UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

DATE:  	December 15, 2014

SUBJECT:	Metconazole  -  Human Health Risk Assessment for a Section 3 Registration of New Uses on Dry Shelled Pea and Beans (Except Soybean) Crop Subgroup 6C and Sunflower Crop Subgroup 20B; Crop Group Expansion to Rapeseed Subgroup 20A; and Crop Group Conversions to Fruit, Stone, Group 12-12; and Nut, Tree, Group 14-12.

PC Code:  125619
DP Barcode:  D418671
Decision No.:  487580
Registration No.:  59639-147
Petition No.:  4E8244
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.:  125116-23-6
MRID No.:  NA
40 CFR:  180.617

FROM:	Barry O'Keefe, Senior Biologist
		Myron S. Ottley, Senior Biologist
		Nancy Dodd, Chemist
		Kristin Rury, Biologist
		Risk Assessment Branch III (RAB III)
		Health Effects Division (7509P)

THROUGH:	Christine Olinger, Branch Chief
		Risk Assessment Branch III (RAB III)
		Health Effects Division (7509P)

TO:		Laura Nollen, Risk Manager
		Barbara Madden, Branch Chief
		Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)
		Registration Division (7505P)

			And

		Hope Johnson, PM21
		Fungicide Branch
		Registration Division (7505P)

This document and attachments provide an assessment of the human health risk resulting from the proposed and registered uses of metconazole.  The toxicology reevaluation was performed by Myron Ottley, the drinking water assessment was conducted by Faruque Khan (EPA Environmental Fate and Effects Division (EFED)), the review of the residue chemistry data and dietary exposure assessment were conducted by Nancy Dodd, the occupational and residential exposure assessment was conducted by Kristin Rury, and the human health risk assessment was conducted by Barry O'Keefe.
                               Table of Contents

1.0	Executive Summary	5
2.0	HED Recommendations	8
2.1	Data Deficiencies	8
2.2.1	Enforcement Analytical Method	8
2.2.2	Recommended Tolerances	9
2.2.3	Revisions to Petitioned-For Tolerances	9
2.2.4	International Harmonization	9
2.2.5	Label Modifications	10
3.0	Introduction	10
3.1	Chemical Identity	10
3.2	Physical/Chemical Characteristics	11
3.3	Pesticide Use Pattern	11
3.4	Anticipated Exposure Pathways	17
3.5	Consideration of Environmental Justice	17
4.0	Hazard Characterization and Dose-Response Assessment	17
4.1	Summary of Toxicological Effects	18
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)	20
4.2.1	Completeness of the Toxicology Database	20
4.2.2	Evidence of Neurotoxicity	20
4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	20
4.2.4	Residual Uncertainty in the Exposure Database	20
4.3	Toxicity Endpoint and Point of Departure Selections	21
4.3.1	Dose-Response Assessment	21
4.3.2	Recommendation for Combining Routes of Exposure for Risk Assessment	22
4.3.3	Cancer Classification and Risk Assessment Recommendation	23
4.3.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	23
5.0	Dietary Exposure and Risk Assessment	25
5.1	Residues of Concern Summary and Rationale	25
5.2	Food Residue Profile	26
5.3	Water Residue Profile	27
5.4	Dietary Risk Assessment	28
5.4.1	Description of Residue Data Used in Dietary Assessment	28
5.4.2	Percent Crop Treated Used in Dietary Assessment	29
5.4.3	Acute Dietary Risk Assessment	29
5.4.4	Chronic Dietary Risk Assessments	29
5.4.5	Summary Table	29
5.4.6	Dietary Assessment of Free Triazole and its Conjugates	30
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	30
6.1	Residential Handler Exposure	30
6.2	Post-Application Exposure	30
6.3	Residential Risk Estimates for Use in Aggregate Assessment	32
6.4	Residential Bystander Post-application Inhalation Exposure	32
6.5	Spray Drift	33
7.0	Aggregate Exposure/Risk Characterization	33
7.1	Acute Aggregate Risk	33
7.2	Short-Term Aggregate Risk	33
7.3	Chronic Aggregate Risk	34
8.0	Cumulative Exposure/Risk Characterization	34
9.0	Occupational Exposure/Risk Characterization	35
9.1	Short-/Intermediate-Term Handler Risk	35
9.2	Short-and Intermediate-Term Post-Application Risk	36
9.2.1	Dermal Post-Application Risk	36
9.2.2	Inhalation Post-Application Risk	37
10.0	References	38
Appendix A.  Toxicology Profile and Executive Summaries	39
A.1	Toxicology Data Requirements	39
A.2	Toxicity Profiles	40
Appendix B.  Physicochemical Properties of Metconazole.	47
Appendix C.  Review of Human Research	48
Appendix D.  Residential Handler and Post-application Exposure and Risk Estimates	49
Appendix E.  Occupational Handler Exposure and Risk Estimates	51
Appendix F.  Summaries of Field Residue Data	55
Appendix G.  International Residue Limits Status Sheet	58

1.0	Executive Summary

Introduction
Metconazole 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.  Metconazole is currently registered on numerous agricultural crops and on turf and ornamentals in residential settings.

Use Profile
The Interregional Research Project No. 4 (IR-4) has proposed for use of metconazole at a maximum single application rate of 0.125 lb ai/A for dry shelled pea and bean (except soybean) crop subgroup 6C and sunflower crop subgroup 20B.  IR-4 is also proposing for the expansion of rapeseed crop subgroup 20A, and the conversion of stone fruit crop group 12-12, the maximum single registered application rate is 0.125 lb ai/A.  For the crop group conversions of tree nut crop group 14-12, the maximum single application rate is 0.11 lb ai/A.  The maximum proposed/registered yearly application rates range from 0.125 lb ai/A to 0.50 lb ai/A.  Applicators and other handlers must wear long-sleeved shirts, long pants, chemical resistant gloves, socks, and shoes.  Metconazole may be applied using ground, aerial, airblast, chemigation, and handheld equipment.  The proposed restricted entry interval (REI) is 12 hours.

Exposure Profile
Exposure pathways include dietary (food and drinking water), residential, and occupational exposure sources.  Dietary exposures are expected for acute and chronic durations.  Existing residential uses result in short-term handler exposures for adults, and short-term post-application exposures for adults and children.  Occupational handler and post-application exposures are expected for short- and intermediate-term durations.

Hazard Assessment
The liver is the primary target organ (with observed effects such as increased liver weight and enzyme activity, increased incidence of hypertrophy and vacuolization) in the mouse, rat, and dog following oral exposure to metconazole during subchronic or chronic exposure durations.  Other adverse effects observed in oral studies were decreased body weight, 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).  Metconazole is considered nongenotoxic and is classified as "not likely to be carcinogenic to humans" based on an absence of tumors in rats and mice.

Developmental studies in rabbits show evidence of developmental effects, but only at dose levels that are maternally toxic.  There is quantitative evidence of susceptibility in the rat developmental study; however, the concern is low since the developmental effects are well-characterized, the no observable adverse effect levels (NOAELs) are well defined, and that dose/endpoint is used for acute dietary risk assessment for the sensitive population.  Metconazole did not demonstrate the potential for neurotoxicity in any of the four species (mouse, rat, dog and rabbit) in the database.  For these reasons, the Food Quality Protection Act (FQPA) Safety Factor has been reduced to 1X.  In accordance with the revised 40 CFR Part 158 data requirements, a subchronic inhalation study is required for this risk assessment but was not included in the existing database; therefore, a 10X database uncertainty factor has been applied to inhalation exposure scenarios (HASPOC, TXR0057053, J. Leshin, 10/09/2014).

Dietary Exposure
The residue chemistry and environmental fate data are adequate to assess human dietary exposure.  The assessments are based on reliable data and will not underestimate exposure or risk.  Estimated drinking water concentrations (EDWCs) were incorporated directly into the dietary exposure assessments.

Since no observed effects could be attributed to a single dose for the general population, including infants and children, an acute endpoint was not established.  Therefore, an acute dietary exposure assessment was not conducted for these population groups.  However, an unrefined acute dietary (food and drinking water) analysis was conducted for females 13 to 49 years old.  Results of the analysis are below HED's level of concern (LOC).  The acute dietary exposure for food and drinking water for females 13 to 49 years old is 4.6% of the acute Population Adjusted Dose (aPAD).

The results of the unrefined chronic dietary (food and drinking water) analysis are below HED's LOC for all population subgroups.  The dietary exposure for food and drinking water for the general U.S. population is 6.6% of the chronic Population Adjusted Dose (cPAD) and 14% of the cPAD for children 1 to <2 years old, the population subgroup with the highest estimated chronic dietary exposure to metconazole.

Residential Exposure
No new residential uses were requested in this action.  However, metconazole is currently registered for use on residential turf and ornamentals.  Residential exposures from existing residential uses were reassessed using the updated 2012 HED Residential Standard Operating Procedures (SOPs).  Residential exposure is expected to be short-term only.  Because dermal toxicity endpoints for the appropriate duration of exposure (short-term) were not identified up to the limit dose, only adult residential handler inhalation exposures, and residential post-application incidental oral exposures for children have been assessed.

All residential handler inhalation exposure risk estimates were not of concern to HED (i.e., all margins of exposure (MOEs) >1,000), with MOE values ranging from 6,300 to 23,000,000.  All residential post-application incidental oral exposure risk estimates were also not of concern to HED (i.e., all MOEs >100), with MOEs ranging from 1,000 to 450,000.

Aggregate Exposure
There is potential for short-term and chronic aggregate exposure to metconazole.  The short-term aggregate exposure results from dietary (which is considered background exposure) and residential (which is considered primary) exposure pathways.  The chronic aggregate exposure is the same as chronic dietary exposure from food and drinking water, which are all below the HED's level of concern.  The short-term aggregate MOE of 630 for children 1 to <2 years old is not of concern to HED.  For adults, oral dietary and inhalation risk estimates were combined using the total aggregated risk index (ARI) methodology since the LOCs for oral dietary exposure (100) and inhalation exposure (1,000) are different.  The LOC ARI is 1; therefore, ARIs of less than 1 are risk estimates of concern.  The short-term aggregate ARI of 5.3 is not of concern to HED.

Occupational Exposure
Although occupational dermal exposure is expected during treatment of agricultural crops, dermal hazard was not identified for metconazole.  Therefore, a quantitative handler dermal risk assessment was not conducted.  For the proposed use pattern of metconazole, all short- and intermediate-term occupational handler inhalation MOEs are not of concern at baseline personal protective equipment (PPE) except for mixing/loading water dispersible granules (WDG) for aerial application to canola (crop subgroup 20A), sunflower (crop subgroup 20B), and dry beans and peas (crop subgroup 6C) (short-term MOE = 540; intermediate-term MOE =1,900; LOC = 1,000).  With the addition of a PF5 respirator, mixing/loading WDG for aerial application to these crops is not of concern (MOE = 2,700).

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for metconazole at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for metconazole.  Although occupational dermal exposure is expected following treatment of agricultural crops, dermal hazard was not identified for metconazole.  Therefore, a quantitative post-application dermal risk assessment was not conducted.

The 12 hour restricted entry interval (REI) listed on the label is adequate for worker protection.

Review of Human Research
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database, Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF), and the Residential SOPs (lawns and turf) are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

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

2.0	HED Recommendations

HED has examined the toxicology, residue chemistry, and exposure databases for metconazole.  Pending submission of a revised Section B and a revised label as described in section 2.2.5, there are no toxicology or residue chemistry issues that would preclude granting the requested registration and establishing the recommended tolerances for metconazole on the pea and bean, dried shelled, except soybean, subgroup 6C and the sunflower subgroup 20B; expansion of the canola tolerance to the rapeseed subgroup 20A; and conversion of the established tolerances and registrations for the stone fruit crop group 12 and tree nut crop group 14 to the stone fruit crop group 12-12 and the tree nut crop group 14-12.  Additional data are needed, as outlined below in Section 2.1.  The specific tolerance recommendations are discussed in Section 2.2.

2.1	Data Deficiencies

870.3465 Subchronic Inhalation Study

   * A subchronic inhalation study is required because the use of an oral point of departure (POD) for inhalation exposure results in MOEs as low as 380 for occupational exposure, which does not meet the target of 1000 for a waiver (TXR0057053, J. Leshin, 10/09/2014).  Therefore, a 10X database uncertainty factor has been added for inhalation exposures in the absence of the required inhalation toxicity study.

Data that may be required for future uses

If additional uses increase the dairy cattle dietary burden, additional ruminant feeding studies conducted at higher rates may be needed.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An adequate gas chromatography method with nitrogen-phosphorus-detection (GC/NPD) method, Valent Method RM-41C-1-1, is available for enforcement of tolerances for residues of metconazole (cis- and trans- isomers) in plant commodities.  A confirmatory liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, Method RM-41C-4, is available.  For both methods, the reported limit of quantitation (LOQ) is 0.02 ppm for each isomer in each matrix.  The method has been validated by the ACB/BEAD and was found adequate for enforcing tolerances for residues of metconazole in plant commodities.  No radiovalidation data were submitted for method RM-41C-1-1; however, HED has concluded that because the extraction solvent used for the proposed enforcement method is similar to the aqueous organic solvent mixtures used in the plant metabolism studies, radiovalidation of the method is not required.

An adequate GC/NPD method is available for enforcement of tolerances for residues of metconazole (cis- and trans-isomers) in livestock commodities.  The enforcement method is a modified version of the German multiresidue method DFG S19.  The LOQ is 0.01 ppm for each isomer in each matrix, for an LOQ of 0.02 ppm for total metconazole residues.  An acceptable confirmatory procedure (gas chromatography/mass spectrometry (GC/MS)) is included for the method.  The method has been validated by ACB/BEAD and was found adequate for enforcing tolerances for residues of metconazole (cis- and trans-isomers) in/on livestock commodities.  No radiovalidation data were submitted; however, because DFG S19 is an established multiresidue method, these data are not required.

2.2.2	Recommended Tolerances

The petitioner's proposed residue definition (tolerance expression) is adequate and is consistent with the S. Knizner memo dated 5/27/09.  A summary of the proposed and recommended tolerances may be found in Table 2.2.2 below.

Table 2.2.2.  Tolerance Summary for Metconazole.
                                   Commodity
                     Established/Proposed Tolerance (ppm)
                        HED RecommendedTolerance (ppm)
                                   Comments
                        (correct commodity definition)
 Pea and bean, dried shelled, except soybean, subgroup 6C
                                     0.15
                                     0.15
The 0.15 ppm level harmonizes with the Canadian MRL.
 Sunflower subgroup 20B
                                      0.9
                                      0.7

 Rapeseed subgroup 20A
                                     0.04
                                     0.08
The 0.08 ppm level harmonizes with the Canadian MRL.
 Fruit, stone, group 12-12
                                      0.2
                                      0.2

 Nut, tree, group 14-12
                                     0.04
                                     0.04

 Canola seed
                                     0.04
                                     None
Remove upon establishment of rapeseed subgroup 20A tolerance.
 Fruit, stone, group 12
                                     0.20
                                     None
Remove upon establishment of fruit, stone, group 12-12 tolerance.
 Nut, tree, group 14
                                     0.04
                                     None
Remove upon establishment of nut, tree, group 14-12 tolerance
 Pistachio
                                     0.04
                                     None
Remove upon establishment of nut, tree, group 14-12 tolerance

2.2.3	Revisions to Petitioned-For Tolerances

The proposed tolerance on the sunflower subgroup 20B is 0.9 ppm; HED is recommending a decrease to 0.7 ppm based on the Office of Economic Cooperation and Development (OECD) tolerance calculation procedures.

The proposed tolerance for the rapeseed subgroup 20A is 0.04 ppm.  HED is recommending an increase to 0.08 ppm to harmonize with the Canadian MRL.  Based on calculations using the OECD calculator for canola, a tolerance of 0.04 ppm would have been recommended.

2.2.4	International Harmonization

There are no Codex maximum residue limits (MRLs) established for metconazole.

Residue definitions are harmonized with Canada.  Tolerances in the US are established for residues of metconazole, including its metabolites and degradates.  In both the US and Canada, compliance with the tolerance/MRL levels is determined by measuring only metconazole.  The recommended tolerance levels are harmonized with Canada.  Refer to the International Residue Limits (IRL) table in Appendix G.

2.2.5	Label Modifications

860.1200 Directions for Use

The Section B/label (EPA Reg. No. 59639-147) must be revised to include the following statement for the dried shelled pea and bean, except soybean, subgroup 6C:  "Do not apply to cowpea or field pea used for livestock feed."

The Section B/label should be revised to include the interval between applications for pecan and pistachio.

HED recommends that a PF5 respirator be required when mixing/loading WDG metconazole (EPA Reg. No. 59636-147) for use on canola (crop subgroup 20A), sunflower (crop subgroup 20B), and dry beans and peas (crop subgroup 6C).

3.0	Introduction

Metconazole 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.

Metconazole is currently registered on numerous agricultural crops and on turf and ornamentals in residential settings.

With the current action, the Interregional Research Project No. 4 (IR-4), on behalf of the IR-4 Project and the Agricultural Experiment Stations of Montana, South Dakota, North Dakota, and Colorado (dry bean), Montana, South Dakota, Idaho, and North Dakota (dry pea), and Kansas, Montana, South Dakota and North Dakota (sunflower), requested the establishment of permanent tolerances and registration for use on the pea and bean, dried shelled, except soybean, subgroup 6C, and the sunflower subgroup 20B; expansion of the canola tolerance to the rapeseed subgroup 20A; and conversion of the established stone fruit crop group 12 and tree nut crop group 14 to the stone fruit crop group 12-12 and the tree nut crop group 14-12.

3.1	Chemical Identity

The chemical structure and nomenclature of metconazole are presented in Table 3.1.

Table 3.1.  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
(1RS,5RS;1RS,5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol
CAS name
5-[(4-chlorophenyl)methyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol
CAS #
125116-23-6 (cis- and trans-isomers)
115850-27-6 (cis-isomer)
115850-28-7 (trans-isomer)
End-use product/EP
Metconazole 50 WDG Fungicide (EPA Reg. No. 59639-147), a water-dispersible granule formulation containing 50% active ingredient.
Quash 50 WDG (EPA Reg. No. 59639-147), also known as V-10116 50 WDG

3.2	Physical/Chemical Characteristics

If released to air, a vapor pressure of 1.23x10[-][5] Pa or 9.23 x 10[-][8] mm Hg indicates metconazole will exist solely in the particulate phase in the atmosphere.  Particulate-phase metconazole will be removed from the atmosphere by wet or dry deposition.  Metconazole will not volatilize from dry soil surfaces based upon its vapor pressure.  The physiochemical properties of metconazole are summarized in Appendix B.

3.3	Pesticide Use Pattern

Metconazole 50 WDG Fungicide (EPA Reg. No. 59639-147) is a water-dispersible granule formulation containing 50% active ingredient (ai).  Applications are to be made as broadcast foliar sprays in sufficient water for thorough coverage using ground equipment (including chemigation) or aerial equipment.  Depending on the crop and the targeted fungal disease, single application rates range from 0.0625-0.125 lb ai/A.  Depending on the crop, a maximum of one to four applications can be made with minimum retreatment intervals (RTIs) ranging from 7 to 14 days except for pecan (interval not specified) and pistachio (2-3 week interval); the yearly application rates range from 0.125 to 0.500 lb ai/A.  Preharvest intervals (PHIs) range from 14-35 days.  Immediate plant-back is allowed for barley, corn, cotton, oat, peanut, rye, soybean, sugar beet, triticale, wheat, and those crops listed on the label.  A 30-day plant-back interval (PBI) is required for Brassica leafy vegetables and leafy vegetables.  A 120-day PBI applies to other crops.

The proposed uses of metconazole are summarized in Table 3.3.

Table 3.3.  Summary of Proposed Directions for Use of Metconazole.
Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate
                                   (lb ai/A)
                           Max. No. Applic. per Year
                           Max. Yearly Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                       Use Directions and Limitations[1]
            Dried Shelled Pea and Bean, Except Soybean, Subgroup 6C
[Dried cultivars of bean (Lupinus); bean (Phaseolus) (includes field bean, kidney bean, lima bean (dry), navy bean, pinto bean, tepary bean); bean (Vigna) (includes adzuki bean, blackeyed pea, catjang, cowpea, crowder pea, moth bean, mung bean, rice bean, southern pea, urd bean); broad bean (dry); chickpea; guar; lablab bean; lentil; pea (Pisum) (includes field pea); pigeon pea]
Postemergence; Broadcast foliar sprays;
Ground or aerial equipment; Chemigation
                                    50% WDG
                                  [59639-147]
                                 0.08 - 0.125
                                       2
                                     0.25
                                      21
Apply when conditions favor disease development and prior to infection.
A second application may be made at a 7- to 10-day interval.
Apply in sufficient water to obtain thorough coverage of the plant.
Apply with ground equipment in a minimum of 20 gallons per acre (GPA) or by air in a minimum of 5 GPA.
Two applications may be made sequentially.  Use a non-group 3 fungicide in alternation with Metconazole 50 WDG Fungicide.
                             Rapeseed Subgroup 20A
(Borage; crambe; cuphea; exchium; flax seed; gold of pleasure; hare's ear mustard; lesquerella; lunaria; meadowfoam; milkweed; mustard seed; oil radish; poppy seed; rapeseed (canola varieties only); sesame; sweet rocket; cultivars, varieties and/or hybrids of these)
Broadcast foliar spray during flowering; ground or aerial equipment.
                                    50% WDG
                                  [59639-147]
                                 0.0625-0.125
                                       1

                                     0.125
                                      35
Make application between 20% and 50% bloom.  Apply in sufficient water to obtain thorough coverage of the plant.  Apply with ground equipment in 10-20 GPA or by air in a minimum of 5 GPA.
                         Stone Fruit, Crop Group 12-12
(Black cherry; capulin; Chinese Jujube; Nanking cherry; sweet cherry; tart cherry; cultivars, varieties and/or hybrids of these)
Broadcast foliar spray;
ground  or
aerial equipment

                                    50% WDG
                                  [59639-147]
                                  0.078-0.125
                                       3

                                     0.375
                                      14
Timing:
For brown rot/blossom blight, green fruit rot/jacket rot, or cherry leaf spot, begin applications at green tip.  If conditions are favorable for disease development, make additional applications at full bloom and at petal fall.

For fruit brown rot, make applications 14 to 21 days prior to harvest.

For powdery mildew, follow the brown rot/blossom blight schedule; make additional applications on a 10-14 day interval until terminal growth ceases; application can be made after harvest.

Apply as a foliar spray in sufficient water to obtain thorough coverage of blossoms, foliage, and or fruit.

Apply with ground equipment in 100-400 GPA or by air in a minimum of 20 GPA.

Do not make more than 2 applications after petal fall.
                         Stone Fruit, Crop Group 12-12
               (Apricot; Japanese apricot; nectarine and peach)
Broadcast foliar sprays;
ground  or
aerial equipment

                                    50% WDG
                                  [59639-147]
                                  0.078-0.125
                                       3

                                     0.375
                                      14
Timing:
For brown rot/blossom blight, green fruit rot/jacket rot, scab, or shot hole, begin applications at early pink bud stage before infection occurs.  If conditions are favorable for disease development, make additional applications at full bloom and at petal fall.

For fruit brown rot, make applications 14-21 days prior to harvest.

For powdery mildew, follow the brown rot/blossom blight schedule; make additional applications on a 10-14 day interval until terminal growth ceases.  Begin applications prior to disease development and continue at a 7-10 day interval.

For rust, begin application when bud tissue is susceptible to disease development (i.e., pink, white, or red bud).  If conditions are favorable for disease development, make a second application at full bloom or at petal fall.

Apply as a foliar spray in sufficient water to obtain thorough coverage of blossoms, foliage, and or fruit.

Apply with ground equipment in 100-400 GPA or by air in a minimum of 20 GPA.

Do not make more than 2 applications after petal fall.
                         Stone Fruit, Crop Group 12-12
(American plum; beach plum; Canada plum; cherry plum; Chickasaw plum; Damson plum; Japanese plum; Klamath plum; plum; plumcot; prune plum; sloe)
Broadcast foliar spray;
ground  or
aerial equipment

                                    50% WDG
                                  [59639-147]
                                  0.078-0.125
                                       3

                                     0.375
                                      14
Timing:
For brown rot/blossom blight and rust, begin applications at green tip.  If conditions are favorable for disease development, make additional applications at full bloom and at petal fall.

For powdery mildew, follow the brown rot/blossom blight schedule; make additional applications on a 10-14 day interval until terminal growth ceases.

Apply as a foliar spray in sufficient water to obtain thorough coverage of blossoms, foliage, and or fruit.

Apply with ground equipment in 100-400 GPA or by air in a minimum of 20 GPA.

Do not make more than 2 applications after petal fall

Do not apply Metconazole 50 WDG Fungicide to "Stanley" type plums."
                            Sunflower Subgroup 20B
(Calendula; castor oil plant; Chinese tallowtree; euphorbia; evening primrose; jojoba; niger seed; rose hip; safflower; stokes aster; sunflower; tallowwood; tea oil plant; vernonia; cultivars, varieties, and/or hybrids of these)
Postemergence; Broadcast foliar spray;
Ground or aerial equipment
                                    50% WDG
                                  [59639-147]
                                 0.078 - 0.125
                                       2
                                     0.25
                                      21
Apply when conditions favor disease development and prior to infection.
A second application may be made on a 7- to 14-day interval.
Apply as a foliar spray in sufficient water to obtain thorough coverage of leaves.
Apply by ground in a minimum of 20 GPA or by air in a minimum of 5 GPA.
Two applications may be made sequentially.
Use a non-group 3 fungicide in alternation with Metconazole 50 WDG Fungicide.
       Tree Nuts, Crop Group 14-12, Except Filbert, Pecan, and Pistachio
(African nut-tree; almond; beechnut; black walnut; Brazil nut; Brazilian pine; bunya; bur oak; butternut; Cajou nut; candlenut; cashew; chestnut; chinquapin; coconut; coquito nut; dika nut; English walnut; ginkgo; Guiana chestnut; heartnut; hickory nut; Japanese horse-chestnut; macadamia nut; mongongo nut; monkey-pot; monkey  puzzle nut; Okari nut; Pachira nut; peach palm nut; pequi; Pili nut; pine nut; Sapucaia nut; tropical almond; yellowhorn; cultivars, varieties and/or hybrids of these)
Broadcast foliar spray;
Ground or aerial equipment
                                    50% WDG
                                  [59639-147]
                                  0.078-0.11

                                       4

                                     0.44

                                      25
Begin applications prior to disease development and continue at a 7 to 14 day interval throughout the year.

Apply as a foliar spray in sufficient water to obtain thorough coverage of blossoms, foliage and/or fruit.

Apply in 100-400 GPA with ground equipment or in a minimum of 20 GPA by air.

Do not make more than 2 applications after petal fall.
                              Filbert (Hazelnut)
Broadcast foliar spray;
Ground or aerial equipment
                                    50% WDG
                                  [59639-147]
                                     0.11

                                       4

                                     0.44

                                      25
Begin applications starting at bud swell to bud break and continue at 10 or 14-day intervals.

Apply as a foliar spray in sufficient water to obtain thorough coverage of all branches.

Apply in 100-400 GPA with ground equipment or in a minimum of 20 GPA by air.

Do not make more than 2 sequential applications before switching to a non-Group 3 fungicide for resistance management.
                                     Pecan
Broadcast foliar spray;
Ground or aerial equipment
                                    50% WDG
                                  [59639-147]
                                  0.078-0.11

                                       4

                                     0.44

                                      25
Begin applications when leaves reach one-half mature size.  Continue to make scab applications if scab model predicts need.

Apply as a foliar spray in sufficient water to obtain thorough coverage of blossoms, foliage and/or fruit.

Apply in 100-400 GPA with ground equipment or in a minimum of 20 GPA by air.

Do not make more than 2 sequential applications before switching to a non-Group 3 fungicide for resistance management.
                                   Pistachio
Broadcast foliar spray;
Ground or aerial equipment
                                    50% WDG
                                  [59639-147]
                                     0.125
                                       4

                                    0.500
                                      25
Apply prior to onset of disease development and continue on a 2 to 3 week interval.

Apply as a foliar spray in sufficient water to obtain thorough coverage of blossoms, foliage and/or fruit.

Apply in 100-400 GPA with ground equipment or in a minimum of 20 GPA by air.

Do not make more than 2 sequential applications before switching to a non-Group 3 fungicide for resistance management.
1 Rotational Crop Restrictions: Immediate plant-back is allowed for barley, corn, cotton, oat, peanut, rye, soybean, sugar beet, triticale, wheat, and those crops listed on the label.  A 30-day plant-back interval is required for Brassica Leafy Vegetables and Leafy Vegetables.  Do not plant any crop, except barley, corn, cotton, oat, peanut, rye, soybean, sugar beet, triticale, wheat, Brassica Leafy Vegetables, Leafy Vegetables and those crops listed on the label, earlier than 120 days after applying Metconazole 50 WDG Fungicide.

3.4	Anticipated Exposure Pathways

Humans may be exposed to metconazole in food and drinking water, since metconazole may be applied directly to growing crops and application may result in metconazole reaching surface and ground water drinking water sources.  There are existing residential uses of metconazole so there is exposure to residential handlers and those entering treated areas following application.  In occupational settings, applicators may be exposed while handling metconazole.  There is a potential for post-application exposure for workers re-entering treated fields and residents re-entering treated areas.

Risk assessments have been completed for proposed and existing uses of metconazole.  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of metconazole, but also considers existing uses of metconazole, particularly in the dietary and residential exposure assessments.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age and ethnic group.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

These sections are based on the hazard characterization derived from previous risk assessments:  D350369, B. O'Keefe, 10/20/08; D386421, B. O'Keefe, 09/30/2011.

4.1	Summary of Toxicological Effects

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

Overall, metconazole appears to affect the liver, kidney, spleen, and various blood parameters in all the species tested.  Dose levels at which these effects occur are similar across species.  Like other triazoles, a primary target organ in mammalian toxicity studies is the liver.   Liver toxicity was seen in the mouse, rat, and dog following oral exposure to metconazole via subchronic or chronic exposure durations.  While liver effects, including changes in liver weight and enzyme activity, have been reported consistently across multiple exposure durations and species, these effects were considered slight or minimal in some studies and appeared to be "adaptive" responses.  However, based on the weight of evidence from the consistency of these reported effects and evidence that these effects increase in severity with exposure duration, leading to liver tumors in the chronic mouse study, they were considered "adverse" and formed the basis of the study LOAELs.  Metconazole is considered non-genotoxic and the liver tumors appear to have been formed via a mitogenic mode of action and therefore, metconazole is classified as "not likely to be carcinogenic to humans" at levels that do not cause mitogenesis (see section 4.3.3).  The established chronic RfD would be protective of mitogenesis/carcinogenesis.

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

Developmental studies in rats and rabbits show evidence of developmental effects such as skeletal anomalies, fetal death (resorptions, post-implantation loss, decreased viability indices) and malformations including hydrocephaly.  There was no quantitative or qualitative susceptibility to the fetuses of rabbits following in utero exposure to metconazole.  In the two available prenatal developmental toxicity studies in rabbits, developmental effects (increased post-implantation loss and reduced fetal body weights) were observed at the same dose that caused maternal toxicity (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, increased incidence of fatty hepatocyte changes in male parental animals and increased incidence of spleen congestion in F1 parental females. In one developmental study in rats, no susceptibility was shown.  However, in a second ratdevelopmental toxicity study, skeletal variations (predominantly lumbar ribs) occurred at the LOAEL in the absence of maternal toxicity, and more severe effects such as increased incidence of post-implantation loss, hydrocephaly and visceral anomaliea (cranial hemorrhage, dilated renal pelvis, dilated ureters, and displaced testis were reported at the next higher dose, again in the absence of maternal toxicity. While quantitative susceptibility is demonstrated in this study, it was not duplicated in the other rat developmental study, the two rabbit developmental studies or the multi-generation reproduction study.  Furthermore, the endpoint and point of departure for risk assessment are based on the developmental effects seen in the fetus, for which there is a clear NOAEL.  Therefore, it is concluded that there is low concern and no residual uncertainty for pre- and/or post-natal toxicity.

Metconazole did not demonstrate neurotoxicity in the available subchronic neurotoxicity study.  Information available from the submitted studies including acute, subchronic and chronic studies in several species, developmental toxicity studies in the rat and rabbit and a two generation reproduction study in the rat do not indicate any neurotoxic signs.  No effects were noted on brain weights and no clinical signs possibly related to neurotoxicity were noted up to and including the high doses in all studies.  Therefore, the requirement for an acute neurotoxicity study has been waived (TXR0056405, K. Rury, 08/09/2012).

Toxicity via the inhalation route has not been evaluated because the data requirement for a route-specific subchronic inhalation study has not been met and remains outstanding (TXR0057053, J. Leshin, 10/09/2014).

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

The absorption, distribution, metabolism and excretion of metconazole were investigated in rats following single oral doses of cis and or cis/trans metconazole radiolabeled at the cyclopentyl or triazole ring (cis only).  Metconazole was significantly absorbed, with the time to maximum plasma concentrations for male and female rats treated with either the low- or high-dose occurring with 4hr. The plasma half-life of low- and high-dose rats was slightly shorter in males than females, ~20-25 hours and ~34 hours, respectively.  Plasma pharmacokinetic studies showed a low potential for bioaccumulation following single or multiple dosing regimens.  Relatively higher concentrations were found in the gastrointestinal tract, adrenals and liver.

The pattern of metabolites was similar at the low and high 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.

Initial studies showed less than 2% of the dose was expired in the air.  Excretion was primarily via feces (80% male, 67% female) with biliary excretion being the prominent route of elimination with the urine being the secondary route.  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.

The dermal absorption factor is 16% based on the results of an in vivo dermal absorption study (MRID 46808450).

4.2	Safety Factor for Infants and Children (FQPA Safety Factor)

The toxicity database is considered complete and adequate for risk assessment.  There was no evidence of neurotoxicity in the database; there is low or no concern for developmental or reproductive toxicity, and for susceptibility in the developing or young animal.  There are no residual uncertainties identified in the exposure databases.  Therefore, the FQPA Safety Factor has been reduced to 1X.

4.2.1	Completeness of the Toxicology Database

The toxicity database is considered complete and adequate for risk assessment, with the exception of a subchronic inhalation study.  All studies needed to assess susceptibility concerns, such as developmental and reproduction studies, have been submitted.  Additional studies needed to assess neurotoxicity are also available.  A subchronic inhalation study is required because the use of an oral point of departure (POD) results in MOEs as low as 380 for occupational exposure with the current proposed use, which the Hazard and Science Policy Council has determined is not sufficient to alleviate concern (TXR0057053. J. Leshin. 10/09/2014).  Therefore, a 10X database uncertainty factor has been added for inhalation exposure.

4.2.2	Evidence of Neurotoxicity

In accordance with the revised 40 CFR Part 158 data requirements, an acute and subchronic neurotoxicity battery is required for this risk assessment.  However, requirement for an acute neurotoxicity study has been waived (TXR0056405, K. Rury, 08/09/2012), and an acceptable subchronic neurotoxicity study showed no neurotoxic effects at levels that produced systemic toxicity in the study, as well as in other subchronic and chronic studies.

4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

As discussed in section 4.1, the toxicity database contains five relevant guideline studies: two developmental studies in the rat, two developmental studies in the rabbit, and one multigeneration reproduction study.  There was evidence of quantitative susceptibility in one developmental rat study, but not in the four other studies. Concern is for susceptibility low since susceptibility was not corroborated by the other studies; concern is low also because the NOAELs are well defined, and the dose/endpoint is used for acute dietary risk assessment for the sensitive population.

4.2.4	Residual Uncertainty in the Exposure Database

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

4.3	Toxicity Endpoint and Point of Departure Selections

4.3.1	Dose-Response Assessment

The endpoints and points of departure (POD) for this risk assessment are based on those of a previous risk assessment.  The rationales for each selection, along with a detailed description of the toxicity studies used for various exposure scenarios are presented in that risk assessment document (D308794. B. O'Keefe. 07/06/2006).  Following is a summary:

Acute dietary endpoints: There was no appropriate single-dose endpoint identified for acute oral exposure of the general population to metconazole.  For the Females aged 13  -  49 population group, the POD of 12 mg/kg bw/day was established from the NOAEL of a developmental toxicity study, based on the increased incidence of skeletal anomalies including extra lumbar ribs, cervical ribs and extra pre-sacral vertebra at the LOAEL of 30 mg/kg/day.  While these skeletal anomalies are not usually considered single dose effects, they are used as the basis for an acute endpoint in this case because more severe, single-dose effects occur at the next higher dose level (75 mg/kg/day) such as increased incidence of post-implantation loss, hydrocephaly and visceral anomaliea (cranial hemorrhage, dilated renal pelvis, dilated ureters, and displaced testis.

Chronic dietary endpoint:  HED selected the NOAEL of 4.3 mg/kg/day from a two-year chronic study in the rat for establishing the chronic RfD, based increased spleen and liver weights and increased hepatocellular vacuolation and hypertrophy at the LOAEL of 13.1 mg/kg bw/day.  These effects at the LOAEL are part of a dose-related progression of toxicity seen in this study, which includes adverse hematology and clinical chemistry changes as well as histopathological changes such as increased incidence of  eosinophilic and clear-cell hepatocellular foci at the next higher dose level.  Other studies such as the 28-day, 90-day, and subchronic neurotoxicity studies all confirm the chronic NOAEL of 4.3 mg/kg/day, with NOAELs of 9.1, 6.4, and 4.8 mg/kg/day, respectively, based collectively on decreased body weight, increased liver, kidney and spleen weights, hepatocellular hypertrophy and vacuolation at the LOAELs of 15.7 mg/kg/day and above.  Therefore, the NOAEL of 4.3 mg/kg/day is considered the appropriate POD for this exposure scenario.

For short-term incidental oral exposure the POD of 9.1 mg/kg/day was selected from the NOAEL of a 28-day oral study in rats, with a NOAEL of 9.1 mg/kg/day and a LOAEL of 90.5 mg/kg/day), based on decreased body weight, increased liver and kidney weights, hepatocellular vacuolation and hypertrophy.  This study was selected because (1) endpoints identified were observed at the appropriate duration of exposure (1-30 days) and (2) the route of exposure (oral) and populations and endpoints are appropriate for the populations of concern including adults, infants and children (this POD is protective of the developmental effects seen in the rat).

The intermediate-term incidental oral endpoint was selected from the 90-day subchronic study in rats. The NOAEL for this study is 6.4 mg/kg/day and the LOAEL is 19.2 mg/kg/day based on increased hepatocellular fatty vacuolation and increased spleen weight in females.  This study was selected because (1) endpoints identified were observed at the appropriate duration of exposure (1-6 months) and (2) the route of exposure (oral) and endpoints are appropriate for the populations of concern including adults, infants and children (this POD is protective of the developmental effects seen in the rat).

Short- and Intermediate- Term dermal endpoints were not selected because quantification of dermal risk is not required.  No systemic or dermal toxicity was seen at the limit dose in a 21-day dermal toxicity study in the rat. There are no neurotoxicity, developmental or reproductive issues which would raise concern for these toxicities, which are not looked for in the 21-day dermal study. Also, the DAF is established at 16% which suggests that any toxicities seen in the developmental, reproduction and neurotoxicity studies via the oral route, would be expected to be seen at a significantly higher dose level via the dermal exposure route.  Hence the dermal risk quantification is not required.

For Short-term inhalation exposures, the POD of 9.1 mg/kg/day (no observed adverse effect level (NOAEL)) is based on an oral 28-day rat toxicity study.  In the study, the effects observed at the lowest observed adverse effect level (LOAEL) were decreased body weight (males), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (males and females).  In the absence of repeated exposure inhalation toxicity studies, an oral study for this population subgroup was selected and a 10X database uncertainty factor was added.

For intermediate-term inhalation exposures, the POD of 6.4 mg/kg/day (NOAEL) is based on an oral 90-day rat toxicity study.  In the study, the effects observed at the LOAEL were increased spleen weight (females) and hepatic vacuolation (males). In the absence of repeated exposure inhalation toxicity studies, an oral study for this population subgroup was selected and a 10X database uncertainty factor was added.

4.3.2	Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures.  For short- and intermediate-term risk assessments, the oral and inhalation routes can be combined due to the common endpoint (liver toxicity) via the oral and inhalation (oral equivalent) routes.  Quantification of dermal risk is not required.  There are no potential long-term dermal or inhalation exposures to metconazole under the current uses.

4.3.3	Cancer Classification and Risk Assessment Recommendation

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

4.3.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table <IP_ADDRESS>.  Summary of Toxicological Doses and Endpoints for Metconazole for Use in Dietary and Non-Occupational Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty/FQPA Safety Factors
RfD, PAD, Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)

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

Acute Dietary
(Females 13-49 years of age)
NOAEL= 12 mg/kg/day
UFA= 10X
UFH= 10X
FQPA SF= 1X

Acute RfD = 0.12 mg/kg/day

aPAD= 0.12 mg/kg/day
Developmental toxicity in rats: LOAEL= 30 mg/kg/day based on increases in skeletal variations.  At 75 mg/kg/day (the next higher dose level) increased incidence of post-implantation loss, hydrocephaly and visceral anomaliea (cranial hemorrhage, dilated renal pelvis, dilated ureters, and displaced testis) were reported.
Chronic Dietary (All Populations)
NOAEL= 4.3 mg/kg/day
UFA=10X
UFH= 10X
FQPA SF= 1X

Chronic RfD = 0.04 mg/kg/day

cPAD = 0.04 mg/kg/day
Chronic oral toxicity study in rats: LOAEL = 13.1 mg/kg/day based on increased liver (M) weights and associated  hepatocellular  lipid vacuolation (M) and centrilobular hypertrophy(M).  Similar effects were observed in females at 54 mg/kg/day, plus increased spleen weight.
Incidental Oral Short-Term (1-30 days)
NOAEL= 9.1 mg/kg/day
UFA= 10X
UFH=10X
FQPA SF= 1X

Residential LOC for MOE = 100
28-Day oral toxicity study in rats: LOAEL = 90.5 mg/kg/day based on decreased body weight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F).
Incidental Oral Intermediate-Term (1-6 months)
NOAEL= 6.4 mg/kg/day
UFA= 10X
UFH=10X
FQPA SF= 1X
Residential LOC for MOE = 100
90-Day oral toxicity study in rats: LOAEL = 19.2 based on increased spleen wt (F) and hepatic vacuolation (M).
Dermal Short- (1-30 days) & Intermediate-Term (1-6 months)
Quantification of dermal risk is not required due to lack of systemic or dermal toxicity at the Limit Dose in a 21-day dermal toxicity study in the rat, the lack of neurotoxicity, and the lack of developmental and/or reproductive toxicity in the absence of parental effects, which were not looked for in the dermal toxicity.
Inhalation Short- Term (1-30 days)
NOAEL= 9.1 mg/kg/day
UFA= 10X
UFH=10X
UFDB=10X
FQPA SF= 1X

Residential LOC for MOE = 1000
28-Day oral toxicity study in rats: LOAEL = 90.5 mg/kg/day based on decreased body weight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F).
Inhalation Intermediate-Term (1-6 months)
NOAEL= 6.4 mg/kg/day
UFA= 10X
UFH=10X
UFDB=10X
FQPA SF= 1X

Residential LOC for MOE = 1000

90-Day oral toxicity study in rats: LOAEL = 19.2 mg/kg/day based on increased spleen wt (F) and hepatic vacuolation (M).
Cancer (oral, dermal, inhalation)
Classification:  "Not likely to be Carcinogenic to Humans"
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFDB = to account for the absence of key data (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

Table <IP_ADDRESS>.  Summary of Toxicological Doses and Endpoints for Metconazole for Use in Occupational Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty Factors
Level of Concern for Risk Assessment
Study and Toxicological Effects
Dermal Short- (1-30 days) & Intermediate-Term (1-6 months)
Quantification of dermal risk is not required due to lack of systemic or dermal toxicity at the Limit Dose in a 21-day dermal toxicity study in the rat, the lack of target organ toxicity or neurotoxicity, and the lack of developmental and/or reproductive toxicity in the absence of parental effects which were not looked for in the dermal toxicity.
Inhalation Short-Term (1-30 days)
NOAEL=9.1 mg/kg/day
UFA= 10X
UFH=10X
UFDB=10X
Occupational LOC for MOE = 1000
28-Day oral toxicity study in rats: LOAEL = 90.5 mg/kg/day based on decreased body weight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F).
Inhalation Intermediate-term (1-6 months)
NOAEL=6.4 mg/kg/day
UFA= 10X
UFH=10X
UFDB=10X

Occupational LOC for MOE = 1000
90-Day oral toxicity study in rats: LOAEL = 19.2 mg/kg/day based on increased spleen wt (F) and hepatic vacuolation (M).
Cancer (oral, dermal, inhalation)
Classification:  "Not Likely to be Carcinogenic to Humans"
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFDB = to account for the absence of key date (i.e., lack of a critical study).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

5.0	Dietary Exposure and Risk Assessment

5.1	Residues of Concern Summary and Rationale

The nature of the residue in crops is adequately understood based on metabolism studies on banana, canola, mandarin, pea, and wheat.  The metabolism of metconazole was similar in all crops investigated.  Metconazole (parent) is the residue of concern for the tolerance expression for primary and rotational crops.  Metconazole is the residue of concern for risk assessment purposes in primary and rotational crops except for cereal grains; the residues of concern for risk assessment in cereal grains (as both primary and rotational crops) are metconazole and the metabolite M11.

HED also has concern for residues of 1,2,4-triazole, TA, and TAA in plants as a result of the use of metconazole.  However, because separate endpoints for these compounds have been established, exposure and risks from free triazole and its conjugates will be addressed separately.

The nature of the residue in livestock (ruminants and poultry) is adequately understood.  The residue of concern for the tolerance expression in livestock commodities is metconazole.  The residues of concern in livestock for purposes of the risk assessment are metconazole and metabolites M1 (free and its glucuronic acid conjugate), M12, and M31 (free and its glucuronic acid conjugate).

HED also has concern for residues of 1,2,4-triazole, TA, and TAA in livestock as a result of the use of metconazole.  However, because separate endpoints for these compounds have been established, exposure and risks from free triazole and its conjugates will be addressed separately.

For drinking water, the residue of concern for metconazole is the parent only.

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.
                                    Matrix
                    Residues Included In Risk Assessment[a]
                   Residues Included In Tolerance Expression
                                    Plants
              Primary and Rotational Crops, except Cereal Grains
                                  Metconazole
                                  Metconazole

               Primary and Rotational Crops, Cereal Grains only
                              Metconazole and M11
                                  Metconazole
                                   Livestock
                                   Ruminant
Metconazole; M1 and its glucuronic acid conjugate; M12; M31 and its glucuronic acid conjugate
                                  Metconazole

                                    Poultry

                                Drinking Water
                                  Metconazole
                                Not Applicable
Note:  For all triazole-containing pesticides, the triazole-containing metabolites 1,2,4-T, TA, and TAA should also be included as residues of concern for risk assessment purposes only for plant and livestock commodities.  Since these metabolites are common to the entire class of triazole-derivative fungicides and because of differential toxicity between the metabolites and the various parent compounds, risks associated with exposure to 1,2,4-T and to TA/TAA are addressed in separate risk assessment documents.

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

5.2	Food Residue Profile

IR-4 submitted field trial data on dry bean (MRID 49297801), dry pea (MRID 49297802), and sunflower (MRID 49297803).  The data reflect the proposed use patterns.  The number of trials and geographic distribution are acceptable.  The analytical method used is adequate for determination of the residue of concern, and the samples were stored frozen for intervals supported by the storage stability results.  A summary of the residue data from the crop field trials is presented in Appendix F, Tables F.1 through F.5.  The existing field trial data for the crop group conversions are adequate.

The previously submitted field trial data on canola, cherry, peach, plum, almond, and pecan are adequate to support the rapeseed subgroup 20A, the stone fruit subgroup 12-12, and the tree nut group 14-12.  The number of field trials and geographic representations are adequate.  Adequate storage stability data are available to support the field trial data.  An adequate data collection method, the GC/NPD method RM-41C-1, was used to determine metconazole (cis- and trans- isomers) in canola, stone fruit, and tree nuts.  Residues of 1,2,4-triazole, TA, and TAA were determined in canola seed using an adequate LC/MS/MS method (Morse Laboratories Method 160).  Although stone fruit and tree nut samples were not analyzed for the triazole metabolites, field trial data for triazoles are not required for those petitions submitted in 2006.

Processed Food and Feed
Adequate processing studies have been submitted on canola, plum, and sunflower.

Canola:  Metconazole (the sum of cis- and trans-isomers) was non-detectable in/on canola seed, meal and refined oil samples reflecting treatment at a 5x rate; therefore, separate tolerances are not required for canola meal and oil.  Residues of 1,2,4-triazole were also not detectable in canola seed, meal and refined oil reflecting treatment at 5X.  Residues of TA and TAA do not concentrate in oil.  However, residues of TA and TAA concentrated in canola meal by 2.1X and 1.4X, respectively.

Plum:  Metconazole (the sum of cis- and trans-isomers) concentrates 2.3X in prunes.

Sunflower:  Metconazole (the sum of cis- and trans-isomers) does not concentrate in sunflower meal and oil.  Residues of TA concentrate 2.9X in sunflower meal, but do not concentrate in oil.

Livestock
Adequate cattle and poultry feeding studies were previously submitted and reviewed.  Based on the cattle feeding study and the calculated dietary burden based on the maximum reasonably balanced diet (Table 1 Feedstuffs, June 2008), no changes are required in the established livestock tolerances as a result of the proposed/expanded uses.  The established tolerances for meat byproducts of cattle, goat, horse, and sheep at 0.04 ppm and for egg at 0.04 ppm are adequate.  No tolerances are established for milk; fat and meat of cattle, goat, hog, horse, poultry, and sheep; or meat byproducts of hog and poultry since residues are not expected to occur in those commodities.  If additional uses increase the dairy cattle dietary burden, additional ruminant feeding studies conducted at higher rates may be needed.

Rotational Crops
Adequate limited field rotational crop studies have previously been submitted.  Based on the limited field rotational crop trials, rotational crop restrictions are included on the registered Metconazole 50 WDG label (EPA Reg. No. 59639-147).  The same rotational crop restrictions on the proposed Metconazole 50 WDG label are adequate.

5.3	Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided EFED (D418674, F. Khan, 9/30/2014) and incorporated directly into this dietary assessment in the DEEM-FCID into the food categories "water, direct, all sources" and "water, indirect, all sources."

Parent metconazole is the only residue of concern considered in the drinking water assessment.  HED determined that degradates of metconazole were not to be included (Residues of Concern Knowledgebase Subcommittee (ROCKS), USEPA, 2008, D348234).

For surface water, the Surface Water Concentration Calculator (SWCC v 1.106) model was used to generate EDWCs for the Tier II aquatic exposure assessment based on cranberry use.  The SWCC is a graphical user interface that runs the Pesticide Root Zone Model (PRZM, v 5, November 15, 2006) and the Variable Volume Water Body Model (VVWM, 3/6/2014) (USEPA, 2006b).  The default percent cropped area (PCA) factor of 1.0 was used.
For peak exposure and annual mean exposure, lower EDWCs for surface water were generated using the Tier II Pesticide Root Zone Model and Exposure Analysis Modeling System (PRZM-EXAMS), based on metconazole use on PA turf with a PCA factor of 1.  The use on turf reflected the highest application rate (i.e., five applications at 0.6 lb ai/A/application with a 14-day retreatment interval).  The modeled EDWCs for pea/bean (dried shelled) and sunflower did not exceed the concentrations from PA turf.
For ground water, the PRZM-Ground Water (PRZM-GW) model was used to estimate EDWCs.  The highest application rate, which was the application rate for turf, was modeled in estimating metconazole EDWCs for ground water.  Since application rates for proposed uses are lower than turf, no additional PRZM-GW modeling was conducted.

The EDWCs used in HED's human health dietary risk assessment are bolded in summary Table 5.3.1 below.  The ground water EDWC of 51.8 ug/L (ppb) was used in the acute dietary assessment. The surface water EDWC of 43.9 ug/L (ppb) was used in the chronic dietary assessment.

The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.
Table 5.3.1.  Recommended EDWCs for the Proposed Uses of Metconazole for Drinking Water Sources[1]
Drinking Water Source
Crop Scenario (Model)
                                 Peak Exposure
                                    (Acute)
                                    (ug/L)
                             Annual Mean Exposure
                             (Non-Cancer Chronic)
                                    (μg/L)
                            30-year Mean Exposure
                               (Cancer Chronic)
                                   (ug/L)
Surface Water
Turf [2]
                                     45.5
                                     31.3
                                     22.8

Cranberry[3]
                                     49.6
                                     43.9
                                     NA[5]
Ground water
WI Central Sand Scenario[4]
                                     51.8
                                     NA[5]
                                     20.0
[1] Bolded values are the recommended EDWCs for assessing acute and chronic dietary exposures from metconazole uses.
2 The Tier II model PRZM/EXAMS was used to generate EDWCs for surface water, based on metconazole use on PA turf.  A percent cropped area (PCA) factor of 1 was used.
[3] The SWCC v 1.106 model was used to generate EDWCs for the Tier II aquatic exposure assessment. The SWCC is a graphical user interface that runs the Pesticide Root Zone Model (PRZM, v 5, November 15, 2006) and the Variable Volume Water Body Model (VVWM, 3/6/2014) (USEPA, 2006b). The default PCA factor of 1.0 was used.
[4] The Tier 1 PRZM-GW model was used to reassess ground water EDWCs for the turf use, which has the highest application rate (5 applications at of 0.6 lbs ai/A/application).
[5] Not applicable.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

The dietary exposure analysis incorporates all current and proposed tolerances for residues of metconazole, including its metabolites and degradates.

An unrefined acute dietary (food and drinking water) exposure assessment was conducted.  The residue levels used in the assessment were the established or recommended tolerance levels except for cereal grains and livestock commodities.  Since cereal grains and livestock commodities include metabolites as residues of concern in the risk assessment, maximum residue values for the metabolites from field trials were added to the metconazole tolerance levels.  DEEM default processing factors or empirical processing factors were used, as available.  It was assumed that 100% of the crops were treated.

The EDWC used in the acute dietary assessment was provided by the EFED and incorporated directly into the acute assessment.  The ground water EDWC of 51.8 ug/L (ppb) generated by the PRZM-GW model was used in the acute dietary assessment.  The highest application rate, which was the application rate for turf, was modeled using the WI Central Sand Scenario in estimating metconazole EDWCs for ground water.

An unrefined chronic dietary (food and drinking water) exposure assessment was conducted.  The residue levels used in the assessment were the established or recommended tolerance levels except for cereal grains and livestock commodities.  Since cereal grains and livestock commodities include metabolites as residues of concern in the risk assessment, maximum residue values for the metabolites from field trials were added to the metconazole tolerance levels.  DEEM default processing factors or empirical processing factors were used, as available.  It was assumed that 100% of the crops were treated.

The EDWC used in the chronic dietary assessment was provided by EFED and incorporated directly into the chronic assessment.  The surface water EDWC of 43.9 ug/L (ppb) generated by the SWCC model was used in the chronic dietary assessment.  The SWCC model was used to generate EDWCs for the Tier II aquatic exposure assessment based on the cranberry scenario.

Metconazole is classified as "not likely to be carcinogenic to humans".  Therefore, a cancer dietary exposure assessment was not conducted.

5.4.2	Percent Crop Treated Used in Dietary Assessment

It was assumed that 100% of the crops were treated for all commodities.

5.4.3	Acute Dietary Risk Assessment

For the general U.S. population, including infants and children, an appropriate dose/endpoint attributable to a single dose was not observed in the available oral toxicity studies.  The acute dietary (food and drinking water) exposure to metconazole is below HED's level of concern for females 13-49 years old, the only population subgroup of concern.  For females 13-49 years old, the acute dietary exposure estimate at the 95[th] percentile utilized 4.6% of the acute population adjusted dose (aPAD), and is not of concern.

5.4.4	Chronic Dietary Risk Assessments

The chronic dietary (food and drinking water) exposure to metconazole is below HED's level of concern for the general U.S. population and all population subgroups.  The chronic dietary exposure estimates utilize 6.6% of the chronic population adjusted dose (cPAD) for the general U.S. population and 14% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.

5.4.5	Summary Table

 Table 5.4.5.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Metconazole.
                              Population Subgroup
                                 Acute Dietary
                              (95[th] Percentile)
                                Chronic Dietary

                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
 General U.S. Population
                                       NA
                                       NA
                                    0.002653
                                      6.6
 All Infants (<1 year old)

                                    0.004963
                                       12
 Children 1-2 years old*

                                    0.005391
                                       14
 Children 3-5 years old

                                    0.004749
                                       12
 Children 6-12 years old

                                    0.003241
                                      8.1
 Youth 13-19 years old

                                    0.002045
                                      5.1
 Adults 20-49 years old

                                    0.002549
                                      6.4
 Adults 50-99 years old

                                    0.002166
                                      5.4
 Females 13-49 years old*
                                    0.005500
                                      4.6
                                    0.002179
                                      5.4
*The subpopulations with the highest risk estimates are bolded.
NA = not applicable.

5.4.6	Dietary Assessment of Free Triazole and its Conjugates

The proposed new uses of metconazole did not result in an increase in dietary exposure estimates for free triazole or conjugated triazoles.  Therefore, the last dietary exposure analyses for the triazole metabolites (D414951, T. Morton, 10/24/2013) did not need to be updated.  The past assessment will still adequately cover these uses.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

No new residential uses are being proposed at this time.  However, there are existing uses of metconazole on turf and ornamentals in residential settings that have been reassessed in this document to reflect HED's 2012 Residential SOPs along with policy changes for body weight assumptions.  Because dermal toxicity endpoints for the appropriate duration of exposure (short-term) were not identified up to the limit dose, only residential handler inhalation exposures/risks for adults, and residential post-application incidental oral exposures/risks for children have been assessed.

6.1	Residential Handler Exposure

Summaries of the short-term inhalation risk estimates for residential handlers are included in Appendix D, Table D.1.  The maximum application rate for each exposure scenario is presented as the worst case scenario.  All inhalation risk estimates are greater than the LOC of 1,000; and therefore are not of concern (MOEs range from 6,300 to 23,000,000).  Dermal handler risk assessments were not conducted because an adverse systemic dermal hazard was not identified for metconazole.

6.2	Post-Application Exposure

Summaries of the short-term post-application incidental oral risk estimates for children 1 to <2 years old are included in Appendix D, Table D.2.  The maximum application rate for each exposure scenario is presented as the worst-case scenario.  All incidental oral risk estimates are greater than the LOC of 100; and therefore are not of concern (MOEs range from 1,000 to 450,000).  Dermal post-application risk assessments were not conducted because an adverse systemic dermal hazard was not identified for metconazole.

Guideline 875.2100 - Turf Transferable Residues (TTR)
In accordance with 40CFR158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post-application exposure to turf.  In the absence of chemical-specific TTR data, EPA uses default values.  The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, which resulted in the selection of revised liquid and granular default values for the fraction of the application rate available for transfer after a turf application (FAR).  These values are based on an analysis of 59 TTR studies performed with the Modified California Roller Method (36 studies using liquids, 11 studies using wettable powders/water dispersible granules, and 12 studies using granules).  The liquid results (N=131) indicate a range of FAR values from 0.0005% to 6.1% and the granular results (N=37) indicate a range of 0.00064% to 0.69%.  In both the liquid and granular data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g. humidity); or many other difficult to quantify factors.  Although witnessed across multiple chemicals, this range in FAR values is not expected when considering TTR data for a single chemical.  HED selected 1% and 0.2% as high-end default values for liquid and granular products, respectively.  Because TTR data are not available for metconazole, EPA is using the default value of the currently registered residential products.  Although there may be a small degree of uncertainty in the use of the default TTR value for metconazole (i.e., there is a small chance that the FAR value may exceed the applicable default value), it is likely that the health-protective aspects of EPA's residential post-application turf assessment methodology will more than compensate for this potential uncertainty (i.e. the methodology is likely to overestimate exposure by a factor greater than the factor than the highest measured FAR values exceed the defaults).  For example, when assessing residential post-application turf exposure, EPA assumes the following: exposures occur to zero-day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn't rain, the grass is not mowed, etc); individuals perform the same post-application activities performed in the turf transfer coefficient study day after day (e.g. tumbling, playing on turf with toys, etc.); and individuals engage in these post-application activities for a high-end amount of time every day that is represented by data reflecting time children spend outdoors and not specifically engaged in activities on turf, when in actuality children do not spend all of their outdoor time on turf and high-end levels of activity will not occur every day.

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the estimated residential turf post-application exposure for residential turf using default TTR values for metconazole is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 10 times higher than the level of concern, MOE = 1,000 compared to the LOC of 100); EPA is waiving the 40 CFR TTR data requirement.  In this instance, it is unlikely that chemical-specific TTR data would be needed to further refine exposure assessments or would add appreciably to our general understanding of the availability of turf transferable pesticide residues.

Guideline 875.2100 - Dislodgeable Foliar Residue (DFR)
In accordance with 40 CFR 158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post-application exposure to foliage.  Since metconazole does not result in adverse systemic toxicity via the dermal route of exposure, EPA is waiving the 40 CFR DFR data requirement at this time.

6.3	Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate assessment for metconazole.

   * The recommended residential exposure estimate for use in the adult aggregate assessment reflects inhalation exposure from WDG applications to turf with a manually pressurized handwand.
   * The recommended residential exposure estimate for use in the children 1<2 years old aggregate assessment reflects hand-to-mouth exposures from WDG metconazole application to turf.

Table 6.3.1.  Recommendations for the Residential Exposures for the Metconazole Aggregate Assessment.
                                   Lifestage
                               Exposure Scenario
                              Dose (mg/kg/day)[1]
                                    MOE[2]

                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                     Adult
                Manually Pressurized Handwand Lawns/Turf (WDG)
                                      N/A
                                    0.00024
                                      N/A
                                    0.00024
                                      N/A
                                     6,300
                                      N/A
                                     6,300
                              Child (Short-Term)
               Hand-to-Mouth from WDG Application to Lawns/Turf
                                      N/A
                                      N/A
                                    0.0091
                                    0.0091
                                      N/A
                                      N/A
                                     1,000
                                     1,000
1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed.  Table D.1.in Appendix D presents that Residential Handler Exposure and Risk Estimates and Table D.2 in Appendix D presents the Residential Post-application Exposure and Risk Estimates.
2 MOE = the MOEs associated with the highest residential doses.

6.4	Residential Bystander Post-application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for metconazole.

6.5	Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for metconazole.  The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.

7.0 Aggregate Exposure/Risk Characterization

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

7.1	Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of metconazole in food and drinking water, and does not include dermal, inhalation, or incidental oral exposure.  As demonstrated under section 5.4.3, acute aggregate risks are not of concern.

55.2 Short-Term Aggregate Risk

There is potential short-term exposure to metconazole via dietary (which is considered background exposure) and residential (which is considered primary) exposure pathways.  For adults, these pathways lead to exposure via oral (background) as well as dermal and inhalation (primary) routes.  The most conservative scenarios were chosen for each.  For a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.3.

The short-term aggregate MOE is 630 for children 1 to <2 years old, which are not of concern to HED.  For adults, oral dietary and inhalation risk estimates were combined using the total aggregated risk index (ARI) methodology since the LOCs for oral dietary exposure (100) and inhalation exposure (1,000) are different.  The LOC ARI is 1; therefore, ARIs of less than 1 are risk estimates of concern.  The short-term aggregate ARI of 5.3 is not of concern to HED.

Table 7.2.1.  Short-Term Aggregate Risk Calculations
                                   Lifestage
                         Residential Exposure Scenario
                    Incidental Oral or Inhalation Exposure
                             Oral Dietary Exposure
                             Total Combined MOE[2]
                             Total Combined ARI[3]

                                     NOAEL
                                   mg/kg/day
                                   Exposure
                                   mg/kg/day
                                    MOE[1]
                                NOAEL mg/kg/day
                   Chronic Dietary (Food + Water) mg/kg/day
                                    MOE[1]

                             Child 1 to <2 yrs
           Post-application hand-to-mouth activities on treated turf
                                      9.1
                                    0.0091
                                     1,000
                                      9.1
                                   0.005391
                                     1,700
                                      630
                                      NA
                                     Adult
                    Inhalation Exposure to Handlers on Turf
                                      9.1
                                    0.00024
                                     6,300
                                      9.1
                                   0.002653
                                     3,400
                                      NA
                                      5.3
[1] The Level of Concern MOE is 100.
[2] Total Combined MOE = 1/ [(1/MOEDermal) + (1/MOEOral)]
[3] Aggregate Risk Index (ARI) = 1/ (1 / RIoral dietary) + (1 / RIinhalation)
   Risk Index (RI) = MOE / LOC; Inhalation LOC = 1,000 and Oral Dietary LOC = 100

Updated Aggregate Assessment of Free Triazole & its Conjugates
The addition of the new proposed uses does not increase the aggregate exposure to free triazoles and its conjugates.  Therefore, the recently updated aggregate human health risk assessment for free triazoles and its conjugates remains unchanged and the aggregate estimates are below HED's level of concern (D414952, T. Morton, 10/24/2013).

7.3	Chronic Aggregate Risk

Chronic exposure from the residential pathway is not anticipated based on the current metconazole use pattern.  The chronic aggregate risk (food and drinking water) is below HED's LOC (i.e., <100% cPAD for the general U.S. population and all population subgroups).  See Section 5.4.4 for details.

6.0 Cumulative Exposure/Risk Characterization

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

Metconazole is a triazole-derived pesticide.  This class of compounds can form the common metabolite 1,2,4-triazole and two triazole conjugates (triazolylalanine and triazolylacetic acid).  To support existing tolerances and to establish new tolerances for triazole-derivative pesticides, including metconazole, U.S. EPA conducted a human health risk assessment for exposure to 1,2,4-triazole, triazolylalanine, and triazolylacetic acid resulting from the use of all current and pending uses of any triazole-derived fungicide.  The risk assessment is a highly conservative, screening-level evaluation in terms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary and non-dietary exposures (i.e., high end estimates of both dietary and non-dietary exposures).  In addition, the Agency retained the additional 10X FQPA safety factor for the protection of infants and children.  The assessment includes evaluations of risks for various subgroups, including those comprised of infants and children.  The Agency's complete risk assessment is found in the propiconazole reregistration docket at http://www.regulations.gov, Docket Identification (ID) Number EPA-HQ-OPP-2005-0497.

7.0 Occupational Exposure/Risk Characterization

Metconazole has been proposed for use on dry shelled pea and beans (except soybean) crop subgroup 6C and sunflower crop subgroup 20B.  The petitioner also requested a crop group expansion to rapeseed crop subgroup 20A; and crop group conversions to stone fruit crop group 12-12, and tree nut crop group 14-12.  HED reevaluated the existing occupational uses for rapeseed crop subgroup 20A, stone fruit crop group 12-12, and tree nut crop group 14-12 to incorporate updated occupational exposure assessment assumptions and the revised LOC for inhalation exposure assessment.  The application rates presented for rapeseed crop subgroup 20A, stone fruit crop group 12-12, and tree nut crop group 14-12 represent the maximum registered application rates, or the worst-case exposure scenarios.

9.1	Short-/Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns from the proposed label, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  Because dermal toxicity endpoints for the appropriate duration of exposure (short- and intermediate-term) were not identified up to the limit dose, only occupational handler inhalation exposures/risks have been assessed.  For inhalation exposures, an additional 10X uncertainty factor is added because of the lack of an available subchronic inhalation toxicity study.  Therefore, the total uncertainty factor that has been applied to the inhalation assessments of metconazole is 1000X for handler exposure.  Occupational inhalation exposure and risk resulting in MOEs greater than or equal to 1000 will not be of concern to HED (LOC = 1000).

For the proposed uses of metconazole, all short- and intermediate-term occupational handler MOEs are not of concern at baseline PPE except for mixing/loading WDG for aerial application to canola (crop subgroup 20A), sunflower (crop subgroup 20B), dry beans and peas (crop subgroup 6C) (short-term MOE = 540; intermediate-term MOE =1,900; LOC = 1,000).  With the addition of a PF5 respirator, mixing/loading WDG for aerial application to these crops is not of concern (MOE = 2,700).  Summaries of the short- and intermediate-term risk estimates for occupational handlers applying metconazole are provided in Appendix E, Tables E.1 and E.2.

9.2	Short-and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1	Dermal Post-Application Risk

Because dermal toxicity endpoints for the appropriate duration of exposure (short- and intermediate-term) were not identified up to the limit dose, post-application dermal exposures/risks were not assessed.

Guideline 875.2100 - Dislodgeable Foliar Residue
In accordance with 40 CFR 158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post-application exposure to foliage.  Since metconazole does not result in adverse systemic toxicity via the dermal route of exposure, EPA is waiving the 40 CFR DFR data requirement at this time.  In this instance, it is unlikely that chemical-specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pesticide residues for metconazole.

Restricted Entry Interval
Since a quantitative dermal assessment was not required, the REI is based on the acute toxicity of metconazole.  Metconazole is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential.  It is not a skin sensitizer.  Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement REI of 12 hours is adequate to protect agricultural workers from post-application exposures to metconazole.

9.2.2	Inhalation Post-Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for metconazole.

In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

It should be noted that there is the potential for inhalation exposure during the mechanical sweeping and windrowing of the tree nuts.  However, since there is a long PHI of 25 days, the post-application inhalation exposure potential is negligible and was not quantitatively assessed.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting is another potential source of post-application inhalation exposure.  However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post-application inhalation exposure during these dusty mechanical harvesting activities.  The non-cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE >1,000)

10.0	References

N. Dodd, 11/07/2014, D423622.  Metconazole Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Actions on Pea and Bean, Dried Shelled, except Soybean, Subgroup 6C and the Sunflower Subgroup 20B; Expansion of the Canola Tolerance to the Rapeseed Subgroup 20A; and Conversion of the Established Stone Fruit and Tree Nut Crop Groups to the Stone Fruit Group 12-12 and the Tree Nut Group 14-12.

N. Dodd, 11/04/2014, D423623.  Metconazole. Petition for the Establishment of Permanent Tolerances and Registration for Use on the Pea and Bean, Dried Shelled, except Soybean, Subgroup 6C and the Sunflower Subgroup 20B; Expansion of the Canola Tolerance to the Rapeseed Subgroup 20A; and Conversion of the Established Stone Fruit and Tree Nut Crop Groups to the Stone Fruit Group 12-12 and the Tree Nut Group 14-12.  Summary of Analytical Chemistry and Residue Data.

K. Rury, 12/11/2014, D423992. METCONAZOLE. Occupational and Residential Exposure Assessment for  Proposed Uses on Dry Shelled Pea and Beans (Except Soybean) Crop Subgroup 6C and Sunflower Crop Subgroup 20B; Crop Group Expansion to Rapeseed Subgroup 20A; and Crop Group Conversions to Fruit, Stone, Group 12-12; and Nut, Tree, Group 14-12.  Also a Re-Evaluation of all existing Residential Uses of Metconazole.

F. Khan, 09/30/2014, D418674.  Drinking Water Exposure Assessment for the Section 3 New Use of Metconazole on Pea and Bean (Dried Shelled, Subgroup 6C), and Sunflower (Subgroup 20B).

T. Morton, 10/24/2013, D414951.  Common Triazole Metabolites:  Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The New Section 3 Registrations For Use of Propiconazole on Rapeseed Crop Subgroup 20A; Use of Difenoconazole on Rapeseed Crop Subgroup 20A; and Use of Tebuconazole on Imported Oranges.

T. Morton, 10/24/2013, D414952.  Common Triazole Metabolites:  Updated Aggregate Human Health Risk Assessment to Address The New Section 3 Registrations For Use of Propiconazole on Rapeseed Crop Subgroup 20A; Use of Difenoconazole on Rapeseed Crop Subgroup 20A; and Use of Tebuconazole on Imported Oranges.

Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses of metconazole are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Test

                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)
870.3150    Oral Subchronic (nonrodent)
870.3200    21-Day Dermal
870.3250    90-Day Dermal
870.3465    90-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                      --
                                      no*
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (nonrodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)
870.4100b  Chronic Toxicity (nonrodent)
870.4200a  Oncogenicity (rat)
870.4200b  Oncogenicity (mouse)
870.4300    Chronic/Oncogenicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial
870.5300    Mutagenicity -- Gene Mutation - mammalian
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations
870.5xxx    Mutagenicity -- Other Genotoxic Effects
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotox. (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotox. Screening Battery (rat)
870.6200b  90-Day Neuro. Screening Battery (rat)
870.6300    Develop. Neuro
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                      no
                                      no
                                   waived **
                                      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
*	TXR0057053, J. Leshin, 10/09/2014 waiver not granted
**	TXR0056405, K. Rury, 08/09/2012 waiver granted

A.2	Toxicity Profiles
 Table A.2.1.  Acute Toxicity of Metconazole

Table A.2.1.	Acute Toxicity Profile  -  Metconazole Technical

                                 Guideline No.

Study Type

MRID(s)

                                    Results

                               Toxicity Category

870.1100

Acute oral [mouse]

                                   44721512

LD50 = >566 mg/kg

                                      III

870.1100

Acute oral [rat]

                                   44721512

LD50 = >566 mg/kg

                                      III

870.1100

Acute oral [rat]

                                   44721513

LD50 = >1459 mg/kg

                                      III

870.1100

Acute oral [rat]

                                   44721514

LD50 = >5000 mg/kg

                                      IV

870.1200

Acute dermal [rat]

                                   44721512

Dermal LD50 > 2000

                                      III

870.1200

Acute dermal [rabbit]

                                   44721512

Dermal LD50 > 2000

                                      III

870.1200

Acute inhalation [rat]

                                   44721512

LD50 = >5.6 mg/L

                                      IV

870.2400

Acute eye irritation [rat]

                                   44721513
moderate irritant
                                      III

870.2500

Acute dermal irritation [rabbit]

                                   44721513
mild irritant
                                      IV

870.2600

Skin sensitization [guinea pig]

                                   44721513
neg.
                                       -

 Table A.2.2.  Non-acute Toxicity Profile for Metconazole

Table A.2.2.	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 of body weight in M, liver and kidney weight increases with associated histopathological effects (hypertrophy and fatty vacuolation) in liver only.
870.3100
90-Day oral toxicity rodents (rat)
44721517 (1991)
M/F: 0, 30, 100, 300, 1000, 3000 ppm
M: 0, 1.94, 6.4, 19.2, 64.3, 192.7 mg/kg/day
F: 0, 2.1, 7.2, 22.1, 71.4, 208.0 mg/kg/day
Acceptable/guideline
NOAEL (M/F) = 6.4/7.2 mg/kg/day
LOAEL (M/F) = 19.2/22.1 mg/kg/day based on increased spleen weight in females and hepatic vacuolation in males.
870.3100
90-Day oral toxicity rodents (mouse)
44721519 (1991)
M/F: 0, 30, 300, 3000 (wk 1)/2000(wk 2-13) ppm
M: 0, 9.58, 50.5, 341.1 mg/kg/day
F: 0, 6.94, 60.7, 438.5 mg/kg/day
Acceptable/guideline
NOAEL (M/F) = 9.58/6.94 mg/kg/day
LOAEL (M/F) = 50.5/60.7 mg/kg/day based on increase in absolute and relative liver weights, hepatocellular hypertrophy and vacuolation, and increase in relative spleen weight (F), elevated AST and ALT activity.
870.3150
28-Day oral toxicity non-rodents (dog)
44721520 (1991)
M/F: 0, 100, 1000, and 7000-10000 ppm in diet
Unacceptable/non-guideline (some preliminary test data provided)
NOAEL (M/F) = 100 ppm in diet
LOAEL (M/F) = 1000 ppm in diet (increase in relative and absolute thyroid wt. in one/two females)
Deficiencies: low n (2M/2F per dose); decrease in food consumption means low exposure to test compound; actual dose received per dose group not provided.
870.3150
90-Day oral
toxicity non-rodents (dog)

44721521 (1991)
M/F: 0, 60, 600, 6000 ppm in diet
M: 0, 2.5, 24.4, 225.2 mg/kg/day
F: 0, 2.6, 24.3, 206.6 mg/kg/day
Acceptable/guideline
NOAEL (M/F) = 2.5/2.6 mg/kg/day
LOAEL (M/F) = 24.4/24.3 mg/kg/day based on decreased food consumption in females and elevated platelets and reticulocytes in males.
870.3200
21-day Dermal Toxicity
46808439 (2006)
0, 250, 500, 1000 mg/kg/day
Acceptable/guideline
NOAEL: 1000 mg/kg

LOAEL: > 1000 mg/kg
No evidence of dermal toxicity.
870.6200
Subchronic (13-week) Oral Neurotoxicity- rat
46808440 (2002)
0, 50, 170, 500 ppm
M: 0, 4.84, 15.69, 47.08 mg/kg/day
F: 0, 5.10, 17.62, 49.82 mg/kg/day
Acceptable/Non-guideline
Systemic NOAEL (M/F) = 4.84/5.10  mg/kg/
Systemic LOAEL (M/F) = 15.69/ 17.62 mg/kg/ based on decreases in body weight and food consumption.

Neurotoxicity NOAEL (M/F)  47.08/49.82 mg/kg/day
870.3700
Prenatal development in rodents (rat)
44721522 (1991)
0, 12, 30, 75  mg/kg/day
Gavage
Acceptable/Guideline
Maternal NOAEL = 75 mg/kg/day
LOAEL > 75 mg/kg/day, not established.
Decreased body weight gain was observed at 30 mg/kg/day and higher, upon which the maternal LOAEL was based in previous risk assessments. However, body weight gain changes without changes in absolute body weight are not currently considered an adverse effect, so there is currently no maternal LOAEL.

Developmental NOAEL = 12 mg/kg/day
LOAEL = 30 mg/kg/day based on increased incidence of skeletal variations (predominantly lumbar ribs). At 75 mg/kg/day increased incidence of post-implantation loss, hydrocephaly and visceral anomaliea (cranial hemorrhage, dilated renal pelvis, dilated ureters, and displaced testis) were reported.
870.3700
Prenatal development in rodents (rat)
46808443 (2002)
0, 1, 4, 16, 64 mg/kg/day
Gavage
Acceptable/Guideline
Maternal NOAEL= 16 mg/kg/day
LOAEL= 64 mg/kg/day based on decreased body weight and food consumption, increased placental weight and increased incidence of swollen placenta.

Developmental NOAEL= 16 mg/kg/day
LOAEL= 64 mg/kg/day based on based on an increase in early and late resorptions, decreased fetal body weight and increased incidence of incomplete ossification of sternebrae.
870.3700
Prenatal developmental in non-rodents (rabbit)

Definitive Study
44721602 (1997)
0, 5, 10, 20, 40 mg/kg/day gavage
Acceptable/Guideline
Maternal NOAEL = 20 mg/kg/day
LOAEL = 40 mg/kg/day based on reduction in food consumption, and changes in various hematology parameters (reductions in hematocrit, hemoglobin, mean corpuscular volume and increases in platelet counts and alkaline phosphatase activity).

Developmental NOAEL = 20 mg/kg/day
LOAEL = 40 mg/kg/day based on increases in post-implantation losses.
870.3700
Prenatal developmental in non-rodents (rabbit)
44721603 (1991)
0, 4, 10, 25, 62.5 mg/kg/day (Exp. #1)
0, 2, 4, 10 mg/kg/day (Exp. #2)
Acceptable/Guideline
Maternal NOAEL = 25 mg/kg/day
LOAEL = 62.5 mg/kg/day based on body weight changes and slight clinical signs (anorexia/reduced or altered fecal output, cold ears).

Developmental NOAEL = 4 mg/kg/day
LOAEL = 10 mg/kg/day based on examining data from the two experiments.  Effects at 62.5 mg/kg/day show total litter loss, decreased live fetuses, increased early and late resorptions.  Effects at 25 mg/kg/day show some malformations: hydrocephaly (4 fetuses from 4 different litters, but NOT seen at 62.5 mg/kg/day) and limb effects (2 fetuses from 2 different litters, with one fetus with same effect at 62.5 mg/kg/d).  Hydrocephaly and limb effects were observed at 10 mg/kg/day in Experiment #2, but not at that same dose in Experiment #1.
870.3800
Reproduction and fertility effects
2-generation- rat
46808447 (2002)
0, 30, 150 and 750 ppm
M/F: 0/0, 2/2, 10.8/10.6, 53.2/53.0  mg/kg/day
Acceptable/Guideline
Parental/Systemic NOAEL (M/F) = 9.8/10.8 mg/kg/day
LOAEL (M/F) = 49.4/53.2 mg/kg/day based on: decreased body weight and decreased weight gain in male and female parental animals, increased incidence of fatty hepatocyte change in male parental animals, and increased incidence of spleen congestion in F1 parental females.

Reproductive NOAEL (M/F) = 49.4/ 10.8 mg/kg/day
LOAEL (M/F) = 53.2 mg/kg/day based on increased gestation length and decreased gestation index driven by dystocia (difficult labor).

Offspring NOAEL (M/F) = 9.8/10.8 mg/kg/day
LOAEL (M/F) = 49.4/53.2 mg/kg/day based decreased viability on lactation day 0 and decreased body weight in F2 offspring.
870.4100a
Chronic toxicity rodents (rat)
4472109 (1992)
0, 10, 100, 300, 1000 ppm
M: 0, 0.44, 4.3, 13.1, 43.9 mg/kg/day
F: 0, 0.52, 5.3, 16.0, 53.8 mg/kg/day
Acceptable/Guideline
NOAEL = (M/F) = 4.3/16.0 mg/kg/day
LOAEL = (M/F) = 13.1/ 53.8 mg/kg/day based on an increase in mean adjusted liver weights at 12 months (M) and 24 months (F), increase in spleen weights at 24 months (F), and increased hepatocellular lipid vacuolation  (M/F) and centrilobular hypertrophy (M/F).
870.4100b
Chronic toxicity- dog
44721610
0, 30, 300, 1000, 3000 ppm in diet
M: 0, 1.1, 12.0, 38.5, 110.0 mg/kg/day
F: 0, 1.1, 10.3, 36.8, 113.7 mg/kg/day
Acceptable/Guideline
NOAEL (M/F) = 12.0/10.3 mg/kg/day
LOAEL (M/F) = 38.5/36.8 mg/kg/day based on increased alkaline phosphatase activity (both sexes) and increased incidence of Kupffer cell pigmentation (females).
870.4200a
Carcinogenicity -
rat
44721611 (1992)
0, 100, 300, 1000 ppm
M: 0, 4.6, 13.8, 46.5 mg/kg/day
 F: 0, 5.5, 16.6, 56.2 mg/kg/day
Acceptable/Guideline
Non-neoplastic findings at (M/F) 13.8/56.2 mg/kg/day: increased incidence of hepatocellular lipid vacuolation  (M/F), centrilobular hypertrophy (M/F), liver pigment deposition (M), histiocytic foci in the spleen (M/F),and  increase in severity of chronic renal nephropathy (M). Evidence of mononuclear cell leukemia (F).
870.4200b
Carcinogenicity- mouse
44721612 (1992)
0, 30, 300, 1000 ppm
M: 0, 4.5, 39.5, 166.9 mg/kg/day
 F: 0, 5.9, 58.1, 195.5 mg/kg/day
Acceptable/Guideline
Non-neoplastic findings at (M/F) 166.9/58.1 mg/kg/day: increase in vacuolation, hypertrophy, splenic atrophy and adrenal corticomedullary pigmentation, sinusoidal hypercellularity/single cell necrosis. Neoplastic findings: increase in liver cell tumors at high dose (M/F): Increased incidence of hepatocellular adenomas in males and hepatocellular carcinomas in females.
870.5100
Salmonella typhimurium and Escherichia coli Reverse Mutation Assay
44721613 (1990)
Up to limit dose of 5000 μg/ plate (S. typhimurium) and  (E. coli) in the presence and absence of metabolic activation
(+ S9)
Acceptable/Guideline
Test material was not cytotoxic with or without S9 activation in five S. typhimurium strains and one strain of E. coli, and did not induce a genotoxic response in any strain.
870.5300
In vitro Mouse Lymphoma Mutagenesis Assay
WL136184*

*cis only isomer
44721615 (1991)
Six doses up to 125 μg/ml (toxicity was observed above that dose)  in the presence and absence of metabolic activation
(+ S9)
Acceptable/Guideline
There was no evidence of biologically significant induction of mutant colonies.
870.5375
In vitro Cytogenetics Test
44721616 (1991)
From 6.25 to 400 g/ml, with and without metabolic activation (+ S9) Acceptable/Guideline
Weakly positive (induced chromosome aberrations in Chinese hamster ovary cells) in the presence of S9 activation, negative without S9 activation.
870.5395
In vivo Mammalian Erythrocyte Micronucleus Test: Mouse
44721618 (1995)
Up to the limit dose of 2000 mg/kg
Acceptable/Guideline
There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or collection time.
870.5550
In vivo/in vitro Mammalian UDS test
Rat
44721620 (1995)
Up to the limit dose of 2000 mg/kg
Acceptable/Guideline
Negative for unscheduled DNA synthesis.
870.6200b
Subchronic Neurotoxicity- rat
46808440 (2002)
0, 50, 170, 500 ppm
M: 0, 4.84, 15.69, 47.08 mg/kg/day
F: 0, 5.10, 17.62, 49.82 mg/kg/day
Acceptable/Non-guideline
Systemic NOAEL (M/F) = 4.84/5.10  mg/kg/
Systemic LOAEL (M/F) = 15.69/ 17.62 mg/kg/ based on decreases in body weight and food consumption.

Neurotoxicity NOAEL (M/F)  47.08/49.82 mg/kg/day
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%) and 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 pharmacokinetics: rat
46808449 (2002)
male/female rat
single low dose: 2 mg/kg
single high dose: 200 mg/kg
repeated dose: 2 mg/kg
Acceptable/Non-guideline
Low potential for bioaccumulation following single or multiple dosing regimen.  The time to maximum plasma concentration for male and female rats treated with either 2 mg/kg or 200 mg/kg was the earliest sampling interval, 0.25 hours and 4 hours, respectively The plasma half-life of low- and high-dose rats was slightly shorter in males than females, ~20-25 hours and ~34 hours, respectively.
870.7600
In Vivo Dermal Penetration Study
46808450 (1990)
Acceptable/Non-guideline
Dermal absorption= 16%  (72 hrs)
870.7800
Immunotoxicity Study:  male rat
48107301 (2010)

0, 70, 210, 6300 ppm
0, 5.4, 17, 52 mg/kg/day