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"  <IP_ADDRESS>	Studies Available and Considered
(Animal, Human, General Literature)	  PAGEREF _Toc248563592 \h  12

  HYPERLINK \l "_Toc248563593"  <IP_ADDRESS>	Mode of Pesticidal Action
PAGEREF _Toc248563593 \h  13

  HYPERLINK \l "_Toc248563594"  <IP_ADDRESS>	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

<IP_ADDRESS>	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)

<IP_ADDRESS>	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.

<IP_ADDRESS>	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 <IP_ADDRESS> 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 <IP_ADDRESS>  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 <IP_ADDRESS>. 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 <IP_ADDRESS>  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 <IP_ADDRESS>.  A
revised Section F is requested.

Table <IP_ADDRESS>.  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