Document ID: EPA-HQ-OPP-2011-0179-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-05-04T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

CHEMICAL SAFETY AND

POLLUTION PREVENTION

DATE:	September 30, 2011

MEMORANDUM

SUBJECT:	Metconazole:  Human Health Risk Assessment for Proposed Uses on
Sugarcane.

PC Code:  125619	DP Barcode:  D386421

Decision No.:  442406	Registration No.:  7969-246

Petition No.:  0F7807	Regulatory Action:  Section 3 Registration 

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

TXR No.:  NA	CAS No.:  125116-23-6

MRID No.:  NA	40 CFR:  §180.617

FROM:	Barry O’Keefe, Senior Biologist

		Amelia Acierto, Chemist

		Myron Ottley, Senior Toxicologist

		Nancy Tsaur, Chemist

		Risk Assessment Branch III

		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief

		Risk Assessment Branch III

		Health Effects Division (7509P)

TO:		Tracy Keigwin/Mary Waller, RM21

		Fungicide Branch

		Registration Division (7505P)

Introduction

BASF Corporation (BASF) is proposing a new foliar use of metconazole on
sugarcane.  The proposed formulated end-use product is Caramba™
Fungicide (EPA Reg. No. 7969-246).  Caramba™ Fungicide is a soluble
liquid (SL) formulation, containing 8.6% active ingredient (ai),
equivalent to 0.75 pounds of metconazole per gallon of product.

The Registration Division (RD) requested that the Health Effects
Division (HED) evaluate toxicology and residue chemistry data and
conduct dietary, aggregate, and occupational exposure and risk
assessments, as needed, to estimate the risk to human health that will
result from this new use and tolerance.

A summary of the findings and an assessment of human risk resulting from
the registered and proposed new uses of metconazole are provided in this
document.  The risk assessment was provided by Barry O’Keefe, the
hazard characterization by Myron Ottley, the residue chemistry data
review and the dietary assessment by Amelia Acierto, and the
occupational assessment by Nancy Tsaur.  The drinking water assessment
was provided by Faruque Khan of the Environmental Fate and Effects
Division (EFED).

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc305397635 \h  5 

2.0	Regulatory Conclusions and Recommendations	  PAGEREF _Toc305397636
\h  8 

2.1	Data Deficiencies/ Conditions of Registration	  PAGEREF
_Toc305397637 \h  8 

2.2	Tolerance Considerations	  PAGEREF _Toc305397638 \h  8 

2.2.1	Enforcement Analytical Method	  PAGEREF _Toc305397639 \h  8 

2.2.2	International Harmonization	  PAGEREF _Toc305397640 \h  9 

2.2.3	Recommended Tolerances	  PAGEREF _Toc305397641 \h  9 

2.2.4	Revisions to Petitioned-For Tolerances	  PAGEREF _Toc305397642 \h 
9 

2.3	Label Modifications	  PAGEREF _Toc305397643 \h  10 

3.0	Ingredient Profile	  PAGEREF _Toc305397644 \h  10 

3.1	Summary of Proposed Uses	  PAGEREF _Toc305397645 \h  10 

3.2	Structure and Nomenclature	  PAGEREF _Toc305397646 \h  11 

3.3	Physical and Chemical Properties	  PAGEREF _Toc305397647 \h  12 

3.4	Anticipated Exposure Pathways	  PAGEREF _Toc305397648 \h  12 

3.5	Consideration of Environmental Justice	  PAGEREF _Toc305397649 \h 
12 

4.0	Hazard Characterization/Assessment	  PAGEREF _Toc305397650 \h  13 

4.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc305397651 \h
 13 

4.1.1	Database Summary	  PAGEREF _Toc305397652 \h  13 

4.1.2	Studies Available and Considered	  PAGEREF _Toc305397653 \h  13 

4.1.3	Sufficiency of Studies/Data	  PAGEREF _Toc305397654 \h  13 

4.1.4	Toxicological Effects	  PAGEREF _Toc305397655 \h  13 

4.1.5	Cancer Classification	  PAGEREF _Toc305397656 \h  14 

4.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc305397657 \h  15 

4.3	FQPA Considerations	  PAGEREF _Toc305397658 \h  16 

4.4	FQPA Safety Factor for Infants and Children	  PAGEREF _Toc305397659
\h  16 

4.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc305397660 \h  17 

4.5.1	Recommendation for combining routes of exposure for risk
assessment	  PAGEREF _Toc305397661 \h  19 

4.6	Endocrine Disruption	  PAGEREF _Toc305397662 \h  19 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc305397663 \h 
20 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc305397664 \h  20 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc305397665 \h  20 

5.1.2	Metabolism in Livestock	  PAGEREF _Toc305397666 \h  20 

5.1.3	Drinking Water Residue Profile	  PAGEREF _Toc305397667 \h  21 

5.1.4	Food Residue Profile	  PAGEREF _Toc305397668 \h  22 

5.2	Dietary Exposure and Risk	  PAGEREF _Toc305397669 \h  26 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc305397670 \h  27 

6.1	Residential Handler Exposure and Risk Characterization	  PAGEREF
_Toc305397671 \h  27 

6.2	Residential Postapplication Exposure and Risk Characterization	 
PAGEREF _Toc305397672 \h  28 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc305397673 \h  29 

7.1	Acute & Chronic Aggregate Risk	  PAGEREF _Toc305397674 \h  30 

7.2	Short- and Intermediate-Term Aggregate Risk	  PAGEREF _Toc305397675
\h  30 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc305397676
\h  31 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc305397677 \h  32 

9.1	Short- and Intermediate-Term Handler Risk	  PAGEREF _Toc305397678 \h
 32 

9.2	Short-and Intermediate-Term Postapplication Risk	  PAGEREF
_Toc305397679 \h  33 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc305397680 \h  35 

A.1  Toxicology Data Requirements	  PAGEREF _Toc305397681 \h  35 

A.2  Toxicity Profiles	  PAGEREF _Toc305397682 \h  36 

Appendix B:  EPA Review of Human Research	  PAGEREF _Toc305397683 \h  42

Appendix C:  Physical and Chemical Properties of Metconazole	  PAGEREF
_Toc305397684 \h  42 

Appendix D:  International Residue Limit Status	  PAGEREF _Toc305397685
\h  44 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Metconazole
(5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)
cyclopentanol) is a broad-spectrum triazole fungicide that works
systemically by preventing spore formation and inhibiting mycelial
growth.  Metconazole acts primarily as an inhibitor of ergosterol
biosynthesis, thereby interfering with synthesis of fungal cell
membranes and providing systemic seed and seedling protection.  

BASF Corporation (BASF) is proposing a new Section 3 foliar use of
metconazole on sugarcane.  There is currently a Section 18 foliar use on
sugarcane.  The proposed formulated end-use product is Caramba™
Fungicide (EPA Reg. No. 7969-246).  Caramba™ Fungicide is a soluble
liquid (SL) formulation, containing 8.6% active ingredient (ai),
equivalent to 0.75 pounds of metconazole per gallon of product.

Use Profile

Caramba™ Fungicide is a triazole fungicide used to control brown and
orange rust on sugarcane.  The proposed maximum single application rate
is 0.082 lb ai/A (0.33 lb ai/A/season, with a maximum of four
applications per season).  To limit the potential for development of
resistance, no more than two sequential applications should be made
before alternating to another fungicide with a different mode of action.
 Caramba™ Fungicide may be applied foliarly by aerial, groundboom, or
chemigation methods.  The preharvest interval (PHI) is 14 days.

Toxicity/Hazard

The toxicological database for metconazole is sufficient for the purpose
of this risk assessment.  The liver is the primary target organ (with
observed adverse effects such as increased liver weight and enzyme
activity, increased incidence of hypertrophy and vacuolization) in the
mouse, rat and dog following oral exposure to metconazole via subchronic
or chronic exposure durations.  Other adverse effects observed in oral
studies were decreased body weight, decreased body weight gains, and
blood effects (reductions in erythrocyte and/or platelet parameters) in
the mouse, rat, dog and/or rabbit.  Splenic effects including increased
spleen weight and hyperplasia were observed in the mouse, rat and dog at
dose levels where liver effects were also observed.  In dogs, lenticular
degeneration (cataracts) and gastrointestinal irritation were observed
at the high dose level(s).

Developmental studies in rats and rabbits show evidence of developmental
effects, but only at dose levels that are maternally toxic.  There is
qualitative evidence of susceptibility in the rat developmental study,
however the concern is low since the developmental effects are
well-characterized, occur in the presence of maternal toxicity, the no
observable adverse effect levels (NOAELs) are well defined, and the
dose/endpoint is used for acute dietary risk assessment for the
sensitive population.  Metconazole did not demonstrate the potential for
neurotoxicity in the four species (mouse, rat, dog and rabbit) tested. 
Metconazole is considered nongenotoxic and is classified as "not likely
to be carcinogenic to humans".  In accordance with the revised 40 CFR
Part 158 data requirements, an acute neurotoxicity study is required. 
The existing database does not include this study does not include this
acute neurotoxicity study, and this data deficiency remains.

Drinking Water

Estimated drinking water concentrations (EDWCs) of metconazole in
drinking water from use on the existing crops and sugarcane were
provided by the Environmental Fate and Effects Division (EFED).  The
drinking water assessment used PRZM/EXAMS modeling for surface water and
the SCI-GROW model for ground water.  The highest surface water EDWCs
for sugarcane (9.96 µg/L for acute, 3.6 µg/L for chronic) in the
current assessment are lower than the acute EDWC for turf (45.48 µg/L)
and the chronic EDWC for cranberry (38.16 µg/L) reported in the
previous drinking water assessment, and therefore EFED recommended the
use of the previous EDWCs.  For ground water, an acute and chronic
ground water EDWC of 0.0431 µg/L was estimated for sugarcane, which is
less than the 0.38 µg/L EDWC for turf in a previous assessment.

Dietary Exposure (food and drinking water)

A new dietary assessment is not needed for the proposed Section 3 use on
sugarcane because a previous dietary assessment for an existing Section
18 use on sugarcane was conducted using residues of metconazole in/on
sugarcane, cane at a tolerance level of 1.6 ppm, which resulted in
exposure and risk well below HED’s level of concern (LOC).  The
proposed Section 3 use on sugarcane results in a tolerance residue of
0.06 ppm for sugarcane, cane, and a separate tolerance for sugarcane,
molasses is no longer needed.

Additionally, the requested use of metconazole on sugarcane did not
result in an increase in dietary exposure estimates for free triazole or
conjugated triazoles.  Therefore, the last dietary exposure analyses for
the triazole metabolites did not need to be updated.  

Residential Exposure

This document presents the assessment of the proposed new agricultural
uses of metconazole.  No new residential uses are being requested at
this time.  However, adults, adolescents and children may be exposed to
metconazole from its currently registered use on turf and ornamentals.

Aggregate Risk

Dietary, incidental oral and inhalation routes of exposure have the same
toxicity endpoints, and therefore, can be aggregated.  Acute and chronic
aggregate risk assessments include only food and drinking water, and the
results are covered in the dietary section of this executive summary.

The short- and intermediate-term aggregate risk assessments for
metconazole consider average (chronic) exposure estimates from dietary
consumption of metconazole (food and drinking water) and
non-occupational/residential use on turf (inhalation for adults and
incidental oral for children).  Postapplication exposures from the use
on turf are considered predominantly short-term (1-30 days).  Although
exposures are expected via the dermal route, quantification of dermal
risk was not conducted, since a dermal endpoint was not identified for
short- or intermediate-term exposures.  Therefore, short- and
intermediate-term post-application aggregate risk assessments were
conducted only for average dietary and incidental oral exposures to
children, and average dietary and inhalation exposures to adults.

The short-and intermediate-term aggregate margins of exposure (MOEs)
from dietary exposure (food + drinking water) and
non-occupational/residential handler exposure (inhalation) for adults
are both 1700, which are not of concern to HED, since these MOEs are
greater than the level of concern MOE of 100.

The short-and intermediate-term aggregate MOEs from dietary exposure
(food + drinking water) and non-occupational/residential exposure
(incidental oral) for children 1-2 years old are 420 and 460,
respectively; which are not of concern to HED, since these MOEs are
greater than the level of concern MOE of 100.

These aggregate exposure assessments are considered conservative
estimates that should not underestimate risks for the following reasons:
1) the dietary inputs used tolerance-level residues, 100% crop treated,
and screening level drinking water modeling data; and 2) screening-level
residential SOPs and upper level estimates of exposure were employed.

Aggregate Assessment of Free Triazole & its Conjugates

The addition of the new proposed use on sugarcane does not increase the
aggregate exposure to free triazoles and its conjugates.  Therefore, the
recently updated aggregate human health risk assessment for free
triazoles and its conjugates remains unchanged and the aggregate
estimates remain below HED’s level of concern.

Occupational Exposure and Risk

Handlers: Based on the proposed uses, there is a potential for short-
and intermediate-term occupational exposure to metconazole during
handling activities (e.g. mixing, loading, application).  The results of
the occupational handler exposure and risk assessment indicate that
short- and intermediate-term inhalation risks do not exceed HED’s LOC
of an MOE <100.  For short-term exposure, the handler inhalation MOEs
ranged from 63,000 to 440,000 at baseline (i.e., with no respirator),
and for intermediate-term exposure, the handler inhalation MOEs ranged
from 45,000 to 310,000 at baseline.

Post-application Workers: There is a potential for short- and
intermediate-term occupational exposure during post-application
activities.  However, since there is no dermal endpoint identified up to
the limit dose, a dermal post-application assessment is not needed. 
Under the Worker Protection Standard (WPS) for Agricultural Pesticides,
the 12-hour REI on the label is acceptable.

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.  These studies (listed in Appendix B) have been determined to
require a review of their ethical conduct, and have received that
review.

2.0	Regulatory Conclusions and Recommendations  TC \l1 "2.0	Regulatory
Conclusions and Recommendations 

HED can recommend for a conditional registration and a permanent
tolerance for the proposed use of metconazole on sugarcane.  Additional
data are needed as conditions of registration as outlined in Section 2.1
below.  The specific tolerance recommendations are discussed in Section
2.2, and label modifications are discussed in Section 2.3.

Data Deficiencies/Conditions of Registration  TC \l2 "2.1	Data
Deficiencies/ Conditions of Registration 

Note to PM:

860.1520 Processed Food/Feed

Residues of triazole-related compounds in blackstrap molasses are
apparently misstated in the Executive Summary (page 13) of MRID 4823740
where it is stated that TA concentrated by a factor of 4.3X in molasses.
 The data listed in the tables (p 309 – 311) of the document indicate
that TAA concentrates by a factor of 4.3X in molasses and that TA does
not concentrate, and this is also indicated in the Table 18, page 42, of
the Results and Discussion of the submission.  It appears from the
analytical data that TAA concentrated, not TA.  BASF should confirm
this.

The following data are required as a condition of registration:

TOXICOLOGY

870.6200a Acute Neurotoxicity Study

An acute neurotoxicity study is required in accordance with the revised
40 CFR Part 158 data requirements, as part of a neurotoxicity battery. 
The existing database includes a subchronic neurotoxicity study, but not
an acute neurotoxicity study, and this remains a data deficiency.  

Tolerance Considerations  TC \l2 "2.2	Tolerance Considerations 

2.2.1	Enforcement Analytical Method  TC \l3 "2.2.1	Enforcement
Analytical Method 

Adequate high performance liquid chromatography/tandem mass spectrometry
(HPLC/MS/MS) method BASF D0604 is available for enforcement of tolerance
and for data collection for residues of metconazole parent isomers (cis-
and trans- metconazole) and metconazole metabolites in plant
commodities. The method was adequately validated prior to and
concurrently with the analyses of crop field and processed commodity
samples.  The validated limit of quantitation (LOQ) is 0.01 ppm each for
parent metconazole (sum of cis- and trans-isomers at 0.005 ppm each) and
the metabolites M11, M21, and M30 in the RAC and processed commodity
samples.  The LOQ is 0.01 ppm for 1,2,4-triazole (T) and triazolylacetic
acid (TAA), and 0.05 ppm for triazolylalanine (TA) in all sugarcane RAC
and processed commodity samples.  All residues of the analytes (parent,
metabolites M11, M21, and M30 and 1,2,4-T, TA, and TAA) in the untreated
RAC, refined sugar and blackstrap molasses samples were non-detectable. 
Representative chromatograms were provided.

2.2.2	International Harmonization  TC \l3 "2.2.2	International
Harmonization 

There are currently no established Codex, Canadian, or Mexican maximum
residue limits (MRLs) for metconazole on sugarcane.  An International
Residue Limit (IRL) status sheet is appended to this document as
Appendix D.

2.2.3	Recommended Tolerances  TC \l3 "2.2.3	Recommended Tolerances 

In accordance with HED’s Interim Guidance on Tolerance Expressions
(5/27/09, S. Knizner), the tolerance expression for metconazole should
be stated as follows:

Tolerances are established for residues of metconazole, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only metconazole
[5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)
cyclopentanol] as the sum of its cis- and trans-isomers.

The proposed use and the submitted data support the following tolerance
for residues of metconazole on/on the following raw agricultural
commodity.

Sugarcane, cane	0.06 ppm

2.2.4	Revisions to Petitioned-For Tolerances  TC \l3 "2.2.4	Revisions to
Petitioned-For Tolerances 

Permanent tolerances have been proposed by BASF for the combined
residues of the fungicide metconazole in/or on sugarcane, cane at 0.06
and sugarcane, molasses at 0.08 ppm.  

For purposes of the tolerance expression, HED has determined that the
residue of concern is metconazole (the sum of cis- and trans- isomers)
for both primary and rotational crops and for livestock commodities. 
The tolerance expression for metconazole in 40 CFR §180.617(a)(1)
should be stated according to HED’s Interim Guidance on Tolerance
Expression (5/27/09, S. Knizer) as specified in Section 2.2.3.

Section 18 emergency exemption tolerances are currently established for
metconazole residues in/on sugarcane, cane at 1.6 ppm and sugarcane,
molasses at 3.2 ppm under 40 CFR §180.617(b).  These tolerances should
now be deleted and a new tolerance should be listed under 40 CFR
§180.617(a)(1) for sugarcane, cane at 0.06 ppm.  

Adequate crop field trial data reflecting the proposed use patterns were
submitted for purposes of establishing tolerances on sugarcane.  The
OECD MRL Calculator was utilized in determining the appropriate
tolerance level for sugarcane, cane.

The highest metconazole residue from the sugarcane field trials (1X) is
0.036 ppm.  This residue multiplied by the processing factor for
molasses (0.036 X 2.1) yields 0.043 ppm.  As this is less than the
recommended tolerance for sugarcane, cane at 0.06 ppm, the sugarcane,
cane tolerance will cover molasses.  No separate tolerance for molasses
is necessary.

The proposed and recommended tolerances for metconazole as a result of
the subject action are presented in Table 1.

Table 1. Tolerance Summary for Metconazole.

Commodity	Proposed Tolerance

(ppm)	Recommended Tolerance

(ppm)	Comments

40 CFR §180.617(a)(1)

Sugarcane, cane	0.06	0.06

	Sugarcane, molasses	0.08	none	Molasses is covered by the recommended
sugarcane, cane tolerance.

2.3	Label Modifications  TC \l2 "2.3	Label Modifications 

The product has been referred to and described in the submission as a
soluble liquid (SL), but this designation is not reflected in the
product name and/or proposed label.  The label should be revised to
indicate the formulation type.

3.0	Ingredient Profile  TC \l1 "3.0	Ingredient Profile 

3.1	Summary of Proposed Uses  TC \l2 "3.1	Summary of Proposed Uses 

roduct is Caramba™ Fungicide (EPA Reg. No. 7969-246).  Caramba™
Fungicide is a soluble liquid formulation, containing 8.6% active
ingredient (ai), equivalent to 0.75 pounds of metconazole per gallon of
product.  Caramba™ Fungicide is a triazole fungicide used to control
brown and orange rust on sugarcane.  The proposed maximum single
application rate is 0.082 lb ai/A (0.33 lb ai/A/season, with a maximum
of four applications per season).  Caramba™ Fungicide application
should ensure thorough coverage of foliage, blooms, and fruit.  To limit
the potential for development of resistance, no more than two sequential
applications should be made before alternating to another fungicide with
a different mode of action.  Caramba™ Fungicide may be applied
foliarly by aerial, groundboom, or chemigation methods.  The PHI is 14
days.  A summary of the proposed use directions for the intended crops
is presented in Table 2.  

Table 2.  Summary of Directions for Use of Metconazole on Sugarcane

Application Timing, Type, and Equipment1	Formulation

[EPA Reg. No.]	Application

Rate

(lb ai/A)	Max. No. Applications per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Foliar (Broadcast, Ground sprayer, Aerial or through Sprinkler
Irrigation Systems)	8.6% SL [7969-246]	0.082	4	0.33	14	Apply at first
sign of disease.  Continue applications on a 14-28-day interval if
conditions for disease development persist.  Use shorter interval when
disease pressure is high.  Do not make more than 2 sequential
applications of Caramba or other DMI (Group 3) fungicides before
alternating to another fungicide with a different mode of action.

1 The original label (EPA Registration No. 7969-246; 05/22/2009) states
in the general instructions that a nonionic surfactant may be used at
the lowest labeled rate (for ground applications). 

3.2	Structure and Nomenclature  TC \l2 "3.2	Structure and Nomenclature 

Structure and nomenclature are reported in Table 3.

Table 3.  Metconazole Nomenclature.

Chemical structure	

 

trans-isomer

Common name	Metconazole

Company experimental name	KNF-S-474m (Kureha); BAS 555 F (BASF); V-10116
(Valent)

IUPAC name	  SEQ CHAPTER \h \r 1
(1RS,5RS:1RS,5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-
ylmethyl)cyclopentanol

CAS name	  SEQ CHAPTER \h \r 1
5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)c
yclopentanol

CAS registry number	  SEQ CHAPTER \h \r 1 125116-23-6 (cis- and
trans-isomers)

115850-27-6 (cis-isomer)

Caramba™ Fungicide (EPA File Symbol 7969-246)

3.3	Physical and Chemical Properties  TC \l2 "3.3	Physical and Chemical
Properties 

The physicochemical properties of metconazole are reported in Appendix
C.  

3.4	Anticipated Exposure Pathways  TC \l2 "3.4	Anticipated Exposure
Pathways 

The Registration Division has requested an assessment of human health
risk to support the proposed new use of metconazole on sugarcane.  For
domestic uses, humans may be exposed to metconazole in food and drinking
water, since metconazole may be applied directly to growing crops and
application may result in metconazole reaching surface and ground water
sources of drinking water.  In an occupational setting, applicators may
be exposed while handling the pesticide prior to application, as well as
during application.  There is a potential for post-application exposure
for workers re-entering treated fields.  There are also residential uses
of metconazole, so there is exposure in residential or non-occupational
settings.

Risk assessments have been previously prepared for the existing uses of
metconazole.  This risk assessment considers all of the aforementioned
exposure pathways based on the proposed new use of metconazole, but also
considers the existing uses as well, particularly for the dietary
exposure assessment.

3.5	Consideration of Environmental Justice  TC \l2 "3.5	Consideration of
Environmental Justice 

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, “Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations,”   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf .

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake 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, nondietary 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.

4.0	Hazard Characterization/Assessment  TC \l1 "4.0	Hazard
Characterization/Assessment 

4.1	Hazard and Dose-Response Characterization  TC \l2 "4.1	Hazard and
Dose-Response Characterization 

4.1.1	Database Summary  TC \l3 "4.1.1	Database Summary 

The toxicological database for metconazole is adequate for the purpose
of this risk assessment.  

Two recent risk assessment documents (HED memoranda B. O’Keefe,
09/06/07, DP328676 and Y. Donovan, 03/12/08, DP331937) contain detailed
and up-to-date discussions of the toxicology and hazard evaluation of
metconazole.  Please refer to these documents for further extensive
details.  Also, please refer to Appendix 2 of this current risk
assessment document for the toxicity profile tables.

4.1.2	Studies Available and Considered  TC \l3 "4.1.2	Studies Available
and Considered 

The following data are available:

Acute- Oral rat, dermal rat, inhalation rat, eye irritation rabbit,
dermal irritation rabbit, and skin sensitization guinea pig.

Subchronic- Oral 28-day rat; oral 90-day rat, oral 90-day mouse, and
oral 90-day dog;

Chronic- Oral rat and dog;

Reproductive/developmental- Oral developmental rabbit and rat,
2-generation reproductive rat

Other- Oral rat and mouse cancer studies, 21-day dermal toxicity and
dermal penetration studies, subchronic neurotoxicity, mutagenicity
screens and mechanistic studies.

4.1.3	Sufficiency of Studies/Data  TC \l3 "4.1.3	Sufficiency of
Studies/Data 

The toxicity database for metconazole is adequate for the purpose of
this risk assessment (see Appendixes for Toxicity Profile tables).  

4.1.4	Toxicological Effects  TC \l3 "4.1.4	Toxicological Effects 

Metconazole is a member of the triazole class of systemic fungicides and
acts primarily as an inhibitor of ergosterol biosynthesis.   The
proposed mode of action for metconazole is via inhibition of sterol
(ergosterol) biosynthesis in fungi which is consistent with altered
cholesterol levels observed in mice and rats.  

Overall, metconazole appears to affect the liver, kidney, spleen, and
certain blood parameters in all the species tested.  Dose levels at
which these effects occur are similar across species with the rat and
dog being slightly more sensitive than the mouse.  Like other triazoles,
a primary target organ in mammalian toxicity studies is the liver.  
Liver toxicity was seen in the mouse, rat and dog following oral
exposure to metconazole via subchronic or chronic exposure durations. 
While liver effects have been reported consistently across multiple
durations and species, these effects were considered slight and minimal
in some studies and appeared to be "adaptive" responses.  However, based
on the weight of evidence from the consistency of these reported effects
and evidence that these effects increase in severity with duration, and
leading to liver tumors in the chronic mouse study, they were considered
"adverse" and formed the basis of the study LOAELs.  Metconazole is
considered nongenotoxic and the liver tumors appear to have been formed
via a mitogenic mode of action and therefore, metconazole is classified
as "not likely to be carcinogenic to humans" at levels that do not cause
mitogenesis (see section 4.1.5).  The established chronic RfD would be
protective of mitogenesis/carcinogenesis.

Other major critical effects observed in oral studies were decreased
body weight, decreased body weight gains, and blood effects (reductions
in erythrocyte and/or platelet parameters) in the mouse, rat, dog and/or
rabbit.  Splenic effects including increased spleen weight and
hyperplasia were observed in the mouse, rat and dog at dose levels where
liver effects were also observed.  In dogs, lenticular degeneration
(cataracts) was observed at the highest dose tested (114 mg/kg/day). 
Furthermore, at high dietary levels, there is evidence that metconazole
is a gastrointestinal irritant in the dog.

Developmental studies in rats and rabbits show some evidence of
developmental effects, but only at dose levels that are maternally
toxic.  There was no quantitative susceptibility to the fetuses of rats
or rabbits following in utero exposure to metconazole.  In the
developmental toxicity study in rats, skeletal variations (predominantly
lumbar ribs) occurred in the presence of maternal toxicity (decreased
body weight gains).  In the prenatal developmental toxicity study in
rabbits, developmental effects (increased post-implantation loss and
reduced fetal body weights) were observed at the same dose that caused
maternal toxicity (decreased body weight gains, reduced food consumption
and alterations in hematology parameters).  In the two-generation
reproduction study in rats, offspring toxicity (reduced fetal body
weights F2 offspring and decreased viability in F1 and F2 offspring) was
observed only at the highest tested dose, a dose which also resulted in
parental toxicity as evidenced by reduced parental body weight and body
weight gains, increased incidence of fatty hepatocyte changes in male
parental animals and increased incidence of spleen congestion in F1
parental females.  In the rat study, there is low concern for
qualitative susceptibility (skeletal variation in the presence of
minimal maternal toxicity) due to the presence of more severe effects at
higher dose levels such as post-implantation loss, hydrocephaly and
visceral anomalies.  However, there is a clear NOAEL for these effects
and the point of departure for this endpoint is based on skeletal
variations. Therefore, it is concluded that there is no residual
uncertainty for pre- and/or post-natal toxicity.  

Metconazole did not demonstrate neurotoxicity in the standard battery of
tests submitted.  Information available from the submitted studies
including acute, subchronic and chronic studies in several species,
developmental toxicity studies in the rat and rabbit and a two
generation reproduction study in the rat do not indicate any neurotoxic
signs.  No effects were noted on brain weights and no clinical signs
possibly related to neurotoxicity were noted up to and including the
high doses in all studies.  However, in accordance with the revised 40
CFR Part 158 data requirements, an acute neurotoxicity study is
required.  The existeing database does not inclue an acute neurotoxicity
study, and this remains a data deficiency.

Acute oral and dermal toxicities are Category III, while acute
inhalation is Category IV.  Metconazole is a moderate eye irritant
(Category III) and a mild skin irritant (Category IV).  It is not a skin
sensitizer.  

4.1.5	Cancer Classification  TC \l3 "4.1.5	Cancer Classification 

The Cancer Assessment Review Committee (CARC) Classification is: “Not
Likely to be Carcinogenic to Humans” based on convincing evidence that
a non-genotoxic mode of action for liver tumors was established in the
mouse and that the carcinogenic effects were not likely below a defined
dose that doesn’t cause mitogenesis based on bioassays in the rat and
the mouse, combined with a lack of in vitro or in vivo mutagenicity
(memo, J. Kidwell, TXR# 0054211, 4/14/06).  No quantification is
required.

4.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "4.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

The absorption, distribution, metabolism and excretion of metconazole
were investigated in rats following single oral doses of cis and or
cis/trans metconazole radiolabeled at the cyclopentyl or triazole ring
(cis only).  

Regarding aborption, the time to maximum plasma concentration for male
and female rats treated with either 2 mg/kg or 200 mg/kg was at the
earliest sampling intervals of 0.25 hours and 4 hours, respectively. The
plasma half-life of low- and high-dose rats was slightly shorter in
males than females, ~20-25 hours and ~34 hours, respectively. Plasma
pharmacokinetic studies showed a low potential for bioaccumulation
following single or multiple dosing regimen.

Radioactivity measurements of tissues showed higher concentrations in
the gastrointestinal tract, adrenals and liver. The pattern of
metabolites was similar at the low and high dose.  Analysis of fecal and
urine samples showed little or no parent compound with ten key
metabolites representing over 50% of the administered dose.  Metconazole
metabolites consist primarily of mono- and poly-hydroxylated derivatives
of the parent molecule.  Hydroxylation occurs mainly on the alkyl
constituents of the phenyl and cyclopentyl rings.  Sulfate conjugation
to the cyclopentyl ring hydroxyl groups was also identified. 
Monohydroxy metabolites were found in the feces and di- and tri- hydroxy
compounds were found more often in the urine.  Administration of 200
mg/kg radiolabeled cis metconazole (14C-triazole ring) showed
approximately 5% of the administered dose excreted as free triazole. 

Initial studies showed less than 2% of the cyclopentyl-labeled dose was
expired in the air.  Following a single oral administration of low dose
(2 mg/kg) 14C-cyclopentyl (cis/trans metconazole), greater than 80% of
the administered dose was excreted in 24 hours with total excretion
exceeding 90% in three days.  Excretion was primarily via feces (80%
male, 67% female) with biliary excretion being the prominent route of
elimination.  At 72 hours, 15% and 26% of the radioactivity was excreted
via urine in males and females, respectively.  A delay in excretion was
observed following the administration of high dose (164 mg/kg)
14C-cyclopentyl (cis/trans metconazole); however by 72 hours, 80% or
more of the radioactivity was excreted.  Males excreted lower amounts of
radioactivity in the urine and greater amounts of radioactivity in the
feces than females at low and high dose.

4.3	FQPA Considerations  TC \l2 "4.3	FQPA Considerations 

The toxicology database used to assess pre- and post-natal exposure to
metconazole is considered adequate.  

4.4	FQPA Safety Factor for Infants and Children  TC \l2 "4.4	FQPA Safety
Factor for Infants and Children 

The metconazole risk assessment team evaluated the quality of the
toxicity and exposure data and, based on these data, recommended that
the FQPA Safety Factor be reduced to 1X.  The recommendation is based on
the following:

The toxicology database for metconazole is complete for purposes of this
risk assessment and the characterization of potential pre-natal and/or
post-natal risks to infants and children.

There is no evidence of susceptibility following in utero exposure in
the rabbit. In the rat there is qualitative evidence of susceptibility,
however the concern is low since the developmental effects are
characterized as variations (not malformations), occur in the presence
of maternal toxicity, the NOAELs are well defined, and the dose/endpoint
is used for acute dietary risk assessment for the sensitive population. 
There is no evidence of increased susceptibility in the offspring based
on the result of the two-generation reproduction study.

In accordance with the revised 40 CFR Part 158 data requirements, a
neurotoxicity battery is required for this risk assessment.  The
existing database does not include an acute neurotoxicity study, and
this remains a data deficiency.  However, an acceptable subchronic
neurotoxicity study showed no neurotoxic effects at levels that produced
systemic toxicity in the study, as well as in other subchronic and
chronic studies.  Therefore, concern for potential neurotoxicity is low
and the 10X FQPA factor is not retained.  

There is no evidence of increased susceptibility in the offspring based
on the result of the two-generation reproduction study.

Dietary exposure assessments were conducted using tolerance level
residues and assumed 100% crop treated.  Therefore, the acute and
chronic dietary (food only) exposure is considered an upper bound
conservative estimate.  The contribution from drinking water is minimal.
 HED concludes that the acute and chronic exposure estimates in this
analysis are unlikely to underestimate actual exposure.  The drinking
water component of the dietary assessment utilizes water concentration
values generated by model and associated modeling parameters which are
designed to provide conservative, health protective, high-end estimates
of water concentrations which will not likely be exceeded.  While there
is potential for postapplication residential exposure, the best data and
approaches currently available were used in the metconazole residential
assessment.  The Agency used the current conservative approaches for
residential assessment, many of which include recent upgrades to the
SOPs.  The Agency believes that the calculated risks represent
conservative estimates of exposure because maximum application rates are
used to define residue levels upon which the calculations are based. 
Exposures are unlikely to be under estimated because the assessment was
a screening level assessment.

4.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "4.5
Hazard Identification and Toxicity Endpoint Selection 

Doses and endpoints were selected for exposure routes (i.e., oral,
dermal and inhalation) depending upon the appropriateness of the
endpoint and the relevancy of the endpoints to the population of
concern.  Developmental (in utero exposure) endpoints were selected to
assess dietary risks for Females 13-49 years of age, whereas
non-developmental (systemic toxicity) endpoints were selected to assess
dietary and non-occupational (residential) risks to the general
population, including children and infants.

A summary of toxicological endpoints for use in human health risk
assessment is presented below:

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

Exposure/

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

Acute Dietary (General Population, including Infants and Children)	

An appropriate dose/endpoint attributable to a single dose was not
observed in the available oral toxicity studies reviewed.	

Acute Dietary

(Females 13-49 years of age)	NOAEL= 12 mg/kg/day	UFA= 10X

UFH= 10X

FQPA SF= 1X

	Acute RfD = 0.12 mg/kg/day

aPAD= 0.12 mg/kg/day	Developmental toxicity in rats: LOAEL= 30 mg/kg/day
based on increases in skeletal variations.  At 75 mg/kg/day increased
incidence of post-implantation loss, hydrocephaly and visceral anomaliea
(cranial hemorrhage, dilated renal pelvis, dilated ureters, and
displaced testis) were reported.

Chronic Dietary (All Populations)	NOAEL= 4.3 mg/kg/day	UFA=10X

UFH= 10X

FQPA SF= 1X

	Chronic RfD = 0.04 mg/kg/day

cPAD = 0.04 mg/kg/day	Chronic oral toxicity study in rats: LOAEL = 13.1
mg/kg/day based on increased liver (M) weights and associated 
hepatocellular  lipid vacuolation (M) and centrilobular hypertrophy(M). 
Similar effects were observed in females at 54 mg/kg/day, plus increased
spleen weight.

Incidental Oral Short-Term (1-30 days)	NOAEL= 9.1 mg/kg/day	UFA= 10X

UFH=10X

FQPA SF= 1X

	Residential LOC for MOE = 100	28-Day oral toxicity study in rats: LOAEL
= 90.5 mg/kg/day based on decreased body weight (M), increased liver and
kidney weight and hepatocellular hypertrophy and vacuolation (M/F).

Incidental Oral Intermediate-Term (1-6 months)	NOAEL= 6.4 mg/kg/day	UFA=
10X

UFH=10X

FQPA SF= 1X	Residential LOC for MOE = 100	90-Day oral toxicity study in
rats: LOAEL = 19.2 based on increased spleen wt (F) and hepatic
vacuolation (M).

Dermal Short- (1-30 days) & Intermediate-Term (1-6 months)
Quantification of dermal risk is not required due to lack of systemic or
dermal toxicity at the Limit Dose in a 21-day dermal toxicity study in
the rat, the lack of target organ toxicity or neurotoxicity, and the
lack of developmental or reproductive toxicity in the absence of
parental effects which were looked for in the dermal toxicity.

Inhalation Short- Term (1-30 days)	NOAEL= 9.1 mg/kg/day	UFA= 10X

UFH=10X

FQPA SF= 1X

	Residential LOC for MOE = 100	28-Day oral toxicity study in rats: LOAEL
= 90.5 mg/kg/day based on decreased body weight (M), increased liver and
kidney weight and hepatocellular hypertrophy and vacuolation (M/F).

Inhalation Intermediate-Term (1-6 months)	NOAEL= 6.4 mg/kg/day	UFA= 10X

UFH=10X

FQPA SF= 1X

	Residential LOC for MOE = 100

	90-Day oral toxicity study in rats: LOAEL = 19.2 mg/kg/day based on
increased spleen wt (F) and hepatic vacuolation (M).

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans”

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

A summary of toxicological doses and endpoints for metconazole for use
in occupational human health risk assessments is presented below:

Table 5.  Summary of Toxicological Doses and Endpoints for Metconazole
for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short- (1-30 days) & Intermediate-Term (1-6 months)
Quantification of dermal risk is not required due to lack of systemic or
dermal toxicity at the Limit Dose in a 21-day dermal toxicity study in
the rat, the lack of target organ toxicity or neurotoxicity, and the
lack of developmental or reproductive toxicity in the absence of
parental effects which were looked for in the dermal toxicity.

Inhalation Short-Term (1-30 days)	NOAEL=9.1 mg/kg/day	UFA=10X

UFH=10X	Occupational LOC for MOE = 100	28-Day oral toxicity study in
rats: LOAEL = 90.5 mg/kg/day based on decreased body weight (M),
increased liver and kidney weight and hepatocellular hypertrophy and
vacuolation (M/F).

Inhalation Intermediate-term (1-6 months)	NOAEL=6.4 mg/kg/day	UFA=10X

UFH=10X	Occupational LOC for MOE = 100	90-Day oral toxicity study in
rats: LOAEL = 19.2 mg/kg/day based on increased spleen wt (F) and
hepatic vacuolation (M).

Cancer (oral, dermal, inhalation)	Classification:  “Not Likely to be
Carcinogenic to Humans”

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

Based on the available toxicity database and the Agency's current
practices, the inhalation risk for metconazole was assessed using an
oral toxicity study.  The Agency sought expert advice and input on
issues related to this route to route extrapolation approach (i.e. the
use of oral toxicity studies for inhalation risk assessment) from its
Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory
Panel (SAP) in December 2009.  The Agency received the SAP’s final
report on March 2, 2010
(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The
Agency is in the process of evaluating the SAP report and may, as
appropriate, reexamine and develop new policies and procedures for
conducting inhalation risk assessments, including route to route
extrapolation of toxicity data.  If any new policies or procedures are
developed, the Agency may revisit the need for an inhalation toxicity
study for metconazole and/or a reexamination of the inhalation toxicity
risk assessment.

4.5.1	Recommendation for combining routes of exposure for risk
assessment  TC \l3 "4.5.1	Recommendation for combining routes of
exposure for risk assessment 

For short- and intermediate-term risk assessments, the oral and
inhalation routes can be combined due to the common endpoint (liver
toxicity) via the oral and inhalation (oral equivalent) routes. 
Quantification of dermal risk is not required.  There are no potential
long-term dermal or inhalation exposures to metconazole.

4.6	Endocrine Disruption  TC \l2 "4.6	Endocrine Disruption 	

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess
potential adverse outcomes from exposure to chemicals.  Collectively,
these studies include acute, subchronic and chronic toxicity, including
assessments of carcinogenicity, neurotoxicity, developmental,
reproductive, and general or systemic toxicity. These studies include
endpoints which may be susceptible to endocrine influence, including
effects on endocrine target organ histopathology, organ weights, estrus
cyclicity, sexual maturation, fertility, pregnancy rates, reproductive
loss, and sex ratios in offspring.  For ecological hazard assessments,
EPA evaluates acute tests and chronic studies that assess growth,
developmental and reproductive effects in different taxonomic groups. 
As part of its most recent registration decision, EPA reviewed these
data and selected the most sensitive endpoints for relevant risk
assessment scenarios from the existing hazard database.  However, as
required by FFDCA section 408(p), Metconazole is subject to the
endocrine screening part of the Endocrine Disruptor Screening Program
(EDSP). 

EPA has developed the EDSP to determine whether certain substances
(including pesticide active and other ingredients) may have an effect in
humans or wildlife similar to an effect produced by a “naturally
occurring estrogen, or other such endocrine effects as the Administrator
may designate.”  The EDSP employs a two-tiered approach to making the
statutorily required determinations. Tier 1 consists of a battery of 11
screening assays to identify the potential of a chemical substance to
interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal
systems.  Chemicals that go through Tier 1 screening and are found to
have the potential to interact with E, A, or T hormonal systems will
proceed to the next stage of the EDSP where EPA will determine which, if
any, of the Tier 2 tests are necessary based on the available data. Tier
2 testing is designed to identify any adverse endocrine-related effects
caused by the substance, and establish a dose-response relationship
between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide
chemicals.  Between October 2009 and February 2010, EPA issued test
orders/data call-ins for the first group of 67 chemicals, which contains
58 pesticide active ingredients and 9 inert ingredients.  Metconazole is
not among the group of 58 pesticide active ingredients on the initial
list to be screened under the EDSP.  Accordingly, as part of
registration review, EPA will issue future EDSP orders/data call-ins,
requiring the submission of EDSP screening assays for metconazole.  For
further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, future lists, the test guidelines
and the Tier 1 screening battery, please visit our website:   HYPERLINK
"http://www.epa.gov/endo/" http://www.epa.gov/endo/ .

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

Reference: Metconazole.  Petition for Establishment of Permanent
Tolerances on Sugarcane and Waiver Request for Additional Sweet Corn
Stover Field Trial. Summary of Analytical Chemistry and Residue Data. A.
Acierto, DP386784, 7/27/11.

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

No new metabolism data were submitted with the subject petition. 
Metabolism studies with banana, canola, mandarin, pea, and wheat were
previously submitted.  The metabolism of metconazole was found to be
similar in all crops investigated.  The main metabolic route of
metconazole in crops is via oxidative hydroxylation of the methylene
groups, the methyl groups on the cyclopentyl ring, and possibly the
cyclopentyl ring.  In addition, monohydroxylation may occur at the
various pro-chiral carbons of metconazole, giving rise to
chromatographically distinguishable stereoisomeric structures.  The
detection of TA and triazole conjugates in the canola, pea, and wheat
studies indicates that the methylene group between the triazole and
cyclopentyl rings is susceptible to oxidative hydroxylation.  HED has
determined that metconazole (parent) is the residue of concern for both
the tolerance expression and risk assessment purposes in plants except
for cereal grains; the residues of concern for risk assessment in cereal
grains are metconazole and the metabolite M11.  For the purpose of the
subject petition, the nature of the residue in plants is adequately
understood.

5.1.2	Metabolism in Livestock  TC \l3 "5.1.2	Metabolism in Livestock 

No new metabolism data were submitted with the subject petition. 
Adequate ruminant and poultry metabolism studies are available, and the
data indicate that the metabolism of metconazole in ruminants and
poultry is generally similar.  The major routes of metabolism involve
oxidation and/or oxidative hydroxylation of the methyl group at position
2 of the cyclopentyl ring and oxidative hydroxylation of the phenyl
ring.  Glucuronic acid conjugates were observed in the goat metabolism
studies, and sulfate ester conjugates were observed in the hen
metabolism study.  In addition, in the hen metabolism study with
triazole-labeled metconazole, C-N bond cleavage releasing 1,2,4-T was
observed.  Based on the available data, HED has determined that the
residue of concern for the tolerance expression in livestock commodities
is metconazole (parent).  The residues of concern in livestock for
purposes of the risk assessment are metconazole and metabolites M1 (free
and conjugated), M12, and M31 (free and conjugated).  For the purpose of
the subject petition, the nature of the residue in livestock is
adequately understood.

5.1.3	Drinking Water Residue Profile TC \l3 "5.1.3	Drinking Water
Residue Profile 

Reference:  Drinking Water Exposure Assessment to Establish Tolerances
of Parent Metconazole for Sugarcane. DP387533, F. Khan, 5/12/11.

A drinking water assessment for the proposed use on sugarcane was
performed using PRZM/EXAMS modeling.  Estimated drinking water
concentrations (EDWCs) of metconazole in drinking water from use on the
existing crops and sugarcane were provided by EFED.  The EDWCs are based
on the maximum proposed rates specified on the existing labels and on
the proposed label.  For surface water, the EDWCs for the proposed crop
modeled in the assessment (highest concentration of 9.96 µg/L for
aerial application to sugarcane in LA scenario) did not exceed the acute
EDWC of 45.48 µg/L for turf reported in a previous drinking water
assessment (DP340378, 2007).  Since the highest EDWC for the crop
modeled in the current assessment is lower than the acute EDWC for turf
reported in the previous drinking water assessment, EFED recommended the
use of the previous EDWC.  Additionally, the surface water annual mean
(chronic) EDWCs for the proposed crop modeled in the assessment (highest
concentration of 3.6 µg/L for aerial application to sugarcane in LA
scenario) did not exceed the chronic EDWC of 38.16 µg/L for the
cranberry scenario (DP380513, 2010).  Since the highest EDWC for the
crop modeled in the current assessment is lower than the chronic EDWC
for cranberry reported in the previous drinking water assessment, EFED
recommended the use of the previous EDWC.

EFED calculated screening level ground water estimates for metconazole
using the SCI-GROW model.  An acute and chronic ground water EDWC of
0.0431 µg/L was estimated for the currently proposed uses.  This EDWC
is less than the 0.38 µg/L EDWC from non-agricultural uses generated
from the maximum application rate for turf in a previous assessment
(DP340378, 2007).

Drinking Water Data for Free Triazoles

Residues of 1,2,4-triazole in drinking water were provided to HED by the
EFED (I. Maher, DP320682, 28 Feb 2006).  Due to the inter-conversion
between 1,2,4-triazole, triazole alanine, and triazole acetic acid that
may occur in the environment, the residue estimates used in these
assessments are a summation of all three residues and, therefore,
represent an overestimate of actual concentrations of the common
triazole metabolites in drinking water.  The Tier II PRZM/EXAMS (surface
water) and SCIGROW (ground water) residue estimates are summarized in
Table 5.  HED notes that there were no detects of 1,2,4-triazole in any
of the 271 water samples analyzed by PDP, with a limit of quantification
of 730 parts-per-trillion (0.73 ppb).  The surface water estimates are
significantly greater than those for ground water, and were used in the
assessments for free triazole as well as the conjugated metabolites. 
EFED stated that the new metconazole uses are covered by the previous
drinking water assessment for 1,2,4-triazole (DP320682, I. Maher,
2/28/06).

Table 6.  Summary of Estimated Drinking Water Concentrations of
1,2,4-Triazole.

Exposure Duration	Surface Water Concentration, ppm	Ground Water
Concentration, ppm

Acute	0.041	0.001

Chronic	0.011	0.001

5.1.4	Food Residue Profile  TC \l3 "5.1.4	Food Residue Profile 

Residues of Concern

Reference:  Metconazole: FQPA Human Health Risk Assessment for Proposed
New Uses on Small Grains, Stone Fruits, Tree Nuts, Peanuts, Soybeans,
and Sugar Beets. PP#6F7094 and PP#6F7095. PC Code: 125619, DP331937 and
DP331926. Y. Donovan, 3/12/08.

A summary of the metabolites and degradates to be included in the risk
assessment and tolerance expression are presented below in Table 7. 
Detailed rationale for these conclusions were presented in a previous
risk assessment document (DP331926, Y. Donovan, 03/12/08).

Table 7.  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression.

Matrix	Residues Included In Risk Assessment	Residues Included In
Tolerance Expression

Plants

	Primary and Rotational Crops, except Cereal Grains	Metconazole
Metconazole

	Primary and Rotational Crops, Cereal Grains only	Metconazole and M11
Metconazole

Livestock

Metconazole; M1 and its glucuronic acid conjugate; M12; M31 and its
glucuronic acid conjugate	Metconazole

Drinking Water

	Metconazole	Not Applicable

Note:  For all triazole-containing pesticides, the triazole-containing
metabolites 1,2,4-T, TA, and TAA should also be included as residues of
concern for risk assessment purposes only for plant and livestock
commodities. Since these metabolites are common to the entire class of
triazole-derivative fungicides and because of differential toxicity
between the metabolites and the various parent compounds, risks
associated with exposure to 1,2,4-T and to TA/TAA are addressed in
separate risk assessment documents.

M1 =
5-[(4-chlorophenyl)methyl]-2-methoxyl-2-methyl-1-(1H-1,2,4-triazol-1-ylm
ethyl)-1-cyclopentanol;  M11 =
5-[(4-chlorophenyl)methoxyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl
)-1-cyclopentanol; M12 =
5-[(4-chlorophenyl)methyl]-2-carboxyl-2-methyl-1-(1H-1,2,4-triazol-1-ylm
ethyl)-1-cyclopentanol; M31 = (1S*,3R*,5S*)-3-hydroxy-cis-metconazole;
1,2,4-T = 1H-1,2,4-triazole; TAA = 1H-1,2,4-triazol-1-yl acetic acid; TA
= 2-amino-3-(1H-1,2,4-triazol-1-yl)propanoic acid.

Crop Field Trials

BASF submitted field trial data for metconazole on sugarcane (MRID
48237401).  These data are adequate and support the use of metconazole
on sugarcane.  These data reflect the use of metconazole as four foliar
broadcast applications at a 1x rate targeting 0.328 lb ai/A/season and a
5x (exaggerated) rate targeting 1.64 lb ai/A/season to sugarcane
beginning at the vegetative or blooming stage with 14-day intervals. 
The field trials support a PHI of 14 or 28 days.  From samples treated
at 1x rate and harvested at a 14-day PHI, the maximum total residues of
parent metconazole (sum of cis- and trans-isomers) were 0.036 ppm in/on
sugarcane RAC samples; residues of metabolites M11, M21, and M30 were
<LOQ (<0.01 ppm).  From 1x-treated RAC samples harvested at 27-28 day
PHIs, the total residues of parent metconazole (sum of cis- and
trans-isomers) were <0.01-<0.022 ppm; residues of metabolites M11, M21,
and M30 were <LOQ (<0.01 ppm) in all samples.

From the 5x-treated samples harvested at a 14-day PHI, the maximum total
residues of parent metconazole (sum of cis- and trans-isomers) were
<0.017-0.139 ppm in/on sugarcane RAC samples; metabolites M11, M21, and
M30 were <LOQ (<0.01 ppm) in all samples.  From samples harvested at
27-28 day PHIs, the total parent metconazole residues (sum of cis- and
trans-isomers) were <0.011-0.131 ppm; residues of metabolites M11, M21,
and M30 were <LOQ (<0.01 ppm) in all samples.  Residues of 1,2,4-T and
TA were <LOQ (<0.01 ppm) and <0.05 ppm for TAA in the sugarcane RAC
samples collected from all field trials.

The data support the use of metonazole SL on sugarcane for up to four
broadcast foliar applications during bloom stage at the rate of 0.33 lb
ai/A/application/season.  The data support a minimum retreatment
interval (RTI) of 14 days and a minimum PHI of 14 days.  

The results of the sugarcane field trials are summarized in Tables 8 and
9.

Table 8.  Summary of Residue Data from Sugarcane Field Trials with
Metconazole at 1X Application Rate.

Commodity	Total Applic. Rate

lb ai/A	Analyte	PHI

(days)	Residue Levels1 (ppm)

n	Min.	Max.	HAFT2	Median3

(STMdR)	Mean4

(STMR)	Std. Dev.

1x Rate

Sugarcane RAC	0.33	Cis-metconazole	13-14	16	<0.005	0.0304	0.0303	0.0162
0.0160	0.0087

Trans-metconazole

	<0.005	0.0054	0.0052	0.005	0.005	0.0001

metconazole

	<0.01	0.0359	0.0355	0.0212	0.0212	0.0088

M11

	<0.01	<0.01	0.01	0.01	0.01	0.00

M21

	<0.01	<0.01	0.01	0.01	0.01	0.00

M30

	<0.01	<0.01	0.01	0.01	0.01	0.00

1,2,4-T

	<0.01	<0.01	0.01	0.01	0.01	0.00

TA

	<0.05	<0.01	0.05	0.05	0.05	0.00

TAA

	<0.01	<0.01	0.01	0.01	0.01	0.00

Sugarcane RAC	0.33	Cis-metconazole	27-28	16	<0.005	0.0173	0.0150	0.0113
0.0106	0.0043

Trans-metconazole

	<0.005	<0.005	0.005	0.005	0.005	0.00

metconazole

	<0.01	<0.0223	0.0200	0.0163	0.0156	0.0043

M11

	<0.01	<0.01	0.01	0.01	0.01	0.00

M21

	<0.01	<0.01	0.01	0.01	0.01	0.00

M30

	<0.01	<0.01	0.01	0.01	0.01	0.01

1,2,4-T

	<0.01	<0.01	0.01	0.01	0.01	0.00

TA

	<0.05	<0.05	0.05	0.05	0.05	0.00

TAA

	<0.01	<0.01	0.01	0.01	0.01	0.00

1Includes residues of metconazole and metabolites.  No conversion
factors were applied.

2HAFT = highest average field trial.

3STMdR = Supervised Trial Median Residue.

4 STMR = Supervised Total Mean Residue

Table 9.  Summary of Residue Data from Sugarcane Field Trials with
Metconazole at 5X Application Rate.

Commodity	Total Applic. Rate

(lb ai/A)	Analyte	PHI

(days)	Residue Levels1 (ppm)

n	Min.	Max.	HAFT2	Median3

(STMdR)	Mean4

(STMR)	Std. Dev.

5x Rate

Sugarcane RAC	1.64	Cis-metconazole	14	4	0.0120	0.1169	0.1048	0.0528
0.0587	0.0542

Trans-metconazole

	<0.005	0.0218	0.0198	0.0114	0.0124	0.0087

metconazole

	<0.0170	0.1387	0.1246	0.0642	0.0711	0.0629

M11

	<0.01	<0.01	0.01	0.01	0.01	0.00

M21

	<0.01	<0.01	0.01	0.01	0.01	0.00

M30

	<0.01	<0.01	0.01	0.01	0.01	0.00

1,2,4-T

	<0.01	<0.01	0.01	0.01	0.01	0.00

TA

	<0.05	<0.05	0.05	0.05	0.05	0.00

TAA

	<0.01	<0.01	0.01	0.01	0.01	0.00

Sugarcane RAC	1.64	Cis-metconazole	28	4	<0.0061	0.1091	0.0837	0.0322
0.0449	0.0494

Trans-metconazole

	<0.005	0.0217	0.0162	0.0079	0.0106	0.0079

metconazole

	<0.0111	0.1308	0.0999	0.0401	0.0555	0.0571

M11

	<0.01	<0.01	0.01	0.01	0.01	0.00

M21

	<0.01	<0.01	0.01	0.01	0.01	0.00

M30

	<0.01	<0.01	0.01	0.01	0.01	0.00

1,2,4-T

	<0.01	<0.01	0.01	0.01	0.01	0.00

TA

	<0.05	<0.05	0.05	0.05	0.05	0.00

TAA

	<0.01	<0.01	0.01	0.01	0.01	0.00

1Includes residues of metconazole and metabolites M11, M21, and M30.  No
conversion factors were applied.

2HAFT = highest average field trial.

3STMdR = Supervised Trial Median Residue.

4 STMR = Supervised Total Mean Residue

Processed Food and Feed

BASF submitted a processing study for metconazole on sugarcane.  The
processing data for sugarcane indicate that residues of metconazole and
triazole metabolites do not concentrate in the sugarcane processed
commodities except for TAA, which concentrated by a factor of 4.3x in
molasses and for metconazole which concentrated slightly by a factor of
1.2x in blackstap molasses.  This conclusion for TAA is based on the
data provided in the BASF data tables but must be verified since the
information provided in the BASF Summary text indicates that residues of
the triazole-related metabolites were <LOQ in refined sugar and
blackstrap molasses except for TA residues which concentrated in
blackstrap molasses by a factor of 4.3x.  An acceptable method was used
for quantitation of residues in sugarcane RAC and processed commodities.
 The residue data from the processing study is summarized in Table 10
for metconazole residues and Table 11 for the residues of the
triazole-related processed fractions.

Table 10.  Metconazole Residues in Sugarcane Processed Fractions.

Study Location (City, State/Year	Processed Commodity	Total Rate

lb ai/A	PHI

(days)	Metconazole Residue (ppm)	Processing Factor1

Parent Metconazole	Metabolites

	trans	cis	Total	M11	M21	M30

	08-TX24

Weslaco, TX

2008	Sugarcane RAC	1.65	14	0.0168	0.0813	0.0981	<0.01	<0.01	<0.01	N/A

	Refined Sugar

	0.005	<0.005	<0.01	<0.01	<0.01	<0.01	<0.1

	Blackstrap molasses

	0.0226	0.1021	0.1247	<0.01	<0.01	<0.01	1.3

1The processing factor was calculated by dividing the metconazole
residue in the processed commodity by the metconazole residue in the
cane RAC sample, e.g., 0.1247 / 0.0981 = 1.3.  The validated LOQ is 0.01
each for parent metconazole (sum of cis- and trans-metconazole) in/on
sugarcane RAC and processed commodities.  For calculations, values <LOQ
were considered to be 0.005 ppm for each parent.

NA = not applicable.

Table 11.  Residues of Triazole-related Compounds in Sugarcane Processed
Fractions

Study Location (City, State/Year	Processed Commodity	Total Rate

lb ai/A	PHI

(days)	Residue of Triazole Related Compounds (ppm)

T	Processing Factor1	TA	Processing Factor1	TAA	Processing Factor1

08-TX24

Weslaco, TX

2008	Sugarcane RAC	1.65	14	<0.01	NA	<0.05	NA	<0.01	NA

	Refined Sugar

	<0.01	1.0x	<0.05	1.0x	<0.01	1.0x

	Blackstrap molasses

	<0.01	1.0x	<0.05	1.0x	0.043	4.3x

1The processing factor was calculated by dividing the residue in the
processed commodity by the residue in the cane RAC sample.  The
validated LOQ is 0.01 ppm each for T and TAA and 0.05 ppm for TA in/on
sugarcane RAC and processed commodities.  For calculations, values <LOQ
were considered to be 0.01 ppm for T and TAA and 0.05 ppm for TA. 

NA = not applicable.

Meat, Milk, Poultry, and Eggs

Adequate cattle and poultry feeding studies are available.  The only
livestock feed item associated with the proposed use on sugarcane is
molasses. Molasses was previously considered in developing the livestock
diet, and a metconazole concentration of 3.2 ppm was utilized (DP350367,
N. Dodd, 09/18/08).   Therefore, the established livestock tolerances
are adequate to cover residues resulting from the proposed use.

Field Accumulation in Rotational Crops

No new field studies have been submitted.  The earlier reviews required
that end-use labels include plant-back restrictions of 30 days for leafy
vegetables and Brassica leafy vegetables and 120 days for all remaining
crops other than those with labeled uses.  This requirement has been
fulfilled and the statement now appears in the master label.

5.2	Dietary Exposure and Risk TC \l2 "5.2	Dietary Exposure and Risk 

Reference: Metconazole:  Acute and Chronic Dietary (Food and Drinking
Water) Exposure and Risk Assessment for Residues in/on Vegetables,
Tuberous & Corm, Subgroup 1C and Bushberry Subgroup 13-07B. A. Acierto,
DP387504.drs, 3/28/11.

A new dietary assessment is not needed for the proposed Section 3 use on
sugarcane because a previous dietary assessment for an existing Section
18 use on sugarcane was conducted using residues of metconazole in/on
sugarcane, cane at a tolerance level of 1.6 ppm and sugarcane, molasses
at a tolerance of 3.2 ppm, which resulted in exposure and risk estimates
well below HED’s level of concern (DP350663 N. Dodd, 9/23/2008).  The
proposed Section 3 use on sugarcane results in a tolerance residue of
0.06 ppm for sugarcane, cane, and a separate tolerance for sugarcane,
molasses is no longer needed.  Therefore, the dietary risk estimates
from the most recent dietary assessment (DP387504, A. Acierto, 3/28/11)
should still be used to estimate aggregate risks; see Table 12.

Table 12.  Summary of Dietary (Food and Drinking Water) Exposure Risk
for Metconazolet1.

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary

	Dietary Exposure (mg/kg/day)	% aPAD	Dietary Exposure

(mg/kg/day)	% cPAD

General U.S. Population	NA	NA	0.002434                	6

All Infants (<1 year old)

	0.004831                	12.1

Children 1-2 years old

	0.005026                	12.6

Children 3-5 years old

	0..004800                	12

Children 6-12 years old

	0.003289                	8.2

Youth 13-19 years old

	0.001961                	4.9

Adults 20-49 years old

	0.002158                	5.4

Adults 50+ years old

	0.001868                	4.7

Females 13-49 years old	0.004578     	3.8	0.001874                	4.7

1 The values for the highest exposed population for each type of risk
assessment are bolded.

Dietary Assessment of Free Triazole and its Conjugates

Reference:  Common Triazole Metabolites:  Updated Dietary (Food + Water)
Exposure and Risk Assessment to Address The Amended Metconazole Section
3 Registration to Add Uses on Tuberous and Corm Vegetables (Group 1C)
and Bushberry Subgroup 13-07B. T. Morton, DP388469.drs, 4/27/11.

The proposed Section 3 use of metconazole on sugarcane did not result in
an increase in dietary exposure estimates for free triazole or
conjugated triazoles.  Therefore, the last dietary exposure analyses for
the triazole metabolites (DP388469, T. Morton, 4/27/11) did not need to
be updated.  

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

No new residential uses are being requested at this time.  However,
adults, adolescents, and children may be exposed to metconazole from its
currently registered uses on turf and ornamentals.  These risks have
been previously assessed (DP341832, J. Arthur, 8/3/07).  Because dermal
toxicity endpoints for the appropriate duration of exposure (short- and
intermediate-term) were not identified up to the limit dose, only
residential handler inhalation exposures/risks for adults, and
residential post-application incidental oral exposures/risks for
children have been assessed.  

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application (a method proposed to be employed for metconazole), but, to
a lesser extent, could also be a potential source of exposure from the
ground application method also employed for metconazole.  The Agency has
been working with the Spray Drift Task Force, EPA Regional Offices, and
State Lead Agencies for pesticide regulation and other parties to
develop the best spray drift management practices.  On a chemical by
chemical basis, the Agency is now requiring interim mitigation measures
for aerial applications that must be placed on product labels/labeling. 
The Agency has completed its evaluation of the new database submitted by
the Spray Drift Task Force, a membership of U.S. pesticide registrants,
and is developing a policy on how to appropriately apply the data and
the AgDRIFT computer model to its risk assessments for pesticides
applied by air, orchard airblast, and ground hydraulic methods.  After
the policy is in place, the Agency may impose further refinements in
spray drift management practices to reduce off-target drift with
specific products with significant risks associated with drift.

6.1	Residential Handler Exposure and Risk Characterization  TC \l2 "6.1
Residential Handler Exposure and Risk Characterization 

Residential handler exposures are expected to be short-term in duration.
 An MOE (100 is adequate to protect residential pesticide handlers.  All
metconazole residential handler MOEs are estimated to be >100 for the
established residential uses, and therefore, do not cause concern for
HED.  A summary of these exposures and risks is presented in Table 13.

Although a point of departue from an oral study was used to assess
residential handler inhalation risks for metconazole, HED does not
believe this assessment is under-protective of adult handlers.  MOEs
calculated for residential handlers were all >71,000, thus providing an
ample margin of safety to account for any uncertainties in
route-to-route extrapolation.  Short-term inhalation risks were not of
concern to HED.  

Table 13. Residential Handler Short-term Inhalation Exposures and Risks.

Scenario	Exposure Route	Max. Rate Application 	Unit Exposure	Amount
Treated/Day	Daily Dose

(mg/kg/day)1	Inhalation MOE2

1) mixer/loader/applicator w/ hose-end sprayer (ornamentals)	Inhalation
0.0025 lb ai/gal	0.017 mg/lb ai	100 Gal.	0.000061	150,000

2) mixer/loader/applicator w/ low-pressure hand-wand sprayer
(ornamentals)	Inhalation	0.0025 lb ai/gal	0.03 mg/lb ai	5 Gal.	0.0000054
1,700,000

3) mixer/loader/applicator w/ hose-end sprayer (turf)	Inhalation	0.6 lb
ai/A	0.017 mg/lb ai	0.023 Acre = 1000 ft2	0.0000034	2,700,000

4) mixer/loader/applicator w/ low-pressure hand-wand sprayer (turf)
Inhalation	0.6 lb ai/A	0.03 mg/lb ai	0.5 Acre	0.00013	71,000

1. Daily Dose = Application Rate * Unit Exposure * Amount Treated *
Absorption factor (100% for inhalation)/Body Weight (70 kg).

2. Inhalation MOE = Inhalation short-term NOAEL (9.1 mg/kg/day) ÷ Daily
Dose 

6.2	Residential Post-Application Exposure and Risk Characterization  TC
\l2 "6.2	Residential Postapplication Exposure and Risk Characterization 

Adults, adolescents, and children may be exposed to metconazole from its
proposed residential uses.  Adults and adolescents may experience short-
and intermediate-term dermal exposure from golfing and other activities
on treated turf, as well as from tending treated ornamentals.  Children
age 3 to <6 years old may experience short- and intermediate-term dermal
and incidental oral exposure from activities on treated turf.   However,
because dermal toxicity endpoints for the appropriate durations of
exposure were not identified up to the limit dose, and because
inhalation exposure is considered to be insignificant for
post-application exposures, only children age 3 to <6 years old
incidental oral post-application exposures have been assessed.  

Post-application risks to children following the application of
metconazole to home lawns were calculated for short- and
intermediate-term incidental oral exposures.  A summary of the estimated
exposures and risks, along with the algorithms used for each small child
exposure scenario are presented below in Tables 14 through 16.  All MOEs
for toddler lawn exposure scenarios were >100 and, therefore, are not of
concern to HED.  In addition, the total MOEs for combined toddler
exposures (i.e., short-term and intermediate-term hand-to-mouth,
object-to-mouth, and incidental ingestion of soil) are >100 (see Table
17), and therefore, do not concern HED.



Table 14. Oral Hand-to-mouth Short- (ST) and Intermediate-term (IT)
Exposures and Risks for Children from Treated Lawns.

Application Rate (lb ai/A)	Fraction of ai Available	Turf Transferrable
Residue at Day “0" (µg/cm2)1	Exposure Time (hrs/day)	Extraction by
saliva	Hand Surface Area (cm2/event)	Frequency (events/ hr)	Body Weight
(kg)	Daily Dose2

(mg/kg/day)	MOE3

0.6	0.05	0.34	2	0.5	20	20 (ST)	15	0.0091 (ST)	1000 (ST)

9.5 (IT)

0.0043 (IT)	1500 (IT)

1Turf Transferrable Residue (µg/cm2) = Application rate (lb ai/A) x
Fraction of ai Available x 4.54E+8 µg/lb x 2.47E-8 A/cm2

2 Daily Dose = (Turf Transferrable Residue x Extraction by Saliva x Hand
Surface Area x Frequency x 1E-3 mg/ µg x Exposure Time) / (Body Weight)

3 MOE = Short-term Oral NOAEL (9.1 mg/kg/day) or Intermediate-Term Oral
NOAEL (6.4 mg/kg/day) /Daily Dose.

Table 15. Oral Object-to-mouth (Turfgrass) Short- (ST) and
Intermediate-term (IT) Exposures and Risks for Children from Treated
Lawns.

Application Rate (lb ai/A)	Fraction of ai Available	Grass Residue at Day
“0" (µg/cm2)1	Surface Area Mouthed (cm2/day)	Body Weight

(kg)	Daily Dose2

(mg/kg/day)	MOE3

0.6	0.20	1.3	25	15	0.0022	

4100 (ST)

2900 (IT)

1Grass Residue (µg/cm2) = = Application rate (lb ai/A) x Fraction of ai
Available x 4.54E+8 µg/lb x 2.47E-8 A/cm2

2 Daily Dose = [Grass residue (µg/cm2) x Surface Area Mouthed (cm2/day)
x 1E-3 mg/µg] / [Body Weight (kg)]

3 MOE = Short-term Oral NOAEL (9.1 mg/kg/day) or Intermediate-Term Oral
NOAEL (6.4 mg/kg/day) /Daily Dose  

Table 16. Short- (ST) and Intermediate-term (IT) Exposure and Risk for
Children from  Ingestion of Soil from Treated Lawns.

Application Rate

(lb ai/A)	Fraction of ai Available	Soil Residue at Day “0"(µg/g)1
Ingestion Rate

(mg/day)	Body

Weight (kg)	Daily Dose2

(mg/kg/day)	MOE3

0.6	1	4.51	100	15	0.00003	

300,000 (ST)

210,000 (IT)

1 Soil residue (µg/g) = [Application Rate (lbs ai/A) x Fraction of ai
Available x 4.54E+8 µg/lb x 2.47E-8 A/cm2 x 0.67 cm3/g soil]

2 Daily Dose = [Soil residue (µg/g) x Ingestion rate (mg/day) x 1E-6
g/µg] / [Body Weight (kg)]

3 MOE = Short-term Oral NOAEL (9.1 mg/kg/day) or Intermediate-Term Oral
NOAEL (6.4 mg/kg/day) /Daily Dose

Table 17. Children’s Residential Combined Short- and Intermediate-term
Risk from Treated Turf.

Route	Daily Dose (mg/kg/day)	MOE	Total ST MOE1	Total IT MOE2

Hand-to-Mouth	0.0091 (ST)	1000 (ST)	810	1000

	0.0043 (IT)	1500 (IT)

Object-to-Mouth	0.0022	4100 (ST)

2900 (IT)

Soil Ingestion	0.00003	310,000 (ST)

220,000 (IT)

Total ST MOE = 1 ÷ [(1/ST Hand-to-Mouth MOE) + (1/ST Object-to-Mouth
MOE) + (1/ST Soil Ingestion MOE)]

Total IT MOE = 1 ÷ [(1/IT Hand-to-Mouth MOE) + (1/IT Object-to-Mouth
MOE) + (1/IT Soil Ingestion MOE)]

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

7.1	Acute & Chronic Aggregate Risk TC \l2 "7.1	Acute & Chronic Aggregate
Risk 

Acute and chronic aggregate exposures include food plus drinking water
exposures.  As demonstrated under Section 5.2, acute and chronic
aggregate risks are not of concern.

7.2	Short- and Intermediate-Term Aggregate Risk  TC \l2 "7.2	Short- and
Intermediate-Term Aggregate Risk 

The short- and intermediate-term aggregate risk assessments consider
average (chronic) exposure estimates from dietary consumption of
metconazole (food and drinking water) and non-occupational/residential
use on turf (dermal and inhalation exposures for adults, and dermal plus
incidental oral exposures for children).  

For adults applying metconazole to turf, short- and intermediate-term
exposures were aggregated.  The exposure scenario with the highest daily
dose and lowest MOE was used; i.e., mixer/loader/applicator with a low
pressure handwand sprayer.  

The short-and intermediate-term aggregate MOEs from dietary exposure
(food + drinking water) and non-occupational/residential handler
exposure (inhalation) for adults are 1,700 and 1,700, respectively;
which are not of concern to HED (see Table 18 below), since they are
greater than the level of concern MOE of 100.  

Table 18. Short- and Intermediate-Term Aggregate Risk Calculations for
Adult Handlers

Population/

Exposure Duration	Inhalation Exposure	Dietary Exposure	Short- or
Intermediate-Term Aggregate MOE2

	NOAEL (mg/kg/day)	Exposure (mg/kg/day)	MOE1	NOAEL (mg/kg/day)	Exposure
(mg/kg/day)	MOE1

	Adult ST	9.1	0.00013	70,000	4.3	0.002434	1,800	1,700 ST

Adult IT	6.4	0.00013	49,000	4.3	0.002434	1,800	1,700 ST

1 MOE = NOAEL / Exposure; The Level of Concern MOE is 100.

2 Aggregate MOE = 1/ [(1/MOEInhalation) + (1/MOEFood + Drinking Water)]

Post-application exposures from the use on turf are considered
predominantly short-term (1-30 days).  Although exposures are expected
via the dermal route, quantification of dermal risk is not required,
since a dermal endpoint was not identified for short-, or
intermediate-term exposures.  Therefore, short- and intermediate-term
post-application aggregate risk assessments were conducted only for
average dietary and incidental oral exposures to toddlers.  The
short-and intermediate-term aggregate MOEs from dietary exposure (food +
drinking water) and non-occupational/residential exposure (incidental
oral) for children 1-2 years old are 420 and 460, respectively; these
MOEs are not of concern to HED (see Table 19 below), since they are
greater than the level of concern MOE of 100.  



Table 19. Short-and Intermediate-Term Aggregate Risk Calculations for
Postapplication Exposures

Population/ Exposure Duration	Incidental Oral Exposure	Dietary Exposure
Short-or Intermediate-Term Aggregate MOE2

	NOAEL (mg/kg/day)	Exposure (mg/kg/day)	MOE1	NOAEL (mg/kg/day)	Exposure
(mg/kg/day)	MOE1

	Kids 1-2 yrs/ST	9.1	0.01123	810	4.3	0.005026	860	420 ST

Kids 1-2 yrs/IT	6.4	0.00643	1000	4.3	0.005026	860	460 IT

1 MOE = NOAEL / Exposure; The Level of Concern MOE is 100.

2 Aggregate MOE = 1/ [(1/MOEIncidental Oral) + (1/MOEFood + Drinking
Water)]

These aggregate exposure assessments are considered conservative
estimates, that should not underestimate risks, for the following
reasons: 1) the dietary inputs used tolerance-level residues, 100% crop
treated, and crop specific (turf) screening level drinking water
modeling data (i.e., surface water modeling); 2) maximum application
rates and minimum application intervals were used; and 3) conservative
SOPs and upper level estimates of exposure were employed.

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference:  Common Triazole Metabolites:  Updated Aggregate Human Health
Risk Assessment to Address Tolerance Petitions for Metconazole.
DP389080, T. Morton, 4/27/11.

The addition of the new proposed use on sugarcane does not increase the
aggregate exposure to free triazoles and its conjugates.  Therefore, the
recently updated aggregate human health risk assessment for free
triazoles and its conjugates remains unchanged and the aggregate
estimates are below HED’s level of concern (DP389080, T. Morton,
4/27/11).

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative
Risk Characterization/Assessment 

Metconazole 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.

Metconazole is a triazole-derived pesticide.  This class of compounds
can form the common metabolite 1,2,4-triazole and two triazole
conjugates (triazolylalanine and triazolylacetic acid).  To support
existing tolerances and to establish new tolerances for
triazole-derivative pesticides, including metconazole, U.S. EPA
conducted a human health risk assessment for exposure to 1,2,4-triazole,
triazolylalanine, and triazolylacetic acid 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 safety factor 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 Exposure/Risk Pathway  TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

Reference: The occupational exposure and risk assessment was reviewed by
the Exposure Science Advisory Council, the information provided in this
Section comes from:. Metconazole. Occupational and Residential Exposure
Assessment for Proposed New Foliar Use on Sugarcane. DP386786, N. Tsaur,
6/8/11.

Occupational handler exposure to metconazole is expected for individuals
involved in foliar applications to sugarcane (mixing, loading, and
applying).  Agricultural workers performing typical post-application
activities may receive exposure to metconazole residues.

9.1	Short- and Intermediate-Term Handler Risk  TC \l2 "9.1	Short- and
Intermediate-Term Handler Risk 

Caramba™ Fungicide can be applied to sugarcane for foliar disease
control via groundboom, aircraft, or chemigation.  The proposed use
pattern is summarized in Table 2.  Handler exposure is expected to be
short- or intermediate-term based on information provided on the
proposed label.  The label states that all handlers must wear the proper
personal protective equipment (PPE): a long-sleeved shirt, long pants,
chemical resistant gloves, shoes, and socks.

The quantitative exposure/risk assessment developed for occupational
handlers is based on the following exposure scenarios: 

Mixer/Loaders

Mixing/loading liquid to support groundboom applications, 

Mixing/loading liquid to support aerial and chemigation applications,

Flaggers

Flagging to support aerial application,

Applicators

Applying sprays with groundboom equipment,

Applying sprays with aerial equipment,

Unit Exposures

Chemical-specific data for assessing exposure during pesticide handling
activities (mixing/loading, applying, and mixing/loading/applying) were
not submitted to the Agency in support of this petition.  To assess
handler exposures for regulatory actions when chemical-specific
monitoring data are not available, HED relies on the most
scientifically-reliable surrogate data currently available from various
sources such as the Pesticide Handler Exposure Database (PHED), the
Agricultural Handler Exposure Task Force (AHETF), and the Outdoor
Residential Exposure Task Force (ORETF).  Some of these data, such as
the industry task force data, are compensatory, subject to the data
protection provisions of FIFRA.  HED policy on use of surrogate data is
described in more detail on the Agency's website
(http://www.epa.gov/pesticides/science/handler-exposure-data.html). 
Scenario-specific surrogate exposure data, including their sources, are
presented in the “Occupational Pesticide Handler Unit Exposure
Surrogate Reference Table”
(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf).

Summaries of the short- and intermediate-term risks for occupational
handlers are included in Table 20.  The maximum application rate for
each exposure scenario is presented as the worst case scenario.  All
handler scenarios (mixer/loader, applicator, and flagger) resulted in
short- and intermediate-term inhalation MOEs greater than the level of
concern (MOEs ranged from 63,000 to 440,000 for short-term exposure and
45,000 to 310,000 for intermediate-term exposure) at some level of risk
mitigation and therefore do not exceed HED’s level of concern.

Table 20.  Metconazole Short- and Intermediate-Term Occupational
Inhalation Exposures and Risks.

Exposure Scenario	Application Rate a	Area Treated Daily b	Inhalation
Unit Exposures c	Inhalation Dose d	Short-Term Inhalation MOE e	Int-Term
Inhalation MOE e

	lb ai/A	acres	µg/lb ai	mg/kg/day	LOC = 100	LOC = 100

Mixer/Loader

Mixing/Loading Liquids

for Groundboom Applications	0.082	80	0.219	0.0000205	440,000	310,000

Mixing/Loading Liquids

for Aerial and Chemigation Applications	0.082	350	0.219	0.0000898
100,000	71,000

Flagger

Flagging for Aerial Application	0.082	350	0.35	0.000144	63,000	45,000

Applicator

Applying Sprays

via Groundboom Equipment	0.082	80	0.34	0.0000319	290,000	200,000

Applying Sprays

via Aerial Equipment	0.082	350	0.068	0.0000279	330,000	230,000

a	Application Rates based on proposed uses for metconazole (Caramba™
Fungicide, EPA Reg. No. 7969-246).

b	Acres Treated Per Day is taken from Exposure Science Advisory Council
(ExpoSAC) Policy No. 9.1.

c	Unit Exposures based on PHED Version 1.1 or AHETF data.  Baseline = no
respirator.

d	Inhalation Dose (mg/kg/day) = daily unit exposure (μg/lb ai) x
application rate (lb ai/acre) x amount handled /day (acres/day) x
conversion factor (1 mg/1,000 μg) x absorption factor (100%) / body
weight (70 kg).

e	MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day). ST NOAEL = 9.1 mg/kg/day.
IT NOAEL = 6.4 mg/kg/day.

9.2	Short- and Intermediate-Term Post-Application Risk  TC \l2 "9.2
Short-and Intermediate-Term Postapplication Risk 

Agricultural workers performing typical post-application activities may
receive exposure to metconazole residues.  However, since there is no
dermal endpoint identified up to the limit dose, a dermal
post-application assessment is not needed.

Occupational Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative occupational
post-application inhalation exposure assessment was not performed for
metconazole at this time because the chemical has low vapor pressure
(9.23 x 10-8 mmHg), is applied at a low rate (0.082 lb ai/A), and is not
applied using airblast.  However, there are multiple potential sources
of post-application inhalation exposure to individuals performing
post-application activities in previously treated fields.  These
potential sources include volatilization of pesticides and resuspension
of dusts and/or particulates that contain pesticides.  The Agency sought
expert advice and input on issues related to volatilization of
pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act
Scientific Advisory Panel (SAP) in December 2009.  The Agency received
the SAP’s final report on March 2, 2010 ( HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html"
http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and is
in the process of evaluating the SAP report as well as available
post-application inhalation exposure data generated by the Agricultural
Reentry Task Force.  The Agency may, as appropriate, develop policies
and procedures to identify the need for and, subsequently, the way to
incorporate occupational post-application inhalation exposure into the
Agency's risk assessments.  If new policies or procedures are put into
place, the Agency may revisit the need for a quantitative occupational
post-application inhalation exposure assessment for metconazole.

Restricted Entry Interval

REIs are typically based on the acute toxicity of technical chemical
material.  Under WPS, active ingredients classified as acute Toxicity
Category III or IV for Acute Dermal and Primary Skin Irritation are
assigned a 12-hour REI.  Thus, the 12-hour REI on the label is
acceptable.

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

Table A.1.  Metconazole Toxicology Data Requirements

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

yes

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

yes

yes	yes

yes

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	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    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. Neuro		no

no

yes

yes

no	no

no

no

yes

no

870.7485    General Metabolism	

870.7600    Dermal Penetration	

870.7800    Immunotoxicity		yes

no

yes	yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

no

no

no

A.2  Toxicity Profiles TC \l2 "A.2  Toxicity Profiles 

Table A.2	Acute Toxicity Profile – Metconazole Technical

Guideline No.	

Study Type	

MRID(s)	

Results	

Toxicity Category

870.1100	

Acute oral [mouse]	

44721512	

LD50 = >566 mg/kg	

III

870.1100	

Acute oral [rat]	

44721512	

LD50 = >566 mg/kg	

III

870.1100	

Acute oral [rat]	

44721513	

LD50 = >1459 mg/kg	

III

870.1100	

Acute oral [rat]	

44721514	

LD50 = >5000 mg/kg	

IV

870.1200	

Acute dermal [rat]	

44721512	

Dermal LD50 > 2000	

III

870.1200	

Acute dermal [rabbit]	

44721512	

Dermal LD50 > 2000	

III

870.1200	

Acute inhalation [rat]	

44721512	

LD50 = >5.6 mg/L	

IV

870.2400	

Acute eye irritation [rat]	

44721513	moderate irritant	III

870.2500	

Acute dermal irritation [rabbit]	

44721513	mild irritant	IV

870.2600	

Skin sensitization [guinea pig]	

44721513	neg.	-

Table A.3	Subchronic, Chronic and Other Toxicity Profile for Metconazole
Technical1 

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

870.3100	28-Day oral toxicity rodents (rat)

	44721515 (1990)

M/F: 0, 30, 100, 1000, 3000 ppm

M: 0, 2.7, 9.1, 90.5, 261.1 mg/kg/day 

F: 0, 3.1, 10.1, 97, 287.4 mg/kg/day

Acceptable/guideline	NOAEL (M/F) = 9.1/10.1 mg/kg/day

LOAEL (M/F) = 90.5/97 mg/kg/day based on depression of body weight in M,
liver and kidney weight increases with associated histopathological
effects (hypertrophy and fatty vacuolation) in liver only.

870.3100	90-Day oral toxicity rodents (rat)	44721517 (1991)

M/F: 0, 30, 100, 300, 1000, 3000 ppm

M: 0, 1.94, 6.4, 19.2, 64.3, 192.7 mg/kg/day 

F: 0, 2.1, 7.2, 22.1, 71.4, 208.0 mg/kg/day

Acceptable/guideline	NOAEL (M/F) = 6.4/7.2 mg/kg/day

LOAEL (M/F) = 19.2/22.1 mg/kg/day based on increased spleen weight in
females and hepatic vacuolation in males.

870.3100	90-Day oral toxicity rodents (mouse)	44721519 (1991)

M/F: 0, 30, 300, 3000 (wk 1)/2000(wk 2-13) ppm

M: 0, 9.58, 50.5, 341.1 mg/kg/day 

F: 0, 6.94, 60.7, 438.5 mg/kg/day

Acceptable/guideline	NOAEL (M/F) = 9.58/6.94 mg/kg/day

LOAEL (M/F) = 50.5/60.7 mg/kg/day based on increase in absolute and
relative liver weights, hepatocellular hypertrophy and vacuolation, and
increase in relative spleen weight (F), elevated AST and ALT activity. 

870.3150	28-Day oral toxicity non-rodents (dog)	44721520 (1991)

M/F: 0, 100, 1000, and 7000-10000 ppm in diet

Unacceptable/non-guideline (some preliminary test data provided)	NOAEL
(M/F) = 100 ppm in diet

LOAEL (M/F) = 1000 ppm in diet (increase in relative and absolute
thyroid wt. in one/two females)

Deficiencies: low n (2M/2F per dose); decrease in food consumption means
low exposure to test compound; actual dose received per dose group not
provided.

870.3150	90-Day oral

toxicity non-rodents (dog)

	44721521 (1991)

M/F: 0, 60, 600, 6000 ppm in diet

M: 0, 2.5, 24.4, 225.2 mg/kg/day 

F: 0, 2.6, 24.3, 206.6 mg/kg/day

Acceptable/guideline	NOAEL (M/F) = 2.5/2.6 mg/kg/day

LOAEL (M/F) = 24.4/24.3 mg/kg/day based on decreased food consumption
and body weight gain in females and elevated platelets and reticulocytes
in males.

870.3200 	21-day Dermal Toxicity	46808439 (2006)

0, 250, 500, 1000 mg/kg/day 

Acceptable/guideline	NOAEL: 1000 mg/kg

LOAEL: > 1000 mg/kg

No evidence of dermal toxicity

870.6200	Subchronic (13-week) Oral Neurotoxicity- rat	46808440 (2002)

0, 50, 170, 500 ppm

M: 0, 4.84, 15.69, 47.08 mg/kg/day

F: 0, 5.10, 17.62, 49.82 mg/kg/day

Acceptable/Non-guideline	Systemic NOAEL (M/F) = 4.84/5.10  mg/kg/ 

Systemic LOAEL (M/F) = 15.69/ 17.62 mg/kg/ based on decreases in body
weight and food consumption. 

Neurotoxicity NOAEL (M/F) ( 47.08/49.82 mg/kg/day 

870.3700	Prenatal development in rodents (rat)	44721522 (1991)

0, 12, 30, 75  mg/kg/day

Gavage

Acceptable/Guideline	Maternal NOAEL = 12 mg/kg/day

LOAEL = 30 mg/kg/day based on decrease in body weight gain.

Developmental NOAEL = 12 mg/kg/day

LOAEL = 30 mg/kg/day based on increased incidence of skeletal variations
(predominantly lumbar ribs).

870.3700	Prenatal development in rodents (rat)	46808443 (2002)

0, 1, 4, 16, 64 mg/kg/day

Gavage

Acceptable/Guideline	Maternal NOAEL= 16 mg/kg/day

LOAEL= 64 mg/kg/day based on decreased body weight and food consumption,
increased placental weight and increased incidence of swollen placenta.

Developmental NOAEL= 16 mg/kg/day 

LOAEL= 64 mg/kg/day based on based on an increase in early and late
resorptions, decreased fetal body weight and increased incidence of
incomplete ossification of sternebrae.

870.3700	Prenatal developmental in non-rodents (rabbit)

Definitive Study	44721602 (1997)

0, 5, 10, 20, 40 mg/kg/day gavage

Acceptable/Guideline	Maternal NOAEL = 20 mg/kg/day

LOAEL = 40 mg/kg/day based on reductions in body weight gain, food
consumption, and changes in various hematology parameters (reductions in
hematocrit, hemoglobin, mean corpuscular volume and increases in
platelet counts and alkaline phosphatase activity).

Developmental NOAEL = 20 mg/kg/day

LOAEL = 40 mg/kg/day based on increases in post-implantation losses.

870.3700	Prenatal developmental in non-rodents (rabbit)	44721603 (1991)

0, 4, 10, 25, 62.5 mg/kg/day (Exp. #1)

0, 2, 4, 10 mg/kg/day (Exp. #2)

Acceptable/Guideline	Maternal NOAEL = 25 mg/kg/day

LOAEL = 62.5 mg/kg/day based on body weight changes and slight clinical
signs (anorexia/reduced or altered fecal output, cold ears).

Developmental NOAEL = 4 mg/kg/day

LOAEL = 10 mg/kg/day based on examining data from the two experiments. 
Effects at 62.5 mg/kg/day show total litter loss, decreased live
fetuses, increased early and late resorptions.  Effects at 25 mg/kg/day
show some malformations: hydrocephaly (4 fetuses from 4 different
litters, but NOT seen at 62.5 mg/kg/day) and limb effects (2 fetuses
from 2 different litters, with one fetus with same effect at 62.5
mg/kg/d).  Hydrocephaly and limb effects were observed at 10 mg/kg/day
in Experiment #2, but not at that same dose in Experiment #1.

870.3800	Reproduction and fertility effects

2-generation- rat	46808447 (2002)

0, 30, 150 and 750 ppm 

M/F: 0/0, 2/2, 10.8/10.6, 53.2/53.0  mg/kg/day

Acceptable/Guideline	Parental/Systemic NOAEL (M/F) = 9.8/10.8 mg/kg/day

LOAEL (M/F) = 49.4/53.2 mg/kg/day based on: decreased body weight and
decreased weight gain in male and female parental animals, increased
incidence of fatty hepatocyte change in male parental animals, and
increased incidence of spleen congestion in F1 parental females. 

Reproductive NOAEL (M/F) = (49.4/ 10.8 mg/kg/day

LOAEL (M/F) = 53.2 mg/kg/day based on increased gestation length and
decreased gestation index driven by dystocia (difficult labor).

Offspring NOAEL (M/F) = 9.8/10.8 mg/kg/day

LOAEL (M/F) = 49.4/53.2 mg/kg/day based decreased viability on lactation
day 0 and decreased body weight in F2 offspring. 

870.4100a	Chronic toxicity rodents (rat)	4472109 (1992)

0, 10, 100, 300, 1000 ppm

M: 0, 0.44, 4.3, 13.1, 43.9 mg/kg/day

F: 0, 0.52, 5.3, 16.0, 53.8 mg/kg/day

Acceptable/Guideline	NOAEL = (M/F) = 4.3/16.0 mg/kg/day

LOAEL = (M/F) = 13.1/ 53.8 mg/kg/day based on an increase in mean
adjusted liver weights at 12 months (M) and 24 months (F), increase in
spleen weights at 24 months (F), and increased hepatocellular lipid
vacuolation  (M/F) and centrilobular hypertrophy (M/F).

870.4100b	Chronic toxicity- dog	44721610

0, 30, 300, 1000, 3000 ppm in diet

M: 0, 1.1, 12.0, 38.5, 110.0 mg/kg/day

F: 0, 1.1, 10.3, 36.8, 113.7 mg/kg/day

Acceptable/Guideline	NOAEL (M/F) = 12.0/10.3 mg/kg/day

LOAEL (M/F) = 38.5/36.8 mg/kg/day based on decreased body weight gain
weeks 1-13 (males), increased alkaline phosphatase activity (both sexes)
and increased incidence of Kupffer cell pigmentation (females).

870.4200a	Carcinogenicity -

rat	44721611 (1992)

0, 100, 300, 1000 ppm

M: 0, 4.6, 13.8, 46.5 mg/kg/day

 F: 0, 5.5, 16.6, 56.2 mg/kg/day

Acceptable/Guideline	Non-neoplastic findings at (M/F) 13.8/56.2
mg/kg/day: increased incidence of hepatocellular lipid vacuolation 
(M/F), centrilobular hypertrophy (M/F), liver pigment deposition (M),
histiocytic foci in the spleen (M/F),and  increase in severity of
chronic renal nephropathy (M). Evidence of mononuclear cell leukemia
(F).

870.4200b	Carcinogenicity- mouse	44721612 (1992)

0, 30, 300, 1000 ppm

M: 0, 4.5, 39.5, 166.9 mg/kg/day

 F: 0, 5.9, 58.1, 195.5 mg/kg/day

Acceptable/Guideline	Non-neoplastic findings at (M/F) 166.9/58.1
mg/kg/day: increase in vacuolation, hypertrophy, splenic atrophy and
adrenal corticomedullary pigmentation, sinusoidal
hypercellularity/single cell necrosis. Neoplastic findings: increase in
liver cell tumors at high dose (M/F): Increased incidence of
hepatocellular adenomas in males and hepatocellular carcinomas in
females.  

870.5100	Salmonella typhimurium and Escherichia coli Reverse Mutation
Assay	44721613 (1990)

Up to limit dose of 5000 μg/ plate (S. typhimurium) and  (E. coli) in
the presence and absence of metabolic activation

(+ S9)

Acceptable/Guideline	Test material was not cytotoxic with or without S9
activation in five S. typhimurium strains and one strain of E. coli, and
did not induce a genotoxic response in any strain.

870.5300	In vitro Mouse Lymphoma Mutagenesis
Assay圍ㅌ㘳㠱⨴഍挪獩漠汮⁹獩浯牥㐇㜴ㄲㄶ‵ㄨ㤹⤱

Six doses up to 125 μg/ml (toxicity was observed above that dose)  in
the presence and absence of metabolic activation 

(+ S9)

Acceptable/Guideline	There was no evidence of biologically significant
induction of mutant colonies. 

870.5375	In vitro Cytogenetics Test	44721616 (1991)

From 6.25 to 400 (g/ml, with and without metabolic activation (+ S9)
Acceptable/Guideline	Weakly positive (induced chromosome aberrations in
Chinese hamster ovary cells) in the presence of S9 activation, negative
without S9 activation. 

870.5395	In vivo Mammalian Erythrocyte Micronucleus Test: Mouse	44721618
(1995)

Up to the limit dose of 2000 mg/kg

Acceptable/Guideline	There was no statistically significant increase in
the frequency of micronucleated polychromatic erythrocytes in mouse bone
marrow at any dose or collection time.

870.5550	In vivo/in vitro Mammalian UDS test

Rat	44721620 (1995)

Up to the limit dose of 2000 mg/kg

Acceptable/Guideline	Negative for unscheduled DNA synthesis.

870.6200b	Subchronic Neurotoxicity- rat	46808440 (2002)

0, 50, 170, 500 ppm

M: 0, 4.84, 15.69, 47.08 mg/kg/day

F: 0, 5.10, 17.62, 49.82 mg/kg/day

Acceptable/Non-guideline	Systemic NOAEL (M/F) = 4.84/5.10  mg/kg/ 

Systemic LOAEL (M/F) = 15.69/ 17.62 mg/kg/ based on decreases in body
weight and food consumption. 

Neurotoxicity NOAEL (M/F) ( 47.08/49.82 mg/kg/day 

870.7485	Metabolism and pharmacokinetics: rat	44721622 (1992)

single high dose: 164 mg/kg

Radiolabel: 

(cyclopentyl-14C )

Acceptable/Guideline	Approximately 94% of radioactivity in excreta after
five days: feces (males - 81.3%, females - 65.5%) and urine (males -
13.6%, females - 28.4%)

870.7485	Metabolism and pharmacokinetics: rat	44721623 (1991)

single low dose: 2 mg/kg

Radiolabel: 

(cyclopentyl-14C)

Acceptable/Guideline	Approximately 94% of radioactivity in excreta after
72 hrs: feces (males - 80%, females - 67%) and urine (males - 14.8%,
females - 26%).  Metabolite information presented.

870.7485	Metabolism and pharmacokinetics: rat

WL136184*

*cis only isomer	44721624 (1991)

single high dose: 200 mg/kg (males only)

Radiolabel: 

(Triazole - 14C)

Acceptable/Guideline	Approximately 96% of radioactivity in excreta after
seven days: feces (76%) and urine (20%).  Metabolite information
presented.

870.7485	Metabolism and pharmacokinetics: rat

WL136184*

*cis only isomer	44721625 (1991)

single low dose: 2 mg/kg

Radiolabel: 

(Cyclopentyl - 14C)

Acceptable/Guideline	Excretion/retention in bile-duct cannulated rats. 
Approximately 80% of radioactivity was excreted in the bile after 48
hrs: males (78.7%) and females (83.3%). 

870.7485	Metabolism and pharmacokinetics: rat	46808449 (2002)

male/female rat

single low dose: 2 mg/kg

single high dose: 200 mg/kg

repeated dose: 2 mg/kg

Acceptable/Non-guideline	Low potential for bioaccumulation following
single or multiple dosing regimen.  The time to maximum plasma
concentration for male and female rats treated with either 2 mg/kg or
200 mg/kg was the earliest sampling interval, 0.25 hours and 4 hours,
respectively The plasma half-life of low- and high-dose rats was
slightly shorter in males than females, ~20-25 hours and ~34 hours,
respectively.

870.7600	In Vivo Dermal Penetration Study	46808450 (1990)

Acceptable/Non-guideline	Dermal absorption= 16%  (72 hrs)

870.7800	Immunotoxicity Study:  male rat	48107301 (2010)

0, 70, 210, 6300 ppm

0, 5.4, 17, 52 mg/kg/day

Acceptable/Guideline	Systemic 

NOAEL:  17 mg/kg/day.

LOAEL:  52 mg/kg/day based on reduced body weight gain at day 7 and 14
of the study.  

Immunotoxicity 

NOAEL:  52 mg/kg/day.  

LOAEL:  > 52 mg/kg/day

	Effects on rat/mice liver enzymes

WL136184*

*cis only isomer	44721626 (1991)

0, 300 ppm in diet (mice) and 0, 1000 ppm in diet (rats)  for seven or
28 days 

Acceptable/Non-guideline	Increased liver weight, cytochrome P450,
ethoxycoumarin O-deethylase, ethylmorphine N-demethylase, and lauric
acid 11-hydroxylase in both rats and mice.  No effect on ethoxyresorufin
O-deethylase, palmitoyl-CoA oxidation, or peroxisome proliferation (in
terms of peroxisome number or morphology). 

	14-day Mechanistic Study	46665403 (2004)

0, 30, 300, 1000 ppm in diet (mice) for 14 days.

F: 4.5, 48, 151 mg/kg/day

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	1000 ppm) at days 3, 7 and 14; hepatic hypertrophy and vacuolation (300
and 1000 ppm) at day 14; increased ALT and AST activities at 1000 ppm
(day 14); increased lipid peroxide (300 and 1000) at day 14; increased
PCNA labeling at 1000 ppm at day 3 and 7.  

1 cis/trans ratio is 85:15.  All studies used cis/trans mixture unless
otherwise noted.

Appendix B:  EPA Review of Human Research TC \l1 " Appendix B:  EPA
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.  These studies were determined to require a review of their
ethical conduct, have received that review and have been determined to
be ethical.

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.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The
Occupational Handler Unit Exposure Surrogate Reference Table.  U.S.
Environmental Protection Agency.  Released June 21, 2011.

Appendix C:  Physical and Chemical Properties of Metconazole TC \l1 "
Appendix C:  Physical and Chemical Properties of Metconazole 

Table C. Physicochemical Properties of Metconazole

Parameter	Value	References*

(MRID)	

Melting point/range	  SEQ CHAPTER \h \r 1 100.0-108.4°C (using
Electrothermal Digital Melting Point Apparatus) (AC900,768 technical
grade)	44721505

pH	5.81 at 25ºC (1% aqueous suspension)	46808402

Relative density (20°C)	  SEQ CHAPTER \h \r 1 1.14 (relative density to
water at 4°C, using capillary-stoppered, density-specific gravity
bottle)    (Lot No. AC 8879-140B)	44721505

Water solubility (20ºC)	Using shake-flask method:

  SEQ CHAPTER \h \r 1 18.7 ± 1.0 mg/L (cis-isomer, WL148271,
KNF-S-474m)

13.6 ± 1.7 mg/L (trans-isomer, WL148271, KNF-S-474m)	44721505

Solvent solubility (g/L) at 20ºC	Solvent	Metconazole	cis	trans	44721505

	acetone	363	251	117

methanol	403	294	117

dichloromethane	481	343	141

ethyl acetate	260	173	90.0

propanol	132	86.6	46.7

toluene	103	66.2	38.0

Hexane	1.40	0.929	0.483

	Vapor pressure (20°C)	Using gas-saturation method:

  SEQ CHAPTER \h \r 1 < 1.23x10-5 Pa or 9.23 x 10-8 mm Hg (metconazole)

< 1.04x10-5 Pa or 7.80 x 10-8 mm Hg (cis-isomer)

< 1.96x10-6 Pa or 1.47 x 10-8 mm Hg (trans-isomer)  SEQ CHAPTER \h \r 1 
44721505

Dissociation constant (pKa)	  SEQ CHAPTER \h \r 1 11.38±0.03 and
1.06±0.03 (in water at 29.1°C using spectrophotometric method; Lot No.
AC 8879-140B) 	44721505

Octanol/water partition coefficient, Log(KOW)	At 20 ºC (using flask
shaking method):

  SEQ CHAPTER \h \r 1  Kow (log Kow) = 7090±989 (3.85) (Lot No. AC
8879-140B)  (TGAI)

 Kow (log Kow) = 7150±803 (3.85) (cis-isomer, CL 354,801)

λ	A	log ε	46808403

	cis-isomer

2.0	221.4	0.828	4.03

6.8

0.8452	4.04

7.0

0.9126	4.08

10.3

0.7226	3.98

trans-isomer

2.0	221.4	0.9053	4.07

7.0

0.9547	4.10

10.1

0.9893	4.11

	* Product Chemistry Reviews: DP #256877, Shyam Mathur, Ph.D., 9/12/2000
and DP #329168, Shyam Mathur, Ph.D., 7/13/07.

Appendix D:  International Residue Limit Status  TC \l1 "Appendix D: 
International Residue Limit Status 

Metconazole (PC Code 125619; 07/27/11)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US	Canada	Mexico2	Codex

40 CFR 180.617:

Plants/Livestock: Metconazole
[5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)
cyclopentanol] as the sum of its cis- and trans- isomers	None

None

Commodity1	Tolerance (ppm) /Maximum Residue Limit (mg/kg)

	US	Canada	Mexico2	Codex

Sugarcane, cane	0.06

	Completed:  M. Negussie; 07/27/2011

1 Includes only commodities of interest for this action.  Tolerance
values should be the HED recommendations and not those proposed by the
applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

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