1 of 94 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: February 7, 2006 MEMORANDUM SUBJECT: 1,2,4 Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health Aggregate Risk Assessment in Support of Reregistration and Registration Actions for Triazole derivative Fungicide Compounds. Risk Assessment Type: Single Chemical Aggregate PC Code: 600074   1,2,4 Triazole 600011   Triazole Alanine 600082   Triazole Acetic Acid DP Number: 322215 FROM: Michael Doherty, Ph. D., Chemist, RAB 2; Kathleen Raffaele, Ph. D., Toxicologist, RAB 3; Kit Farwell, DVM, Toxicologist, RRB 1; Steve Dapson, Ph. D., Branch Senior Scientist, RAB 3; Kelly Schumacher, M. S., Toxicologist, RAB 2; Jack Arthur, Environmental Health Scientist, RAB 3; David Hrdy, Biologist, CEB; Health Effects Division ( 7509C)

Iwona Maher, Chemist, ERB 1 Environmental Fate and Effects Division ( 7507C)

THROUGH: Richard Loranger, Ph. D., Branch Senior Scientist Registration Action Branch 2 Health Effects Division ( 7509C)

TO: Tamue Gibson/ Cynthia Giles Parker, FB Registration Division ( 7505C)

Michael Goodis, RRB 3 Special Review and Reregistration Division ( 7508C)

Susan Lewis, RRB 1 Special Review and Reregistration Division ( 7508C) 2 of 94 Table of Contents 1.0 Executive Summary..................................................................................................... 5 Preface and General Information................................................................................................. 7 2.0 Chemical Profile.......................................................................................................... 8 2.1 Summary of Registered/ Proposed Uses Considered in These Assessments .............. 8 3.0 Metabolism Assessment ............................................................................................ 12 3.1 Comparative Metabolic Profile .............................................................................. 12 1,2,4 Triazole ........................................................................................................................... 13 4.0 Hazard Characterization/ Assessment ......................................................................... 13 4.1 Hazard Characterization......................................................................................... 13 4.2 FQPA Hazard Considerations ................................................................................ 17 4.2.1 Adequacy of the Toxicity Data Base .............................................................. 17 4.2.2 Evidence of Neurotoxicity.............................................................................. 17 4.2.3 Developmental Toxicity Studies..................................................................... 18 4.2.4 Reproductive Toxicity Study.......................................................................... 18 4.2.5 Additional Information from Literature Sources............................................. 18 4.2.6 Pre and/ or Postnatal Toxicity......................................................................... 18 <IP_ADDRESS> Determination of Susceptibility.................................................................. 18 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Postnatal Susceptibility .................................................................................................... 19 4.3 Recommendation for a Developmental Neurotoxicity Study.................................. 19 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study.......... 20 4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study.... 20 <IP_ADDRESS> Rationale for the UFDB ( when a DNT is recommended).............................. 21 4.4 Hazard Identification and Toxicity Endpoint Selection .......................................... 21 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49........................................ 21 4.4.2 Acute Reference Dose ( aRfD)  General Population....................................... 21 4.4.3 Chronic Reference Dose ( cRfD)..................................................................... 21 4.4.4 Incidental Oral Exposure ( Short Term) .......................................................... 22 4.4.5 Incidental Oral Exposure ( Intermediate Term) ............................................... 22 4.4.6 Dermal Absorption......................................................................................... 22 4.4.7 Dermal and Inhalation Exposure ( Short Term)............................................... 23 4.4.8 Dermal and Inhalation Exposure ( Intermediate and Long Term)................... 23 4.4.9 Margins of Exposure and Levels of Concern.................................................. 23 4.4.10 Recommendation for Aggregate Exposure Risk Assessments......................... 23 4.4.11 Classification of Carcinogenic Potential ......................................................... 24 4.5 Special FQPA Safety Factor .................................................................................. 25 4.6 Endocrine disruption.............................................................................................. 26 5.0 Public Health Data..................................................................................................... 27 6.0 Exposure Characterization/ Assessment...................................................................... 27 6.1 Dietary Exposure/ Risk Pathway............................................................................. 27 6.1.1 Residue Profile .............................................................................................. 27 <IP_ADDRESS> Residues in Food........................................................................................ 27 3 of 94 <IP_ADDRESS> Residues in Water ...................................................................................... 32 6.1.2 Acute and Chronic Dietary Exposure and Risk............................................... 32 6.2 Residential ( Non Occupational) Exposure/ Risk Pathway....................................... 34 6.2.1 Home Uses .................................................................................................... 34 <IP_ADDRESS> Application Scenarios ................................................................................ 34 <IP_ADDRESS> Postapplication Scenarios........................................................................... 37 6.2.2 Recreational Use Sites ................................................................................... 40 6.2.3 Other ( Spray Drift, etc.) ................................................................................. 40 6.2.4 Pharmaceutical Uses ...................................................................................... 41 7.0 Aggregate Risk Assessments and Risk Characterization ............................................ 41 7.1 Short term Aggregate Risk .................................................................................... 42 7.2 Intermediate term Aggregate Risk ......................................................................... 42 8.0 Cumulative Risk Characterization/ Assessment .......................................................... 43 9.0 Occupational Exposure/ Risk Pathway........................................................................ 44 10.0 Data Needs and Label Requirements ......................................................................... 44 10.1 Toxicology ............................................................................................................ 44 10.2 Residue Chemistry................................................................................................. 44 10.3 Occupational and Residential Exposure ................................................................. 44 11.0 Hazard Characterization/ Assessment ............................................................................ 45 11.1 Hazard Characterization......................................................................................... 45 11.1.1 Database Summary ........................................................................................ 45 <IP_ADDRESS> Studies available and considered ............................................................... 45 <IP_ADDRESS> Mode of action, metabolism, and toxicokinetic data .................................. 45 <IP_ADDRESS> Sufficiency of studies/ data ........................................................................ 46 11.1.2 Toxicological Effects ..................................................................................... 47 <IP_ADDRESS> Acute toxicity .............................................................................................. 47 <IP_ADDRESS> Subchronic, Chronic, and Other Toxicity .................................................... 48 11.1.3 Dose Response .............................................................................................. 51 11.2 FQPA Hazard Considerations ................................................................................ 61 11.2.1 Adequacy of the Toxicity Data Base .............................................................. 61 11.2.2 Evidence of Neurotoxicity.............................................................................. 61 11.2.3 Developmental Toxicity Studies..................................................................... 62 <IP_ADDRESS> Developmental Toxicity Study in Rats ...................................................... 62 <IP_ADDRESS> Developmental Toxicity Study in Rabbits ................................................. 62 11.2.4 Reproductive Toxicity Study.......................................................................... 62 11.2.5 Additional Information from Literature Sources............................................. 63 11.2.6 Pre and/ or Postnatal Toxicity......................................................................... 63 <IP_ADDRESS> Determination of Susceptibility................................................................. 63 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Postnatal Susceptibility.............................................................................................. 63 11.3 Recommendation for a Developmental Neurotoxicity Study.................................. 64 11.3.1 Evidence that supports requiring a Developmental Neurotoxicity Study......... 64 11.3.2 Evidence that supports not requiring a Developmental Neurotoxicity Study... 64 <IP_ADDRESS> Rationale for the UFDB .............................................................................. 64 11.4 Hazard Identification and Toxicity Endpoint Selection .......................................... 64 11.4.1 Acute Reference Dose ( aRfD)  Females ( 13 to 49 years of age) .................... 64 4 of 94 11.4.2 Acute Reference Dose ( aRfD)  General Population....................................... 65 11.4.3 Chronic Reference Dose ( cRfD)..................................................................... 65 11.4.4 Incidental Oral Exposure................................................................................ 66 11.4.5 Dermal Absorption......................................................................................... 66 11.4.6 Dermal Exposure ( Short, Intermediate, and Long term)............................... 66 11.4.7 Inhalation Exposure ( Short, Intermediate, and Long term)........................... 66 11.4.8 Margins of Exposure and Levels of Concern.................................................. 66 11.4.9 Recommendation for Aggregate Exposure Risk Assessments......................... 67 11.4.10 Classification of Carcinogenic Potential ..................................................... 67 11.5 Special FQPA Safety Factor .................................................................................. 67 11.6 Endocrine Disruption............................................................................................. 69 12.0 Public Health Data..................................................................................................... 69 13.0 Exposure Characterization/ Assessment...................................................................... 69 13.1 Dietary Exposure/ Risk Pathway............................................................................. 69 13.1.1 Residue Profile .............................................................................................. 69 <IP_ADDRESS> Residues in Food....................................................................................... 69 <IP_ADDRESS> Residues in Drinking Water ...................................................................... 71 13.1.2 Acute and Chronic Dietary Exposure and Risk............................................... 72 13.2 Residential ( Non Occupational) Exposure/ Risk Pathway....................................... 72 14.0 Aggregate Risk Assessments and Risk Characterization ............................................ 72 15.0 Cumulative Risk Characterization/ Assessment .......................................................... 72 16.0 Occupational Exposure/ Risk Pathway........................................................................ 73 17.0 Data Needs and Label Requirements ......................................................................... 73 17.1 Toxicology ............................................................................................................ 73 17.2 Residue Chemistry................................................................................................. 73 17.3 Occupational and Residential Exposure ................................................................. 73 References ................................................................................................................................ 73 Attachment 1: Report of the Ad Hoc Triazole HED Peer Review Committee ........................... 75 Attachment 2: Second Report of the Ad Hoc Triazole HED Peer Review Committee ............... 82 Attachment 3: Triazole Summaries  Additional Data Summaries/ Literature Articles............... 87 5 of 94 1.0 Executive Summary The Office of Pesticide Program's Health Effects Division ( HED) has conducted aggregate human health risk assessments for 1,2,4 triazole and triazole conjugates ( triazole alanine and triazole acetic acid). These assessments include evaluation of risks for various population subgroups, including those comprised of infants and children. 1,2,4 Triazole and its conjugates are common metabolites to the class of compounds know as the triazoles ( a. k. a. triazolederivative fungicides, T D fungicides, conazoles). These compounds all have a triazole ring with nitrogen atoms at the 1, 2, and 4 positions. In 2000, the Agency delayed granting registration of any new triazole pesticides or new uses of already registered triazole pesticides pending resolution of a number of toxicological, occupational/ residential, and dietary exposure concerns, and issued data call ins for a number of studies. At this time sufficient data are available to support a risk assessment for these metabolites. Based on the toxicological information available at this time, HED has conducted two assessments: one for 1,2,4 triazole ( 1,2,4 T) and one for combined exposure to triazole alanine ( TA) and triazole acetic acid ( TAA). Both assessments are highly conservative, screening level evaluations in terms of the hazards associated with these compounds ( e. g., use of the maximum combination of uncertainty factors) and potential dietary and non dietary exposures ( i. e., high end estimates of both dietary and non dietary exposures).

Triazole alanine and triazole acetic acid residues are primarily associated with plant commodities whereas 1,2,4 triazole is associated with rats and livestock, with lesser amounts being found in plants. All three metabolites may occur in the environment, with their relative proportions depending on a variety of environmental conditions. The degree of formation of these metabolites in plants, animals, and the environment is highly dependent on the properties of the various parent triazole pesticides.

Available studies indicate that 1,2,4 triazole affects the central and peripheral nervous systems, reproductive tissues of both sexes, and the hematological system. Developmental and reproductive effects have been noted for this compound. Based on the available metabolism data from rats and livestock, 1,2,4 triazole may form in humans following exposure to parent triazole compounds. In estimating exposures, HED has included direct exposure to residues of 1,2,4 triazole as well as indirect exposure via exposure to parent triazole pesticides and subsequent conversion to 1,2,4 triazole. Triazole derivative fungicides ( T D fungicides) have registered or requested uses for a number of food commodities as well as registered and proposed uses for turf and ornamental plantings. HED has assessed potential dietary and non dietary exposures. The assessments are based on health protective assumptions regarding the toxicology of and exposure to 1,2,4 triazole. For all individual exposure pathways as well as for aggregate exposure, risk estimates fall below HED's level of concern for all population subgroups.

Relative to triazole alanine, fewer studies are available depicting the toxicological effects of the triazole conjugates. For purposes of this risk assessment, HED has assumed that the triazole conjugates are all toxicologically equivalent to triazole alanine. The available studies found developmental skeletal effects, decreased body weight and body weight gain, and decreased leukocytes and triglycerides. The triazole conjugates are generally not found in animal metabolism studies; therefore, HED has only assessed the direct exposure to these compounds. Furthermore, residues of TA and TAA are formed, and remain, within plant structures, making 6 of 94 them unavailable for dermal or hand to mouth exposures. Therefore, HED has assessed exposure to the triazole conjugates for the dietary pathway only. Exposure estimates for the triazole conjugates indicate that risk associated with these compounds is below HED's level of concern. The exposure estimates are based on health protective assumptions regarding residues of the triazole conjugates.

Based on the available information and on conservative estimates of hazard and exposure, there are no human health risk issues associated with 1,2,4 triazole or its metabolites that would preclude re registration of the triazole derivative fungicides registered to date or conditional registration of the triazole derivative fungicide uses that have been proposed as of September 1, 2005. HED recommends that resolution of the following issues be a condition of registration for new uses and new active ingredients.

  Chemistry:  Final two year storage stability study with 1,2,4 triazole;  Resolution of concerns regarding the prevalence of conjugated residues of TA and the ability of the analytical method to quantify them.   Toxicology:  Free triazole:

  Developmental neurotoxicity study in rats;

  Chronic toxicity/ oncogenicity study in male rats and female mice [ This study, included in the original data call in, has not been submitted. A previous waiver request for this study was denied; a new waiver request submitted in August, 2005, is under review];

  Acute neurotoxicity study in rats [ This study, included in the original data call in, was placed in reserve pending the results of the combined subchronic/ neurotoxicity study, in response to a previous waiver request. A new waiver request for this study was submitted in August 2005, and is under review.];  Triazole alanine:

  Developmental toxicity study in rabbits;

  Chronic toxicity study in rats, conducted according to current guidelines that include neurobehavioral assessments, with additional neuropathology evaluations conducted according to the neurotoxicity guidelines;  Triazole acetic acid:

  Developmental toxicity study in rabbits;

  Combined 90 day feeding/ neurotoxicity study in rats;   Occupational/ Residential Assessment:  None. HED has agreed to waive previous requirements for dislodgeable foliar and turftransferable residue studies.

New uses for triazole pesticides should also be examined in terms of potential residues of 1,2,4 triazole and its conjugates. This assessment may require revision if new uses are for sites not already addressed by the current list of registered or proposed uses, if the formation of the metabolites exceeds the estimates used herein, or if required toxicity data raise concerns not addressed by the current risk assessment. 7 of 94 Preface and General Information This document addresses human health risks associated with metabolites that are common to the class of compounds know as triazoles. These compounds all contain a triazole ring with nitrogen atoms at the 1,2, and 4 positions ( Figure 1.1). The HED has identified 1,2,4 triazole ( 1,2,4 T) and its conjugates, triazole alanine ( TA), triazole acetic acid ( TAA), triazole pyruvic acid, and triazole lactic acid as compounds with potentially significant toxicological properties. The occurrence of triazole pyruvic acid and triazole lactic acid in metabolism studies is low; therefore, those two metabolites have not been explicitly included in this risk assessment. In 2000 the Agency delayed granting the registration of any new triazole derivative fungicides ( T D fungicides) or new uses of registered T D fungicides pending resolution of issues regarding toxicology, dietary exposure, and non dietary exposure. At this time, the HED has enough information to proceed with risk assessments for these compounds, conditional on submission of additional toxicological and residue chemistry data as discussed in Sections 10 and 17.

This risk assessment is intended to serve as a support document for registration and reregistration activities of the triazole derivative fungicides. There are large number of new active ingredients and new uses that are pending for this class of compounds due to the five year period that has elapsed since the Agency noted 1,2,4 triazole and its conjugates as residues of concern. This assessment takes into consideration the compounds and use sites that are being evaluated for reregistration, as well as the new compounds and new use sites that have been submitted to the Agency ( as of 9/ 1/ 05). OPP is expecting to receive a significant number of additional new active ingredient and new use requests. HED has designed the assessments presented herein to be extremely conservative so that the assumptions associated with the risk estimates will remain valid for the majority of these expected requests. Reexamination of the risk estimates for 1,2,4 triazole, triazole alanine, and triazole acetic acid will be required:   For crops or use sites that have not been included in the current established/ requested set of uses ( e. g., potatoes)   Upon review of metabolic information for a new compound or a new use showing formation of 1,2,4 triazole, triazole alanine, triazole acetic acid, and/ or labile conjugates that exceeds the maxima assumed in this assessment.   Upon review of the required toxicology data for 1,2,4 triazole and its conjugates as discussed below.

In examining exposure to 1,2,4 triazole, HED has considered both direct exposure to this compound and indirect exposure resulting from the in vivo formation of 1,2,4 triazole following exposure to parent triazole derivative compounds. At this time, the degree to which the pharamcokinetics ( PK) and pharamacodynamics ( PD) of exogenous 1,2,4 triazole are the same as the PK and PD of 1,2,4 triazole formed following in vivo metabolism is unknown. Specifically, this analysis assumes that the target tissue, the dose at the target tissue, and timing of exposure and toxic effect are similar between the exogenous and internally generated forms of 1,2,4 triazole. As the purpose of the current risk assessment is to provide high end, screening level risk estimates, HED has made the conservative assumption that the direct and indirect exposures can occur simultaneously and are toxicologically equivalent. 8 of 94 2.0 Chemical Profile Following application of a triazole derivative fungicide, biological and/ or chemical processes may cause the triazole ring to be released from the parent compound. In rats and livestock, 1,2,4 triazole is relatively stable and is the terminal form of the triazole ring. In plants, the 1,2,4 triazole molecule may become conjugated to serine. The resulting compound, triazole alanine, may be oxidized to form triazole acetic acid. Triazole alanine and triazole acetic acid are the primary terminal forms of the triazole ring in plants, though some 1,2,4 triazole may remain. All three compounds were identified in environmental fate studies and there is evidence that in the environment there is significant conversion between all three forms. The degree of formation of any given form of the triazole ring is highly dependent on the nature and properties of the parent compound. Although other triazole conjugates such as triazole lactic acid and triazole pyruvate have been observed in plant metabolism studies, HED has concluded that TA and TAA are the predominant conjugates that need to be included in the dietary risk assessment.

NH N N 1,2,4 Triazole ( a. ka. 1,2,4 T; free triazole) CAS No. 288 88 0 PC Code: 600074 Molecular wgt.: 69.07 N N N NH2 O OH Triazole Alanine ( a. ka. TA) CAS No. 86362 20 1 PC Code: 600011 Molecular wgt.: 156.15 N N N O OH Triazole Acetic Acid ( a. k. a. TAA) CAS No. 28711 29 7 PC Code: 600082 Molecular wgt.: 127.10 Figure 1.1. Chemical structures for 1,2,4 triazole, triazole alanine, and triazole acetic acid Based on the currently available toxicology data, the toxicological effects of 1,2,4 T are sufficiently different from those of the conjugates ( TA, TAA) that it is appropriate to consider their risks separately. As such, this document consists of two risk assessments, one for 1,2,4 T ( Sections 4   10) and one for combined residues of TA and TAA ( Sections 11   17).

We note that in conducting these assessments we have used maximum metabolic conversion factors and have not made an effort to maintain mass balance with respect to residues of 1,2,4 T versus TA/ TAA. As a result, a summation of the residue estimates used in these assessments results in a total residue estimate that may be greater than physically possible based on conservation of mass.

2.1 Summary of Registered/ Proposed Uses Considered in These Assessments At this time, there are 13 registered triazole derivative fungicides with 53 uses on foods and 11 uses on non foods ( i. e., ornamental plants, turf, etc.). Additionally, the Agency has been petitioned to establish registrations for 14 triazole derivative fungicides with 69 food uses and 4 non food uses. This risk assessment addresses all registered and requested uses as of September 1, 2005. These uses are summarized in Table 2.1. 9 of 94 Table 2.1. Summary of Triazole derivative Fungicides and Uses Addressed in these Risk Assessments.

Sorted by Active Ingredient Sorted by Use Site Active Ingredient Use Site Use Site Active Ingredient Bitertanol Banana Fenbuconazole Banana Myclobutanil Ornamentals Almond Propiconazole Bromuconazole Turf Apple Difenoconazole Coffee Myclobutanil Soybean Artichoke Triadimefon Cyproconazole Turf Myclobutanil Apple Tebuconazole Banana Asparagus Triadimefon Barley Bitertanol Canola Bromuconazole Grape Difenoconazole Sweet Corn Epoxiconazole Difenoconazole Wheat Fenbuconazole Epoxiconazole Banana Hexaconazole Almond Metconazole Banana Myclobutanil Blueberry Propiconazole Citrus Fruit Group Tebuconazole Cranberry Tetraconazole Grape Banana Triadimenol Ornamentals Difenoconazole Peanut Prothioconazole Pecan Tebuconazole Pome Fruit Group Barley Triticonazole Stone Fruit Group Berry Group Propiconazole Sugarbeat Blueberry Fenbuconazole Turf Propiconazole Fenbuconazole Wheat Bulb Vegetable Group Tebuconazole Flusilazole Soybean Myclobutanil Hexaconazole Banana Caneberry Triadimefon Cucurbit Vegetable Group Difenoconazole Ornamentals Canola Prothioconazole Sweet Corn Carrot Propiconazole Ipconazole Turf Celery Propiconazole Banana Propiconazole Metconazole Soybean Cereal Grain Group Triadimenol Almond Fenbuconazole Artichoke Citrus Fruit Group Propiconazole Asparagus Cyproconazole Myclobutanil Banana Coffee Tebuconazole 10 of 94 Table 2.1. Summary of Triazole derivative Fungicides and Uses Addressed in these Risk Assessments.

Sorted by Active Ingredient Sorted by Use Site Active Ingredient Use Site Use Site Active Ingredient Caneberry Triadimefon Cotton Propiconazole Cucurbit Vegetable Group Tebuconazole Currant/ Gooseberry Corn Triadimenol Grape Myclobutanil Hops Tebuconazole Mayhaw Cotton Triadimenol Ornamentals Fenbuconazole Peppermint/ Spearmint Cranberry Propiconazole Peppers Ipconazole Pome Fruit Group Myclobutanil Snap Bean Cucurbit Vegetable Group Tebuconazole Stone Fruit Group Myclobutanil Strawberry Currant/ Gooseberry Propiconazole Sugar Beet Prothioconazole Tomato Dry Bean and Pea Group Tebuconazole Turf Difenoconazole Ornamentals Fenbuconazole Paclobutrazol Turf Myclobutanil Almond Tebuconazole Banana Grape Triadimefon Berry Group Propiconazole Bulb Vegetable Group Grass Grown for Seed Tebuconazole Carrot Myclobutanil Celery Hops Tebuconazole Cereal Grain Group Lychee Tebuconazole Citrus Fruit Group Mango Tebuconazole Corn Myclobutanil Cranberry Mayhaw Triadimefon Currant/ Gooseberry Oats Tebuconazole Grass Grown for Seed Okra Tebuconazole Ornamentals Bromuconazole Peanut Fenbuconazole Pecan Ipconazole Pineapple Myclobutanil Pistachio Paclobutrazole Sorghum Propiconazole Soybean Tebuconazole Stone Fruit Group Ornamentals Triadimefon Strawberry Fenbuconazole Sugar Beet Propiconazole Propiconazole Sugarcane Peanut Prothioconazole 11 of 94 Table 2.1. Summary of Triazole derivative Fungicides and Uses Addressed in these Risk Assessments.

Sorted by Active Ingredient Sorted by Use Site Active Ingredient Use Site Use Site Active Ingredient Turf Tebuconazole Wild Rice Tetraconazole Barley Fenbuconazole Canola Pecan Propiconazole Dry Bean and Pea Group Peppermint/ Spearmint Myclobutanil Peanut Peppers Myclobutanil Rice Propiconazole Soybean Pineapple Triadimefon Prothioconazole Wheat Propiconazole Asparagus Pistachio Tebuconazole Banana Fenbuconazole Barley Myclobutanil Bulb Vegetable Group Tebuconazole Coffee Pome Fruit Group Triadimefon Corn Rice Prothioconazole Cotton Snap Bean Myclobutanil Cucurbit Vegetable Group Propiconazole Dry Bean and Pea Group Sorghum Triadimenol Grape Cyproconazole Grass Grown for Seed Flusilazole Hops Metconazole Lychee Propiconazole Mango Prothioconazole Oats Tebuconazole Okra Soybean Tetraconazole Ornamentals Fenbuconazole Peanut Myclobutanil Pistachio Propiconazole Pome Fruit Group Stone Fruit Group Tebuconazole Soybean Myclobutanil Stone Fruit Group Strawberry Propiconazole Sunflower Myclobutanil Tree Nuts Group Propiconazole Turf Tetraconazole Turnip Sugar Beet Fenbuconazole Tebuconazole Wheat Sugarcane Propiconazole Banana Sunflower Tebuconazole Peanut Difenoconazole Soybean Sweet Corn Ipconazole Sugar Beet Tomato Myclobutanil Tetraconazole Turf Tree Nuts Group Tebuconazole Triadimefon Artichoke Turf Bromuconazole 12 of 94 Table 2.1. Summary of Triazole derivative Fungicides and Uses Addressed in these Risk Assessments.

Sorted by Active Ingredient Sorted by Use Site Active Ingredient Use Site Use Site Active Ingredient Asparagus Cyproconazole Caneberry Fenbuconazole Coffee Ipconazole Grape Myclobutanil Mayhaw Paclobutrazole Ornamentals Propiconazole Pineapple Tebuconazole Pome Fruit Group Tetraconazole Turf Triadimefon Banana Triticonazole Cereal Grain Group Turnip Tebuconazole Corn Difenoconazole Cotton Fenbuconazole Triadimenol Sorghum Prothioconazole Barley Tebuconazole Turf Wheat Triticonazole Triticonazole Wheat Wild Rice Propiconazole 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile 1,2,4 Triazole; triazole alanine; and triazole acetic acid are common metabolites to the class of compounds known as triazoles. In plants, 1,2,4 T is rapidly conjugated with serine to form TA. The TA can then be oxidized to form TAA. The extent to which 1,2,4 T, TA, and/ or TAA forms in a given plant or animal is primarily dependent on the parent triazole derivative fungicide. Across the various parent compounds, maximum formation of 1,2 4 T in plants ranges from 0% of the total radioactive residue ( TRR) to 17% TRR, with the majority of compounds yielding 1,2,4 T at around 5 10% TRR. In rats, goats, and hens, maximum 1,2,4 T formation ranges from 0 to 77% TRR. Formation of 1,2,4 T in the rat is less than 20% TRR for the majority ( approximately 80%) of the triazole derivative fungicides for which data are available. Formation of TA ranges from 0 to 89% TRR in plants. Triazole acetic acid formation in plants ranges from 0 to 76% TRR. Triazole alanine and triazole acetic acid have generally not been found to be significant metabolites in rats, lactating goats, or laying hens. The exception to this appears to be fenbuconazole. In studies with radio labeled fenbuconazole fed to goats and hens, TA formation ranges from 0 to 35% TRR; formation of TA from fenbuconazole was not noted in the rat metabolism studies. There is evidence from toxicological studies that there can be limited reduction of TA to 1,2,4 T following oral exposure to TA.

In environmental fate studies, all three forms of triazole ( 1,2,4 T, TA, and TAA) have been found and there is evidence that the three can inter convert in soil and aquatic systems. At this time, there are not reliable data available for making general descriptions about the relative rates of formation of these compounds or any steady state equilibria that may occur. 13 of 94 1,2,4 Triazole 4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization 1,2,4 triazole ( free triazole) is a metabolite common to a number of triazole derivative pesticides, and is found in both mammalian ( rat) and plant metabolism studies. Although for most pesticides, mammals convert only a small proportion to free triazole ( less than 25%), two compounds ( tetraconazole and flusilazole) demonstrate relatively high conversion ( 68 77%) in rat metabolism studies. As a plant metabolite, and given the wide use of triazole derivative pesticides ( used as fungicides on many crops as well as on turf) free triazole is found in a variety of food commodities, including animal byproducts. 1,2,4 triazole appears to be relatively stable in the environment, and may be found in rotational crops as well as in water.

The available toxicology database for 1,2,4 triazole consists of 2 developmental toxicity studies ( in rats and rabbits), a reproductive toxicity study ( in rats), a combined subchronic/ neurotoxicity study ( in rats), and 28 and 90 day toxicity studies in mice. Two additional non guideline studies in rats ( a 30 day gavage study and an unacceptable 90 day subchronic study) provide limited additional information. No reliable data are available for dogs ( an incomplete study examining ocular toxicity only was submitted, but included very limited procedural information), and no chronic or oncogenicity studies have been submitted. Although limited chronic toxicity data ( chronic toxicity/ oncogenicity studies in male rats and female mice) were called in by RD in 2002 ( see TXR # 0052011), these studies have not been conducted and a new request to waive those studies has been recently submitted ( August 2005). HED has not yet completed an evaluation of the request and, to date, the data requirement remains. A previous waiver request, submitted by USTTF in March 2003 [ DP Barcode 289197], was reviewed by an HED peer review committee in June 2003, and was denied [ see attached memorandum, August 5, 2003, K. Raffaele to Bob Tomerlin, TXR# 0052012].

Available unacceptable metabolism studies indicate that 1,2,4 triazole is rapidly absorbed after oral administration and widely distributed in all evaluated tissues. Excretion occurs mostly via the urine, largely as unchanged parent ( 80 95%), although biliary canulation results suggest the possibility of some enterohepatic recirculation. With an estimated half life of 8 10 hours, excretion is largely completed within 48 hours of administration of a single dose.

Limited acute toxicity data for 1,2,4 triazole are available, but no complete guideline studies have been submitted ( Table 4.1). Available acute data indicate that 1,2,4 triazole is slightly toxic by the oral route ( Category III, with oral LD50 values ranging from 666 mg/ kg in rabbits to 3650 mg/ kg in mice) and slightly to moderately toxic by the dermal route ( dermal LD50s were less than 2000 mg/ kg in rabbits, and 3000 4000 mg/ kg in rats). Limited available information indicates that 1,2,4 triazole is slightly irritating or non irritating to the skin, but severely irritating to the eye. Based on the limited acute toxicity data, as well as the available developmental toxicity data ( see below), it appears that rabbits may be substantially more susceptible to 1,2,4 triazole than are rats or mice. 14 of 94 In spite of the limitations of the available database, a number of target organs and critical effects have been identified. 1,2,4 triazole targets the nervous system, both central and peripheral, as brain lesions ( most notably in the cerebellum) were seen in both rats and mice, and peripheral nerve degeneration was also seen in the subchronic neurotoxicity study in rats. In addition, brain weight decreases were seen in several studies, including in the offspring in the reproductive toxicity study. In the subchronic/ neurotoxicity study, there is evidence that effects progress over time, with an increase in incidence of clinical signs ( including tremors and muscle fasciculations) during weeks 8 and 13 that were not seen during earlier evaluations. Effects were also seen on reproductive organs in both sexes, most notably ovaries ( in rats) and testes ( in rats and mice), in both the reproductive toxicity and subchronic toxicity studies. Hematological changes, including slightly decreased hemoglobin and/ or hematocrit, have also been seen in multiple studies and species ( in rats at doses of 33 mg/ kg/ day and above, and in mice at doses of 487 mg/ kg/ day and above). Studies depicting the effects of chronic exposure to free triazole or its conjugates are not currently available. A request to waive chronic/ oncogenicity studies has been received by the Agency and is currently under review.

1,2,4 triazole also causes developmental toxicity in both rats and rabbits, including malformations, at doses similar to those inducing maternal toxicity ( decreased body weight gain in rats and clinical signs and mortality in rabbits). Developmental toxicity was also seen in the reproductive toxicity study, with offspring showing adverse effects on multiple endpoints ( including decreased brain and body weight) at doses lower than those at which effects were seen in parents. In addition, reproductive toxicity was seen in both sexes: at the highest dose ( 3000 ppm), only two F1 litters ( one pup/ litter) were produced, and neither survived to adulthood.

No data are available to directly evaluate the potential for carcinogenicity of 1,2,4 triazole. Available mutagenicity data are limited ( salmonella assays submitted by the USTTF and a Russian literature report ( MRID 45284011) of chromosomal aberrations in rat marrow cells), but negative. A large number of parent triazole derivative pesticides have been classified as carcinogens ( most also non mutagenic), but the relevance of that finding to expected effects of free triazole may be limited. The types of tumors associated with exposure to the parent chemicals are most commonly hepatocellular adenomas/ carcinomas in mice. Other tumor types vary considerably ( including liver tumors, thyroid tumors, ovarian tumors, testicular tumors, and bladder tumors). None of the tumor types are clearly associated with the proportion of free triazole formed in available rat metabolism studies. The previous HED peer review committee concluded that it was not possible to predict toxicity of free triazole based on toxicity seen with parent compounds: these conclusions and their rationale are discussed in the memoranda from those meetings ( see TXR Nos. 0052011 and 0052012, attached). This conclusion is supported by the recently submitted subchronic and reproductive toxicity studies for free triazole, identifying effects not consistently seen in toxicity studies with parent compound ( including pathologic lesions in the nervous system and reproductive failure seen at the high dose in the reproductive toxicity study). 15 of 94 Table 4.1. Acute Toxicity Profile   1,2,4 Triazole. Note that values on this table are based on submitted summary data; full study reports are not available. Guideline No. Study Type MRID( s) Results Toxicity Category 870.1100 Acute oral [ rat] 45284004, 45284001 LD50 = 1648 3080 mg/ kg III 870.1100 Acute oral [ mice] 45284001 LD50 = 3650 mg/ kg III 870.1100 Acute oral [ rabbit] 45324301 LD50 = 666 mg/ kg III 870.1200 Acute dermal [ rat] 45284004 LD50 = 3129 4200 mg/ kg III 870.1200 Acute dermal [ rabbit] 45324301, 45284006 LD50 = < 2000 mg/ kg II 870.1300 Acute inhalation [ mice] 45284011 LC50 4 h = 2200 mg/ m3 870.1300 Acute inhalation [ rats] 45284011 LC50 4 h = 2050 mg/ m3 870.2400 Acute eye irritation [ rabbit] 45284004, 45324301, 45284006 severe 870.2500 Acute dermal irritation [ rabbit] 45284004, 45324301, 45284006 not irritating to slightly irritating IV 870.2600 Skin sensitization [ species] No studies available unknown TABLE 4.2 Toxicity Profile for 1,2,4 triazole. Gdln Study Type/ Classification MRID Number Doses Results 870.3050 28 Day oral toxicity in mice Acceptable/ nonguideline 46467301 0, 50,250, 500, 2000 ppm M: 9, 47, 90, 356 mkd F: 12, 60, 120, 479 mkd NOAEL: 90 mg/ kg/ day LOAEL: 356 mg/ kg/ day ( male) based on testicular degeneration 870.3100 90 Day oral toxicity in mice Acceptable/ guideline 46467302 0, 500, 1000, 3000, 6000 ppm M: 80, 161, 487, 988 mkd F: 105, 215, 663, 1346 mkd NOAEL: 80 mg/ kg/ day LOAEL: 161 mg/ kg/ day based on   testicular wt and microscopic testicular changes At 487 mg/ kg/ day, also tremors,   brain wt, slight hematology changes. At 988 mg/ kg/ day, also cerebellar degeneration. 870.3050 30 Day oral toxicity in rats  gavage Acceptable/ nonguideline 45537401 0, 8, 57, 400 mg/ kg/ day NOAEL: < 8 mg/ kg/ day LOAEL: 8 mg/ kg/ day based on   adrenal wt At 57 mg/ kg/ day, also slight hematology changes. At 400 mg/ kg/ day, also clinical signs ( staggering, tremors, hunched)   BW 870.3100 90 Day oral toxicity in rats Unacceptable 45284007 0, 100, 500, 2500 ppm M: 8, 38, 212 mg/ kg/ day F: 10, 54, 267 mg/ kg/ day NOAEL: 38 mg/ kg/ day LOAEL: 212 mg/ kg/ day based on   BW, convulsions, fatty infiltration of liver in males 870.3100 870.6200 90 Day oral toxicity/ neurotoxicity in rats. Acceptable/ guideline 46467303 0, 250, 500, 3000, 1000/ 4000 ppm M: 16, 33, 183, 210 mkd F: 19, 41, 234, 275 mkd NOAEL: 16 mg/ kg/ day LOAEL: 33 mg/ kg/ day ( male) based on   TSH Also at 183 mg/ kg/ day and above:   BW, tremors and other FOB,   brain wt, neuropath in peripheral nerves and brain ( most prominently cerebellum); also slight   hematology, sl   CL. 870.3150 90 day oral toxicity study in nonrodents   No study available 16 of 94 TABLE 4.2 Toxicity Profile for 1,2,4 triazole. Gdln Study Type/ Classification MRID Number Doses Results 870.3200 21/ 28 Day dermal toxicity ( species)   No study available 870.3250 90 Day dermal toxicity ( species)   No study available 870.3465 90 Day inhalation toxicity ( species)   No study available 870.3700 Developmental toxicity in rats Acceptable/ guideline 45223401 45223402 0, 100, 200 mg/ kg/ day 0, 10, 30, 100 mg/ kg/ day Maternal NOAEL: 30 mg/ kg/ day Maternal LOAEL: 100 mg/ kg/ day based on   BW gain Developmental NOAEL: 30 mg/ kg/ day Developmental LOAEL: 100 mg/ kg/ day based on   fetal BW, skeletal variations, undescended testes Also at 200, increased resorptions and decreased number of viable fetuses, cleft palate, hydronephrosis, increased incidence of major malformations 870.3700 Developmental toxicity in rabbits Acceptable/ guideline 46492903 0, 5, 15, 30, 45 mg/ kg/ day Maternal NOAEL: 30 mg/ kg/ day Maternal LOAEL: 45 mg/ kg/ day based on mortality and clinical signs (  motor activity, head tilt, lacrimation, drooping eyelids, diarrhea, salivation) Developmental NOAEL: 30 mg/ kg/ day Developmental LOAEL: 45 mg/ kg/ day based on   fetal wt and urinary tract malformations 870.3800 Reproduction and fertility effects Acceptable 46467304 0, 250, 500, 3000 ppm M: 15, 31, 189 mkd F: 18, 36, 218 mkd Parental NOAEL: < 15 mg/ kg/ day Parental LOAEL: 15 mg/ kg/ day ( male) based on   BW and BWG in F1 males,   spleen weight in F1 females At 218 mg/ kg/ day: cerebellar lesions,   brain weight,   thyroid weight, Offspring NOAEL: < 19 mg/ kg/ day Offspring LOAEL: 19 mg/ kg/ day based on   BW, BWG and brain wt in F2 pups,   spleen weight in F2 female pups. Repro NOAEL: 15 mg/ kg/ day Repro LOAEL: 31 mg/ kg/ day based on abnormal sperm and  # of CL in F1 females At 218 mg/ kg/ day, reproductive failure ( no viable offspring),   CL in F0 parental females 870.4100a Chronic toxicity ( rodent)   No study available 870.4100b Chronic toxicity ( dog)   No study available 870.4200 Carcinogenicity ( rat)   No study available 870.4300 Carcinogenicity ( mouse)   No study available 870.[ ] Gene Mutation   See attached summaries 17 of 94 TABLE 4.2 Toxicity Profile for 1,2,4 triazole. Gdln Study Type/ Classification MRID Number Doses Results 870.[ ] Cytogenetics   No study available 870.[ ] Other Effects   No study available 870.6200a Acute neurotoxicity screening battery   No study available 870.6200b Subchronic neurotoxicity screening battery   See combined subchronic/ neurotoxicity study ( above)

870.6300 Developmental neurotoxicity   No study available 870.7485 Metabolism and pharmacokinetics  rat Unacceptable/ guideline 45284018 intraduodenal 1 mg/ kg i. v. 0.1  100 mg/ kg oral 0.4  866 mg/ kg Oral absorption of 80 95%. Excreted in urine ( 80 95%) and feces (< 15%), biliary excretion of 10% with enterohepatic recirculation. Unchanged triazole accounted for ~ 95% of radioactivity. 870.7600 Dermal penetration ( species)   No study available Special studies    See Attachment 3 4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base The available toxicity data base, including developmental toxicity studies in two species, a rat 2 generation reproductive toxicity study, and a subchronic/ neurotoxicity study in rats, is adequate to evaluate the potential for increased toxicity in infants and children.

4.2.2 Evidence of Neurotoxicity The available toxicity data base includes substantial evidence that exposure to 1,2,4 triazole causes neurotoxicity, including: neuropathological lesions in the brain ( seen in the 90 day subchronic toxicity studies in both mice and rats, and in the reproductive toxicity study in rats [ at doses of 183 mg/ kg/ day and above]); neuropathological lesions in the peripheral nervous system ( seen in the subchronic neurotoxicity study in rats at doses similar to those causing brain lesions); and decreases in brain weight in several studies in both rats and mice ( including decreases in brain weight of offspring in the reproductive toxicity study at doses not causing similar effects in F0 parents [ see below]). In addition, effects indicating potential neurotoxicity were seen in the FOB and motor activity evaluations in the subchronic neurotoxicity study in rats ( including tremors, muscle fasciculations, decreased arousal, decreased rearing, and decreased motor activity [ at doses similar to those causing brain lesions]), and in the developmental toxicity study in rabbits ( decreased motor activity, excessive salivation, hyperpnea, lacrimation, and head tilt [ seen in does at doses of 45 mg/ kg/ day and above]). 18 of 94 4.2.3 Developmental Toxicity Studies There is evidence of developmental toxicity in available studies in rats and rabbits. In rats, reduced fetal body weight, an increased incidence of runts, an increase in skeletal variations and an increase in incidence of undescended testes were seen at the LOAEL of 100 mg/ kg/ day, a dose also causing decreased body weight gain in dams. At 200 mg/ kg/ day in rats, there was an increase in malformations, including cleft palate and hydronephrosis, accompanied by an increase in post implantation loss. In rabbits, there was a decrease in fetal weight and an increase in incidence of urinary tract malformations at doses causing severe effects in does ( weight loss, multiple clinical signs, and increased mortality). The dose response in rabbits appears to be very steep, with no effects seen at 30 mg/ kg/ day, and mortality seen at 45 mg/ kg/ day ( only 15 mg/ kg/ day higher). In summary, there was no increase in quantitative severity in either species. There was an increase in qualitative sensitivity ( more severe effects) in rats, but not in rabbits.

4.2.4 Reproductive Toxicity Study There is evidence of increased offspring sensitivity, both quantitative and qualitative, in the reproductive toxicity study in rats. In adult ( F1) male offspring, decreases in body weight and brain weight were seen at doses of 15 16 mg/ kg/ day and 36 mg/ kg/ day, respectively. Similar effects were seen in parental ( F0) animals only at the highest dose of 189 mg/ kg/ day. Similarly, decreased brain weight and body weight were seen at ( parental) doses of 18.9 mg/ kg/ day in F2 pups, doses below those causing similar effects in F0 animals ( 189 mg/ kg/ day). Decreases in corpora lutea were seen in F1 females at 36 mg/ kg/ day; similar effects were not seen in F0 females ( increases in corpora lutea were seen at the high dose of 218 mg/ kg/ day; no changes were seen in mid dose F0 females).

4.2.5 Additional Information from Literature Sources None.

4.2.6 Pre and/ or Postnatal Toxicity Toxicity was seen in offspring in all studies in which they were evaluated. Pre natal findings include malformations as well as decreases in body weight. Findings in the reproductive toxicity study included effects on multiple organ systems, including decreases in body and brain weight and changes in reproductive organs ( including testes and ovaries). It is not possible to determine whether the effects seen in the reproductive toxicity study were due to pre or post natal exposure.

<IP_ADDRESS> Determination of Susceptibility Available data indicate evidence of increased qualitative sensitivity in the rat developmental toxicity study ( malformations seen at doses causing only decreased body weight gain in dams), and of quantitative sensitivity in the rat reproductive toxicity study ( similar effects seen at lower 19 of 94 doses in offspring). No increase in qualitative or quantitative sensitivity was seen in the rabbit, with malformations occurring at doses causing severe maternal toxicity.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility Although a developmental neurotoxicity study is unavailable, available data ( including nervous system lesions seen in adults and decreased brain weight in offspring) raise concern regarding developmental effects on the nervous system. In an attempt to address this concern, additional brain evaluations, including morphometric measures in weanlings, were performed in the available reproductive toxicity study. Although no effects were seen in either the qualitative or quantitative evaluations performed in pups, similar evaluations were not conducted in adult animals, in spite of evidence ( decreases in brain weight in F1 adults) of persistent effects on the central nervous system. It is also important to note that the highest dose evaluated in offspring, approximately 32 mg/ kg/ day, was substantially lower than that causing nervous system lesions in adults not developmentally dosed ( approximately 183 mg/ kg/ day in males in the subchronic/ neurotoxicity study and 189 mg/ kg/ day in F0 parents in the reproductive toxicity study). Although lesions were found in the peripheral nervous system ( PNS) in adults in the subchronic neurotoxicity study, there has been no evaluation of PNS tissues in offspring. In addition, behavioral evaluations of pups are not available; in the subchronic/ neurotoxicity study in adult rats, behavioral effects were detected during FOB and motor activity evaluations that were not seen in routine clinical observations. It is possible similar effects could occur in offspring during development, that would not have been detected in the reproductive toxicity study. Although the toxicity seen in offspring in the reproductive toxicity study indicates that offspring were exposed, the degree of lactational transfer, and thus the relative exposure of pups and adults, is unknown.

In addition to the nervous system lesions, 1,2,4 triazole also appears to impact the function of the endocrine system, based on reproductive failure at the high dose and delays in sexual maturation seen in the reproductive toxicity study, and on lesions in reproductive organs and changes in corpora lutea counts seen in various studies in rats and/ or mice.

The HED Risk Assessment Review Committee ( RARC) found the residual concern for the above described effects to be low, since the endpoint of concern ( effects in the offspring at the LOAEL in the reproductive toxicity study) is being used as the basis for the current risk assessment, and the appropriate uncertainty factors are being used to account for the residual uncertainty ( RARC Meeting 10/ 4/ 05; see below).

4.3 Recommendation for a Developmental Neurotoxicity Study The triazole toxicology team determined that a Developmental Neurotoxicity study is required based on multiple nervous system and endocrine related findings in available studies, including effects seen in offspring at doses not causing toxicity in F0 parental animals. 20 of 94 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study Pathological lesions of the nervous system have been seen in all evaluated species, in multiple studies:   Cerebellar lesions in the 90 day study in mice at 487/ 663 and 988/ 1346 mg/ kg/ day ( males/ females).   Brain and peripheral nervous system lesions and behavioral effects in rats at 183/ 234 and 210/ 275 mg/ kg/ day in the subchronic/ neurotoxicity study.   Decreases in brain weight and cerebellar lesions in both sexes of F0 adults in the rat reproductive toxicity study at 188/ 218 mg/ kg/ day ( M/ F).   Decreases in brain weight in adult offspring and weanlings in the rat reproductive toxicity study at doses of 16/ 19 and 33/ 41 mg/ kg/ day ( M/ F).   Slight increases in incidence of retinal degeneration in the 90 day subchronic/ neurotoxicity study in rats, at 183/ 234 and 210/ 275 mg/ kg/ day ( M/ F).   Possible changes in lens biochemistry were seen in an ocular toxicity study in dogs.

Clinical signs, indicative of neurobehavioral effects have been seen in multiple studies:   Effects were seen during FOB evaluations ( including tremors, muscle fasciculations, and decreases in rearing) and motor activity evaluations in the subchronic/ neurotoxicity study in rats, at 183/ 234 and 210/ 275 mg/ kg/ day ( M/ F).   Clinical signs, including gait and postural changes, tremors, and slight convulsions, were seen in two older rat toxicity studies ( 30 day gavage and 90 day dietary).   Clinical signs indicative of neurotoxicity were seen in does in the rabbit developmental toxicity study.

Possible endocrine mediated effects have been seen in multiple studies and species:   Testicular changes in mice ( 28 and 90 day mouse studies), sperm abnormalities in rats ( reproductive toxicity study), decreases in testes weight in old rat 30 and 90 day toxicity studies.   Ovarian changes in rats ( 90 day subchronic rat and reproductive toxicity study in rats).   Delays in sexual maturation in rat reproductive toxicity study.   Reproductive failure at high dose in rat reproductive study ( only two litters produced, with no pups surviving lactation).   Increased incidence of undescended testicle in rat developmental toxicity study.   Dose related decreases in TSH at 33 mg/ kg/ day and above in male rats in the subchronic/ neurotoxicity study.

4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study   No effects were seen in morphometric evaluation of weanling rats in the reproductive toxicity study.

  No CNS malformations were seen in available developmental toxicity studies in rats and rabbits. 21 of 94 <IP_ADDRESS> Rationale for the UFDB ( when a DNT is recommended)

Based on the evidence described in Section 4.3.1 regarding the concern for neurotoxic effects in developing offspring, as well as other data gaps ( lack of chronic studies, oncogenicity studies, non rodent toxicity studies), the triazole toxicology team determined that a database UF should be set at 10x. The need for this factor will be re evaluated upon receipt of the additional required toxicology data ( see Section 10.1). A larger factor will be used for some endpoints due to failure to identify a NOAEL in the reproductive toxicity study ( see below).

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 Study Selected: Developmental Toxicity study in rabbits MRID Number: MRID 46492903 Dose and Endpoint for Establishing aRfD: 30 mg/ kg/ day, based on urinary tract malformations seen at the LOAEL of 45 mg/ kg/ day Uncertainty Factor( s): UF= 1000 ( 10x for inter species variability, 10x for intra species variability, and 10x for data gaps and FQPA concerns) Comments about Study/ Endpoint/ Uncertainty Factor: Identified developmental toxicity suitable for this exposure duration. Although changes in birth weight and in weanling brain weight were seen in offspring from the reproductive toxicity study, these were seen at the LOAEL in the F2 generation only, and thus are unlikely to occur following a single exposure.

Acute RfD = 30 mg/ kg/ day ( NOAEL) ÷ 1000 ( UF) = 0.03 mg/ kg/ day 4.4.2 Acute Reference Dose ( aRfD)  General Population Study Selected: Developmental Toxicity study in rabbits MRID Number: MRID 46492903 Dose and Endpoint for Establishing aRfD: NOAEL= 30 mg/ kg/ day, based on clinical signs and mortality in does seen at the LOAEL of 45 mg/ kg/ day, Uncertainty Factor( s): UF= 1000 ( 10x for inter species variability, 10x for intra species variability, and 10x for data gaps and FQPA concerns) Comments about Study/ Endpoint/ Uncertainty Factor: Effects in does were seen starting on Gestation Day 6 or 7, and are therefore suitable for this exposure duration.

Acute RfD = 30 mg/ kg/ day ( NOAEL) ÷ 1000 ( UF) = 0.03 mg/ kg/ day 4.4.3 Chronic Reference Dose ( cRfD)

Study Selected: Reproductive toxicity study in rats ( MRID 46467304) MRID Number: MRID 46467304 Dose and Endpoint for Establishing cRfD: LOAEL= 15 mg/ kg/ day, based on decreased body weight and body weight gain in F1 males, decreased body weight, body weight gain, and brain 22 of 94 weight in F2 pups. A NOAEL was not established for this study ( NOAEL= less than 15 mg/ kg/ day).

Uncertainty Factor( s): UF= 3000 ( 10x for intraspecies, 10x for interspecies, 10x for data gaps ( lack of DNT, chronic studies, oncogenicity studies, non rodent toxicity studies), 3x for extrapolation from LOAEL to NOAEL).

Comments about Study/ Endpoint/ Uncertainty Factor: Longest duration study available, with lowest effect level, in available database.

Chronic RfD = 15 mg/ kg/ day ( LOAEL) ÷ 3000 ( UF) = 0.005 mg/ kg/ day 4.4.4 Incidental Oral Exposure ( Short Term)

Study Selected: Developmental Toxicity study in rabbits MRID Number: MRID 46492903 Dose and Endpoint: NOAEL= 30 mg/ kg/ day, based on clinical signs and mortality in does seen at the LOAEL of 45 mg/ kg/ day, Uncertainty Factor( s): UF= 1000 ( 10x for inter species variability, 10x for intra species variability, and 10x for data gaps and FQPA concerns)

Comments about Study/ Endpoint/ MOE: Duration appropriate for this time frame ( up to 28 days). MOE= 1000 ( 10x for intraspecies, 10x for interspecies, 10x for data gaps and FQPA concerns).

4.4.5 Incidental Oral Exposure ( Intermediate Term)

Study Selected: Reproductive toxicity study in rats MRID Number: 46467304 Dose and Endpoint: LOAEL= 15 mg/ kg/ day, based on decreased body weight and body weight gain in F1 males, decreased body weight, body weight gain, and brain weight in F2 pups. A NOAEL was not established in this study ( less than 15 mg/ kg/ day).

Comments about Study/ Endpoint/ MOE: Duration appropriate for this time frame ( 28 days to 6 months). MOE= 3000 ( 10x for intraspecies, 10x for interspecies, 10x for data gaps ( lack of DNT, chronic studies, oncogenicity studies, non rodent toxicity studies), 3x for extrapolation from LOAEL to NOAEL).

4.4.6 Dermal Absorption No data are available regarding dermal absorption of 1,2,4 triazole, therefore if direct dermal exposure to 1,2,4 triazole is anticipated, a default assumption of 100% dermal absorption should be used. For evaluation of risk from estimated exposure to 1,2,4 triazole occurring as a result of metabolism following dermal exposure to parent conazole compounds, dermal absorption estimates for parent compounds should be used. 23 of 94 4.4.7 Dermal and Inhalation Exposure ( Short Term)

Study Selected: Developmental Toxicity study in rabbits MRID Number: MRID 46492903 Dose and Endpoint: NOAEL= 30 mg/ kg/ day, based on clinical signs and mortality in does seen at the LOAEL of 45 mg/ kg/ day, Uncertainty Factor( s): UF= 1000 ( 10x for inter species variability, 10x for intra species variability, and 10x for data gaps and FQPA concerns)

Comments about Study/ Endpoint/ MOE: Duration appropriate for this time frame ( up to 28 days). MOE= 1000 ( 10x for intraspecies, 10x for interspecies, 10x for data gaps and FQPA concerns).

4.4.8 Dermal and Inhalation Exposure ( Intermediate and Long Term)

Study Selected: Reproductive toxicity study in rats MRID Number: 46467304 Dose and Endpoint: LOAEL= 15 mg/ kg/ day, based on decreased body weight and body weight gain in F1 males, decreased body weight, body weight gain, and brain weight in F2 pups. NOAEL was not established in this study ( less than 15 mg/ kg/ day).

Comments about Study/ Endpoint/ MOE: Duration appropriate for this time frame ( 28 days to lifetime). No longer term study is available. MOE= 3000 ( 10x for intraspecies, 10x for interspecies, 10x for data gaps ( lack of DNT, chronic studies, oncogenicity studies, non rodent toxicity studies), 3x for extrapolation from LOAEL to NOAEL)

4.4.9 Margins of Exposure and Levels of Concern The levels of concern ( LOC) for residential and occupational risk assessment are as follows:

Table 4.3. Summary of Levels of Concern for Residential and Occupational Risk Assessments for 1,2,4 triazole. Duration of Exposure Route of Exposure Short Term ( 1 30 Days) Intermediate Term ( 1 6 Months) Long Term (> 6 Months) Occupational Exposure Dermal 1000 3000 3000 Inhalation 1000 3000 3000 Residential Exposure Incidental Oral 1000 3000 3000 Dermal 1000 3000 3000 Inhalation 1000 3000 3000 4.4.10 Recommendation for Aggregate Exposure Risk Assessments For a given duration of exposure, the same study and endpoint is being used for all exposure pathways; therefore, HED is assuming that the toxicological effects following exposure via those routes are the same. Exposure from all routes should be aggregated. 24 of 94 4.4.11 Classification of Carcinogenic Potential There are no available cancer bioassay studies on 1,2,4 triazole. 1,2,4 triazole and its conjugate ( triazole alanine), however, are not mutagenic. The mutagenicity data on the parent triazole fungicides ( i. e., the conazoles) indicate that this class of compounds also generally lacks genotoxic potential. Some parent triazole fungicides have been shown to be carcinogenic in rodents, in particular some have produced mouse liver tumors while other have produced rat thyroid tumors, and a few produced both tumor types. Other tumor types noted with several individual triazoles include ovarian tumors, testicular tumors, and bladder tumors. For the last several years, the EPA's National Health and Environmental Effects Research Laboratory ( NHEERL) has been conducting research on the potential mode of carcinogenic action underlying the rodent hepatic and thyroid follicular cell tumor responses found for the parent triazole fungicides. The NHEERL cancer mechanistic studies on fluconazole, myclobutanil, propiconazole, and triadimefon are just beginning to appear in the scientific literature ( Sun et al., 2004; Wolf et al., 2005; Allen et al., 2005; Goetz et al., 2005; Hester et al., 2005; Ren et al., 2005; Ward et al., 2005). NHEERL used both traditional toxicology endpoints and DNA microarrays to profile gene expression in their investigations on potential modes of carcinogenic action. This recent evidence indicates that the parent triazole compounds appear to result in a tumor response subsequent to perturbation of liver metabolism, specifically xenobiotic and fatty acid metabolic pathways. Some of the altered pathways are regulated by CAR, PXR, and other nuclear receptors. In addition the thyroid response appears to be secondary to perturbation of thyroid homeostasis. Thus, the conazoles appear to drive a tumor response secondary to epigenetic effects and not from direct interaction with the DNA. An epigenetic mode of action would be consistent with a nonlinear process.

The toxicity profile of 1,2,4 triazole is not similar to those of related conazole pesticides showing a high rate of metabolic conversion to 1,2,4 triazole ( see Appendix). Unlike the conazoles currently being studied by NHEERL, 1,2,4 triazole did not alter thyroid hormones and did not cause any of the pre neoplastic changes in liver or thyroid typically observed following subchronic exposures. There were decreases in liver weights reported in the 30 day and 2 generation reproductive rat studies but these effects were not associated with preneoplastic changes. Also, a decrease in serum TSH was reported in a subchronic neurotoxicity study which is inconsistent with the mode of thyroid carcinogenic action which requires increased circulating TSH and subsequent thyroid follicular cell hyperplasia. The available toxicity studies on 1,2,4 triazole indicate that the nervous system and reproductive tissue are primary targets and thus those toxicities should be considered in the risk assessment.

In summary, because a chronic cancer study is not available, it is recommended that a margin of exposure or RfD approach based on the most sensitive toxicity endpoint with the inclusion of a database uncertainty factor to account for the absence of chronic toxicity studies should be used. This approach should be adequately protective of human health and would be consistent with the recently reported cancer related findings for a series of triazole derivative fungicides. 25 of 94 4.5 Special FQPA Safety Factor Based on the hazard data, the RARC recommended the special FQPA SF be reduced to 1x because there are low residual concerns and no residual uncertainties with regard to pre and/ or postnatal toxicity. The 1,2,4 triazole risk assessment team evaluated the quality of the exposure data and, based on these data, recommended that the special FQPA SF be reduced to 1x. The recommendation is based on the following:

  The dietary exposure assessment is based on 100% CT information for all food commodities and conservatively estimated anticipated residue levels. Estimates for drinking water were generated by models and associated modeling parameters which are designed to provide conservative, health protective, high end estimates of water concentrations. By using these screening level assessments, dietary exposures/ risks will not be underestimated.

  The residential exposure assessment is based on high end assumptions regarding incidental oral and dermal exposures to 1,2,4 T.

Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments. Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( females 13 49) NOAEL = 30 mg/ kg UF= 1000 Acute RfD= 0.03 mg/ kg FQPA SF = 1 aPAD = acute RfD FQPA SF = 0.03 mg/ kg/ day Developmental Toxicity study in rabbits LOAEL= 45 mg/ kg based on urinary tract malformations in fetuses Acute Dietary ( general population) NOAEL = 30 mg/ kg UF= 1000 Acute RfD= 0.03 mg/ kg FQPA SF = 1 aPAD = acute RfD FQPA SF = 0.03 mg/ kg/ day Developmental Toxicity study in rabbits LOAEL= 45 mg/ kg based on clinical signs and mortality in does starting on Gestation Day 6 or 7 Chronic Dietary ( all populations) LOAEL = 15 mg/ kg/ day UF = 3000 Chronic RfD = 0.005 mg/ kg/ day FQPA SF = 1 cPAD = chronic RfD FQPA SF = 0.005 mg/ kg/ day Reproductive Toxicity study in rats LOAEL = 15 mg/ kg/ day based on decreased body weight in adult males, decreased body weight and brain weight in offspring Incidental Oral Short term ( 1 30 days) NOAEL = 30 mg/ kg/ day FQPA SF = 1 LOC= 1000 Developmental Toxicity study in rabbits LOAEL= 45 mg/ kg/ day based on clinical signs and mortality in does starting on Gestation Day 6 or 7 26 of 94 Table 4.4. Summary of Toxicological Doses and Endpoints for Chemical for Use in Human Risk Assessments. Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Incidental Oral Intermediate or Long term ( 30 days to 6 months) LOAEL = 15 mg/ kg/ day FQPA SF = 1 LOC= 3000 Reproductive Toxicity study in rats LOAEL = 15 mg/ kg/ day based on decreased body weight in adult males, decreased body weight and brain weight in offspring Dermal Short term ( 1 30 days) NOAEL = 30 mg/ kg/ day LOC= 1000 Developmental Toxicity study in rabbits LOAEL= 45 mg/ kg/ day based on clinical signs and mortality in does starting on Gestation Day 6 or 7 Dermal Intermediate or Long term ( 30 days to 6 months) LOAEL = 15 mg/ kg/ day LOC= 3000 Reproductive Toxicity study in rats LOAEL = 15 mg/ kg/ day based on decreased body weight in adult males, decreased body weight and brain weight in offspring Inhalation Short term ( 1  30 days) LOAEL = 15 mg/ kg/ day LOC= 3000 Reproductive Toxicity study in rats LOAEL = 15 mg/ kg/ day based on decreased body weight in adult males, decreased body weight and brain weight in offspring Inhalation Intermediate or Long term ( 30 days to 6 months) LOAEL = 15 mg/ kg/ day LOC= 3000 Reproductive Toxicity study in rats LOAEL = 15 mg/ kg/ day based on decreased body weight in adult males, decreased body weight and brain weight in offspring Cancer ( oral, dermal, inhalation) Classification: Not determined. Evaluate by RfD approach.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable * Refer to Section 4.5 4.6 Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the 27 of 94 wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

Effects were observed in tests which indicated potential estrogen, androgen, and/ or thyroid mediated toxicity.

  Testicular changes in mice ( 28 and 90 day mouse studies), sperm abnormalities in rats ( reproductive toxicity study), decreases in testes weight in old rat 30 and 90 day toxicity studies.   Ovarian changes in rats ( 90 day subchronic rat and reproductive toxicity study in rats).   Delays in sexual maturation in rat reproductive toxicity study.   Reproductive failure at high dose in rat reproductive study ( only two litters produced, with no pups surviving lactation).   Increased incidence of undescended testicle in rat developmental toxicity study.   Dose related decreases in TSH at 33 mg/ kg/ day and above in male rats in the subchronic/ neurotoxicity study.

When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, 1,2,4 triazole may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 Public Health Data No incidents involving 1,2,4 triazole were found from a search of the Incident Data System ( 1992 to present), the Poison Control Center Data ( 1993 2003), California ( 1982 2003, or NIOSH ( 1998 2003).

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway ( M. Doherty, DP 322238, 11/ 1/ 05)

6.1.1 Residue Profile <IP_ADDRESS> Residues in Food Exposure to 1,2,4 triazole may occur through direct or indirect means. For purposes of this assessment, direct exposure is defined as exposure to residues of 1,2,4 triazole, per se. Indirect exposure to 1,2,4 triazole may occur when there is exposure to a triazole derivative fungicide. Indirect exposure is defined as exposure to 1,2,4 triazole that occurs from exposure to a triazole fungicide and subsequent metabolic conversion of the parent compound to 1,2,4 triazole within the human system. For assessing direct and indirect dietary exposure, residue levels of 1,2,4 triazole were estimated from parent triazole derivative fungicide tolerances. For each food/ parent fungicide tolerance combination, a residue estimate was calculated by multiplying the tolerance by a metabolic conversion factor and by a molecular weight conversion factor. Direct exposure residue levels used the metabolic factors from plant metabolism studies for crop 28 of 94 commodities and from livestock metabolism studies for livestock commodities. Indirectexposure residue levels used metabolic factors from rat metabolism studies. For some compounds metabolic conversion factors were not readily available and the maximum factors from the entire class of compounds were used ( 20% for plants, 77% for livestock).

Through a joint effort by the U. S. Triazole Task Force ( USTTF) and USDA's Pesticide Data Program ( PDP), monitoring data depicting residues of 1,2,4 triazole are available for apples, peaches, wheat flour, bananas, eggs, peanut butter, soybeans, finished water, strawberry, milk, grapes, and tomato. Most of the monitoring data for 1,2,4 triazole were reported as being below the level of quantification.

The following rules were used to select residues for the dietary exposure analysis: 1. If no monitoring data were available for the crop, or from a representative commodity, the calculated residue value was used. 2. If the monitoring dataset contains values that are greater than the LOQ, the monitoring data were used. 3. If the monitoring data are all less than the reported LOQ and the calculated residue value is less than ½ LOQ, the calculated residue values were used. 4. If the monitoring data are less than the reported LOQ and the calculated residue value is greater than the LOQ, a value of ½ LOQ was used. 5. Average residue estimates from the indirect exposure pathway were added to either the maximum direct residue estimate for acute assessments or the average direct residue estimate for chronic assessments.

For the indirect exposure part of the analysis, average indirect residue estimates were used for both the acute and chronic assessments. The average value was selected due to the fact that this indirect exposure is addressed, at least in part, by the toxicology studies and risk assessment for the various triazole derivative parent fungicides. A summary of the values used in the assessments and their sources is shown in Table 6.1. Field trial studies for some triazolederivative fungicides include analyses for 1,2,4 triazole. These data could be used to refine the exposure and risk estimates; however, due to timing issues, resource constraints, and the various stages of review of the submissions, they were not considered for these assessments.

1,2,4 Triazole is not currently listed in 40 CFR Section 180, nor is it included in the tolerance expression for any triazole derivative fungicide. Due to the multiple potential sources of 1,2,4 triazole and its occurrence in the environment, HED believes that 1,2,4 triazole is not an appropriate analyte for tolerance enforcement purposes and is not recommending that tolerances for this compound be established. 29 of 94 Table 6.1. Summary of Direct and Indirect Residue Estimates Used to Assess Dietary Exposure to 1,2,4 Triazole.

Direct Exposure 2 Dietary Model Input, ppm 1 Selected Residue Estimate, ppm 3 Calculated Data,

ppm 4 Monitoring Data, ppm 5 Item Acute Chronic Acute Acute Source Chronic Chronic Source Max. Avg. LOQ Max. Avg. Average Indirect Residue Estimate, ppm 6 Pome Fruit ( Apple) 0.0253 0.0253 0.0100 1/ 2 LOQ 0.0100 1/ 2 LOQ 0.0470 0.0182 0.02000 0.02000 0.02000 0.0153 Artichoke 0.0753 0.0655 0.0478 Max. Calc'd 0.0380 Avg. Calc'd 0.0478 0.0380    0.0275 Asparagus 0.0099 0.0056 0.0071 Max. Calc'd 0.0028 Avg. Calc'd 0.0071 0.0028    0.0028 Banana 0.0238 0.0238 0.0050 1/ 2 LOQ 0.0050 1/ 2 LOQ 0.1913 0.0279 0.01000 0.00315 0.00036 0.0188 Dry Bean 0.0230 0.0137 0.0202 Max. Calc'd 0.0109 Avg. Calc'd 0.0202 0.0109    0.0028 Succulent Bean 0.0568 0.0291 0.0478 Max. Calc'd 0.0201 Avg. Calc'd 0.0478 0.0201    0.0090 Blueberry 0.0462 0.0321 0.0404 Max. Calc'd 0.0263 Avg. Calc'd 0.0404 0.0263    0.0058 Caneberry 0.1495 0.1305 0.0957 Max. Calc'd 0.0767 Avg. Calc'd 0.0957 0.0767    0.0538 Canola 0.0100 0.0082 0.0040 Max. Calc'd 0.0022 Avg. Calc'd 0.0040 0.0022    0.0060 Carrot 0.0101 0.0101 0.0081 Max. Calc'd 0.0081 Avg. Calc'd 0.0081 0.0081    0.0020 Leafy Petioles 0.2523 0.2523 0.2018 Max. Calc'd 0.2018 Avg. Calc'd 0.2018 0.2018    0.0505 Barley 0.0055 0.0043 0.0040 Max. Calc'd 0.0028 Avg. Calc'd 0.0040 0.0028    0.0015 Oats 0.0056 0.0046 0.0040 Max. Calc'd 0.0030 Avg. Calc'd 0.0040 0.0030    0.0016 Rice 0.3073 0.1236 0.2826 Max. Calc'd 0.0989 Avg. Calc'd 0.2826 0.0989    0.0247 Rye 0.0058 0.0050 0.0040 Max. Calc'd 0.0032 Avg. Calc'd 0.0040 0.0032    0.0018 Wheat 0.0053 0.0040 0.0040 Max. Calc'd 0.0027 Avg. Calc'd 0.0040 0.0027    0.0013 Wheat Flour 0.0053 0.0040 0.0040 Max. Calc'd 0.0027 Avg. Calc'd 0.0040 0.0027 0.01000 0.01000 0.01000 0.0013 Wild Rice 0.0252 0.0252 0.0202 Max. Calc'd 0.0202 Avg. Calc'd 0.0202 0.0202    0.0050 Citrus Group 0.0436 0.0436 0.0410 Max. Calc'd 0.0410 Avg. Calc'd 0.0410 0.0410    0.0026 Coffee 0.0411 0.0005 0.0410 Max. Calc'd 0.0004 Avg. Calc'd 0.0410 0.0004    0.0001 Field Corn 0.0052 0.0035 0.0040 Max. Calc'd 0.0023 Avg. Calc'd 0.0040 0.0023    0.0012 Sweet Corn 0.0051 0.0033 0.0040 Max. Calc'd 0.0022 Avg. Calc'd 0.0040 0.0022    0.0011 Cotton 0.0965 0.0300 0.0898 Max. Calc'd 0.0233 Avg. Calc'd 0.0898 0.0233    0.0067 Cranberry 0.0460 0.0266 0.0404 Max. Calc'd 0.0210 Avg. Calc'd 0.0404 0.0210    0.0056 Cucurbits 0.0126 0.0100 0.0096 Max. Calc'd 0.0070 Avg. Calc'd 0.0096 0.0070    0.0030 Curant 0.1844 0.1328 0.1435 Max. Calc'd 0.0919 Avg. Calc'd 0.1435 0.0919    0.0409 Elderberry 0.0505 0.0505 0.0404 Max. Calc'd 0.0404 Avg. Calc'd 0.0404 0.0404    0.0101 Grape 0.0500 0.0337 0.0213 Max. Mon. 0.0050 Avg. Mon. 0.2244 0.0727 0.01000 0.02130 0.00150 0.0287 30 of 94 Table 6.1. Summary of Direct and Indirect Residue Estimates Used to Assess Dietary Exposure to 1,2,4 Triazole.

Direct Exposure 2 Dietary Model Input, ppm 1 Selected Residue Estimate, ppm 3 Calculated Data,

ppm 4 Monitoring Data, ppm 5 Item Acute Chronic Acute Acute Source Chronic Chronic Source Max. Avg. LOQ Max. Avg. Average Indirect Residue Estimate, ppm 6 Raisin 0.5932 0.5132 0.4800 Max. Calc'd 0.4000 Avg. Calc'd 0.4800 0.4000    0.1132 Hops 1.5278 1.5278 1.3460 Max. Calc'd 1.3460 Avg. Calc'd 1.3460 1.3460    0.1818 Lychee 0.0855 0.0855 0.0673 Max. Calc'd 0.0673 Avg. Calc'd 0.0673 0.0673    0.0182 Mango 0.0114 0.0114 0.0090 Max. Calc'd 0.0090 Avg. Calc'd 0.0090 0.0090    0.0024 Mayhaw 0.0419 0.0419 0.0335 Max. Calc'd 0.0335 Avg. Calc'd 0.0335 0.0335    0.0084 Bulb Vegetables 0.0142 0.0104 0.0121 Max. Calc'd 0.0083 Avg. Calc'd 0.0121 0.0083    0.0021 Green Onion 0.3350 0.3350 0.3229 Max. Calc'd 0.3229 Avg. Calc'd 0.3229 0.3229    0.0121 Okra 0.0570 0.0570 0.0449 Max. Calc'd 0.0449 Avg. Calc'd 0.0449 0.0449    0.0121 Peanut 0.0097 0.0053 0.0081 Max. Calc'd 0.0037 Avg. Calc'd 0.0081 0.0037    0.0016 Peanut Butter 0.0779 0.0266 0.0763 Max. Mon. 0.0250 Avg. Mon. 0.0081 0.0037 0.01000 0.07630 0.02500 0.0016 Peppers 0.0717 0.0717 0.0478 Max. Calc'd 0.0478 Avg. Calc'd 0.0478 0.0478    0.0239 Peppermint 0.2153 0.2153 0.1435 Max. Calc'd 0.1435 Avg. Calc'd 0.1435 0.1435    0.0718 Pineapple 0.2192 0.1507 0.1411 Max. Calc'd 0.0726 Avg. Calc'd 0.1411 0.0726    0.0781 Sorghum 0.0094 0.0056 0.0081 Max. Calc'd 0.0043 Avg. Calc'd 0.0081 0.0043    0.0013 Soybean 0.0145 0.0145 0.0050 1/ 2 LOQ 0.0050 1/ 2 LOQ 0.0807 0.0290 0.01000 0.00290 0.00060 0.0095 Spearmint 0.2153 0.2153 0.1435 Max. Calc'd 0.1435 Avg. Calc'd 0.1435 0.1435    0.0718 Stone Fruit no cherry 0.1158 0.0858 0.0957 Max. Calc'd 0.0657 Avg. Calc'd 0.0957 0.0657 0.21000 0.21000 0.21000 0.0201 Cherry 0.2863 0.1824 0.2392 Max. Calc'd 0.1353 Avg. Calc'd 0.2392 0.1353    0.0471 Strawberry 0.0315 0.0315 0.0180 1/ 2 LOQ 0.0180 1/ 2 LOQ 0.0605 0.0422 0.03600 0.03600 0.03600 0.0135 Sugar Beet 0.0152 0.0092 0.0121 Max. Calc'd 0.0061 Avg. Calc'd 0.0121 0.0061    0.0031 Sugar Beet Molasses 0.1520 0.0920 0.1210 Max. Calc'd 0.0610 Avg. Calc'd 0.1210 0.0610    0.0310 Sunflower 0.0028 0.0028 0.0022 Max. Calc'd 0.0022 Avg. Calc'd 0.0022 0.0022    0.0006 Tomato 0.0122 0.0122 0.0050 1/ 2 LOQ 0.0050 1/ 2 LOQ 0.0144 0.0144 0.01000 0.01000 0.01000 0.0072 Turnip 0.0228 0.0228 0.0180 Max. Calc'd 0.0180 Avg. Calc'd 0.0180 0.0180    0.0048 Turnip Greens 0.3638 0.3638 0.3590 Max. Calc'd 0.3590 Avg. Calc'd 0.3590 0.3590    0.0048 Tree Nuts 0.0048 0.0039 0.0040 Max. Calc'd 0.0031 Avg. Calc'd 0.0040 0.0031    0.0008 Almond 0.0186 0.0120 0.0164 Max. Calc'd 0.0098 Avg. Calc'd 0.0164 0.0098    0.0022 Pecan 0.0049 0.0049 0.0041 Max. Calc'd 0.0041 Avg. Calc'd 0.0041 0.0041    0.0008 Pistachio 0.0048 0.0039 0.0040 Max. Calc'd 0.0031 Avg. Calc'd 0.0040 0.0031    0.0008 31 of 94 Table 6.1. Summary of Direct and Indirect Residue Estimates Used to Assess Dietary Exposure to 1,2,4 Triazole.

Direct Exposure 2 Dietary Model Input, ppm 1 Selected Residue Estimate, ppm 3 Calculated Data,

ppm 4 Monitoring Data, ppm 5 Item Acute Chronic Acute Acute Source Chronic Chronic Source Max. Avg. LOQ Max. Avg. Average Indirect Residue Estimate, ppm 6 Poultry Meat 0.0073 0.0051 0.0045 Max. Calc'd 0.0023 Avg. Calc'd 0.0045 0.0023    0.0028 Poultry Fat 0.0064 0.0038 0.0045 Max. Calc'd 0.0019 Avg. Calc'd 0.0045 0.0019    0.0019 Poultry Meat Byprod. 0.0063 0.0036 0.0045 Max. Calc'd 0.0018 Avg. Calc'd 0.0045 0.0018    0.0018 Poultry Liver 0.0073 0.0056 0.0045 Max. Calc'd 0.0028 Avg. Calc'd 0.0045 0.0028    0.0028 Egg 0.0073 0.0056 0.0045 Max. Calc'd 0.0028 Avg. Calc'd 0.0045 0.0028 0.01000 0.00370 0.00050 0.0028 Cattle Meat 0.0644 0.0254 0.0517 Max. Calc'd 0.0127 Avg. Calc'd 0.0517 0.0127    0.0127 Cattle Fat 0.0644 0.0323 0.0517 Max. Calc'd 0.0196 Avg. Calc'd 0.0517 0.0196    0.0127 Cattle Meat Byprod. 0.0644 0.0253 0.0517 Max. Calc'd 0.0126 Avg. Calc'd 0.0517 0.0126    0.0127 Cattle Liver 0.6834 0.2236 0.5716 Max. Calc'd 0.1118 Avg. Calc'd 0.5716 0.1118    0.1118 Cattle Kidney 0.0675 0.0316 0.0517 Max. Calc'd 0.0158 Avg. Calc'd 0.0517 0.0158    0.0158 Milk 0.0080 0.0052 0.0053 Max. Mon. 0.0025 Avg. Mon. 0.0071 0.0027 0.00500 0.00530 0.00140 0.0027 1 Values used in the dietary exposure assessment are a sum of the selected acute or chronic residue estimate and the average indirect residue estimate.

2 Values used to estimate direct ingestion of residues of 1,2,4 triazole. Values were selected from calculated data or monitoring data as indicated.

3 Residue estimates and sources selected from calculated data or monitoring data using the criteria discussed in Section <IP_ADDRESS>.

4 Maximum or average residue estimates based on parent triazole derivative fungicide tolerances after compensating for metabolic and molecular weight factors.

5 Residue data for 1,2,4 triazole from USDA Pesticide Data Program or U. S. Triazole Task Force monitoring data.

6 Average indirect residue estimates based on parent triazole derivative fungicide tolerances after compensating for rat metabolic and molecular weight factors. 32 of 94 <IP_ADDRESS> Residues in Water ( I. Maher, DP 320682, In Preparation)

Residues of 1,2,4 triazole in drinking water were provided to HED by the Environmental Fate and Effects Division. The Tier II PRZM/ EXAMS ( surface water) and SCIGROW ( groundwater) residue estimates are summarized in Table 6.2. The estimated surface water concentrations were used directly in the acute and chronic dietary exposure model. A small scale prospective groundwater monitoring study was conducted in New Jersey for parent triadimefon ( 1997). In that study, the average maximum concentration ( 663 day mean) of 1,2,4 T in pore water at a depth of 9 ft was 0.0167 ppm. That level is significantly greater than the SCIGROW estimate. HED notes that there were no detections of 1,2,4 triazole in any of the 271 water samples analyzed by PDP. The limit of quantification for those analyses is 730 parts per trillion ( 0.73 ppb, 0.00073 ppm), more than two orders of magnitude less than the modeled surface water residue estimates.

Table 6.2. Summary of Tier II Modeled Concentrations of Triazole Metabolites in Drinking Water. Exposure Duration Surface Water Concentration, ppm Groundwater Concentration, ppm Acute 0.041 0.001 Chronic 0.011 0.001 6.1.2 Acute and Chronic Dietary Exposure and Risk Acute and chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model ( DEEM FCID, Version 2.03), which uses food consumption data from the USDA =

s Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. A separate cancer dietary assessment was not conducted. Although there is some concern regarding the carcinogenicity of 1,2,4 T, HED believes that the chronic dietary exposure assessment is sufficiently protective of any cancer related effects.

The acute and chronic assessments include direct dietary exposure to 1,2,4 triazole as well as indirect exposure that may occur due to food borne residues of parent triazole derivative fungicide and the subsequent in vivo conversion of parent compound to 1,2,4 trizole within the human system. For both direct and indirect exposures, residue estimates were derived from parent compound tolerance values, taking into consideration any monitoring data that were available for 1,2,4 triazole. Both acute and chronic assessments make the conservative assumption that 100% of foods with triazole derivative fungicide registrations ( active, pending, and requested) were treated with a triazole derivative fungicide. Both assessments are deterministic and include residue estimates for water.

Acute exposure estimates for 1,2,4 triazole range from 0.0025 to 0.0096 mg/ kg/ day at the 95th percentile of exposure. The maximum exposure estimate is for infants less than 1 year of age and corresponds to a risk estimate of 32% of the acute Population adjusted Dose ( aPAD). Chronic exposure estimates range from 0.0005 to 0.00196 mg/ kg/ day. For the chronic exposure estimates, the maximum is for children aged 1 to 2 years. The risk estimate associated with that group is 39% of the chronic PAD ( cPAD). HED is generally concerned when risk estimates for any representative population subgroup exceed 100% of the PAD. The risk estimates associated with 1,2,4 triazole are below HED's level of concern. These assessments are considered to be 33 of 94 conservative because ( 1) the food residue estimates are derived from parent compound tolerances or from high end residues in monitoring data, ( 2) the residue in drinking water is based on conservatively modeled estimates, ( 3) all food and water in the analysis are assumed to have high end levels of residue, and ( 4) the inclusion of the indirect exposure pathway is already partially addressed by the dietary exposure and risk analyses for the various parent compounds. As shown in Table 6.3, risk estimates for all population subgroups are below HED's level of concern at all presented percentiles of exposure. Based on the conservative nature of this assessment, the 95th percentile is the most appropriate for regulatory purposes.

Although these dietary exposure assessments are principally based on anticipated residues, the data, selection criteria, and assumptions that serve as the source of those residues are conservative in nature. HED has assumed that application of multiple triazole derivative fungicides will not occur for any given crop during a single growing season. Although such a scenario is not currently prohibited via product labeling, HED believes that such practices will be unlikely due to economic and resistance management issues. Overall, this assessment likely overestimates actual direct and indirect dietary exposure to 1,2,4 triazole. Even with the conservatisms in the dietary assessments, risk estimates for the general U. S. population and all representative population subgroups, including those of infants and children, are well below HED's level of concern. Reviewed field trial data depicting measured residues of 1,2,4 triazole in foods are likely to be available as HED progresses with evaluation of new use and new activeingredient petitions. Use of these data, as well as incorporation of the entire distribution of monitoring data, will result in more realistic dietary exposure and risk estimates and may be useful if exposure and risk estimates require refinement.

Table 6.3. Dietary ( Food + Water) Direct and Indirect Exposure and Risk Estimates for 1,2,4 Triazole. Exposure Estimate, mg/ kg/ day Risk Estimate, % aPADa Population Subgroup aPAD, mg/ kg/ day 95th % ile 99th % ile 99.9th % ile 95th % ile 99th % ile 99.9th % ile Acute U. S. Population ( total) 0.03 0.0036 0.0060 0.0108 12 20 36 All infants (< 1 year) 0.03 0.0096 0.0130 0.0212 32 44 71 Children 1 2 yrs 0.03 0.0072 0.0107 0.0145 24 36 48 Children 3 5 yrs 0.03 0.0059 0.0085 0.0144 20 28 48 Children 6 12 yrs 0.03 0.0038 0.0055 0.0082 13 18 27 Youth 13 19 yrs 0.03 0.0027 0.0044 0.0067 9 15 22 Adults 20 49 yrs 0.03 0.0028 0.0044 0.0069 9 15 23 Adults 50+ yrs 0.03 0.0025 0.0034 0.0056 8 11 19 Females 13 49 yrs 0.03 0.0028 0.0043 0.0067 9 14 22 Chronic Population Subgroup cPAD, mg/ kg/ day Exposure Estimate, mg/ kg/ day Risk Estimate, % cPADa U. S. Population ( total) 0.005 0.00069 14 All infants (< 1 year) 0.005 0.00156 31 Children 1 2 yrs 0.005 0.00196 39 Children 3 5 yrs 0.005 0.00149 30 Children 6 12 yrs 0.005 0.00088 18 Youth 13 19 yrs 0.005 0.00054 11 Adults 20 49 yrs 0.005 0.00055 11 Adults 50+ yrs 0.005 0.00055 11 Females 13 49 yrs 0.005 0.00054 11 The values for the population with the highest risk for each type of risk assessment are bolded. a Reported to 2 significant figures. 34 of 94 6.2 Residential ( Non Occupational) Exposure/ Risk Pathway ( J. Arthur, DP 322240, 12/ 9/ 05)

6.2.1 Home Uses There is a potential for exposure to 1,2,4 T for homeowners in residential settings during the application of T D fungicide products on lawns ( turf) and from subsequent contact during activities in such treated areas. As a result, risk assessments have been completed for both residential handler and postapplication scenarios.

Toddlers can be exposed directly to 1,2,4 T by ingesting soil where T D fungicides have been applied due to environmental degradation of the parent compound to 1,2,4 T. Indirect exposure to 1,2,4 T for toddlers can occur from dermal contact and absorption of T D fungicide residues on treated turf, with subsequent internal metabolism to 1,2,4 T. Similarly, indirect exposure also can occur through incidental ingestion of parent residues from hand to mouth and object tomouth activities on T D fungicide treated turf. Indirect 1,2,4 T exposure can occur for adults following direct dermal and inhalation exposure to T D fungicides while applying these products to home lawns. Indirect exposure may also occur after application via the dermal route from subsequent contact with treated lawns. HED believes that formation of 1,2,4 T in plants will occur within the structures of the plant or result from uptake from soil. Therefore surface, dislodgable residues will not be available and direct hand to mouth, object to mouth, or dermal exposure to 1,2,4 T are unlikely.

1,2,4 T exposure is determined by certain key characteristics specific to the parent T D fungicide from which it is formed. These characteristics can be different for each parent T D fungicide and include application rate, environmental and metabolic conversion rates, molecular weight, and dermal absorption factors. HED has based its assessment of residential exposure on the currently registered turf use T D fungicide that results in the highest 1,2,4 T exposure ( i. e., triadimefon)

<IP_ADDRESS> Application Scenarios Non occupational exposure is likely during the handling of T D fungicides in the treatment of residential lawns. The major residential exposure scenarios are mixer/ loader/ applicators using a hose end sprayer or a low pressure hand wand.

The following assumptions and factors are specific to the residential assessment:

  Residential handler exposure scenarios are limited to short term duration due to the episodic uses associated with homeowner products.   Homeowner handler assessments are based on individuals wearing shorts and shortsleeved shirts.   Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including mixing/ loading, if needed, as well as the application.   The Agency always considers the maximum application rates allowed by labels in its risk 35 of 94 assessments to consider what is legally possible based on the label.   The Agency based calculations on what would reasonably be treated by homeowners such as the size of a lawn, or the size of a garden.   A 70 kg body weight is used for adults because the toxicity endpoint is not genderspecific

Residential handlers may be exposed dermally and by inhalation during mixing, loading and application of T D fungicides for short term durations. Because a common toxicity endpoint was identified for both dermal and inhalation routes, a combined risk from both routes of exposure is assessed. Results from these risk calculations for residential handlers are seen in Table 6.4 for triadimefon. 36 of 94 Table 6.4. Non occupational Handler Exposure and Risk Estimates for 1,2,4 Triazole from Triadimefon Application to Turf.

Exposure Scenario Personal Protective Equipment Exposure Route Applic.

Rate,

lb ai/ A Absorption Rate, % Amount Treated per day, acre Unit Exposure,

mg/ lb ai Data Confidence Daily Dose, 1 mg/ kg/ day MOE 2 Total Daily Dose,

mg/ kg/ day Total MOE3 Dermal 8 114 High 0.00091 33,000 M/ L/ A Liquids:

hose end sprayer short sleeves short pants no gloves Inhalation 2.75 100 0.5 0.0164 High 0.000017 1.8E+ 6 0.00093 32,000 Dermal 8 565 Low 0.00021 140,000 M/ L/ A Liquids:

lowpressure hand wand short sleeves short pants no gloves Inhalation 2.75 100 0.023 ( 1000 ft2) 0.00385 Medium 0.00000018 1.7E+ 8 0.00021 140,000 1 Daily Dose = [ Application Rate * MW Ratio ( 0.24) * Metabolic Rate ( 0.22) * Absorption Rate * Amount Treated * Unit Exposure)]/ Body Weight ( 70 kg)

2 MOE = NOAEL/ Daily Dose. The dermal and inhalation NOAEL = 30 mg/ kg/ day, was used for all calculations. The LOC = 1000.

3 Total MOE = NOAEL/( dermal daily dose + inhalation daily dose)

4 Unit exposure values taken from ORETF study ( OMA004), " Mixer/ Loader/ Applicator: Hose end Sprayer. Mix your own."

5 Unit exposure values taken from ORETF study ( OMA005), " Resident Mixer/ loader/ applicator  Handheld Pump Sprayer: Fruit Trees and Ornamentals." 37 of 94 Residential handler risk estimates from exposure to 1,2,4 T do not exceed HED's LOC for lawn use of triadimefon. Dermal absorption factors used in this assessment were taken from the May 2005 assessment ( MRID 46553701) provided by the U. S. Triazole Task Force ( USTTF).

<IP_ADDRESS> Postapplication Scenarios Individuals of varying ages can potentially be exposed from activities on treated turf. Potential routes of exposure include dermal and incidental ingestion ( toddlers only). Residential uses of T D fungicides may result in short term ( 1 to 30 days) postapplication exposures. Available data for 1,2,4 T and various parent T D fungicides indicates that residues of these compounds may persist long enough to warrant assessment of intermediate term exposures (> 30 days to 180 days).

The HED Standard Operating Procedures for Residential Exposure Assessments ( Draft, December 18, 1997) were used as a guideline for performing the residential postapplication assessment. Also used in the assessment were interim changes to these SOPs which were adopted by the HED Exposure Science Advisory Council regarding standard values, including, for turf transferrable residues, turf transfer coefficients and hand to mouth activities ( Policy 11, February 22, 2001). The exposure and risk estimates for the four residential exposure scenarios are assessed for the day of application ( day " 0") because it is assumed that adults and toddlers could contact the lawn immediately after application. On the day of application, it was assumed that 5 percent of the application rate is available from the turf grass as transferable residue ( 20 percent for object to mouth activities).

Assessment of residential postapplication exposure was performed using the same approach as was used for handler exposure above using the T D fungicide triadimefon.

A summary of the estimated exposures and risks, along with the algorithms used for each turf exposure scenario are presented below in Tables 6.5   6.8 for triadimefon. 38 of 94 Table 6.5. Dermal Exposure and Risk for Adults and Children from Treated Lawns ( Triadimefon)

Subgroup exposed Applicati on Rate,

lb ai/ A Fraction of ai Available Turf Transferrable Residue at Day " 0"

( ug/ cm2) 1 Dermal Transfer Coefficient,

cm2/ hr Exposure Time,

hrs/ day Absorption Factor Body Weight,

kg Daily Dose, 2 mg/ kg/ day MOE3 Adult 5.4 0.05 2.94 14,500 2 8% 70 0.0051 5,900 Children 5.4 0.05 2.94 5200 2 8% 15 0.0086 3,500 1 Turf Transferrable Residue ( ug/ cm2) = Application rate ( lb ai/ A) x Fraction of ai Available x 4.54E+ 8 ug/ lb x 2.47E 8 A/ cm2 2 Daily Dose = ( Turf Transferrable Residue x Absorption Factor x 1E 3 mg/ ug x Dermal Transfer Coefficient x Exposure Time x MW ratio ( 0.24) x Metab.

Conv. Rate ( 0.22))/ Body weight 3 MOE = Dermal NOAEL ( 30 mg/ kg/ day) / Daily Dose. LOC = 1000.

Table 6.6. Oral Hand to mouth Exposure and Risk for Children from Treated Lawns ( Triadimefon)

Application Rate,

lb ai/ A Fraction of ai Available Turf Transferrable Residue at Day " 0",

( ug/ cm2) 1 Exposure Time,

hrs/ day Extraction by saliva Hand Surface Area,

cm2/ event Frequency,

events/ hr Body Weight,

kg Daily Dose, 2 mg/ kg/ day MOE3 5.4 0.05 2.94 2 0.5 20 20 15 0.0041 7,300 1Turf Transferrable Residue ( ug/ cm2) = Application rate ( lb ai/ A) x Fraction of ai Available x 4.54E+ 8 ug/ lb x 2.47E 8 A/ cm2 2 Daily Dose = ( Turf Transferrable Residue x Extraction by Saliva x Hand Surface Area x Frequency x 1E 3 mg/ ug x Exposure Time x MW ratio x Metab.

Conv. Rate)/ Body Weight.

3 MOE = Oral NOAEL ( 30 mg/ kg/ day) / Daily Dose. LOC = 1000.

Table 6.7. Oral Object to mouth ( Turfgrass) Exposure and Risk for Children from Treated Lawns ( Triadimefon)

Application Rate,

lb ai/ A Fraction of ai Available Grass Residue at Day " 0",

( ug/ cm2) 1 Surface Area Mouthed,

cm2/ day Body Weight,

kg Daily Dose, 2 mg/ kg/ day MOE3 5.4 0.2 11.6 25 15 0.001 30,000 1Grass Residue ( ug/ cm2) = Application rate ( lb ai/ A) x Fraction of ai Available x 4.54E+ 8 ug/ lb x 2.47E 8 A/ cm2 2 Daily Dose = ( Grass residue x Surface Area Mouthed x 1E 3 mg/ ug x MW ratio ( 0.24) x Metab. Conv. Rate ( 0.22))/ Body Weight.

3 MOE = Oral NOAEL ( 30 mg/ kg/ day) / Daily Dose. LOC = 1000. 39 of 94 Table 6.8 Exposure and Risk for Children from Ingestion of Soil from Treated Lawns ( Triadimefon)

Application Rate,

lb ai/ A Fraction of ai Available Soil Residue at Day " 0",

( ug/ g) 1 1,2,4 T to Parent MW Ratio Max. Soil Conversion Rate to 1,2,4 T, % Ingestion Rate,

mg/ day Body Weight,

kg Daily Dose, 2 mg/ kg/ day MOE3 5.4 1 39.4 0.24 30.7 100 15 0.000019 1,600,000 1 Soil residue ( ug/ g) = [ Application Rate ( lbs ai/ A) x Fraction of ai Available x 4.54E+ 8 ug/ lb x 2.47E 8 A/ cm2 x 0.67 cm3/ g soil]

2 Daily Dose = [ Soil residue ( ug/ g) x Ingestion rate ( mg/ day) x 1E 6 g/ ug] x Soil Conversion Rate x MW ratio / [ Body Weight ( kg)]

3 MOE = Oral NOAEL ( 30 mg/ kg/ day) / Daily Dose. LOC = 1000. 40 of 94 The MOEs for postapplication exposure to the T D fungicide turf product, triadimefon are all > 1000 for individual routes of exposure, and therefore do not exceed HED's level of concern. FQPA requires residential exposures that could reasonably be expected to occur on the same day be combined and compared to the appropriate toxicity endpoint. Toddler dermal and incidental ingestion by hand to mouth, object to mouth and soil ingestion activities may co occur. When the exposure estimates from these routes are combined, the MOE is 2200. As with the individual route MOEs, the aggregate MOE does not exceed HED's LOC.

HED has considered only ingestion of soil borne residues in assessing intermediate term risk. Although residues of parent T D fungicides may persist on turf ( environmental half lives are on the order of 1 3 months), the act of mowing the lawn removes residues from the lawn surface and makes them unavailable for hand to mouth, object to mouth, and dermal exposures. The exposure estimate of 0.00013 mg/ kg/ day from short term soil ingestion is being used as a highly conservative estimate for intermediate term exposure as well. Applying the intermediate term NOAEL of 15 mg/ kg/ day gives a MOE of approximately 120,000, which is significantly greater than the LOC of 3000. Therefore, the estimated intermediate term risk is below HED's level of concern.

The exposure estimates in this assessment are based on some upper percentile ( i. e., maximum application rate) and some central tendency ( i. e., surface area, hand to mouth activity, and body weight) assumptions and are, therefore, considered to be representative of central to high end exposures. The uncertainties associated with this assessment stem from the use of an assumed amount of pesticide available from turf, and assumptions regarding transfer of chemical residues, and hand to mouth activity. Dermal absorption factors used in the assessments were taken from the May 2005 assessment ( MRID 46553701) provided by the USTTF.

6.2.2 Recreational Use Sites T D fungicides may be used on turf at recreational use sites and, therefore may result in postapplication exposure to adults and children involved in recreational activities. Exposures to adults and children from the use of T D fungicides at recreational use sites are assumed to be the same as those assessed for residential use sites, and therefore, a separate recreational exposure assessment was not included. Results from the residential turf exposure assessment are considered upper percentile risk estimates. Therefore, it is not expected that the high end residential exposure scenario would occur on the same day as a high end recreational exposure scenario. Exposures from the residential and recreational scenarios are not aggregated. Rather, the residential risk estimate should serve as a high end estimate for both residential and recreational exposure.

6.2.3 Other ( Spray Drift, etc.)

While the drifting of agricultural spray applications of T D fungicides to nearby residential settings is possible, the T D funcgicide turf uses addressed in the above residential risk assessment are considered to be conservative, worst case scenarios, that would cover any potential 1,2,4 T risks from agricultural spraying operations. 41 of 94 Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the groundboom application. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift and risks associated with aerial as well as other application types where appropriate.

6.2.4 Pharmaceutical Uses Triazole fungicides have proved to be useful tools in combating systemic fungal infections in humans. Examples of these compounds include fluconazole, itraconazole, voriconazole, and posaconazole. The Food and Drug Administration ( FDA) approves uses of pharmaceutical products under FFDCA. EPA is currently working with FDA to derive appropriate exposure assessment methodology to determine how the pharmaceutical uses of triazole fungicides should be considered in the aggregate risk assessments for 1,2,4 triazole and the triazole conjugates ( triazole alanine and triazole acetic acid). A supplementary exposure analysis will be completed, and the incremental impact of exposure to pharmaceutical uses of the triazole fungicides will be considered in the Agency's reregistration decisions for propiconazole, triadimefon, and triadimenol. For additional information, please refer to the EPA memorandum to FDA regarding the pharmaceutical uses of triazole fungicides ( included in the dockets for propiconazole, triadimefon, and triadimenol).

7.0 Aggregate Risk Assessments and Risk Characterization In assessing acute and chronic risk from aggregate exposure to 1,2,4 triazole, the only scenarios appropriate for consideration are dietary exposure ( all non dietary exposures are short to intermediate term in duration). Water was included in the dietary exposure estimates; therefore, the acute and chronic aggregate risk estimates are the same as those presented in Section 6.1.2. Risk estimates for those durations were all less than HED's level of concern. As previously noted, the chronic risk assessment is believed to be protective of any carcinogenic effects attributable to 1,2,4 T and a separate cancer risk assessment has not been completed. Risk estimates for short and intermediate term aggregate exposure are presented below. Evaluation of short and intermediate term risk includes exposures from non dietary sources coupled with chronic dietary exposure estimates, as an approximation of background level exposure by the dietary route. HED notes that this approach implicitly assumes that the non dietary and dietary exposures are constantly co occurring during the short or intermediate term duration being evaluated. The approach does not take into account the temporal variability inherent in exposures from these different pathways. Triadimefon use on turf is being used to cover nondietary exposures for all T D fungicides. 42 of 94 7.1 Short term Aggregate Risk In assessing short term aggregate risk, HED has combined estimates of dietary exposure ( direct and indirect), dermal exposure ( indirect), hand to mouth exposure ( indirect, toddlers only), object to mouth exposure ( indirect, toddlers only) and soil ingestion ( direct, toddlers only). These short term aggregate risk estimates are considered to be very conservative. The pathwayspecific exposure estimates are derived from high end, health protective assumptions. In aggregating these exposure estimates, HED has made the further conservative assumption that the exposures co occur for the duration of the exposure interval ( 1 30 days). The exposure estimates and resulting aggregate MOE are summarized in Table 7.1. Aggregate MOEs are greater than the LOC of 1000 for all population subgroups. Therefore, the estimated risks are not of concern.

Table 7.1. Short term Aggregate Exposure and Risk Estimates for 1,2,4 Triazole. Exposure Estimate, mg/ kg/ day Population Subgroup Dietary Dermal ( M/ L/ A) Dermal ( Post Applic.) Hand to Mouth Objectto Mouth Soil Ingestion Aggregate Aggregate MOE1 U. S. Population ( total) 0.00069 0.00183 0.0051 N/ A N/ A N/ A 0.00762 3,900 All infants (< 1 year) 0.00156 N/ A 0.0086 0.0041 0.0010 0.000019 0.01528 2,000 Children 1 2 yrs 0.00196 N/ A 0.0086 0.0041 0.0010 0.000019 0.01568 1,900 Children 3 5 yrs 0.00149 N/ A 0.0086 0.0041 0.0010 0.000019 0.01521 2,000 Children 6 12 yrs 0.00088 N/ A 0.0086 N/ A N/ A N/ A 0.00948 3,200 Youth 13 19 yrs 0.00054 0.00183 0.0051 N/ A N/ A N/ A 0.00747 4,000 Adults 20 49 yrs 0.00055 0.00183 0.0051 N/ A N/ A N/ A 0.00748 4,000 Adults 50+ yrs 0.00055 0.00183 0.0051 N/ A N/ A N/ A 0.00748 4,000 Females 13 49 yrs 0.00054 0.00183 0.0051 N/ A N/ A N/ A 0.00747 4,000 1 Aggregate MOE = NOAEL ( 30 mg/ kg/ day) ÷ Aggregate Exposure Estimate ( mg/ kg/ day). LOC = 1000.

7.2 Intermediate term Aggregate Risk In assessing intermediate term aggregate risk, HED has combined dietary exposure ( direct and indirect) with soil ingestion ( direct, toddlers only). Other sources of non dietary exposure have not been included. As noted in Section 6.2, many T D fungicides are relatively stable ( half lives on the order of 1 3 months). Although residues may persist into an intermediate term timeframe, they will not be available for hand to mouth, object to mouth, or dermal exposure. Therefore, intermediate term aggregate risk estimates only include pathways of dietary exposure and soil ingestion. Aggregate MOEs for infants and children ages 1 to 2 years are well above the intermediate term LOC of 3000 and, therefore, represent risks that are below HED's level of 43 of 94 concern. Aggregate risk estimates for older populations, where soil ingestion is not an issue, are equivalent to the dietary risk estimates presented in Section 6.1.

Table 7.2. Intermediate term Aggregate Exposure and Risk Estimates for 1,2,4 Triazole. Exposure Estimate, mg/ kg/ day Population Subgroup Dietary Soil Ingestion Aggregate Aggregate MOE1 U. S. Population ( total) 0.00069 N/ A 0.00069 22,000 All infants (< 1 year) 0.00156 0.000019 0.00158 9,500 Children 1 2 yrs 0.00196 0.000019 0.00198 7,600 Children 3 5 yrs 0.00149 0.000019 0.00151 9,900 Children 6 12 yrs 0.00088 N/ A 0.00088 17,000 Youth 13 19 yrs 0.00054 N/ A 0.00054 28,000 Adults 20 49 yrs 0.00055 N/ A 0.00055 27,000 Adults 50+ yrs 0.00055 N/ A 0.00055 27,000 Females 13 49 yrs 0.00054 N/ A 0.00054 28,000 1 Aggregate MOE = NOAEL ( 15 mg/ kg/ day) ÷ Aggregate Exposure Estimate ( mg/ kg/ day). LOC = 3000.

8.0 Cumulative Risk Characterization/ Assessment FQPA ( 1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non occupational exposure to other substances that have a common mechanism of toxicity. The reason for consideration of other substances is due to the possibility that low level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually. A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe.

HED did not perform a cumulative risk assessment as part of this assessment for the triazole metabolites. Investigations into the potential cumulative effects of 1,2,4 triazole, triazole alanine and triazole acetic acid, and parent triazole derivative fungicides are currently being undertaken by the Office of Research and Development. Additionally, EPA has not made a common mechanism of toxicity finding regarding the triazole metabolites and any other substances. For purposes of this assessment, EPA has assumed that 1,2,4 triazole and triazole alanine/ triazole acetic acid do not have a common mechanism of toxicity and that the triazole metabolites do not have a common mechanism of toxicity with other substances.

Before undertaking a cumulative risk assessment, HED will follow procedures for identifying chemicals that have a common mechanism of toxicity as set forth in the " Guidance for Identifying Pesticide Chemicals and Other Substances that Have a Common Mechanism of Toxicity" ( 64 FR 5795 5796, February 5, 1999). For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for 44 of 94 cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

On this basis, the Registrant must submit, upon EPA's request and according to a schedule determined by the Agency, such information as the Agency directs to be submitted in order to evaluate issues related to whether the triazole metabolites share a common mechanism of toxicity with any other substances. If HED identifies other substances that share a common mechanism of toxicity with the triazole metabolites, HED will perform aggregate exposure assessments on each chemical and will begin to conduct a cumulative risk assessment.

As previously noted, this assessment does take into consideration the multiple parent triazolederivative fungicides that may lead to dietary and non dietary exposure to the triazole metabolites.

9.0 Occupational Exposure/ Risk Pathway Occupational exposure to 1,2,4 triazole is likely to occur as a result of activities associated with a single T D compound. The risks associated with occupational exposure to this compound are addressed in the risk assessments for the parent compounds. Those risk estimates inherently include risk associated with occupational exposure to 1,2,4 triazole. Therefore, an occupational exposure and risk assessment for 1,2,4 triazole, per se, is not warranted. This is unlike the case for dietary exposure where it is likely that multiple T D fungicides simultaneously lead to 1,2,4 triazole exposure.

10.0 Data Needs and Label Requirements 10.1 Toxicology   Developmental neurotoxicity study in rats.   Chronic toxicity/ oncogenicity study in male rats and female mice [ This study, included in the original data call in, has not been submitted. As noted above, a previous waiver request for this study was denied. A new waiver request submitted in August, 2005, is under review.]   Acute neurotoxicity study in rats [ This study, included in the original data call in, was placed in reserve pending the results of the combined subchronic/ neurotoxicity study, in response to a previous waiver request. A new waiver request for this study was submitted in August 2005, and is under review.]

10.2 Residue Chemistry   A final two year storage stability study with 1,2,4 triazole remains outstanding. An interim report, depicting residues following one year of storage indicates that 1,2,4 T is stable in frozen food commodities.

10.3 Occupational and Residential Exposure 45 of 94   A study examining dislodgeable foliar residues of the T D fungicide metabolites was requested. However, the USTTF has requested that the Agency waive the study, arguing that any residues of metabolites would be contained within the leaf surface and therefore not dislodgeable. The waiver request has been reviewed by HED and recommended to be granted ( Jack Arthur, D319566, 12/ 22/ 05).

Triazole Alanine and Triazole Acetic Acid 11.0 Hazard Characterization/ Assessment 11.1 Hazard Characterization 11.1.1 Database Summary <IP_ADDRESS> Studies available and considered For triazole alanine, acute toxicity was evaluated using acute oral toxicity studies and a nonguideline acute intraperitoneal toxicity study. Subchronic studies available for hazard characterization included 14 day, 28 day, and 90 day oral toxicity studies in the rat and a 90 day oral toxicity study in the dog. No chronic studies were submitted. Developmental toxicity and two generation reproduction studies in the rat were evaluated; a developmental toxicity study in the rabbit was not available. Multiple mutagenicity and metabolism studies were considered.

For triazole acetic acid, five acceptable studies were available for hazard characterization: an acute oral toxicity study, a non guideline 14 day oral toxicity study in the rat, a bacterial reverse mutation assay, and two non guideline metabolism studies.

For triazole lactic acid and triazole pyruvate, no mammalian toxicology studies were available.

<IP_ADDRESS> Mode of action, metabolism, and toxicokinetic data Mode of action. The parent triazole fungicides act by inhibiting sterol synthesis, particularly by preventing the 14 demethylation of the sterols. The sterols, which are similar to cholesterol in mammals, are important for fungi membrane structure and function. The mode( s) of action for mammalian toxicity associated with 1,2,4 triazole and the triazole conjugates is currently unknown.

Metabolism and toxicokinetic data. Pharmacokinetic studies showed that triazole alanine is rapidly absorbed and excreted following single oral gavage doses of 0.5, 0.56, 5, 54, 56, or 994 mg/ kg, following five daily oral gavage doses of approximately 48 49 mg/ kg/ day, and following a single dose of 5 mg/ kg by i. v. injection. Excretion occurred mostly in the urine, accounting for 81 85% to > 90% of the administered radioactivity in three single oral and i. v. injection studies and ~ 55 63% in the multiple oral dose study at 168 hours. Much less of the radioactivity was excreted in the feces, which accounted for ~ 2 5% of the administered radioactivity in the single dose studies and ~ 11 27% in the multiple oral dose study. Volatiles accounted for < 1% of the 46 of 94 radioactivity. Tissue residues were low in all studies, with the majority of the radiolabel found in tissues located in the liver and kidneys.

The two single oral dose triazole alanine metabolism studies are consistent, since both found high amounts of unchanged triazole alanine ( 72 93% of the radioactivity) recovered in the urine 24 hours after exposure to 0.56 994 mg/ kg, lesser amounts of N acetyl triazole alanine ( 8 30%), and a small percentage of unknown metabolites. There was no mention that triazole acetic acid or 1,2,4 triazole were detected in these urinary samples. ( Note that N acetyl triazole alanine and triazole acetic acid are structurally different.) From the fecal samples taken 24 hours following oral exposure to 56 mg/ kg, a high proportion of the recovered radioactivity was unchanged triazole alanine ( 50%), with less N acetyl triazole alanine identified ( 16%), similar to what was found in the urine. However, 30% of the radioactivity found in the fecal samples consisted of an unknown component that did not appear in the urinary samples.

In the repeated oral dose metabolism study, a large amount ( 63%) of the radioactivity recovered in the urine samples taken 168 hours following 5 doses of ~ 48 49 mg/ kg/ day triazole alanine was identified as unchanged triazole alanine, similar to what was seen 24 hours after a single dose. However, 30% of the urinary radioactivity was identified as triazole acetic acid, and 1.6% was identified as 1,2,4 triazole. These compounds were not seen in the single dose studies; furthermore, N acetyl triazole alanine, which was seen in the single dose studies, was not seen in the repeated dose study. This study also showed that the same three components seen in the urine were found in the feces. However, a much larger percentage of the radioactivity recovered in the feces was identified as triazole acetic acid ( 69%) and 1,2,4 triazole ( 11%), with significantly less excreted as unchanged triazole alanine ( 2%). The remaining radioactivity in the feces was made up of three unknown conjugates, none of which was greater than 7%.

For triazole acetic acid, two metabolism and pharmacokinetic studies showed rapid absorption and excretion following a single oral dose of approximately 0.6, 59, or 1035 mg/ kg or five daily oral doses of approximately 50 51 mg/ kg/ day. Excretion occurred mainly in the urine, as it did for triazole alanine, accounting for ~ 90 104% of the administered radiolabel in the single dose study and ~ 66 75% of the radiolabel in the multiple dose study at 168 hours. The feces accounted for much less of the administered radiolabel: ~ 1 7% in the single dose study and ~ 11 32% in the multiple dose study. In both studies, tissue burdens were very low. Unlike triazole alanine, the sole component identified in both the urinary and fecal extracts from these two studies was triazole acetic acid, indicating that triazole acetic acid administered to the rat is excreted intact without metabolic conversion.

<IP_ADDRESS> Sufficiency of studies/ data Triazole alanine. The partial toxicology database available for triazole alanine is insufficient to fully characterize the hazards associated with this conjugate. However, it was possible to categorize the acute toxicity of triazole alanine, to identify effects following subchronic exposure, to begin examination of the differences in toxicity associated with longer duration of exposure and across species ( i. e., rat and dog), to examine potential reproductive toxicity, to evaluate the differences in susceptibility between rodent parents and offspring, and to examine the potential of triazole alanine to cause mutagenicity. 47 of 94 The toxicity resulting from exposures to triazole alanine longer than 90 days was not determined because no chronic studies were available.

Interspecies differences were not fully examined because no triazole alanine studies were conducted in rabbits or mice. The lack of a developmental toxicity study in rabbits is a particularly important data gap, because mortality and clinical signs were seen in adult rabbits following a single dose of 45 mg/ kg 1,2,4 triazole in a rabbit developmental study ( MRID 46492903). For free triazole, the rabbit was shown to be the most sensitive species; in the absence of data to suggest otherwise, it is likely that rabbits are also more sensitive to triazole alanine.

Triazole acetic acid. The toxicology database for triazole acetic acid consists of five acceptable studies, including three non guideline studies. In the absence of additional data, the studies on triazole acetic acid were compared to corresponding studies on triazole alanine to determine potential differences in potency between these two conjugates.

Other triazole conjugates. No mammalian toxicology studies are available for triazole lactic acid or triazole pyruvate. These compounds occur only infrequently in plant metabolism studies and have not been included in the quantitative risk assessment.

11.1.2 Toxicological Effects <IP_ADDRESS> Acute toxicity Triazole alanine. The acute toxicity of triazole alanine is low, based on acute oral toxicity studies in the the rat and mouse ( Category IV) and an acute intraperitoneal toxicity study in the rat ( LD50 > 5000 mg/ kg). Although triazole alanine was classified as Category III according to results from one acute oral toxicity study ( MRID 00138119), this was because inadequate dose levels were tested. Note that although the acute toxicity of 1,2,4 triazole was greater in the rabbit than in the rat or mouse, a similar comparison of the acute toxicity of triazole alanine across species could not be made since acute rabbit studies were not submitted for the conjugate.