected flutriafol, M1D and unknowns (“each at <10% TRR”, but no
quantitative data were reported), the aqueous phase was not
chromatographically analyzed and contained 18% TRR (0.052 ppm).

2	Accountability = (Total extractable + Total unextractable)/(TRR from
combustion analysis) * 100.

Table B.8:  Summary of Characterization/Identification of TRRs Hen
Matrices Dosed with [Triazole-3,5-14C]Flutriafol or
[Carbinol-14C]Flutriafol in the Diet.

Compound	[Carbinol-14C]Flutriafol at 11.6 ppm in the Diet
[Triazole-3,5-14C]Flutriafol at 13.9 ppm in the Diet

	Eggs Day 6	Eggs Day 8	Muscle	Fat	Liver	Eggs Day 6	Eggs Day 8	Muscle	Fat
Liver

	TRR= 

0.159 ppm	TRR = 

0.134 ppm	TRR= 

0.011 ppm	TRR= 

0.016 ppm	TRR= 

0.359 ppm	TRR= 0.205 ppm	TRR = 0.204 ppm	TRR= 0.064 ppm	TRR= 0.035 ppm
TRR= 0.411 ppm

	% TRR	ppm	%TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	%TRR	ppm	%
TRR	ppm	% TRR	ppm	% TRR	ppm

Flutriafol	74.8	0.119	65.7	0.088	--	--	75.0	0.012	1.9	0.007	48.3	0.099
50.5	0.103	--	--	80.0	0.028	3.2	0.013

T	--	--	--	--	--	--	--	--	--	--	29.3	0.060	27.5	0.056	75.0	0.048	11.4
0.004	16.65	0.068

Hydroxylated flutriafols (M5)	5.7	0.009	7.5	0.010	9.1	0.001	--	--	1.9
0.007	4.4	0.009	4.4	0.009	1.6	0.001	2.9	0.001	1.5	0.006

Unknown M3	13.2	0.021	12.7	0.017	45.5	0.005	6.3	0.001	7.0	0.025	8.8
0.018	11.3	0.023	9.4	0.006	2.9	0.001	6.6	0.027

Unknown M4	3.1	0.005	3.7	0.005	--	--	--	--	7.0	0.025	1.5	0.003	2.9	0.006
--	--	--	--	5.8	0.024

Unknown M2	--	--	--	--	--	--	--	--	2.5	0.009	--	--	--	--	--	--	--	--	--
--

Other unknowns	0.5	0.001	4.5	0.006	9.1	0.001	--	--	12.5	0.045	5.4	0.011
0.5	0.001	7.8	0.005	2.9	0.001	10.5	0.043

Oily phase	--	--	--	--	--	--	5.0	0.001	--	--	--	--	--	--	--	--	3.0	0.001
--	--

Enzyme hydrolysate

–DCM phase	not performed	4.53	0.016	not performed	5.4	0.022

Enzyme hydrolysate

–aqueous phase

16.73	0.060

17.16	0.070

1N HCl hydrolysate

5.84	0.021

4.14	0.017

1M NH4OH hydrolysate

8.14	0.029

8.84	0.036

6N HCl hydrolysate  –DCM phase

5.34	0.019

0.74	0.003

6N HCl hydrolysate  –aqueous phase

25.14	0.090

11.24	0.046

Total identified	80.5	0.128	73.2	0.018	9.1	0.001	75.0	0.012	3.8	0.014
82.0	0.168	82.4	0.168	76.6	0.049	94.3	0.033	21.3	0.087

Total characterized	16.9	0.027	20.9	0.028	54.6	0.006	11.3	0.002	94.5
0.339	15.7	0.032	14.7	0.030	17.2	0.011	8.8	0.003	70.2	0.288

Total extractable	97.5	0.155	94.0	0.126	63.6	0.007	93.8	0.015	98.6	0.354
97.6	0.200	97.1	0.198	93.8	0.060	97.1	0.034	91.5	0.376

Unextractable 1	2.5	0.004	6.0	0.008	36.4	0.004	6.3	0.001	1.4	0.005	2.4
0.005	2.9	0.006	6.3	0.004	2.9	0.001	8.5	0.035

Accountability2	99	101	100	89	105	100	111	107	92	114

1	Residues remaining after exhaustive extractions.

2	Accountability = (Total extractable + Total unextractable)/(TRR from
combustion analysis) * 100.

3	The DCM phase of the enzyme hydrolysate was analyzed by TLC (nothing
identified) and aqueous phase was analyzed by HPLC (nothing identified).
 

4	These hydrolysates were not analyzed further.

5	2.7% TRR found in the enzyme hydrolysate.  

6	The DCM phase of the enzyme hydrolysate was analyzed by TLC (unknowns 
≤2.9% TRR; ≤0.012 ppm) and aqueous phase was analyzed by HPLC.
Confined Rotational Crop Study:  [Carbinol-14C]flutriafol or
[triazole-3,5-14C]flutriafol was incorporated into bare loam soil at a
target rate of 0.22 lb ai/acre (1x the proposed rate for soybean;
47090451.der.doc).  Rotational crops of wheat, pea, sugar beet, and
rapeseed were planted 30, 120, and 365 days after soil treatment and
maintained in a greenhouse.  Samples of wheat (grain, straw, and chaff),
pea (seed, pod, and foliage), sugar beet (root and top), and rapeseed
(seed, pod, and foliage) were harvested at maturity.  Table B.9 is a
summary of the TRRs in the harvested samples (30-day plantback interval
(PBI) rapeseed samples were not analyzed).  TRRs were generally higher
in the triazole-label matrices than in the carbinol-label matrices and
were lowest at the 365-day PBI.  

≤0.05 ppm in all analyzed matrices excluding the following:  carbinol
label - 120-day wheat straw (18% TRR; 0.196 ppm); triazole label -
120-day wheat grain (13% TRR; 0.150 ppm) and 120-day wheat straw (17%
TRR; 0.419 ppm).  

Based on the general extraction flowchart provided in the study, the
extracts were TLC analyzed.  However, no details of the system were
provided and the method of metabolite identification was not described
(no reference standards were listed).  Identified residues accounted for
26-43% TRR in the carbinol labeled samples and 43-67% TRR in the
triazole labeled samples (Table B.10).  The metabolic profile varied
with radiolabel position due to the identification of T, TA, and/or TAA
in the triazole labeled samples.  

The following deficiencies were identified in the confined rotational
crop study:  (1) the study did not include a leafy vegetable crop; (2)
residues in wheat forage were not investigated; (3) sandy loam soil was
not used and no data were provided concerning the soil characteristics;
(4) insufficient information was provided concerning analytical
methodology and a confirmatory method was not used for the
identification of  metabolites; (5) insufficient information was
provided to determine whether identification/characterization of
residues met Agency requirements (e.g., five unknowns designated
“others” accounted for up to >50% of TRR in carbinol-label sugar
beet tops and were not further investigated; reference standards used
not identified); (6) insufficient attempts were made to characterize
nonextractable residues of 120-day wheat straw and grain and 365-day
wheat straw samples; (7) insufficient storage stability data/information
are available to support the storage interval of at least 4 years; and
(8) insufficient information/data in general were provided to support
the study, including details of sample handling at the field site and
analytical laboratory; the distribution of radioactivity into sample
extracts and fractions; representative chromatograms, raw data, or
example calculations; and storage conditions and durations.  



Table B.9:  TRR in Rotated Crop Matrices.1

Crop	Matrix	Plantback interval (days)	[carbinol-14C]flutriafol
[triazole-3,5-14C]flutriafol

	ppm	ppm

Wheat	Grain	30	0.04	1.04

120	0.02	1.22 (1.18)

365	<0.01	0.3 (0.31)

	Straw	30	10.46	6.47

120	0.93 (1.07)	1.32 (2.45)

365	0.13	0.2 (0.16)

	Chaff	30	2.90	1.82

120	0.88	1.58

365	0.10	0.2

Pea	Seed	30	0.01	0.32

120	<0.01	0.32

365	<0.01	0.2

	Pod	30	0.05	0.14

120	0.03	0.10

365	<0.01	0.1

	Foliage	30	1.25	1.08

120	0.33	0.63

365	<0.01	0.1

Sugar beet	Root	30	0.02	0.08

120	<0.01	0.09 (0.12)

365	<0.01	0.03

	Tops	30	0.20	0.60

120	0.19 (0.31)	0.57 (0.56)

365	0.13	0.35

Rapeseed	Seed	30	Not determined

120	0.03	2.16

365	<0.01	0.6

	Pod	30	Not determined

120	0.97	2.13

365	0.13	0.3

	Foliage	30	Not determined

120	0.28	0.67

365	0.04	0.1

1	TRR were initially determined in 1981/1983; TRR re-determined in 1987
are presented in parentheses; only those samples in bold were analyzed
further.

Table B.10:  Summary of Characterization/Identification of TRRs in
Rotational Crop Samples Following Soil Treatment with
[Triazole-3,5-14C]Flutriafol or [Carbinol-14C]Flutriafol.

Compound	[Carbinol-14C]Flutriafol	[Triazole-3,5-14C]Flutriafol

	Sugar beet top 

120-day	Wheat straw

 120-day	Sugar beet root 

120-day	Sugar beet top 

120-day	Wheat grain 

120-day	Wheat grain 

365-day	Wheat straw 

120-day	Wheat straw 

365-day

	TRR = 0.31 ppm	TRR = 1.07 ppm	TRR = 0.12 ppm	TRR = 0.56 ppm	TRR = 1.18
ppm	TRR = 0.31 ppm	TRR = 2.45 ppm	TRR = 0.16 ppm

	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	% TRR	ppm	%
TRR	ppm

Flutriafol	25.7	0.080	43.3	0.463	4.3	0.005	17.0	0.095	--	--	--	--	38.2
0.936	30.7	0.049

4-hydroxy flutriafol	--	--	--	--	--	--	2.5	0.014	--	--	--	--	1.5	0.037
--	--

TA	--	--	--	--	19.6	0.024	2.5	0.014	48.5	0.572	50.5	0.157	--	--	1.1
0.002

TAA	--	--	--	--	2.7	0.003	21.0	0.118	18.8	0.222	14.2	0.044	15.5	0.380
22.2	0.036

T	--	--	--	--	17.3	0.021	--	--	--	--	--	--	--	--	--	--

Others1	51.2	0.159	25.5	0.273	--	--	15.9	0.089	--	--	--	--	16.8	0.412
3.0	0.005

Baseline	--	--	0.7	0.007	4.7	0.006	1.4	0.008	--	--	--	--	--	--	--	--

Remainder	0.5	0.002	1.8	0.019	2.6	0.003	0.5	0.003	4.8	0.057	0.6	0.002
5.5	0.135	3.5	0.006

Total identified	25.7	0.080	43.3	0.463	43.9	0.053	43	0.241	67.3	0.794
64.7	0.201	55.2	1.353	54.0	0.087

Total characterized	51.2	0.161	28.0	0.299	7.3	0.009	15.9	0.100	4.8	0.057
0.6	0.002	22.3	0.547	6.5	0.011

Total extractable2	77.4	0.241	71.3	0.762	51.2	0.062	60.8	0.341	72.1
0.851	65.3	0.203	77.5	1.900	60.5	0.098

Unextractable3	7.0	0.022	18.3	0.196	35.6	0.043	3.6	0.020	12.7	0.150	15.2
0.047	17.1	0.419	31.4	0.050

Accountability4	84.8 (138)	90 (103)	88 (117)	64 (63)	84.8 (82.0)	80.6
(83.3)	94.7 (176)	92.5 (74.0)

1	Consisting of at least 5 compounds in carbinol-label sugar beet tops ,
3 compounds in carbinol-label wheat straw, 2 compounds in 120-day
triazole-label wheat straw, an unspecified number of compounds in
365-day triazole-label wheat straw, and 2 compounds in triazole-label
sugar beet tops.

2	Total identified and characterized residues; actual extraction
distributions were not reported.

3	Residues remaining after extraction.

4	Accountability = (Total extractable + Total unextractable)/(TRR) *
100; values in parentheses are calculated using the initial TRR from
1981/1983.

Appendix C.	Tolerance Summary Table

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萑ː葠ː摧侠ü਀tolerances should be revised to reflect the correct
commodity definition and/or numerical tolerance specified in Table C.1. 
A revised Section F is requested 

Table C.1:  Tolerance Summary for Flutriafol.

Commodity	Proposed Tolerance (ppm)	HED-Recommended Tolerance (ppm)
Comments

Apple	0.2	0.20	Numerical tolerance should be 0.20.

Soybean	0.3	0.35	Based on the field trial data and the tolerance
calculator, the numerical tolerance should be 0.35 ppm and the correct
commodity definition is "Soybean, seed."

Soybean, aspirated grain fractions	0.5	2.2	Based on the field trial and
processing data, the numerical tolerance should be 2.2 ppm and the
correct commodity definition is "Grain, aspirated fractions."

Liver (cattle, goat, hog, horse, sheep)	0.01	--	Incorrect commodity
definition.

Cattle, liver	--	0.02	--

Goat, liver	--	0.02	--

Hog, liver	--	0.02	--

Horse, liver	--	0.02	--

Sheep, liver	--	0.02	--

Eggs	0.01	--	Tolerance not required.

Appendix D:	Chemical Name and Structure Table

Common name;

 

or

 

 Category II, based on no toxicity observed up to 1000 mg/kg/day in the
28-day dermal toxicity study in rat.

Flutriafol	Human-Health Risk Assessment		DP# 372347

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