### Page 1 of 53 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### Date: May 2 4 , 20 1 1

MEMORANDUM

SUBJECT : Metconazole : Human Health Risk Assessment for Proposed Uses on Tuberous

a nd Corm Vegetables Subgroup 1C and Bushberry Subgroup 13

- 07B.

PC Code: 125619 DP Barcode: D 380512

Decision No.: 436782 Registration No. : 59639

- 147

Petition No.: 0 E 7 743 Regulatory Action: Section 3 Registration Risk Assessment Type: Single C hemi cal /

A ggregate Case No.: NA

T XR No.: NA CAS No.: 125116

- 23

- 6

MRID No.: NA 40 CFR: §180. 617

FROM : Barry O’Keefe

, Senior Biologist

Amelia Acierto, Chemist Myron O t tley

, Senior Toxicologist Nancy Tsaur

, Chemist

R isk Assessment Branch III

He alth Effects Division (7509P)

THROUGH : Paula Deschamp , Branch Chief

R isk Assessment Branch III Health Effects Division (7509P)

TO : Barbar a Madden, RM Team 5

Risk Integration, Minor Use, & Emergency Response Branch Registration Division (7505P)

Introduction

On behalf of Valent U.S.A. Corporation (Valent), the Interregional Research Project No. 4 (IR

- 4) of Rutgers, The State University of New Jersey, is proposing new foliar uses of metconazole on bushberries (crop subgroup 1 3

- 07B) and tuberous an d corm vegetables (crop subgroup 1C).

The Registration Division (RD) requested that the Health Effects Division (HED) evaluate toxicology and residue chemistry data and conduct dietary, aggregate, and occupational exposure

### Page 2 of 53

and risk assessments, as neede d, to estimate the risk to human health that will result from these

new uses and tolerances.

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 r isk 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 pr ovided by Faruque Khan of the Environmental Fate and Effects Division (EFED).

### Page 3 of 53 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ .......... 5

2.0 Regulatory Conclusions and Recommendations

................................ ............................ 9

2.1 Data Defici encies/ Conditions of Registration

................................ ....................... 9

2.2 Tolerance Considerations

................................ ................................ ...................... 10

2.2.1 Enforcement Analytical Method

................................ ............................... 10

2.2.2 International Harmonization

................................ ................................ ..... 10

2.2.3 Recommended Tolerances

................................ ................................ ........ 11

2.2.4 Revisions to Petitioned

- For Tolerances

................................ .................... 11

2.3 Label Modifications

................................ ................................ .............................. 12

3.0 Ingredient Profile

................................ ................................ ................................ ............ 12

3.1 Summary of Proposed Uses

................................ ................................ .................. 12

3.2 Structure and Nomenclature

................................ ................................ ................. 14

3.3 Physical and Chemical Properties

................................ ................................ ......... 14

4.0 Hazard Characterization/Assessment

................................ ................................ ........... 14

4.1 Hazard and Dose

- Response Characterization

................................ ....................... 14

4.1.1 Database Summary

................................ ................................ ................... 14

4.1.2 Studies Available and Considered

................................ ............................ 14

4.1.3 Sufficiency of Studies/Da ta

................................ ................................ ...... 15

4.1.4 Toxicological Effects

................................ ................................ ................ 15

4.1.5 Cancer Classification

................................ ................................ ................ 16

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

................................ . 16

4.3 FQ PA Considerations

................................ ................................ ........................... 17

4.4 FQPA Safety Factor for Infants and Children

................................ ...................... 17

4.5 Hazard Identification and Toxicity Endpoint Selection

................................ ........ 18

4.5.1 Recommendation for combinin g routes of exposure for risk assessment

. 21

4.6 Endocrine Disruption

................................ ................................ ............................ 21

5.0 Dietary Exposure/Risk Characterization

................................ ................................ ..... 22

5.1 Pesticide Metabolism and Environmental Degra dation

................................ ........ 22

5.1.1 Metabolism in Primary Crops

................................ ................................ ... 22

5.1.2 Metabolism in Livestock

................................ ................................ ........... 22

5.1.3 Drinking Water Residue Profile

................................ ................................ 23

5.1.4 Food Resid ue Profile

................................ ................................ ................. 24

5.2 Dietary Exposure and Risk

................................ ................................ ................... 29

5.2.1 Acute Dietary Exposure/Risk

................................ ................................ ... 30

5.2.2 Chronic Dietary Exposure/Risk

................................ ................................ 30

5.3 Anticipat ed Residue and Percent Crop Treated (%CT) Information

.................... 30

5.4 Dietary Assessment of Free Triazole and its Conjugates

................................ ..... 31

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................ 32

6.1 Residential Handler Exposure and Risk Characterization

................................ .... 33

6.2 Residential Postapplication Exposure and Risk Characterization

........................ 33

7.0 Aggregate Risk Assessments and Risk Ch aracterization

................................ ............ 36

7.1 Acute & Chronic Aggregate Risk

................................ ................................ ......... 36

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ ..................... 36

8.0 Cumulative Risk Characterization/Assessment

................................ ........................... 39

9.0 Occupational Exposure/Risk Pathway

................................ ................................ .......... 39

### Page 4 of 53

9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................ 40

9.2 Short

- and Intermediate

- Term Postapplication Risk

................................ .............. 42 Appendix A: Toxicology Assessment

................................ ................................ ....................... 43 A.1 Toxicology Data Requirements

................................ ................................ ................ 43 A.2 Toxicity Profiles

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

................................ ................................ ...... 51 Appendix C: Structure, Nomenclature, and Physical and Chemical Properties

................. 51 Appendix D: International Residue Limit Status

................................ ................................ ... 53

### Page 5 of 53

1.0 Executive Summary

Metconazole (5

- [(4

- chlorophenyl)methyl]

- 2,2

- dimethyl

- 1

- (1 H

- 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

.

On behalf of Valent U.S.A. Corporation (Valent), the IR

- 4 of Rutgers, The State University of

Ne w Jersey, is proposing two new foliar uses of metconazole on bushberries (crop subgroup 1 3

- 07B) and tuberous and corm vegetables (crop subgroup 1C). The proposed formulated end

- use product is Metconazole 50 WDG Fungicide (EPA Reg. No. 59639

- 147). Metcona zole 50 WDG Fungicide is a water dispersible granule (WDG), containing 50% active ingredient (ai).

Use Profile

Under the proposed use, four foliar applications can be made to tuberous and corm vegetables at
0.078

- 0.125 lb ai/A/application for a total max imum seasonal rate of 0.500 lb ai/A and three applications will be made to bushberries at 0.078 lb ai/A/application for a total maximum

seasonal rate of 0.234 lb ai/A. However, a maximum of only two sequential applications are

allowed for both tuberous an d corm vegetables and bushberries. For tuberous and corm vegetables the preharvest interval (PHI) is 1 day

. For b ushberries the PHI is 7 days.

Toxicity/Hazard

The toxicological database for metconazole is sufficient for the purpose of this risk assessm ent. The liver is the primary target organ 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 gai ns, and blood effects (reductions in erythrocyte and/or platelet parameters) in the mouse, rat, dog and/or rabbit. Splenic effects including increased spleen weight and hyperplasia were observed in the mouse, rat and dog at dose levels where liver effects were also observed. In dogs, lenticular degeneration (cataracts) and gastrointestinal irritation were observed at the high dose level(s). Developmental studies in rats and rabbits show evidence of developmental effects, but only at

dose levels that are maternally toxic. There is qualitative evidence of susceptibility in the rat developmental study, however the concern is low since the developmental effects are well

characterized, occur in the presence of maternal toxicity, the NOAELs are well defined, a nd 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 a nd is classified as "not likely to be carcinogenic to humans" at levels that do not cause mitogenesis . In accordance with the revised 40 CFR Part 158 data requirements, an immunotoxicity study and a neurotoxicity battery are required. The existing databa se includes a recently submitted and reviewed immunotoxicity study, and a subchronic neurotoxicity study, but not an acute neurotoxicity study, and this remains a data deficiency.

### Page 6 of 53

Drinking Water

A drinking water assessment for the proposed use s on the tuberous/corm vegetables and bushberry were performed using PRZM/EXAMS modeling. Estimated drinking water

concentrations (EDWCs) of metconazole in drinking water from use on the existing and new crops were provided by EFED and incorporated directly into t he acute and chronic dietary

assessments. The EDWCs are based on the maximum proposed rates specified on the label. For surface water, the highest acute EDWC is 45.48 μ g/L fr om the existing use on turf , and the highest chronic EDWC is 38.16 μ g/L fr om the cranberry use scenario

. For ground water, the acute and chronic EDWC is 0.38 μg/L from the existing use on turf.

Dietary Exposure (food and drinking water)

U nrefined dietary (food and drinking water) exposure analyses were performed using DEEM

FCID TM 

### t hat indicate that acute and chronic dietary exposure to metconazole from food and drinking water are well below HED’s level of concern (LOC) for metconazole . The estimated acute exposure of females 13

- 49 years old, the only population subgroup of concern for acute
exposure, represents 3.8 % of the aPAD at the 95 th 

### percentile of exposure. The chronic dietary (food + drinking water) exposure to metconazole is below HED’s level of concern for the general U.S. population and all population subgroups. The chro nic dietary exposure utilized 6 % cPAD for the general U.S. population and <13 % of the cPAD for children 1

- 2 years old , the most highly exposed population subgroup.

Dietary Assessment of Free Triazole and its Conjugates

Metconazole is among the group of pesticides which generate the common triazole metabolites 1,2,4

- triazole (T), triazolylalanine ( triazole alanine; TA), triazolylacetic acid ( triazole acetic acid; TAA), and triazolylpyruvic acid (TP). These triazole residues have been evaluated for the en tire class of triazole compounds. HED has previously completed a comprehensive risk assessment considering these common triazole metabolites based on established and proposed uses of triazole fungicides as of 1

- September

- 2005 (DP322215, M. Doherty et al.

, 2/7/06). In connection with pending new uses, HED has revised the triazole dietary assessment to include the new uses of metconazole and has determined that aggregate risk (food, water and residential)
remains below HED’s level of concern (DP388469, T. M orton, 4/27/11)

. There are no dietary exposure considerations for the common triazole metabolites that would preclude granting the registration requests.

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, a dults, adolescents and children may be exposed to metconazole from its currently registered use on turf and ornamentals.

### Page 7 of 53

Aggregate Risk

Dietary, incidental oral and inha lation 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 take into account average (chronic) exposure estimates from dietary consumption of metconazole (food and drinking water) and non

- occupational/residential use on turf (inhalation f or adults, and incidental oral for children). Postapplication exposures from the use on turf are considered predominantly

short

- term (1

- 30 days) . Although exposures are expected via the dermal route, quantification of dermal risk was not conducted, since a dermal endpoint was not identified for short

- , or intermediate

- term exposures. Therefore, short

- and intermediate

- term postapplication aggregate risk assessments were conducted only for average dietary and incidental oral exposures to children, and ave rage dietary and inhalation exposures to adults.

The short

- and intermediate

- term aggregate MOEs from dietary exposure (food + drinking water)

and non

- occupational/residential handler exposure (inhalation) for adults are 1700 and 1700, respectively, 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 chil dren 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 (i.e., Tier II surface water

model ing ); and 2) screening

- level r esidential SOPs and upper level estima tes of exposure were employed.

Updated Aggregate Assessment of Free Triazole & its Conjugates

As with the dietary assessment, HED has completed an updated aggregate human health risk assessment (DP389080, T. Morton, 4/27/11) for 1,2,4

- triazole and the co njugated triazole metabolites (TA, TAA and TP). The only revisions to the components of the previous aggregate exposure and risk estimates are to the dietary exposure estimates. For the common triazole metabolites, acute and chronic aggregate risks consi st only of dietary components and, therefore, are equivalent to the dietary risk estimates. For short

- and intermediate

- term aggregate scenarios, the revised aggregate estimates are below HED’s level of concern.

### Page 8 of 53

Occupational Exposure and Risk

Handler s: Based on the proposed uses, t here is a potential for short

- and intermediate

- term occupational exposure to metconazole during handling activities (e.g. m ixing, loading, application). The results of the occupational handler exposure and risk assessment in dicate that

short

- and intermediate

- term inhalation risks do not exceed HED ’ s LOC (i.e. an MOE < 100)

. For short

- term exposure, the handler inhalation MOEs ranged from 19,000 to 340,000 at baseline (i.e.

, no respirator)

. F or intermediate

- term exposure, t he handler inhalation MOEs ranged from 13,000 to 240,000 at baseline.

Postapplication Workers : There is a potential for short

- and intermediate

- term occupational exposure during post

- application activities

. However, since no dermal endpoint has been

iden tified, a dermal post

- application assessment is not needed. Under Worker Protection Standards ( WPS )

, t he 12

- hour restricted entry interval ( REI ) on the label is acceptable.

Environmental Justice Considerations

Potential areas of environmental justice co ncerns, 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 l ine 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 cate gorized 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 postapplication are evaluated. Further consid erations 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 speci fic subgroups.

Review of H

uman 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 requ ire a review of their ethical conduct, and have received that review.

### Page 9 of 53

2.0 Regulatory Conclusions and Recommendations

Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are submitt ed, HED can recommend for a conditional registration and permanent tolerances for the proposed uses of

metconazole on tuberous and corm vegetable subgroup 1C and the bushberry subgroup 13

- 07B. Additional data are needed as conditions of registration as ou tlined 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

The following must be provided prior to a tolerance being established or registration

allowed:

860.1200 Directions for Use Since no spray adjuvants were used in the residue field trials on potatoes and b lueberries

, the label must be amended to include a statement that no adjuvant should be used for the tuberous and corm vegetable subgroup 1C and the bushberry subgroup 13

- 07B.

860.1550 Proposed Tolerances Section F should be revised to reflect the correct identification of the chemical being proposed. Propiconazole appears in Section F as the pesticide proposed.

The commodity definition for tuberous and corm vegetables must be changed to Vegetable, tuberous and corm, subgroup 1C as shown in Table 1.

A revised Section F should be submitted to propose a tolerance of 0.04 ppm for Vegetable, tuberous and corm, subgroup 1C and 0.40 ppm for B ushberry subgroup 13

- 07

B as shown inTable 1.

The following d ata are required as condition s of registration :

RESIDUE CHEMISTRY

860.1360 Multiresidue Methods

HED has previously identified the need for metconazole to be tested through OV

- 17 and

OV

- 225 GC columns . This deficiency remains outstanding.

860.1380 Storage Stability Storage stability data for residues of 1,2,4

- triazol e , triazol yl acetic acid, and

triazol yl al anine have not been submitted in conjunction with the subject petition . Although storage stability data for the triazoles are under review by the Agency, more data may be required to support this petition.

### Page 10 of 53

TOXICOLOGY

870.6200a Acute Neurotoxicity Stud y 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 thi s remains a data deficiency.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate gas chromatography method with nitrogen

- phosphorus

- detection (GC /NPD) is available for data collection and enforcement of tolerances for residues of metconazole parent isomers ( cis

- and trans

- metconazole) in plant commodities based on Valent Method RM

- 41C

- 1

, ―Determination of cis and trans

– Metconazole in Crops.‖ An a dequate high performance liquid chromatography (HPLC) method is available for data collection and enforcement of tolerances

for residues of 1,2,4

- triazole (T), triazole alanine (TA), and triazole acetic acid (TAA). The

method is based on Morse Laboratorie s, Inc. analytical method, Meth

- 160, Rev. 2, ―Determination of 1,2,4

- Triazole, Triazole Alanine and Triazole Acetic Acid Residues in Plants
and Animal Matrices.‖ The GC/NPD and HPLC methods were adequately validated prior to and concurrently with the anal yses of the crop field samples. The lowest level of method validation (LLMV) in potato was 0.02 ppm for both metconazole and the triazole metabolites, and in blueberry, the LLMV is 0.05 ppm for metconazole and 0.02 ppm for the triazole metabolites.

For me tconazole residues in potatoes, the calculated limit s of detection (LOD) are 0.0037 an d 0.0056 ppm for cis and trans

- metconazole, respectively

. For the triazole metabolites in potatoes

, the calculated LODs are 0.0052, 0.0066 and 0.0078 ppm for T, TA, and TAA, respectively. For metconazole residues in blueberries, the calculated LOD s are 0.0012 and 0.0092 ppm for cis and

trans

- metconazole, respectively. For T, TA, and TAA in blueberries the calculated LODs are 0.010, 0.0042 and 0.011 ppm , respectively

.

T he limit of quantitation (LOQ) is defined as the lowest fortification level of an analyte at which acceptable recovery data can be achieved. The LOQ is equivalent to the LLMV.

Additional multiresidue method testing data required from a previous petition remain outstanding for metconazole. It was concluded (DP# 361110) that f urther work is required to test the separation of metconazole on OV

- 17 and OV

- 225 columns under Protocol C.

2.2.2 International Harmonization

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

### Page 11 of 53

2.2.3 Recommended To lerances

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

Tolerances are established for residues of met conazole, 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

- (1 H

- 1,2,4

- tr iazol

- 1

- ylmethyl)cyclopentanol] as the

sum of its cis

- and trans

- isomers.

The proposed uses and the submitted data support the following tolerances for residues of metconazole on/on the following raw agricultural commodities.

Bushberry subgroup 13

- 07B

................................ .... 0. 40 p pm Vegetable, tuberous and corm, subgroup 1C

........... 0.04 p pm

2.2. 4 Revisions to Petitioned

- For Tolerances

Permanent tolerances have been proposed by IR

- 4 for the combined residues of the fungicide

metco nazole in/or on the tuberous and corm vegetables subgroup 1C at 0.02 and the bushberry subgroup 13

- 07B at 0.35 ppm.

For purposes of the tolerance expression, HED has determined that the residue of concern is metconazole ( the sum of cis

- and trans

- isome rs) for b oth 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 follows:

Toler ances 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

- chlorop henyl)methyl]

- 2,2

- dimethyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)cyclopentanol] as the

sum of its cis

- and trans

- isomers.

Adequate crop field trial data reflecting the proposed use patterns were submitted for purposes of establishing tolerances on the tuberous a nd corm vegetables subgroup 1C and the bushberry subgroup 13

- 07B. The tolerance spreadsheet in the Agency’s Guidance for Setting Pesticide

Tolerances Based on Field Trial Data was utilized in determining the appropriate tolerance level

for bushberries. T he tolerance spreadsheet was not used to calculate the tolerance for tuberous and corm vegetables because residues in potato es were below the LOQ (<0.04 ppm). The proposed tolerance of 0.02 ppm for tuberous and corm vegetables is too low. The tolerance

s hould be established at 0.04 ppm , reflecting the combined LOQs of the metconazole enforcement method of 0.02 ppm for each of the cis

- and trans

- isomers of metconazole. The proposed tolerance of 0.35 ppm for bushberries is also too low; a tolerance must b e proposed at 0.40 ppm.

### Page 12 of 53

Based on the results of the potato processing study, in which residues of metconazole were <LOQ in potatoes following application at ≥5 X the maximum proposed seasonal rate, tolerances for the processed commodities of potato are n ot needed.

The proposed and recommended tolerances for metconazole as a result of the subject action are presented in Table 1. The proposed tolerances should be revised to reflect the approved tolerance definition specified above, and the correct commodi ty definition and recommended tolerance levels as specified in Table 1.

Table 1

. Tolerance Summary for Metconazole

. Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments

( correct commodity definition )

40 CFR §180. 617 (a)(2)

Tuberous a nd C orm V egetable subgroup 1 C 0.02 0.04 Vegetable, tuberous and corm, subgroup 1C

Bushberry subgroup 13

- 07B 0.35 0.40



### 2.3 Label Modifications

A revised Section B / label is requested

. S ince no spray adjuvants were used in the residue field trials on potatoes and b lueberries , the Section B/ label must be amended to include a statement that no adjuvant should be used for the tuberous and corm vegetable subgroup 1C and the bushberry subgroup 13

- 07B.

3 .0 Ingredient Profile

3.1 Summary of Proposed Uses

IR

- 4 has submitted use directions under Section B of the petition which include the draft labeling

for the 50 % WDG formulation of metconazole ( V

- 101 16 5 0 WDG, EPA Reg. No. 59639

- 147)

. IR

- 4 is proposing new foliar uses of metconazole on bushberries (crop subgroup 13

- 07B) and tuberous and corm vegetables (crop subgroup 1C). A summary of the proposed use directions for the intended crops is presented in Ta ble 2

.

### Page 13 of 53

T able 2

. Summary of Directions for Use of Metconazole.

Applic. Timing, Type, and Equip. 1 Formulation

[EPA Reg. No.] Applic.Rate

oz/A (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitat ions

Tuberous and Corm Vegetables (Subgroup 1C): arracacha; arrowroot; artichoke, Chinese; artichoke, Jerusalem; canna (edible); cassava (bitter and sweet); chayote (root); chufa; dasheen (taro); ginger; leren; potato; sweet potato; tanier; turmeric; yam bean; yam true

Foliar,

B roadcast

, Ground (min. 1 0

GPA 2 ) or aerial (min. 5 GPA) 50% WG

[59639

- 147] 2.5

- 4.0 4

( 0.078

- 0.125) 4

(Maximum

of 2 sequential applications) 16

(0.500) 1 Use as part of an

Integrated Pest Management (IPM)

program 3

. Apply when co nditions

favor disease development, prior to

infection. Continue applications on a 7

- to 14

- day retreatment interval. Do not apply more than 4 applications per season.

Do not make more than 2 sequential applications. Do not apply more than 16 oz/A (0.500 lb ai/A)

/season.

Bushberries (Subgroup 13

- 07B): aronia berry; blueberry, highbush; blueberry, lowbush; buffalo currant; Chilean guava ; cranberry, highbush; currant, black; currant, red; elderberry; European barberry; gooseberry; honeysuckle (edible); h uckleberry; jostaberry; juneberry (Saskatoon berry); lingonberry;

native currant; salal; sea buckthorn; cultivars, varieties and/or hybrids of these.

Foliar,

B roadcast

, Ground (min. 20 GPA) or aerial (min. 10 GPA) 50% WG

[59639

- 147] 2.5

(0.078) 3

(Maximum

of 2 sequential applications) 0.234 7 Apply when conditions

favor disease development, prior to infection, in sufficient water to obtain thorough coverage of blossoms, foliage, and/or fruit. Continue applications on

a 7 to 14

- day retreatment

interval. D o not apply more than 3 applications

per season.

1 Do not apply through any type of irrigation system.

2 Gallons per acre.

3 Appl y in a regularly scheduled spray program in combination and/or rotation with other effective fungicides that

have different modes of action (i.e., non Group 3 fungicides). Avoid rotating with other sterol biosynthesis inhibitors, such as Folicur®, Nova®, Procure® or Tilt®.

4 For the control of white mold ( Sclerotinia sclerotiorum ), use 4 oz /A (0.125 lb ai/A) per application. Make first application prior to infection, generally at row closure and/or first bloom and the second application 14 days later if conditions favor white mold development.



### Since no spray adjuvants were used in the residue field trials on potatoes and bus hberries, the ―Crop Specific Directions/Restrictions and Limitations‖ on the 50% WDG label for Bushberr y,

### Page 14 of 53

Subgroup 13

- 07 B and for Vegetable, Tuberous and Corm

, Subgroup 1C must state that no spray adjuvant should be used for these crops.

3 .2 Structure an d Nomenclature

Structure and nomenclature are reported in Appendix C.

3 .3 Physical and Chemical Properties

The physicochemical properties of metconazole are reported in Appendix C.

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 (B. O’Keefe, 09/06/07, DP328676 and Y. Donovan, 03/12/08, DP331937) contain detailed and up

- to

- date discussio ns 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.

Acute oral and dermal to xicities 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. The liver is the primary target organ in the mouse, rat and dog following oral exposure to metconazole via subchronic or chronic exposure durations. Developmental studies in rats and rabbits show some evidence of developmental effects, but only at dose levels that are maternally toxic. In the rat study, there is only low concern for the qualitative susceptibility (skeletal variation). Therefore, there is no residual uncertainty for pre

- and/or post

natal toxicity. Metconazole did not demonstrate the potential for neurotoxicity in the four species (mouse, rat, dog an d rabbit) tested. Metconazole is ―Not likely to be Carcinogenic to Humans‖ based on convincing evidence that carcinogenic effects are not likely below a defined dose that doesn’t cause mitogenesis.

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, 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 neur otoxicity, mutagenicity screens and mechanistic studies.

### Page 15 of 53

4.1. 3 Sufficiency of Studies/Data

The toxicity database for metconazole is adequate for the purpose of this risk assessment (see Appendix A for T oxicity Profile tables). However, in accordance with the revised 40 CFR Part 158 data requirements, an immunotoxicity study and a neurotoxicity battery are required. The existing database includes a recently submitted and reviewed immunotoxicity study, and a

sub chronic neurotoxicity study, but not an acute neurotoxicity study, and this remains a data deficiency.

4 .1. 4 Toxicological Effects

Metconazole is a member of the triazole class of systemic fungicides and acts prima rily 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, metcona zole 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 tr iazoles, 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 con sistently across multiple durations and species, these effects were considered slight and minimal in some studies and appearing to be "adaptive" responses, but based on the weight of evidence from the consistency of these reported effects and

evidence that these effects increase in severity with duration, and leading to liver tumors in the chronic mouse study, they were considered "adverse" and formed the basis of the study LOAELs. Metconazole is considered nongenotoxic and the liver tumors appear to have been formed via a mitogenic mode of action and therefore, metconazole is classified as "not likely to be carcinogenic to humans" at levels that do not cause mitogenesis. 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 sp leen weight and hyperplasia were observed in the mouse, rat and dog at dose levels where liver effects were also observed. However, a recently submitted and reviewed immunotoxicity study produced no evidence of immunotoxic potential at dose levels that pro duced systemic toxicity in rats. In dogs, lenticular degeneration (cataracts) was observed at the highest dose tested. Furthermore, at high dietary levels, there is evidence that metconazole is a gastrointestinal irritant in the dog.

Developmental s tudies 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 devel opmental 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,

### Page 16 of 53

developmental effects (increased post

- im plantation 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 bod y weight gains, increased incidence of fatty hepatocyte changes in male parental animals and increased incidence of spleen congestion in F1 parental females. In the rat study, there is low

concern for qualitative susceptibility (skeletal variation in the presence of minimal maternal toxicity) due to the presence of more severe effects at higher dose levels such as post

implantation loss, hydrocephaly and visceral anomalies. However, there is a clear NOAEL for these effects and the point of departure for t his 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 subchronic neurotoxicity study or the other

submitte d 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. No effects were noted on brain weights and no clinical signs possibly re lated 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 existing database does not include an acute neur otoxicity 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 sk in sensitizer.

4.1.5 Cancer Classification

Cancer Assessment Review Committee (CARC) Classification: ―Not Likely to be Carcinogenic to Humans‖ based on convincing evidence that a non

- genotoxic mode of action for li ver 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. Ki dwell, TXR# 0054211, 4/14/06). No quantification required.

4 .2 Absorption, Distribution, Metabolism, Excretion (ADME)

The absorption, distribution, metabolism and excretion (ADME) of m etconazole was investigated in rats following single oral doses of cis and or cis/trans metconazole radiolabeled at the cyclopentyl or triazole ring (cis only). Initial studies showed less than 2% of the cyclopentyl

labeled dose was expired in the air. F ollowing a single oral administration of low dose (2 mg/kg)

14 

### C

- 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,

### Page 17 of 53

respectively. A delay in excretion was observed following the administration o f high dose (164 mg/kg) 14 

### C

- 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. Plasma pharmacokinetic studies showed a 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 at the earliest sampling interval s 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.

Radioactivity measurements of tissues showed hi gher 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 ( 14 

### C

- triazole ring) show ed approximately 5% of the administered dose excreted as free triazole.

4 .3 FQPA Considerations

The toxicology databa se used to assess pre

- and post

- natal exposure to metconazole is

considered adequate

.

4 .4 FQPA Safe ty 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 1 X . 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 d eficiency. However, an acceptable

### Page 18 of 53

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 lo w 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 as sumed 100% crop treated. Therefore, t he 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 th is analysis are unlikely to underestimate actual exposure. The drinking water component of the dietary assessment utilizes water concentration values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high

end estimates of water concentrations which will not likely be exceeded. While there is potential for post

- application residential exposure, the best data and approaches currently

available were used in the metconazole residential assessm ent. The Agency used the current conservative approaches for residential assessment, many of which include recent upgrades to the SOPs. The Agency believes that the calculated risks represent conservative estimates of exposure because maximum application rates are used to define residue levels upon which the calculations are based. Exposures are unlikely to be under

estimated.

4 .5 Hazard Identification and Toxicity Endpoint Selection

H azard identification and toxicity endpoint selection were made for two different population subgroups: (1) Females 13

- 49 years of age, and (2) General Population including infants and children. Doses and endpoints were also 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 heal th risk assessment is presented

below:

### Page 19 of 53

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

Occupational Human Health Risk Assessments Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD , PAD, Level

of Concern for

Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) An appropriate dose/endpoint attributable to a single dose was not observed in the available oral

toxicity stud ies reviewed.

Acute Dietary (Females 13

- 49 years of age) NOAEL= 12

mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF= 1 X 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.

Chronic Dietary (All Populations) NOAEL= 4.3

mg/kg/day UF A =10 X

UF H = 10 X FQPA SF= 1 X 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 hepato cellular 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 UF A = 10 X

UF H =10 X FQPA SF= 1 X Residentia l LOC

for MOE = 100 28

- Day oral toxicity study in rats:

LOAEL = 90.5 mg/kg/day based on decreased body weight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F).

Incidental Oral

Intermediate

Term (1

- 6 months) NOAEL = 6.4

mg/kg/day UF A = 10 X

UF H =10 X FQPA SF= 1 X Residential LOC

for MOE = 100 90

- Day oral toxicity study in rats:

LOAEL = 19.2 based on increased spleen wt (F) and hepatic vacuolation (M).

Dermal Short

Term (1

- 30 days) Quantification of dermal risk is not re quired due to lack of systemic or dermal toxicity at the Limit

Dose in a 21

- day dermal toxicity study in the rat and the lack of target organ toxicity, neurotoxicity, developmental or reproductive toxicity.

Dermal

Intermediate

Term (1

- 6 months)

Inhalati on Short

- Term (1

- 30 days) NOAEL= 9.1

mg/kg/day UF A = 10 X

UF H =10 X FQPA SF= 1 X Residential LOC

for MOE = 100 28

- Day oral toxicity study in rats:

LOAEL = 90.5 mg/kg/day based on decreased body weight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F).

Inhalation

Intermediate

Term (1

- 6 months) NOAEL= 6.4

mg/kg/day UF A = 10 X

UF H =10 X FQPA SF= 1 X 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‖

### Page 20 of 53

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beg inning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal t o human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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 exposur e. LOC = level of concern. N/A = not applicable.



### A s ummary of t oxicological d oses and e ndpoints for m etconazole for u se in o ccupational h uman h ealth r isk a ssessments is presented below:

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

Health Risk Assessments Expo sure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern for

Risk Assessment Study and Toxicological Effects

Dermal

Short

- ( 1

- 30 days) &

Intermediate

Term (1

- 6 months) Quantification of dermal risk is not required due to lack of systemic or dermal toxicity at the Limit

Dose in a 21

- day dermal toxicity study in the rat and the lack of target organ toxicity, neurotoxicity, developmental or reproductive toxicity.

Inhalation

Short

- Term (1

- 30 days) NOAEL=9.1

mg/kg/day UF A =10 X

UF H =10 X Occupational LOC for

MOE = 100 28

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

Inhalation

Intermediate

term (1

- 6 months) NOAEL=6.4

m g/kg/day UF A =10 X

UF H =10 X Occupational LOC for

MOE = 100 90

- Day oral toxicity study in rats: LOAEL = 19.2 mg/kg/day based on increased spleen wt (F) and hepatic vacuolation (M). Cancer (oral, dermal, inhalation) Classification: ―Not Likely to be Carcinoge nic 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. UF A = extrapolation from animal to human (int e rspecies). UF H = potential variation in sensitivity among members of the human population ( int ra species). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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

repo rt 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 asse ssments, 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 asse ssment.

### Page 21 of 53

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 b e combined due to the common endpoint (liver toxicity) via the oral and inhalation (oral equivalent) routes. Quantification of dermal risk is not required. There are no potential long

term dermal or inhalation exposures to metconazole.

4 .6 Endocrine D is ruption

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, includin g 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,

org an 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 reproductiv e effects in different taxonomic groups. As part of its most recent registration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), Metconazole is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may h ave 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

determinat ions. 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 un der the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays for metconazole. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

### Page 22 of 53

5 .0 Dietary Exposure/Risk Characterization

Reference: Metconazole. Petition for Registration of Use on Tuberous and Corm Vegetables Subgroup 1C and Bushberry Subgroup 13

- 07B (PP#0E7743). Summary of Analytical Chemistry and Residue Data. A. Acierto, DP380990, 3/24/11.



### 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 hyd roxylation 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 th e subject petition, the nature of the residue in plants is adequately understood.

5 .1. 2 Metabolism in Livestock

No new metabolism data were submitted with the subject petition. Adequate ruminant and poultry metabolism studies are available, and the data indicate that t he 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 positi on 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 metaboli sm 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)

. T he r esidues of concern in livestock for purposes of t he

risk assessment are metconazole and metabolites M1 (free and conjugated), M12, and M31 (free and conjugated)

. For the purpose of th e subject petition, the nature of the residue in livestock is adequately understood.

### Page 23 of 53

5 .1. 3 Drinking Water Residue Profile

Reference: Drinking Water Exposure Assessment to Establish Tolerances of Parent Metconazole for

Tuberous/Corm Vegetables (Subgroup 1C) and Bushberr ies (Subg roup 13

- 07B)

. DP375778 and DP 380513, F

. Khan, 12/16/

10

.



### A drinking water assessment for the proposed use s on the tuberous/corm vegetables and

bushberr ies w as performed using PRZM/EXAMS modeling. Estimated drinking water

concentrations (EDWCs) of metconaz ole in drinking water from use on the existing and new crops were provided by EFED and incorporated directly into the acute and chronic dietary

assessments. The EDWCs are based on the maximum proposed rates specified on the label. For surface water, the EDWCs for the proposed crops modeled in the assessment (highest of 43.77 μg/L for cranberry scenario) did not exceed the acute EDWC of 45.48 μ g/L for turf reported in a previous drinking water assessment (D P 340378, 2007). Since the highest EDWC

for the cr ops 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

. However, t he annual mean (chronic) concentration of 38.16 μ g/L for the cranberry scenario is higher than the previously reported highest EDWC (31.25 μ g/L). Therefore, the 38.16 μ g/L

value is recommended for the chronic non

- cancer EDWC.

EFED calculated screening level ground water estimates for metconazole using the SCI

- GROW

model. An acute and chronic ground water EDWC of 0.064 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 (D P 34037 8, 2007)

.

Drinking Water Data for Free Triazoles

Residues of 1,2,4

- triazole in drinking water were provided to HED by the Environmental Fate and Effects Division ( I. Maher, DP3 20682, 28 Feb 2006). Due to the inter

- conversion between 1,2,4

- triazole, tria zole alanine, and triazole acetic acid that may occur in the environment, the residue estimates used in these assessments are a summation of all three residues and, therefore, represent an overestimate of actual concentrations of the common triazole metabo lites in drinking water. The Tier II PRZM/EXAMS (surface water) and SCIGROW (ground water) residue estimates are summarized in Table 2. 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 o f 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. The Environmental Fate and Effects Division stated in electronic communication (F. Khan, 4/7/2011) 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 Co ncentrations of 1,2,4

- Triazole. Exposure Duration Surface Water Concentration, ppm Groundwater Concentration, ppm

Acute 0.041 0.001

Chronic 0.011 0.001

### Page 24 of 53

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, DP 331937

and D P 331926. Y

. Donovan, 3/12/08.



### A summary of the metab olites and degradates to be included in the risk assessment and tolerance expression are presented in Table 7 below. Detailed rationale for these conclusions were presented in a previous risk assessment document (DP Barcode 331926, 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 Gra ins 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 Metconazol e 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 meta bolites 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 a ssessment documents.

M1 = 5

- [(4

- chlorophenyl)methyl]

- 2

- methoxyl

- 2

- methyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)

- 1

- cyclopentanol; M11 = 5

- [(4

- chlorophenyl)methoxyl]

- 2,2

- dimethyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)

- 1

- cyclopentanol; M12 = 5

- [(4

- chlorophenyl)methyl]

- 2

- carboxyl

- 2

- methyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)

- 1

- cyclopentanol; M31 = (1S*,3R*,5S*)

- 3

- hydroxy

- cis

- metconazole; 1,2,4

- T = 1 H

- 1,2,4

- triazole; TAA = 1 H

- 1,2,4

- triazol

- 1

- yl acetic acid;

TA = 2

- amino

- 3

- (1 H

- 1,2,4

- triazol

- 1

- yl)propanoic acid.



### Crop Field Trials

Potato

The IR

- 4, on behalf of the Agricultural Stations of Idaho, Michigan, North Dakota, North Carolina, and Oregon has submitted field trial data for metconazole on potatoes (MRID 48143301). Pending review of the submitted triazole storage stability data, t he submitted potato field trial data for metconazole are adequate to fulfill data requirements. The number and locations of field trials are in accordance with OPP Guideline 860.1500 for potato, the

### Page 25 of 53

representative crop for the tuberous and corm veg etable subgroup 1C, and the use pattern of the field trials adequately reflects the proposed use pattern for tuberous and corm vegetables. The available field trial data will support a tolerance of 0.04 ppm for tuberous and corm vegetables subgroup 1C, re flecting the combined LOQs of the enforcement method of 0.02 ppm for each of

the cis

- and trans

- isomers of metconazole.

Residues of 1,2,4

- triazole and triazole acetic acid in potato tubers were each <0.02 ppm. In 9 of the 17 field trials, residues of t riazole alanine in the treated samples were at 0. 020

- 0.075 ppm (uncorrected for controls ); residues in the control were 0.006

- 0.069 ppm. In the residue decline study, residues of triazole alanine were observed in one of two sites, although a clear pattern of decline could not be determined. The average triazole alanine residues (uncorrected for controls )

over the 14

- day period ranged from 0.022

- 0.027 ppm and 0.013 ppm in the corresponding

control.

The results of the potato field trials are summarized in Table 8

.

Table 8

. Summary of Residue Data from Potato Field Trials with a Metconazole Formulation (WDG).
Commodity Total

Applic. Rate ( lb ai/ A) E nd

- use

Product PHI 2

(days) Residue Levels (ppm) 1

n Min. Max. HAFT 2 Mean Std. Dev.

cis

- Metconazole

T uber 0.496

- 0.529 V

- 10116

50 WDG 1

- 2 34 <0.020 <0.020 <0.020 <0.020 NA

trans

- Metconazole

Tuber 0.496

- 0.529 V

- 10116

50 WDG 1

- 2 34 <0.020 <0.020 <0.020 <0.020 NA

1,2,4

- Triazole

Tuber 0.496

- 0.529 V

- 10116

50 WDG 1

- 2 34 <0.020 <0.020 <0.020 <0.020 NA

Tri azole Acetic Acid

Tuber 0.496

- 0.529 V

- 10116

50 WDG 1

- 2 34 <0.020 <0.020 <0.020 <0.020 NA

Triazole Alanine

Tuber 0.496

- 0.529 V

- 10116

50 WDG 1

- 2 34 <0.020 0.075 0.075 0.031 0.016

Total 3

Tuber 0.496

- 0.529 V

- 10116

50 WDG 1

- 2 34 <0.040 <0.040 <0.040 <0. 040 NA

1 Residues of total metconazole calculated as the sum of the cis

- and trans

- isomers. The LOQ was 0.04 ppm for

potato.

2 All studies had PHIs of 1 day except for one study with a PHI of 2 days



### . 3 Residues of total metconazole calculated as the sum of the cis

- and trans

- isomers. The LOQ was 0.04 ppm for

potato.



### Blueberry

The IR

- 4 submitted field trial data for metconazole residues in/on blueberry (MRID 48143302)

. Pending review of the submitted triazole storage stability data, t he submitted blu eberry field trial data for metconazole are adequate to fulfill data requirements. The number and locations of field trials are in accordance with the requirements of OCSPP Guideline 860.1500 for blueberry, the

### Page 26 of 53

representative crop of the bushberry subgrou p 13

- 07B, and the use pattern of the field trials adequately reflects the proposed use pattern for bushberries.

The available field trial data will support a tolerance of 0.40 ppm for the bushberry subgroup 13

- 07B as calculated utilizing the tolerance s preadsheet in the Agency’s Guidance for S etting

Pesticide Tolerances Based on Field Trial Data

.

Residues of the triazole metabolites were below the LOQ (<0.02 ppm) in/on all blueberry samples.

The results of the blueberry field trials are summarized in Table 9

.

T able 9

. Summary of Residue Data from Blueberry Field Trials with a Metconazole Formulation (WDG).
Commodity Total

Applic. Rate ( lb ai/ A) E nd

- use

Product PHI

(days) Residue Levels (ppm) 1

n Min. Max. HAFT 2 Mean 3 Std. Dev.

cis

- Metconazole

Berries 0.240

- 0.265 V

- 10116

50 WDG 6

- 8 22 <0.05 0.263 0.246 0.110 0.1

trans

- Metconazole

Berries 0.240

- 0.265 V

- 10116

50 WDG 6

- 8 22 <0.05 0.063 0.056 0.051 0.0

1,2,4

- Triazole

Berries 0.240

- 0.265 V

- 10116

50 WDG 6

- 8 22 <0.02 <0.02 <0.02 <0.02 NA

Tria zole Acetic Acid

Berries 0.240

- 0.265 V

- 10116

50 WDG 6

- 8 22 <0.02 <0.02 <0.02 <0.02 NA

Triazole Alanine

Berries 0.240

- 0.265 V

- 10116

50 WDG 6

- 8 22 <0.02 <0.02 <0.02 <0.02 NA

Total 4

Berries 0.240

- 0.265 V

- 10116

50 WDG 6

- 8 22 <0.10 0.326 0.303 0.160 0.1

1 Residues less than the LOQ were considered to be the LOQ for calculations. The lowest level of method validation (LLMV) is 0.05 ppm for isomers of metconazole and 0.02 ppm for metabolites. Residue levels include residues of metconazole and

metabolite s . No conversion factors were applied.

2 HAFT = highest average field trial.

3 Mean and standard deviations were calculated by the study author. Does not include additional sampling intervals collected f or the residue decline study.

4 Residues of total metconazole calculated as the sum of the cis

- and trans

- isomers. The LOQ was 0.04 ppm for blueberry

.



### Processed Food and Feed

Potato

IR

- 4 submitted a processing study for metconazole on potato ( MRID 48143301)

. R esidues were

below the LOQ in /on potato tubers following application of the WDG formulation at an exaggerated rate of 2.5 or 3.1 lb ai/A (5x or 6.2x the proposed seasonal application rate). An acceptable method was used for quantitation of residues in potato tubers. The submitted potato

proces sing study is acceptable to satisfy data requirements. Because residues of metconazole were below the LOQ in/on samples of potato treated with metconazole at ≥5X the maximum

### Page 27 of 53

proposed seasonal rate, analysis of processed samples is not required. HED concl udes that quantifiable residues of metconazole in potato processed commodities are not expected, and separate tolerances are not needed. The residue data from the processing study is summarized in

Table 10

.

### Page 28 of 53

Table 10

. Residue Data from Potato Processi ng Study with Metconazole.

RAC Processed

Commodity Total Rate

(lb a.i./A) PHI

(days) Residues (ppm) Processing Factor 1

cis

metcon
azole trans

metcon
azole T TAA TA TA

corrected Total

metcon
azole cis

metcon
azole trans

metcon
azole T TAA TA TA

correct
ed Total

metcon
azole Prosser, WA; 2007 (07

- WA33)

Potato Tuber (RAC) 2.498 1 <0.020 <0.020 <0.020 <0.020 0.066 0.027 <0.040

-- -- -- -- -- -- --

Flakes NA NA NA NA NA NA NA NC NC NC NC NC NC NC Chips NA NA NA NA NA NA NA NC NC NC NC NC NC NC Wet p eel NA NA NA NA NA NA NA NC NC NC NC NC NC NC Weslaco, TX; 2007 (07

- TX28)

Potato Tuber (RAC) 3.137 1 <0.020 <0.020 <0.020 <0.020 <0.020

-- <0.040

-- -- -- -- -- -- --

Flakes NA NA NA NA NA NA NA NC NC NC NC NC NC NC Chips NA NA NA NA NA NA NA N C NC NC NC NC NC NC Wet peel NA NA NA NA NA NA NA NC NC NC NC NC NC NC NA = Not analyzed. The LOQ was 0.020 ppm for metconazole and metabolites.

1 NC = Not calculated; processed fractions were not analyzed.

### Page 29 of 53

Meat, Milk, Poultry, and Eggs

No livest ock feed items are associated with bushberries. The only livestock feedstuffs associated with this current petition (PP#0E7743) are processed potato waste and potato culls; these commodities are fed to beef and dairy cattle but are not fed to poultry or s wine. The dietary burdens of metconazole to livestock, based on reasonably balanced diets, were calculated in a previous review ( DP350367 , N. Dodd, 9/18/08). Dietary burdens were 4.2 and 6.6 ppm for beef and dairy cattle, respectively, and 1.9 and 0.64 p pm for poultry and swine, respectively , and were calculated based on tolerances for cereal grain, sugarcane, cotton, and soybean commodities

.

Residues of metconazole from the submitted crop field studies were below the LOQ in/on potatoes following appli cation at 5 X the proposed maximum seasonal application rate; therefore, quantifiable residues of metconazole are not expected in potato processed commodities. Consequently, the addition of the use of metconazole on tuberous and corm vegetables is not

expe cted to alter the dietary exposure of ruminants because residues of metconazole were nonquantifiable in potato treated at 1 X and 5 X the maximum proposed seasonal application rate

. Therefore, no changes are required in the current livestock tolerances for metconazole.

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 Chron ic 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.



### Acute and chronic aggregate dietary (food and drinking water) e xposure and risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM

- FCID TM 

### , Version 2.03), which uses food consumption data from the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. C onservative acute and chronic dietary exposure

assessment s were conducted for all existing and proposed food uses of metconazole and drinking

water. R esidues of the proposed food commodities were based on field trial data on the representative crops (potato and blueberry). The conservative assessment assumed that

metconazole residues are present in all reg istered and proposed f ood commodities at tolerance

levels and that 100% of the crops were treated. All processing factors for the proposed

tuberous/corm vegetable commodities were set to 1 , based on the results of processing studies demonstrating that res idues of metconazole in potato processed commodities would not exceed the raw agricultural commodity (RAC) tolerance

.

### Page 30 of 53

5 .2.1 Acute Dietary Exposure/Risk

The acute dietary exposure assessment was performed only for females 13

- 49 years old since an acute endpoint was not identified for the g eneral U.S. population. Estimated acute dietary exposure to metconazole from food and drinking water is below HED’s level of concern. Combined dietary exposure from food and drinking water at the 95 th 

### percentile of exposure is

estimated to be 0.0045 78 mg/kg/day for females13

- 49 years old, equivalent to 3.8% of the acute Population Adjusted Dose (aPAD); therefore, the exposure is not of concern to HED (i.e., <100% aPAD)

.

5 .2.2 Chronic Dietary Exposure/Risk

Chronic dietary (food and drinking water) exposure estimates are well below HED’s level of concern. Using EDWCs from the cranberry crop scenario, chronic (food and drinking wate r) dietary exposure is estimated at 0.002434 mg/kg/day for the general U.S. population (6.1% of the chronic Population Adjusted Dose (cPAD)) and 0.005026 mg/kg/day (12.6% of the cPAD) for

children 1

- 2 years old, the population subgroup with the highest est imated chronic dietary exposure to metconazole.

Table 11 . Summary of Dietary (Food and Drinking Water) Exposure Risk for Metconazolet 1

.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

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

E xposure (mg/kg/day) % cPAD

General U.S. Population 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

Chil dren 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.



### 5 .3 Anticipated Residue and Percent Crop Treated (%CT) Information

The acute and chronic dietary (food and drinking water) exposure and risk estimates are conservative since they assume that 100% of crops are treated with metconazole and that the residues are present at tolerance levels. In addition, drinking water exposure estimates were

### Page 31 of 53

based on screening level estimates generated by the PRIZM

- EXAMS model. Although not needed at this time, HED could refine the exposure and risk estimates through the use of anticipated residues and percent crop treated data as well as refined estimated drinking water concentrations. However, since estimated exposures and risks using conservative assumptions are well below HED’s level of concern, such refinement is not warranted.

5.4 Dietary Assessment of Free Triazole and i ts Conjugates

Reference: Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to

Address The Amended Metconazole Section 3 Registration to Add Uses o n Tuberous and Corm Vegetables (Group 1C) and Bushberry Subgroup 13

- 07B. T. Morton, DP388469.drs, 4/27/11.



### Since m etconazole is a triazole, a separate updated dietary exposure and risk analysis (DP 388469.drs

, T

. Morton , 4/27/11 ) for the common triazole me tabolites 1,2,4

- triazole (T), triazolylalanine (TA), triazolylacetic acid (TAA), and triazolylpyruvic acid (TP) was conducted.

Th e updated assessment address ed requested new uses of metconazole on tuberous and corm vegetables and bushberries.

Four assess ments were conducted: acute and chronic durations for T, and acute and chronic durations for combined residues of TA, and TAA. Residue chemistry databases for metconazole parent compound included residue measurements for the triazole metabolites in/or tu berous and corm vegetables (Group 1C) and bushberry subgroup 13

- 07B . As with the previous triazole metabolite assessments, this assessment includes exposure estimates resulting from direct consumption of T, TA, and TAA as well as indirect exposure resulti ng from consumption of parent fungicides followed by in vivo conversion to the metabolites. For each food form in the acute assessment, the residue used is the maximum estimate from the various food/triazole fungicide combinations combined with the averag e indirect residue estimate. For the chronic assessments, the residue estimates are the average residue from the food

- specific food/triazole combinations combined with the average indirect residue estimates. All four assessments assume 100% crop treated and include conservative estimates for residues of the metabolites in drinking water. The resulting exposure and risk estimates are based on health

- protective assumptions and should be characterized as conservative.

For all four analyses, risk estimates are below HED’s level of concern for all population subgroups. There are no dietary exposure considerations for the common triazole metabolites that would preclude granting the registration requests for metconazole.

### Page 32 of 53

Table 12 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for the Common Triazole Metabolites Adding the N ew Section 3 Uses for Metconazole.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (m g/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

1,2,4

- Triazole General U.S. Population 0.006 383 2 1 0.001 191 24

Not Applicable Not

Applicable All Infants (< 1 year old) 0.01 1430 38 0.00 1879 38

Children 1

- 2 years old 0.014 129 4 7 0.00 2944 59

Chil dren 3

- 5 years old 0.01 1683 39 0.002 472 49

Children 6

- 12 years old 0.007 713 2 6 0.0016 09 3 2

Youth 13

- 19 years old 0.005 402 18 0.0010 28 2 1

Adults 20

- 49 years old 0.005 101 17 0.00 1004 20 Adults 50+ years old 0.004 639 1 5 0.0009 25 1 9

Females 13

- 4 9 years old 0.004 898 16 0.0009 93 20 Triazolylalanine + Triazolylacetic Acid General U.S. Population

Not Applicable Not

Applicable 0.01 4081 1 6

Not Applicable Not

Applicable All Infants (< 1 year old) 0.0 18206 2 0

Children 1

- 2 years old 0.0 38106 4 2

Children 3

- 5 years old 0.03 0642 3 4

Children 6

- 12 years old 0.01 9145 2 1

Youth 13

- 19 years old 0.01 2441 1 4

Adults 20

- 49 years old 0.01 1755 1 3 Adults 50+ years old 0.0 10510 1 2

Females 13

- 49 years old 0.0 52303 52 0.01 1548 1 3

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



### 6 .0 Residential (Non

- Occupational) Exposure/Risk Characterization

No new residential u ses are being requested at this time. However, a dults, adolescents

, and children may be exposed to metconazole from its currently registered use s on turf and ornamentals. These risks have been previously assessed (DP341832, J. Arthur, 8/3/07) . Because

d ermal toxicity endpoints for the appropriate duration of exposure (short

- and intermediate

- term)

were not identified up to the limit dose , only residential handler and postapplication 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 fo r 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 Agenc ies 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/lab eling. 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

### Page 33 of 53

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 pr esented in Table 1 3

.

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 hand lers were all > 71,000, thus providing an ample margin of safety to account for any uncertainties in route

- to

- route extrapolation. Short

- term
inhalation risks were not of concern to HED.

Table 13

. Residential Handler Short

- term Inhalation Exposures and Risks.

Scenario Exposure

Route Max. Rate

Application Unit

Exposure Amount

Treated/Day Daily Dose

(mg/kg/day) 1 Inhalation

MOE 2
1) mixer/loader/applicator

w/ hose

- end sprayer (ornamentals) Inhalation 0.0025 lb ai/

Gal. 0.017

mg/lb ai 100 Gal. 0.000061 1 50,000

2) mixer/loader/applicator

w/ low

- pressure hand

wand sprayer (ornamentals) Inhalation 0.0025 lb ai/

Gal. 0.03 mg/lb

ai 5 Gal. 0.0000054 1,700,000

3) mixer/loader/applicator

w/ hose

- end sprayer (turf) Inhalation 0.6 lb ai/

Acre 0.017

mg/lb ai 0.023 Acre =

1000 ft 2 0.0000034 2,700,000

4) mixer/loader/applicator

w/ low

- pressure hand

wand sprayer (turf) Inhalation 0.6 lb ai/

Acre 0.03 mg/lb

ai 0.5 Acre 0.00013 71,000

1. Daily Dose = Application Rate * Unit Exposure * Amount Treated * Absorption facto r (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

- A pplication 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 duration s of exposure were not identified up to the limit dose , and because inhalation exposure is considered to be insignificant for post

- application exposures, only toddler incidental oral post

- application exposures have been assessed.

### Page 34 of 53

Residential Post

- A pplic ation Exposure on Treated Lawns

P ost

- 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 wi th the algorithms used for each small child exposure scenario are presented below in Tables 14 through 16

. All MOEs for toddler lawn exposure

scenarios were > 100 and

, therefore, are not of concern to HED

. In addition, the total MOEs for

combined toddler exposures (i.e., short

- term and intermediate

- term hand

- to

- mouth, object

- to

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

HED.

### Page 35 of 53

Table 14

. Oral Hand

- to

- mouth Short

- (ST) and Intermediate

- term (IT) Exposure s and Risks for Children from Treated Lawns

Application Rate (lb ai/A) Fraction of ai

Available Turf Transferrable

Residue at Day ―0" ( μ g/cm 2 ) 1 Exposure

Time ( hrs/day) Extraction

by saliva Hand Surface

Area (cm 2 /event) Frequency

(events/ hr) Bod y Weight

(kg) Daily Dose 2

(mg/kg/day) MOE 3

0. 6 0.05 0.3 4 2 0.5 20 20 (ST) 15 0.009 1 (ST) 1000 (ST)
9.5 (IT) 0.004 3 (IT) 1500 (IT)

1 Turf Transferrable Residue ( μ g/cm 2 ) = Application rate (lb ai/A) x Fraction of ai Available x 4.54E+8 μ g/lb x 2. 47E

- 8 A/cm 2

2 Daily Dose = (Turf Transferrable Residue x Extraction by Saliva x Hand Surface Area x Frequency x 1E

- 3 mg/ μ g x E xposure T ime ) / ( Body Weight )

3 MOE = Short

- term Oral NOAEL (9.1 mg/kg/day) or Intermediate

- Term Oral NOAEL ( 6.4 mg/kg/day) /Dail y 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" ( μ g/cm 2 ) 1 Surface Area Mout hed (cm 2 /day) Body Weight (kg) Daily Dose 2

(mg/kg/day) MOE 3

0.6 0.20 1

. 3 25 15 0.00 22 41 00 (ST)

2900 (IT)

1 Grass Residue ( μ g/cm 2 ) = = Application rate (lb ai/A) x Fraction of ai Available x 4.54E+8 μ g/lb x 2.47E

- 8 A/cm 2

2 Daily Dose = [Grass residue ( μ g/cm2) x Surface Area Mouthed (cm2/day) x 1E

- 3 mg/ μ g] / [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) Expos ure 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" ( μ g/g) 1 Ingestion Rate (mg/day) Body Weight (kg) Daily Dose 2

(mg/kg/day) MOE 3

0.6 1 4. 51 100 15 0.0000 3 300,000 (ST)

21 0

, 000 (IT)

1 Soil residue ( μ g/g) = [Application Rate (lbs ai/A) x Fraction of ai Available x 4.54E+8 μ g/lb x 2.47E

- 8 A/cm 2 x 0.67 cm 3 /g soil]

2 Daily Dose = [Soil residue ( μ g/g) x Ingestion rate (mg/day) x 1E

- 6 g/ μ g] / [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

### Page 36 of 53

Table 17 . Children’s Residential Combined Short

- and Intermediate

- term Risk from Treated Turf

Route Daily Dose (mg/kg/day) MOE Total ST MOE 1 Total IT MOE 2

Hand

- to

- Mouth 0.009 1 (ST) 1000 (ST)

810 1000 0.004 3 (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 MO E ) + ( 1/ST Object

- to

- Mouth MOE ) + ( 1/ST Soil Ingestion MOE) ]

2. Total I T MOE = 1 ÷ [ (1/ I T Hand

- to

- Mouth MOE ) + ( 1/ I T Object

- to

- Mouth MOE ) + ( 1/ I T 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 releva nt 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 expos ure.

7 .1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As

demonstrated under Section 5.2 , a cute 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 non

occupational/residential use on turf (dermal and inhalation exposures for adults, and dermal plus incidental oral exposures for children).

For adults applying metconazole to turf, short

- and intermediate

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

The short

- and intermediate

- term aggregate MOEs from dietary exposure (food + drinking water)

and non

- occupational/residential handler exposure (inhalation) for adults are 1 ,7 00 and 1 ,7 00, respectively; which are not of concern to HED (see Table 18 below), since they are greater than

the level of concern MOE of 100.

### Page 37 of 53

Table 18 . Short

- and Interm ediate

- Term Aggregate Risk Calculations for Adult Handlers

Population/

Exposure

Duration Inhalation Exposure Dietary Exposure Short

- or Intermediate

Term Aggregate

MOE 2 NOAEL (mg/kg/day) Exposure

(mg/kg/day) MOE 1 NOAEL (mg/kg/day) Exposure

(mg/kg/day) MOE 1

Adult ST 9.1 0.00013 70,000 4.3 0.002 434 1, 8 00 1, 7 00 ST

Adult IT 6.4 0.00013 49,000 4.3 0.002 434 1, 8 00 1, 7 00 ST

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

2 Aggregate MOE = 1/ [(1/MOE Inhalation ) + (1/MOE Food + Drinking Water )]



### Pos t

- 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

- , o r 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 diet ary exposure (food + drinking water) and non

occupational/residential exposure (incidental oral) for children 1

- 2 years old are 42 0 and 4 6 0, respectively; these MOEs are not of concern to HED (see Table 19 below), since they are greater
than the level of c oncern MOE of 100.

Table 19 . Short

- and Intermediate

- Term Aggregate Risk Calculations for Postapplication Exposures

Population/ Exposure

Duration Incidental Oral Exposure Dietary Exposure Short

- or Intermediate

Term Aggregate

MOE 2 NOAEL (mg/kg/day) Ex posure

(mg/kg/day) MOE 1 NOAEL (mg/kg/day) Exposure

(mg/kg/day) MOE 1

Kids 1

- 2 yrs/ST 9.1 0.01123 810 4.3 0.00 5026 860 4 2 0 ST

Kids 1

- 2 yrs/IT 6.4 0.00643 1000 4.3 0.00 5026 860 4 6 0 IT

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

2 Aggregate MOE = 1/ [(1/MOE Incidental Oral ) + (1/MOE Food + 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 residue s, 100% crop treated, and crop specific (turf) screening level drinking water modeling data (i.e.,

surface water model ing ); 2) maximum application rates and minimum application intervals were used; and 3) conservative SOPs and upper level estimates of expo sure 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.



### In 2 006, HED issued aggregate human health risk assessments for T and the conjugated triazole metabolites ( DP322215, M. Doherty, et al

., 2/7/ 06). Those assessments addressed a back

- log of triazole use requests that had been held by the Agency pending resoluti on of various toxicological and exposure concerns for the common triazole metabolites. The findings of that

### Page 38 of 53

assessment were that risk estimates for all exposure scenarios were below HED’s level of concern. Since that time, a number of requests for new us es of triazole

- derivative fungicides have been submitted to the Agency. As a result of these requests, new dietary exposure estimates have been made for T and combined residues of TA, TAA, and TP, and new aggregate exposure and risk estimates are necessar y. Neither the toxicological information nor the non

dietary exposure estimates detailed in the 2006 memorandum have changed; thus

, the only alterations to the previous aggregate exposure and risk estimates are due to changes in the dietary exposure estim ates. For complete hazard characterization and non

- dietary exposure assessments for the common triazole metabolites, see the 2006 risk assessment.

The revised aggregate estimates are summarized below for short

- and intermediate

- term scenarios for T (Tabl es 2 0 and 21 , respectively). The conjugated triazole metabolites are formed in plants by the conjugation of 1,2,4

- T to serine. The TA may then be further metabolized to form TAA and/or TP. Because of the nature of this process, HED has assumed that it o ccurs within the plant itself and not on leaf surfaces. Therefore, the residues are not available for dermal, hand

- to

- mouth, or object

- to

- mouth exposures and HED has not conducted a residential exposure assessment for the triazole conjugates. Residues of TA, TAA, and TP may occur in soil. 1,2,4

- Triazole is more toxic than TA/TAA/TP and exposures to these via soil ingestion are unlikely to exceed those of 1,2,4

- T. The assessment for soil ingestion of 1,2,4

- T shows that risk
estimates are below HED’s leve l of concern; therefore, risk estimates for soil ingestion of the conjugates will also be below HED’s level of concern.

Table 2 0 . Short

- term Aggregate Exposure and Risk Estimates for 1,2,4

- Triazole.

Population Subgroup Exposure Estimate, mg/kg/day 1

Aggr egate
MOE 2 Dietary Dermal

(M/L/A) Dermal

(Post

Applic.) Hand

- to

Mouth Object

to

- Mouth Soil

Ingestion Aggregate U.S. Population (total) 0.001191 0.00183 0.0051 N/A N/A N/A 0.008121 3700 All infants (< 1 year) 0.001879 N/A 0.0086 0.0041 0.0010 0.000019 0.015598 1900

Children 1

- 2 yrs 0.002944 N/A 0.0086 0.0041 0.0010 0.000019 0.016663 1800

Children 3

- 5 yrs 0.002472 N/A 0.0086 0.0041 0.0010 0.000019 0.016191 1900

Children 6

- 12 yrs 0.001609 N/A 0.0086 N/A N/A N/A 0.010209 2900

Youth 13

- 19 yrs 0.001028 0 .00183 0.0051 N/A N/A N/A 0.007958 3800

Adults 20

- 49 yrs 0.001004 0.00183 0.0051 N/A N/A N/A 0.007934 3800 Adults 50+ yrs 0.000925 0.00183 0.0051 N/A N/A N/A 0.007855 3800

Females 13

- 49 yrs 0.000993 0.00183 0.0051 N/A N/A N/A 0.007923 3800

1 Exposure e stimates for dermal, hand

- to

- mouth, object

- to

- mouth, and soil ingestion are from J. Arthur, DP 322240, 12/9/05.

2 Aggregate MOE = NOAEL (30 mg/kg/day) ÷ Aggregate Exposure Estimate (mg/kg/day). Level of Concern = 1000.

Table 21 . Intermediate

- term Aggreg ate Exposure and Risk Estimates for 1,2,4

- Triazole.

Population Subgroup Exposure Estimate, mg/kg/day Aggregate MOE 2 Dietary Soil Ingestion 1 Aggregate
U.S. Population (total) 0.001191 N/A 0.001191 13000 All infants (< 1 year) 0.001879 0.000019 0.00189 8 7900

Children 1

- 2 yrs 0.002944 0.000019 0.002963 5100

Children 3

- 5 yrs 0.002472 0.000019 0.002491 6000

Children 6

- 12 yrs 0.001609 N/A 0.001609 9300

Youth 13

- 19 yrs 0.001028 N/A 0.001028 15000

Adults 20

- 49 yrs 0.001004 N/A 0.001004 15000

Adults 50+ yrs 0.000925 N/A 0.000925 16000

Females 13

- 49 yrs 0.000993 N/A 0.000993 15000

1 Soil ingestion estimates are from J. Arthur, DP 322240, 12/9/05

2 Aggregate MOE = NOAEL (15 mg/kg/day) ÷ Aggregate Exposure Estimate (mg/kg/day). Level of Concern = 3000.

### Page 39 of 53

8 .0 Cumulative Risk Characterization/Assessment

Metc onazole is a member of the triazole

- containing class of pesticides. Although conazoles act similarly in plants (fungi) by inhibiting ergosterol b iosynthesis, 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 chemical s 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 ; s ome are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid

tumo rs 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/cumulat ive

.

Met conazole 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 toleranc es for triazole

- derivat ive pesticides, including met conazole, 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 triazol e

- 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 exposure s (i.e., high end estimates of both dietary and non

- dietary exposures). In addition, the Agency retained the additional 10X FQPA safety factor for the protection of infants and children. The assessment includes evaluations of risks for various subgroups, including those comprised of infants and children. The Agency’s complete risk assessment is found in the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPA

HQ

- OPP

- 2005

- 0497.

9 .0 Occupational Exposure /Risk Pathway

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 IR

- 4 Foliar Uses on Bushberries (Crop Subgroup 3

- 07B) and Tuberous and Corm Vegetables (Crop Subgroup 1C). DP380989, N. Tsaur, 2/3/11.



### Occupational handler exposure to metconazole is expected for individua ls involved in foliar applications to bushberries and tuberous and corm vegetables (mixing, loading, and applying)

.

Agricultural workers performing typical post

- application activities such as scouting, irrigation, transplanting/harvesting , etc. may rece ive exposure to metconazole residues.

### Page 40 of 53

9 .1 Short

- and Intermediate

- Term Handler Risk

Metconazole 50 WDG Fungicide can be applied to bushberries and tuberous and corm vegetables for foliar disease con trol via groundboom, aircraft, chemigation, low pressure handwand, handgun, or backpack equipment. 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 prop osed 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 h andlers is based on the following exposure scenarios:

Mixer/Loaders

1. Mixing/loading WDG (dry flowables) to support groundboom applications

, 2. Mixing/loading WDG (dry flowables) to support aerial and chemigation applications

,

Flaggers

3. Flagging to support a erial application,

Applicators

4. Applying sprays with groundboom equipment

, 5. Applying sprays with aerial equipment

,

Mixer/Loader/Applicators

6. Mixing/loading/applying sprays with low pressure handwand equipment,

7. Mixing/loading/applying sprays with handgun equ ipment on a mobile vehicle , and

8. Mixing/loading/applying sprays with backpack equipment.

Unit Exposures

Chemical

- specific data for assessing exposure during pesticide handling activities (mixing/loading, applying, and mixing/loading/applying ) were not sub mitted to the Agency in support of this petition

. It is HED policy to use data from PHED Version 1.1 to assess handler exposures for regulatory actions when chemical

- specific data are not available (HED ExpoSAC Policy No. 7

, January 1999) or from ORETF. ORETF data were designed to replace the present PHED data with higher

- confidence, higher quality data that contain more replicates than the

PHED data for those scenarios. In this assessment, ORETF data was used to assess mixing/loading/applying with handg un equipment (data from MRID 44972201 ).

Summaries of the short

- and intermediate

- term risks for occupational handlers are included in

Table 22

. The maximum application rate for each exposure scenario is presented as the worst

case s cenario. All handler scenarios (mixer/loader, applicator, and mixer/loader/applicator)

resulted in short

- and intermediate

- term MOEs greater than the level of concern (MOEs ranged from 19,000 to 340,000 for short

- term exposure and 13,000 to 240,000 for in termediate

- term

exposure ) at some level of risk mitigation and therefore do not exceed HED’s level of concern.

### Page 41 of 53

Table 22 . Metconazole Short

- and Intermediate

- Term Agricultural Occupational Inhalation Exposures and Risks.

Crop Group Exposure Scenario Ap plication

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

3

- 07B Mixing/Loading Dry Flowables

for Groundbo om Applications 0.078125 80 0.77 0.0000688 130,000 93,000

3

- 07B Mixing/Loading Dry Flowables

for Aerial and Chemigation Applications 0.078125 350 0.77 0.0003008 30,000 21,000

1C Mixing/Loading Dry Flowables

for Groundboom Applications 0.125 80 0.77 0.000 1100 83,000 58,000

1C Mixing/Loading Dry Flowables

for Aerial and Chemigation Applications 0.125 350 0.77 0.0004813 19,000 13,000

Flagger

3

- 07B Flagging for Aerial Application 0.078125 350 0.35 0.0001367 67,000 47,000

1C Flagging for Aerial Application 0.125 350 0.35 0.0002188 42,000 29,000 Applicator

3

- 07B Applying Sprays via Groundboom Equipment 0.078125 80 0.74 0.0000661 140,000 97,000

3

- 07B Applying Sprays via Aerial Equipment 0.078125 350 0.068 0.0000266 340,000 240,000

1C Applying Sprays via G roundboom Equipment 0.125 80 0.74 0.0001057 86,000 61,000

1C Applying Sprays via Aerial Equipment 0.125 350 0.068 0.0000425 210,000 150,000 Mixer/Loader/Applicator

3

- 07B Mixing/Loading/Applying Liquid Concentrates

with Low Pressure Handwand (PHED) 0.078 125 5 30 0.0001674 54,000 38,000

3

- 07B Mixing/Loading/Applying Liquid Concentrates with a Backpack (PHED) 0.078125 5 30 0.0001674 54,000 38,000

3

- 07B Mixing/Loading/Applying Liquid Concentrates

with a Handgun Sprayer (LCO ORETF data) 0.078125 25 1.8 0.00 00502 180,000 130,000

1C Mixing/Loading/Applying Liquid Concentrates

with Low Pressure Handwand (PHED) 0.125 5 30 0.0002679 34,000 24,000

1C Mixing/Loading/Applying Liquid Concentrates

with a Backpack (PHED) 0.125 5 30 0.0002679 34,000 24,000

1C Mixing/ Loading/Applying Liquid Concentrates

with a Handgun Sprayer (LCO ORETF data) 0.125 25 1.8 0.0000804 110,000 80,000

a Application Rates based on proposed uses for metconazole.

b Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoS AC) Policy No. 9.1 for all scenarios except Mixing/Loading/Applying with a Handgun. For this scenario, number of acres treated was based on professional judgment of ExpoSAC.

c Unit Exposures based on PHED Version 1.1 or ORETF data. Baseline = no respira tor.
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 Inhalation MOE = NOAEL (mg/kg/da y) / Inhalation Dose (mg/kg/day). Level of concern = 100. ST NOAEL = 9.1 mg/kg/day. IT NOAEL = 6.4 mg/kg/day.

### Page 42 of 53

9 .2 Short

- and Intermediate

- Term Postapplication Risk

Agricultural workers perfo rming typical post

- application activities such as scouting, irrigation, transplanting/harvesting , etc. may receive exposure to metconazole residues. However, since there is no dermal endpoint identified up to the limit dose , a dermal post

- application asse ssment
is not needed.

Occupational postapplication exposure can also occur via the inhalation route. Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment was not performed for metconazole at this time. However, there are multiple potential sources of postapplication inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization of pesticides and resuspensi on 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 2 009. 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 as well as available postapplication inhalation exposure data ge nerated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational postapplication 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 postapplication inhalation exposure assessment for metconazole

.

Restricted Entry Interval

RE I s are typically based on the acute toxicity of technical chemical material . Under WPS , a ctive ingredients classified as acute T oxici ty Category III or IV for Acute Dermal and Primary Skin

Irritation are assigned a 12

- hour REI. Thus, t he 12

- hour REI on the label is acceptable.

### Page 43 of 53

Appendix A: Toxicolo gy Assessment

A.1 Toxicology Data Requirements

Table A.1. Metconazole Toxicology Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral To xicity

................................ ....................... 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 Developmenta l 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

n o

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 44 of 53

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 LD 50 = >566 mg/kg III

870.1100 Acute oral [rat] 44721512 LD 50 = >566 mg/kg III

870.1100 Acute oral [rat] 44721513 LD 50 = >1459 mg/kg III

870.1100 Acute oral [rat] 44721514 LD 50 = >5000 mg/kg IV

870.1200 Acute dermal [rat] 44721512 Dermal LD 50 > 2000 III

870.1200 Acute dermal [rabbit] 44721512 Dermal LD 50 > 2000 III

870.1200 Acute inhalation [ ra t] 44721512 LD 50 = >5 .6 mg/ L IV

870.2400 Acute eye irritation [rat] 44721513 moderate irritant III

870.2500 Acute dermal irritation [rabbit] 44721513 mild i rritant IV

870.2600 Skin sensitization [guinea pig] 44721513 neg.

-

Table A.3 Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical 1

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 o f 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.

### Page 45 of 53

Table A.3 Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical 1

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral toxicity

rodents (mouse) 44721519 (1991)

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

- 13) ppm M: 0, 9.58, 50.5, 341.1 mg/kg/day F: 0, 6.94, 60.7, 438.5 mg/kg/day Acceptable/guideline NOAEL (M/F) = 9.58/6.94 mg/kg/day LOAEL (M/F) = 50.5/60.7 mg/kg/day based

on increase in absolute and relative liver weights, hepatocellular hypertrophy and vacuolation, and increase in relative spleen weight (F), elevated AST and ALT activity.

870.3150 28

- Day oral toxicity

non

- rodents (dog) 44721520 (1991)

M/F: 0, 100, 1000, and

7000

- 10000 ppm in diet Unacceptable/non

- guideline (some preliminary test data provided) NOAEL (M/F) = 100 ppm in diet LOAEL (M/F) = 1000 ppm in diet (increase in relative and absolute thyroid wt. in one/two females) Deficiencies: low n (2M/2F per dose); decrease in food consumption means low exposure to test compound; actual dose received per dose group not provided.

870.3150 90

- Day oral

toxicity non

- rodents (dog) 44721521 (1991)

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

in diet M: 0, 2.5, 24.4, 225.2 mg/kg/day F: 0, 2.6, 24.3, 206.6 mg/kg/day Acceptable/guideline NOAEL (M/F) = 2.5/2.6 mg/kg/day LOAEL (M/F) = 24.4/24.3 mg/kg/day based on decreased food consumption and body weight gain in females and elevated platelets and reticulocytes in males.

870.3200 21

- d ay 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 46 of 53

Table A.3 Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical 1

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/d ay 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 reso rptions, 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 Materna l 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).

Developmenta l 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 Materna l 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).

Developmenta l 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 l itters, 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 Expe riment #1.

### Page 47 of 53

Table A.3 Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical 1

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 cong estion in F1 parental females.

Reprod uctive 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 ba sed 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 vacuo lation (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).

870.4200 a Carcinogenicity

-

rat 44721611 (1 992)

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 48 of 53

Table A.3 Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical 1

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.42 00 b Carcinogenicity

mouse 44721612 (1992)

0, 30, 300, 1000 ppm M: 0, 4 .5, 39.5, 166.9 mg/kg/day F: 0, 5.9, 58.1, 195.5 mg/kg/day Acceptable/Guideline Non

- neoplastic findings at (M/F) 166.9/58.1 mg/kg/day: increase in vacuolation, hypertrophy, splenic atrophy and adrenal corticomedullary pigmentation, sinusoidal hypercellula rity/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

Reve rse 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. t yphimurium

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 I

n 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.

870.555 0 I

n 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 49 of 53

Table A.3 Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical 1

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: (cyclopentyl

14 C ) Acceptable/Guideline Approximately 94% of radioactivity in excreta after five days: feces (males

- 81.3%, females

- 65.5%) an d urine (males

- 13.6%, females

- 28.4%)

870.7485 Metabolism and

pharmacokinetics: rat 44721623 (1991) single low dose: 2 mg/kg

Radiolabel: (cyclopentyl

14 C) 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

- 14 C ) 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

- 14 C) 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

pharma cokinetics: 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 hour s 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

Ac ceptable/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.

I mmunotoxicity NOAEL: 52 mg/kg/day. LOAEL: > 52 mg/kg/day

Effects on rat/mice liver enzymes

WL136184*

*cis on ly 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

- hydroxy lase in both rats and mice. No effect on ethoxyresorufin O

- deethylase, palmitoyl

CoA oxidation, or peroxisome proliferation (in terms of peroxisome number or morphology).

### Page 50 of 53

Table A.3 Subchronic, Chronic and Other Toxicity Profile for Metconazole Technical 1

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 vacu olation (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 m ixture unless otherwise noted.

### Page 51 of 53

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 pestici de or other chemical. These studies (which compose PHED, listed below) 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 Expo sure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.



### Appendix C : Structure, Nomenclature, and Physical and Chemical Properties

Table C.1. Metconazole Nomenclature

. Chemical structure

cis

- isomer trans

- isomer

Common name Metconazole

Company experimental name KNF

- S

- 474m (Kureha); BAS 555 F (BASF); V

- 10116 (Valent)

IUPAC name (1 RS ,5 RS :1 RS ,5 SR )

- 5

- (4

- chlorobenzyl)

- 2,2

- dimethyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl ) cyclopentanol

CAS name 5

- [(4

- chlorophenyl)methyl]

- 2,2

- dimethyl

- 1

- (1 H

- 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) 50% WDG (Metconazole 50 WDG Fungicide, EPA File Symbol 59639

- 147 )

Table C.2. Physicochemical Properties of Metconazole

Parameter Value Reference s* (MRID)

Melting point/range 100.0

- 108.4 ° C (using Electrothermal Digital Melting Point Apparatus) ( AC900,768 technical grade) 44721505

pH 5.81 at 2 5oC (1% aqueous suspension ) 46808402

Relative d ensity (20°C) 1.14 (relative density to water at 4 ° C , using capillary

stoppered, density

- specific gravity bottle) (Lot No.

AC 8879

- 140B) 44721505

Water solubility ( 20oC) Using shake

- flask method:

18.7 ± 1.0 mg/L ( cis

- isomer , WL148271, KNF

- S

- 474m)

13.6 ± 1.7 mg/L ( trans

- isomer , WL148271, KNF

- S

474m) 44721505

### Page 52 of 53

Table C.2. Physicochemical Properties of Metconazole

Parameter Value Reference s* (MRID)

Solvent solubility ( g/L ) at

2 0oC 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 - 5 Pa or 9.23 x 10 - 8 mm Hg (metconazole)

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

- isomer)

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

- isomer) 44721505

Dissociation constant ( pK

a ) 11.38±0.03 and 1.06±0.03 (in water at 29.1°C using

spe ctrophotometric method; Lot No. AC 8879

- 140B) 44721505

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

ow (log K

ow ) = 7090±989 (3.85) (Lot No. AC 8879

- 140B) (TGAI)

K

ow (log K

ow ) = 7150±803 (3 .85) ( cis

- isomer , CL 354,801 )

K

ow (log K

ow ) = 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

tr ans

- 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 53 of 53

Appendix D : International Residue Limit Status



## Metconazole (PC Code 125619 ; 03/08 /11)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 3



### 40 CFR 180.6 17 : Plant s/Livestock : 

### Metconazole [5

- [(4

- chlorophenyl)methyl]

- 2,2

- dimethyl

- 1

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)cyclopentanol] as the sum of

its cis

- and trans

- isomers None None

Commodity 1 

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

US Canada Mexico 2 

### Codex Vegetable, tuberous and corm, subgroup 1C 0.04

Bushberry subgroup 13

- 07B 0.4

Completed: M. Negussie; 03/10/2011

1 Includes only commodities of interest for this action. Tolerance value s 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.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.