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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 CarambaTM Fungicide (EPA Reg. No. 7969-246). 

CarambaTM 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 
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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).
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Table of Contents

1.0 Executive Summary.......................................................................................................... 5

2.0 Regulatory Conclusions and Recommendations............................................................ 8

2.1 Data Deficiencies/ Conditions of Registration ....................................................... 8

2.2 Tolerance Considerations........................................................................................ 8

2.2.1 Enforcement Analytical Method................................................................. 8

2.2.2 International Harmonization ....................................................................... 9

2.2.3 Recommended Tolerances.......................................................................... 9

2.2.4 Revisions to Petitioned-For Tolerances...................................................... 9

2.3 Label Modifications.............................................................................................. 10

3.0 Ingredient Profile............................................................................................................ 10

3.1 Summary of Proposed Uses.................................................................................. 10

3.2 Structure and Nomenclature ................................................................................. 11

3.3 Physical and Chemical Properties......................................................................... 12

3.4 Anticipated Exposure Pathways ........................................................................... 12

3.5 Consideration of Environmental Justice ............................................................... 12

4.0 Hazard Characterization/Assessment........................................................................... 13

4.1 Hazard and Dose-Response Characterization....................................................... 13

4.1.1 Database Summary ................................................................................... 13

4.1.2 Studies Available and Considered ............................................................ 13

4.1.3 Sufficiency of Studies/Data ...................................................................... 13

4.1.4 Toxicological Effects................................................................................ 13

4.1.5 Cancer Classification ................................................................................ 14

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)................................. 15

4.3 FQPA Considerations ........................................................................................... 16

4.4 FQPA Safety Factor for Infants and Children ...................................................... 16

4.5 Hazard Identification and Toxicity Endpoint Selection........................................ 17

4.5.1 Recommendation for combining routes of exposure for risk assessment. 19

4.6 Endocrine Disruption............................................................................................ 19

5.0 Dietary Exposure/Risk Characterization ..................................................................... 20

5.1 Pesticide Metabolism and Environmental Degradation........................................ 20

5.1.1 Metabolism in Primary Crops................................................................... 20

5.1.2 Metabolism in Livestock........................................................................... 20

5.1.3 Drinking Water Residue Profile................................................................ 21

5.1.4 Food Residue Profile................................................................................. 22

5.2 Dietary Exposure and Risk ................................................................................... 26

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 27

6.1 Residential Handler Exposure and Risk Characterization.................................... 27

6.2 Residential Postapplication Exposure and Risk Characterization ........................ 28

7.0 Aggregate Risk Assessments and Risk Characterization............................................ 29

7.1 Acute & Chronic Aggregate Risk......................................................................... 30

7.2 Short- and Intermediate-Term Aggregate Risk..................................................... 30

8.0 Cumulative Risk Characterization/Assessment........................................................... 31

9.0 Occupational Exposure/Risk Pathway.......................................................................... 32

9.1 Short- and Intermediate-Term Handler Risk ........................................................ 32

9.2 Short-and Intermediate-Term Postapplication Risk.............................................. 33
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Appendix A: Toxicology Assessment ....................................................................................... 35

A.1 Toxicology Data Requirements ................................................................................ 35

A.2 Toxicity Profiles........................................................................................................ 36

Appendix B: EPA Review of Human Research ...................................................................... 42

Appendix C: Physical and Chemical Properties of Metconazole .......................................... 42

Appendix D: International Residue Limit Status................................................................... 44
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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 CarambaTM Fungicide (EPA Reg. No. 7969-246). CarambaTM 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

CarambaTM 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. CarambaTM 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 wellcharacterized, 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
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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 shortterm (1-30 days). Although exposures are expected via the dermal route, quantification of 
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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.
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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

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.

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. 

2.2 Tolerance Considerations

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-
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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

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

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

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. 
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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

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

3.1 Summary of Proposed Uses

BASF is proposing a new foliar use of metconazole on sugarcane. The proposed formulated 

end-use product is CarambaTM Fungicide (EPA Reg. No. 7969-246). CarambaTM Fungicide is a 

soluble liquid formulation, containing 8.6% active ingredient (ai), equivalent to 0.75 pounds of 

metconazole per gallon of product. CarambaTM 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). CarambaTM 

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. CarambaTM 

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. 
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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

Structure and nomenclature are reported in Table 3.

Table 3. Metconazole Nomenclature.

Chemical structure

N

N

N

H C3

H3C

HO

Cl

cis-isomer

N

N

N

H C3

H C3

HO

Cl

trans-isomer

Common name Metconazole

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

IUPAC name (1RS,5RS:1RS,5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-

ylmethyl)cyclopentanol

CAS name 5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-

ylmethyl)cyclopentanol

CAS registry number 125116-23-6 (cis- and trans-isomers)

115850-27-6 (cis-isomer)

115850-28-7 (trans-isomer)

End-use products (EP) CarambaTM Fungicide (EPA File Symbol 7969-246)
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3.3 Physical and Chemical Properties

The physicochemical properties of metconazole are reported in Appendix C. 

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 postapplication 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

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

http://www.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.
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4.0 Hazard Characterization/Assessment

4.1 Hazard and Dose-Response Characterization

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

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

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

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 
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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 postimplantation 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
Page 15 of 44

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)

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.
Page 16 of 44

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

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, highend 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 
Page 17 of 44

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

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 NonOccupational 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 

IntermediateTerm (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).
Page 18 of 44

Table 4. Summary of Toxicological Doses and Endpoints for Metconazole for Use in Dietary and NonOccupational 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

Dermal Short-

(1-30 days) &

IntermediateTerm (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 

IntermediateTerm (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) & 

IntermediateTerm (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 

Intermediateterm (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).
Page 19 of 44

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

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

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 longterm dermal or inhalation exposures to metconazole.

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). 
Page 20 of 44

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 callins, 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: 

http://www.epa.gov/endo/.

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

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
Page 21 of 44

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

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 
Page 22 of 44

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

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.
Page 23 of 44

M1 = 5-[(4-chlorophenyl)methyl]-2-methoxyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)-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-ylmethyl)-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.
Page 24 of 44

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

1

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

2HAFT = highest average field trial.

3

STMdR = 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

Cismetconazole

14 4

0.0120 0.1169 0.1048 0.0528 0.0587 0.0542

Transmetconazole <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

Cismetconazole

28 4

<0.0061 0.1091 0.0837 0.0322 0.0449 0.0494

Transmetconazole <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

1

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

2HAFT = highest average field trial.

3

STMdR = Supervised Trial Median Residue.

4

STMR = Supervised Total Mean Residue

Processed Food and Feed
Page 25 of 44

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.
Page 26 of 44

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

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.
Page 27 of 44

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

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

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 
Page 28 of 44

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 handwand 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 handwand 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

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-tomouth, and incidental ingestion of soil) are >100 (see Table 17), and therefore, do not concern 

HED.
Page 29 of 44

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)

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

2. 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

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.
Page 30 of 44

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

The short- and intermediate-term aggregate risk assessments consider average (chronic) exposure 

estimates from dietary consumption of metconazole (food and drinking water) and nonoccupational/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 

IntermediateTerm

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 nonoccupational/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. 
Page 31 of 44

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

Population/ 

Exposure 

Duration

Incidental Oral Exposure Dietary Exposure Short-or 

IntermediateTerm

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

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.
Page 32 of 44

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 EPAHQ-OPP-2005-0497.

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

CarambaTM 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

1. Mixing/loading liquid to support groundboom applications,

2. Mixing/loading liquid to support aerial and chemigation applications,

Flaggers

3. Flagging to support aerial application,

Applicators

4. Applying sprays with groundboom equipment,

5. Applying sprays with aerial equipment,
Page 33 of 44

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 chemicalspecific 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 (CarambaTM 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
Page 34 of 44

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 (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.
Page 35 of 44

Appendix A: Toxicology Assessment

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
Page 36 of 44

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. 
Page 37 of 44

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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).
Page 38 of 44

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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.
Page 39 of 44

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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).
Page 40 of 44

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200b Carcinogenicitymouse44721612 (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

WL136184*

*cis only isomer

44721615 (1991)

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 
Page 41 of 44

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics: rat

44721622 (1992)

single high dose: 164 

mg/kg

Radiolabel: 

(cyclopentyl14C )

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: 

(cyclopentyl14C)

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, palmitoylCoA oxidation, or peroxisome proliferation (in 

terms of peroxisome number or morphology). 
Page 42 of 44

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

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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

Acceptable/Non-guideline

Increased liver weight (300 and 1000 ppm); 

increased hepatic drug metabolizing enzymes 

(300 and 1000 ppm) after 7 days; enlarged 

livers (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

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

Table C. Physicochemical Properties of Metconazole

Parameter Value References*

(MRID)

Melting point/range 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) 1.14 (relative density to water at 4°C, using capillarystoppered, density-specific gravity bottle) (Lot No. 

AC 8879-140B)

44721505

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

18.7 ± 1.0 mg/L (cis-isomer, WL148271, KNF-S-474m)

13.6 ± 1.7 mg/L (trans-isomer, WL148271, KNF-S474m)

44721505
Page 43 of 44

Table C. Physicochemical Properties of Metconazole

Parameter Value References*

(MRID)

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:

< 1.23x10-5Pa or 9.23 x 10-8 mm Hg (metconazole)

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

< 1.96x10-6Pa or 1.47 x 10-8 mm Hg (trans-isomer)

44721505

Dissociation constant (pKa) 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):

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)

Kow (log Kow) = 6800±1700 (3.8) (trans-isomer, CL 

354,802)

44721505

UV/visible absorption 

spectrum

pH 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.
Page 44 of 44

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.