Page 1 of 44 **UNITED STA TES ENVIRONMENTA**  **L PROTECTION A GENCY** 

WA SHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION **D ATE**  **:** September 30 , 20 1 1 **MEMORANDUM SUBJECT**  : **Metconazole :**  Human Health Risk Assessment for Proposed Uses on Sugarcane . **PC Code:** 125619 **DP Barcode:** D 3 86421 **Decision No.:** 4 42406 **Registration No. :**  7969 - 246 **Petition No.:** 0 F 7 807 **Regulatory Action:** Section 3 Registration **Risk Assessment Type:** Single C hemical/ A ggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 125 116 - 23 - 6 **MRID No.:** NA **40 CFR:** §180. 617 **FROM** : Barry

O’Keefe , Senior Biologist Amelia Acierto, Chemist My ron O ttley , Senior Toxicologist Nancy Tsaur , Chemist Risk Assessment Branch III Health Effects Division (7509P) **THROUGH** : Paula Deschamp , Branch Chief

Risk Assessment Branch III Health Effects Division (7509P) **TO** : Tracy

Keigwin/Mary

Waller, RM21 Fungicide Branch Registration Division (7505P) **Introduction** BASF Corporation (BASF) is proposing a new foliar use of metconazole on sugarcane. The proposed formulated end - use product is CarambaTM Fungicide (EPA Reg. No. 7969 - 246). CarambaTM Fungicide is a soluble liquid (SL) formulation, containing 8.6% active ingredient (ai), equivalent to 0.75 pounds of metconazole per gallon of product. The Registration Division (RD) requested that the Health Effects Division (HED) evaluate toxicology

and residue chemistry

data and conduct dietary , aggregate, and occupational exposurePage 2 of 44

and risk assessments, as needed, to estimate the risk to human health that will result from th is new use and tolerance. A summary

of the findings and an assessment of human risk resulting from the registered and proposed new uses of metconazole are provided in this document. The risk assessment was provided b y Barry O’Kee fe, the hazard characterization by My ron Ottley , the residue chemistry data review and the dietary assessment by

Amelia Acierto, and the occupational assessment by Nancy Tsaur . The drinking water assessment was provided by Faruque Khan of the Environmental Fate and Effects Division (EFED).Page 3 of 44 **Table of Contents 1.0**  **Executive Summary** ................................ ................................ ................................ .......... 5 **2.0 Regulatory Conclusions and Recommendations**  ................................ ............................ 8 2.1 Data Deficiencies/ Conditions of Registration ................................ ....................... 8 2.2 Tolerance Considerations ................................ ................................ ........................ 8 2.2.1 Enforcement Anal ytical Method ................................ ................................ . 8 2.2.2 International Harmonization ................................ ................................ ....... 9 2.2.3 Recommended Tolerances ................................ ................................ .......... 9 2.2.4 Revisions to Petitioned - For Tolerances ................................ ...................... 9 2.3 Label Modifications ................................ ................................ .............................. 10 **3.0 Ingredient Profile**  ................................ ................................ ................................ ............ 10 3.1 Summary

of Proposed Uses ................................ ................................ .................. 10 3.2 Structure and Nomenclature ................................ ................................ ................. 11 3.3 Phy sical and Chemical Properties ................................ ................................ ......... 12 3.4 Anticipated Exposure Pathway s ................................ ................................ ........... 12 3.5 Consideration of Environmental Justice ................................ ............................... 12 **4.0 Hazard Characterization/Assessment**  ................................ ................................ ........... 13 4.1 Hazard and Dose - Response Characterization ................................ ....................... 13 4.1.1 Database Summary ................................ ................................ ................... 13 4.1.2 Studies Available and Considered ................................ ............................ 13 4.1.3 Sufficiency

of Studies/Data ................................ ................................ ...... 13 4.1.4 Toxicological Effects ................................ ................................ ................ 13 4.1.5 Cancer Classification ................................ ................................ ................ 14 4.2 Absorption, Distribution, Metabolism, Excretion (ADME) ................................ . 15 4.3 FQPA Considerations ................................ ................................ ........................... 16 4.4 FQPA Safety Factor for Infants and Children ................................ ...................... 16 4.5 Hazard Identification and Toxicity Endpoint Selection ................................ ........ 17 4.5.1 Recommendation for combining routes of exposure for risk assessment . 19 4.6 Endocrine Disruption ................................ ................................ ............................ 19 **5.0 Dietary Exposure/Risk Cha**  **racterization** ................................ ................................ ..... 20 5.1 Pesticide Metabolism and Environmental Degradation ................................ ........ 20 5.1.1 Metabolism in Primary Crops ................................ ................................ ... 20 5.1.2 Metabolism in Livestock ................................ ................................ ........... 20 5.1.3 Drinking Water Residue Profile ................................ ................................ 21 5.1.4 Food Residue Profile ................................ ................................ ................. 22 5.2 Dietary

Exposure and Risk ................................ ................................ ................... 26 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Chara**  **cterization** ............................ 27 6.1 Residential Handler Exposure and Risk Characterization ................................ .... 27 6.2 Residential Postapplication Exposure and Risk Characterization ........................ 28 **7.0 Aggregate Risk**  **Assessments and Risk Characterization** ................................ ............ 29 7.1 Acute & Chronic Aggregate Risk ................................ ................................ ......... 30 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ..................... 30 **8.0 Cumulative Risk Characterization**  **/Assessment** ................................ ........................... 31 **9.0 Occupational Exposure/Risk Pathway**  ................................ ................................ .......... 32 9.1 Short - and Intermediate - Term Handler Risk ................................ ........................ 32 9.2 Short - and Intermediate - Term Postapplication Risk ................................ .............. 33Page 4 of 44

**Appendix A: Toxicology Assessment** ................................ ................................ ....................... 35 A.1 Toxicology

Data Requirements ................................ ................................ ................ 35 A.2 Toxicity

Profiles ................................ ................................ ................................ ........ 36 **Appendix B: EPA Review of Human Resear ch**  ................................ ................................ ...... 42 **Appendix C: Physical and Chemical Properties of Metconazole** ................................ .......... 42 **Appendix D: International Residue Limit Status** ................................ ................................ ... 44Page 5 of 44

**1.0 Executive Summary**  Metconazole (5 - [(4 - chlorophenyl)methyl] - 2,2 - dimethyl - 1 - (1 H - 1,2,4 - triazol - 1 - ylmethyl) cyclopentanol) is a broad - spectrum triazole fungicide that works s ys temically by preventing spore formation and inhibiting mycelial growth. Metconazole acts p rimarily as an inhibitor of ergosterol bios ynthesis, thereb y interfering with synthesis of fungal cell membranes and providing s ys temic seed and seedling protection . BASF Corporation (BASF) is proposing a new Section 3 foliar use of metconazole on sugarcane. There is currentl y a Section 18 foliar use on sugarcane. The proposed formulated end - use product is CarambaTM Fungicide (EPA Reg. No. 7969 - 246). CarambaTM Fungicide is a soluble liquid (SL) formulation, containing 8.6% active ingredient (ai), equivalent to 0.75 pounds of metconazole per gallon of product. Use Profile CarambaTM Fungicide is a triazole fungicide used to control brown and orange rust on sugarcane. The proposed maximum single application rate is 0.082 lb ai/A (0.33 lb ai/A/season, with a maximum of four applications per season) . To limit the potential for development of resistance, no more than two sequential applications should be made before alternating to another fungicide with a different mode of action. Caramb aTM Fungicide may be applied foliarly

by aerial , groundboom, or chemigation methods. The preharvest interval (PHI) is 14 days. Toxicity/Hazard The toxicological database for metconazole is sufficient for the purpose of this risk assessment. The liver is the primary

target organ (with observed adverse effects such as increased liver weight and enzy

me activity , increased incidence of hy pertrophy and vacuolization) in the mouse, rat and dog following oral exposure to metconazole via subchronic or chronic exposure durations. O ther adverse effects observed in oral studies were decreased body weight, decreased body weight gains, and blood effects (reductions in ery throcy te and/or platelet parameters) in the mouse, rat, dog and/or rabbit. Splenic effects including increased spleen weight and h yp erplasia were observed in the mouse, rat and dog at dose levels where liver effects were also observed. In dogs, lenticular degeneration (cataracts) and gastrointestinal irritation were observed at the high dose level(s). Developmental studies in rats and rabbits show evidence of developmental effects, but only at dose levels that are maternally toxic. There is qualitative evidence of susceptibility in the rat developmental study , however the concern is low since the developmental effects are well characterized, occur in the presence of maternal toxicity, the no observable adverse effect levels (NOAELs ) are well defined, and the dose/endpoint is used for acute dietary risk assessment for the sensitive population. Metconazole did not demon strate the potential for neurotoxicity in the four species (mouse, rat, dog and rabbit) tested. Metconazole is considered nongenotoxic and is classified as "not likely

to be carcinogenic to humans". In accordance with the revised 40 CFR Part 158 data requirements, an acute neurotoxicity study is required. The existing database does not include this study

does not include this acute neurotoxicity study , and this data deficiencyPage 6 of 44

remains. Drinking W

ater Estimated drinking water concentrations (EDWCs) of m etconazole in drinking water from use on the existing crops and sugarcane were provided by the Environmental Fate and Effects Division ( EFED ) . The drinking water assessment us ed PRZM/EXAMS modeling for surface water and the SCI - GROW model for ground water . The highest surface water EDWC s for sugarcane (9.96 μg/L for acute, 3.6 μ g/L for chronic) in the current assessment are lower than the acute EDWC for turf ( 45.48 μ g/L ) and the chronic EDWC for cranberry (38.16 μ g/L ) reported in the previous drinking wat er assessment, and therefore EFED recommended the use of the previous EDWC s . For ground water , an acute and chronic ground water EDWC of 0.0431 μg/L was estimated for sugarcane, which is less than the 0.38 μg/L EDWC for turf in a previous assessment. Die tary Exposure (food and drinking water) A new dietary

assessment i s not needed for the proposed Section 3 use on sugarcane because a previous dietary

assessment for an existing Section 18 use on sugarcane was conducted using residues of metconazole in/on sugarcane, cane at a tolerance level of 1.6 ppm , which resulted in exposure and risk well below HED’s level of concern (LOC). The proposed Section 3 use on sugarcane results in a tolerance residue of 0.06 ppm for sugarcane, cane , and a separate tolerance for sugarcane, molasses is no longer needed. Additionally , the requested use of metconazole on sugarcane did not result in an increase in dietary exposure estimates for free triazole or conjugated triazoles. Therefore, the last dietary exposure anal ys es for the triazole metabolites did not need to be updated. Residential Exposure This document presents the assessment of the proposed new agricultural uses of metconazole . No new residential uses are being requested at this time. However, adults, adole scents and children may be exposed to metconazole from its currentl y registered use on turf and ornamentals. Aggregate Risk Dietary , incidental oral and inhalation routes of exposure have the same toxicity endpoints, and therefore, can be aggregated. Acute and chronic aggregate risk assessments include only food and drinking water, and the results are covered in the dietary section of this executive summary . The short - and intermediate - term aggregate risk assessments for metconazole consider average (chronic) exposure estimates from dietary consumption of metconazole (food and drinking water) and non - occupational/residential use on turf (inhalation for adults and incidental oral for children). Postapplication exposures from the use on turf are considere d predominantly short term (1 - 30 day s). Although exposures are expected via the dermal route, quantification ofPage 7 of 44

dermal risk was not conducted, since a dermal endpoint was not identified for short - or intermediate - term exposures. Therefore, short - and int ermediate - term post - application aggregate risk assessments were conducted only for average dietary

and incidental oral exposures to children, and average dietary and inhalation exposures to adults. The short - and intermediate - term aggregate margins of expo sure ( MOEs ) from dietary exposure (food + drinking water) and non - occupational/residential handler exposure (inhalation) for adults are both 1700, which are not of concern to HED, since these MOEs are greater than the level of concern MOE of 100. The short - and intermediate - term aggregate MOEs from dietary exposure (food + drinking water) and non - occupational/residential exposure (incidental oral) for children 1 - 2 years old are 420 and 460, respectivel y; which are not of concern to HED, since these MOEs are greater than the level of concern MOE of 100. These aggregate exposure assessments are considered conservative estimates that should not underestimate risks for the following reasons : 1) the dietary inputs used tolerance - level residues, 100% crop treated , and screening level drinking water modeling data; and 2) screening - level residential SOPs and upper level estimates of exposure were emplo yed. Aggregate Assessment of Free Triazole &its Conjugates The addition of the new proposed use on sugarcane does not increase the aggregate exposure to free triazoles and its conjugates. Therefore, the recently updated aggregate human health risk assessment for free triazoles and its conjugates remains unchanged and the aggregate estimates remain below HED’s level of concern . Occupational Exposure and Risk Handler s: Based on the proposed uses, there is a potential for short - and intermediate - term occupational exposure to metconazole during handling activities (e.g. m ixing, loading, application). The results of th e occupational handler exposure and risk assessment indicate that short - and intermediate - term inhalation risks do not exceed HED ’ s LOC of an MOE < 100 . For short - term exposure, the handler inhalation MOEs ranged from 63,000 to 440,000 at baseline (i.e. , w ith no respirator) , and for intermediate - term exposure, the handler inhalation MOEs ranged from 45,000 to 310,000 at baseline. Post- application W

orkers : There is a potential for short - and intermediate - term occupational exposure during post - application ac tivities . However, since there is no dermal endpoint identified up to the limit dose, a dermal post - application assessment is not needed. Under the Worker Protection Standard (WPS) for Agricultural Pesticides, the 12 - hour REIon the label is acceptable.Page 8 of 44

Review of H

uman Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies (listed in Appendix B ) have been determined to require a review o f their ethical conduct, and have received that review. **2.0 Regulatory Conclusions and Recommendations**  HED can recommend for a conditional registration and a permanent tolerance for the proposed us e of metconazole on sugarcane . Additional data are needed as conditions of registration as outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3. **2.1 Data Def** 

**iciencies/Conditions of Registration Note to PM:**  860.1520 Processed Food/Feed Residues of triazole - related compounds in blackstrap molasses are apparently misstated in the Executive Summary (pag e 13) of MRID 4823740 where it is stated that TA concentrated b y a factor of 4.3X in molasses. The data listed in the tables (p 309

– 311) of the document indicate that TAA concentrates by a factor of 4.3X in molasses and that TA does not concentrate, and this is also indicated in the Table 18, page 42, of the Results and Discussion of the submission. It appears from the anal ytical data that TAA concentrated, not TA. BASF should confirm this. **The following d ata**  **are required as**  **a condition of registratio**  **n :**  TOXICOLOGY 870.6200a Acute Neurotoxicity Study An acute neurotoxicity

study is required in accordance with the revised 40 CFR Part 158 data requirements, as part of a neurotoxicity battery . The existing database includes a subchronic neurotoxicity

study , but not an acute neurotoxicity study , and this remains a data deficiency . **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate high performance liquid chromatography /tandem mass spectrometry ( HP LC /MS/MS) method BASF D0604 is available for enforcement of tolerance and for data collection for residues of metconazole parent isomers ( cis - and trans - metconazole) and metconazole metabolites in plant co mmodities. The method was adequatel y validated prior to and concurrently

with the analy ses of crop field and processed commodity samples. The validated limit of quantitation (LOQ) is 0.01 ppm each for parent metconazole (sum of cis - and trans -Page 9 of 44

isomers at 0 .005 ppm each) and the metabolites M11, M21 , and M30 in the RAC and processed commodity

samples. The LOQ is 0.01 ppm for 1,2,4 - triazole (T) and triazolylacetic acid (TAA), and 0.05 ppm for triazolylalanine ( TA) in all sugarcane RAC and processed commodity samples. All residues of the anal yt es (parent, metabolites M11, M21, and M30 and 1,2,4 - T, TA, and TAA) in the untreated RAC, refined sugar and blackstrap molasses samples were non - detectable. Representative chromatograms were provided. **2.2.2 Internatio**  **nal Harmonization** There are currently

no established Codex, Canadian, or Mexican maximum residue limits (MRL s) for metconazole on sugarcane. An International Residue L imit (IRL) status sheet is appended to this document as Appendix D. **2.2.3 Recommended Tolerances**  In a ccord ance with HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression for metconazole should be state d as follows : Tolerances are established for residues of metconazole, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring onl y metconazole [5 - [(4 - ch lorophenyl )meth yl ] - 2,2 - dimethyl - 1 - (1 H - 1,2,4 - triazol - 1 - ylmethyl)cyclopentanol] as the sum of its cis - and trans - isomers. The proposed use and the submitted data support the following tolerance for residues of metconazole on/on the following raw agricultural commodity .

Sugarcane, cane ................................ ........................ 0. 06 p pm **2.2. 4**  **Revisions to Petitioned -**  **For Tolerances** Permanent tolerances have been proposed by BASF fo r the combined residues of the fungicide metconazole in/or on sug arcan e , cane at 0.0 6 and sugarcane, molasses at 0. 08 ppm. For purposes of the tolerance expression, HED has determined that the residue of concern is metconazole (the sum of cis - and trans - isomers) for b oth primary and rotational crops and for livestoc k commodities. The tolerance expression for metconazole in 40 CFR §180.617(a)(1) should be stated according to HED’s Interim Guidance on Tolerance Expression (5/27/09, S. Knizer) as specified in Section 2.2.3 . Section 18 emergency

exemption t olerances are currentl y established for metconazole residues in/ on sugarcane, cane at 1.6 ppm and sugarcane, molasses at 3.2 ppm under 40 CFR §180.617(b). These tolerances should now be deleted and a new tolerance should be listed under 40 CFR §180.617(a)(1) for s ugarcane, cane at 0.06 ppm.Page 10 of 44

Adequate crop field trial data reflecting the proposed use patterns were submitted for purposes of establishing tolerances on sugarcane. The OECD MRLCalculator was utilized in determining the appropriate tolerance level for su garcane, cane. The highest metconazole residue from the sugarcane field trials (1X) is 0.036 ppm. This residue multiplied by

the processing factor for molas s es (0.036 X 2.1) yi elds 0.043 ppm. As this is less than the recommended tolerance for sugarcane, cane at 0.06 ppm, the sugarcane , cane tolerance will cover molasses. No separate tolerance for molasses is necessary . The proposed and recommended tolerances for metconazole as a result of the subject action are presented in Table 1. **Table 1**  **. Tolerance Summary for**  **Metconazole .**  **Comm odity**  **Proposed Tolerance (ppm)**  **Recommended Tolerance (ppm)**  **Comments 40 CFR §180.**  **617 (a)(**  **1 )**  Sugarcane, cane 0.0 6 0.06 Sugarcane, molasses 0. 08 none Molasses is covered by the recommended sugarcane, cane tolerance. **2.3 Lab**  **el Modifications** The product has been referred to and described in the submission as a soluble liquid (SL) , but this designation is not reflected in the product name and/or proposed label. The label should be revised to indicate the formulation ty pe. **3 .0**  **Ingredient Profile 3.1**  **Summary of Proposed Uses** BASF is proposing a new foliar use of metconazole on sugarcane. The proposed formulated end - use p roduct is CarambaTM Fungicide (EPA Reg. No. 7969 - 246). CarambaTM Fungicide is a soluble liquid formulation, containing 8.6% active ingredient (ai), equivalent to 0.75 pounds of metconazole per gallon of product. CarambaTM Fungicide is a triazole fungicide u sed to control brown and orange rust on sugarcane. The proposed maximum single application rate is 0.082 lb ai/A (0.33 lb ai/A/season, with a maximum of four applications per season) . CarambaTM Fungicide application should ensure thorough coverage of foli age, blooms, and fruit. To limit the potential for development of resistance, no more than two sequential applications should be made before alternating to another fungicide with a different mode of action. CarambaTM Fungicide may

be applied foliarly

by a erial , groundboom, or chemigation methods. The PHI is 14 day s. A summary

of the proposed use directions for the intended crops is presented in Table 2.Page 11 of 44

**Table 2**  **. Summary of Directions for Use of Metconazole on Sugarcane**  **Application Timing, Type,**  **and Equipment**  **1 Form**  **ulation**

**[EPA Reg. No.]**  **Applic ation** 

**Rate (lb ai/A)**  **Max. No.**

**Applic ations**  **per Season Max.** 

**Seasonal Applic.**  **Rate (lb ai/A)**  **PHI**

**(days) Use Directions and** 

**Limitations**

Foliar ( Broadcast, Ground sprayer, A erial or through S prinkler I rrigation S ys t ems ) 8.6% SL

[7969 - 246] 0.082 4 0.33 14 Apply at first sign of disease . Continue applications on a 14 - 28 - day interval if conditions for disease development persist. Use shorter interval when disease pressure is high. Do not make more than 2 sequential applications of Caramba or other DMI (Group 3) fungicides before alternating to another fungicide with a different mode of action. 1 The original label (EPA Registration No. 7969 - 246; 05/22/2009) states in the general instructions that a nonionic surfactant may be used at the lowest labeled rate (for ground applications). **3 .2**  **Structure and Nomenclature** Structure and nomenclature are reported in Table 3 . **Table 3. Metconazole Nom**  **enclature** . Chemical structure N N N

C H 3 C H 3 O H Cl

ci s - isomer N N N

C H 3 C H 3 O H Cl trans - isomer Common name Metconazole Com pany experimental name KNF - S - 474m (Kureha); BAS 555 F (BASF); V - 10116 (Valent) IUPAC name (1 RS,5 RS :1 RS,5 SR ) - 5 - (4 - chlorobenzyl) - 2,2 - dimethyl - 1 - (1 H - 1,2,4 - triazo l - 1 - ylmethyl ) cyclopentanol CAS name 5 - [(4 - chlorophenyl)methyl] - 2,2 - dimethyl - 1 - (1 H - 1,2,4 - triazol - 1 - ylmethyl)cyclopentanol CAS registry number 125116 - 23 - 6 ( cis - and trans - isomers) 115850 - 27 - 6 ( cis - isomer) 115850 - 28 - 7 ( trans - isomer) End - use products (EP) CarambaTM Fungicide (EPA File Symbol 7969 - 246 )Page 12 of 44

**3 .3**  **Physical and Chemical Properties** The phy sicochemical properties of metconazole are reported in Appendix C. **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new use of metconazole on sugarcane. For domestic uses, humans may be exposed to metconazole in food and drinking water, s ince metconazole may be applied directly

to growing crops and application may result in metconazole reaching surface and ground water sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior to a

pplication, as well as during application. There is a potential for post application exposure for workers re - entering treated fields. There are also residential uses of metconazole, so there is exposure in residential or non - occupational settings. Risk assessments have been previousl y prepared for the existing uses of metconazole. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use of metconazole, but also considers the existing uses as well, particul arl y for the dietary exposure assessment. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations,” http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

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

Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by

subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, nondietary

exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups.Page 13 of 44

**4 .0**  **Hazard Characterization/Assessment 4**  **.1 Hazard and Dose**  **- Response Characterization**  **4 .1.1**  **Database Summary** The toxicological database for metconazole is adequate for the purpose of this risk assessment. Two recent risk assessment documents (HED memoranda B. O’Keefe, 09/06/07, DP328676 and Y. Donovan, 03/12/08, DP331937) contain detailed and up - to - date discussions of the toxicology and hazard evaluation of metconazole. Please refer to these documents for further extensive details. Also, please refer to Appendix 2 of this current risk assessment document for the toxicity profile tables. **4.1.2 Studies Available and Considered**  The following data are available: Acute - Oral rat, dermal rat, inhalation rat, eye irritation rabbit, dermal irritation rabbit, and skin sensitization guinea pig. Subchronic - Oral 28 - day

rat; oral 90 - day

rat, oral 90 - day

mouse, and oral 90 - day

dog; Chronic - Oral rat and dog; Reproductive/developmental - Oral developmental rabbit and rat, 2 - generation reproductive rat Other - Oral rat and mouse cancer studies, 21 - day dermal toxicity

and dermal penetration studies, subchronic neurotoxicity, mutagenicity sc reens and mechanistic studies. **4.1. 3**  **Sufficiency of Studies/Data** The toxicity

database for metconazole is adequate for the purpose of this risk assessment (see Appendixes for Toxicity

Profile tables). **4 .1.**  **4 Toxicological Effects**  Metconazole is a member of the triazole class of systemic fungicides and acts primarily as an inhibitor of ergosterol biosy nthesis. The proposed mode of action for metconazole is via inhibition of sterol (ergosterol) biosynthesis in fungi which is consistent with altered cholesterol levels observed in mice and rats. Overall, metconazole appears to affect the liver, kidney , spleen, and certain blood parameters in all the species tested. Dose levels at which these effects occur are similar across species with the rat and dog being slightly more sensitive than the mouse. Like other triazoles, a primary target organ in mammalian toxicity studies is the liver. Liver toxicity was seen in the mou se, rat and dog following oral exposure to metconazole via subchronic or chronic exposure durations. While liver effects have been reported consistently across multiple durations and species, these effects were considered slight and minimal in some studie s and appeared to be "adaptive" responses. However, based on the weight of evidence from the consistency of these reported effects and evidence that these effects increase in severity with duration, and leading to liver tumors in the chronic mouse study , they were considered "adverse" and formed the basis of thePage 14 of 44

study L OAELs. Metconazole is considered nongenotoxic and the liver tumors appear to have been formed via a mitogenic mode of action and therefore, metconazole is classified as "not likely to be carcinogenic to humans" at levels that do not cause mitogenesis ( see section 4.1.5) . The established chronic RfD would be protective of mitogenesis/carcinogenesis. Other major critical effects observed in oral studies were decreased body weight, decreased body weight gains, and blood effects (reductions in erythrocy te and/or platelet parameters) in the mouse, rat, dog and/or rabbit. Splenic effects including increased spleen weight and hyp erplasia were observed in the mouse, rat and dog at dose levels wher e liver effects were also observed. In dogs, lenticular degeneration (cataracts) was observed at the highest dose tested (114 mg/kg/day). Furthermore, at high dietary levels, there is evidence that metconazole is a gastrointestinal irritant in the dog. Developmental studies in rats and rabbits show some evidence of developmental effects, but only at dose levels that are maternally toxic. There was no quantitative susceptibility to the fetuses of rats or rabbits following in utero exposure to metconazole . In the developmental toxicity study in rats, skeletal variations (predominantl y lumbar ribs) occurred in the presence of maternal toxicity (decreased body weight gains). In the prenatal developmental toxicity study in rabbits, developmental effects (in creased post - implantation loss and reduced fetal body weights) were observed at the same dose that caused maternal toxicity (decreased body weight gains, reduced food consumption and alterations in hematology parameters). In the two - generation reproductio n study

in rats, offspring toxicity (reduced fetal body

weights F2 offspring and decreased viability in F1 and F2 offspring) was observed onl y at the highest tested dose, a dose which also resulted in parental toxicity as evidenced by

reduced parental body weight and body weight gains, increased incidence of fatty hepatocyte changes in male parental animals and increased incidence of spleen congestion in F1 parental females. In the rat study , there is low concern for qualitative susceptibility (skeletal variation in the presence of minimal maternal toxicity ) due to the presence of more severe effects at higher dose levels such as post implantation loss, hydrocephal y and visceral anomalies. However, there is a clear NOAEL for these effects and the point of departure for this endpoint is based on skeletal variations. Therefore, it is concluded that there is no residual uncertainty for pre - and/or post - natal toxicity . Metconazole did not demonstrate neurotoxicity in the standard battery

of tests submitted. In formation available from the submitted studies including acute, subchronic and chronic studies in several species, developmental toxicity studies in the rat and rabbit and a two generation reproduction study in the rat do not indicate any neurotoxic signs. No effects were noted on brain weights and no clinical signs possibly related to neurotoxicity

were noted up to and including the high doses in all studies. However, in accordance with the revised 40 CFR Part 158 data requirements, an acute neurotoxi city study is required. The existeing database does not inclue an acute neurotoxicity study , and this remains a data deficiency . Acute oral and dermal toxicities are Category III, while acute inhalation is Category IV. Metconazole is a moderate eye irri tant (Category III) and a mild skin irritant (Category IV). It is not a skin sensitizer. **4.1.5 Cancer Classification** Page 15 of 44

The Cancer Assessment Review Committee (CARC) Classification is: “Not L ikel y to be Carcinogenic to Humans” based on convincing evidence that a non - genotoxic mode of action for liver tumors was established in the mouse and that the carcinogenic effects were not likel y below a defined dose that doesn’t cause mitogenesis based on bioassay s in the rat an d the mouse, combined with a lack of in vitro or in vivo mutagenicity (memo, J. Kidwell, TXR# 0054211, 4/14/06). No quantification is required. **4 .2**  **Absorption, Distribution, Metabolism, Excretion (ADME)** The absorption, distribution, metabolism and excretion of metconazole were investigated in rats following single oral doses of cis and or cis/trans metconazole radiolabeled at the cyclopentylor triazole ring (cis only). Regarding abo rption, the time to maximum plasma concentration for male and female rats treated with either 2 mg/kg or 200 mg/kg was at the earliest sampling intervals of 0.25 hours and 4 hours, respectively . The plasma half - life of low - and high - dose rats was slightly shorter in males than females, ~20 - 25 hours and ~34 hours, respectivel y. Plasma pharmacokinetic studies showed a low potential for bioaccumulation following single or multiple dosing regimen. Radioactivity

measurements of tissues showed higher concentrati ons in the gastrointestinal tract, adrenals and liver. The pattern of metabolites was similar at the low and high dose. Anal ys is of fecal and urine samples showed little or no parent compound with ten key metabolites representing over 50% of the administered dose. Metconazole metabolites consist primarily of mono - and poly- hydrox ylated derivatives of the parent molecule. Hydrox ylation occurs mainl y on the alkyl constituents of the phenyl and cyclopentyl rings. Sulfate conjugation to the cyclopentylring hydrox yl groups was also identified. Monohydrox y metabolites were found in the feces and di - and tri - hydrox y compounds were found more often in the urine. Administration of 200 mg/kg radiolabeled cis metconazole ( 14 C - triazole ring) showed approximately 5% of the administered dose excreted as free triazole. Initial studies showed less than 2% of the cyclopentyl - labeled dose was expired in the air. Following a single oral administration of low dose (2 mg/kg) 14 C - cyclopentyl (cis/trans metconazole), gre ater than 80% of the administered dose was excreted in 24 hours with total excretion exceeding 90% in three day s. Excretion was primaril y via feces (80% male, 67% female) with biliary

excretion being the prominent route of elimination. At 72 hours, 15% and 26% of the radioactivity

was excreted via urine in males and females, respectivel y. A delay in excretion was observed following the administration of high dose (164 mg/kg) 14 C - cyclopentyl (cis/trans metconazole); however b y 72 hours, 80% or more of the radioactivity was excreted. Males excreted lower amounts of radioactivity in the urine and greater amounts of radioactivity in the feces than females at low and high dose.Page 16 of 44

**4 .3**  **FQ PA Considerations**  The toxicology

databa se used to assess pre - and post - natal exposure to metconazole is considered adequate . **4 .4**  **FQ PA**  **Safety Factor for Infants and Children** The metconazole risk assessment team evaluated the quality o f the toxicity

and exposure data and, based on these data, recommended that the FQPA Safety Factor be reduced to 1 X . The recommendation is based on the following:

 The toxicology

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

 There is no evidence of susceptibility following in utero exposure in the rabbit. In the rat there is qualitative evidence of susceptibility, however the concer n is low since the developmental effects are characterized as variations (not malformations), occur in the presence of maternal toxicity , the NOAELs are well defined, and the dose/endpoint is used for acute dietary

risk assessment for the sensitive population. There is no evidence of increased susceptibility in the offspring based on the result of the two - generation reproduction study.  In accordance with the revised 40 CFR Part 158 data requirements, a neurotoxicity battery is required for this risk asses sment. The existing database does not include an acute neurotoxicity

study, and this remains a data deficiency . However, an acceptable subchronic neurotoxicity

study showed no neurotoxic effects at levels that produced sy stemic toxicity

in the study , as well as in other subchronic and chronic studies. Therefore, concern for potential neurotoxicity is low and the 10X FQPA factor is not retained.

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

exposure assessments were conducted using tolerance level residues and assumed 100% crop treated. Therefore, the acute and chronic dietary (food onl y) exposure is considered an upper bound conservative estimate. The contribution from drinking water is minimal. HED concludes that the acute and chronic exposure estimates in this analy sis are unlikel y to underestimate actual exposure. The drinking water component of the dietary assessment utilizes water concentration values gen erated b y model and associated modeling parameters which are designed to provide conservative, health protective, high end estimates of water concentrations which will not likely be exceeded. While there is potential for postapplication residential exposure, the best data and approaches currently available were used in the metconazole residential assessment. The Agency used the current conservative approaches for residential assessment, many of which include recent upgrades to the SOPs. The Agency believ es that the calculated risks represent conservative estimates of exposure because maximum application rates are used to definePage 17 of 44

residue levels upon which the calculations are based. Exposures are unlikely to be under estimated because the assessment was a screening level assessment . **4 .5**  **Hazard Identification and Toxicity Endpoint Selection** Doses and endpoints were selected for exposure routes (i.e., oral, dermal and inhalation) depending upon the appropriateness of the endpoint and the relevancy of the endpoints to the population of concern. Developmental ( in utero exposure) endpoints were selected to assess dietary risks for Females 13 - 49 years of age, whereas non - developmental (sy stemic toxicity) endpoints were selected to assess dietary and non - occupational (residential) risks to the general population, including children and infants. A summary

of toxicological endpoints for use in human health risk assessment is presented below: **Tabl e**  **4 . Summary of Toxicological Doses and Endpoints for Metconazole for Use in Dietary and Non**  **** **Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD, Level** 

**of Concern for Risk Assessment**  **S tudy and Toxicological Effects**  Ac ute Dietary (General Population, including Infants and Children) An appropriate dose/endpoint attributable to a single dose was not observed in the available oral

toxicity studies revie wed. Ac ute Dietary (Females 13 - 49 years of age) NOAEL= 12

mg/kg/day UF A= 10 X

UF H = 10 X FQPA SF= 1 X Ac ute RfD = 0.12

mg/kg/day aPAD= 0.12 mg/kg/day **Developm ental toxicity in rats:** 

LOAEL = 30 mg/kg/day based on increases in skeletal variations. At 75 mg/kg/day increased incidence of post - i mp lantation loss, hydrocephaly and visceral anomaliea (cranial hemorrhage, dilated renal pelvis, dilated ureters, and displaced testis) were reported. Chronic Dietary (All Populations) NOAEL= 4.3

mg/kg/day UF A=10 X

UF H = 10 X FQPA SF= 1 X Chronic RfD =

0.04 mg/kg/day cPAD = 0.04 mg/kg/day **Chronic oral toxicity study in rats:**

LOAEL = 13.1 mg/kg/day based on increased liver (M) weights and associated hepatocellular lipid vacuolation (M) and centrilobular hypertrophy(M). Similar effects were observed in fema les at 54 mg/kg/day, plus increased spleen weight. Incidental Oral Short - Term

(1 - 30 days) NOAEL= 9.1

mg/kg/day UF A= 10 X

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

for MOE = 100 **28 -**  **Day oral toxicity study in rats:**

LOAEL = 90.5 mg/kg/day based on decreased body w eight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F). Incidental Oral Intermediate Term (1 - 6 mo nths) NOAEL= 6.4

mg/kg/day UF A= 10 X

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

for MOE = 100 **90 -**  **Day oral toxicity study in rats:** 

LOAEL = 19.2 based on increased spleen wt (F) and hepatic vacuolation (M).Page 18 of 44

**Tabl e**  **4 . Summary of Toxicological Doses and Endpoints for Metconazole for Use in Dietary and Non**  **** **Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD, Level** 

**of Concern for Risk Assessment**  **S tudy and Toxicological Effects**  Dermal Short - (1 - 30 days) & Intermediate Term (1 - 6 mo nths) Quantification of dermal risk is not required due to lack of systemic or dermal toxicity at the Limit

Dose in a 21 - day

dermal toxicity study in the rat, the lack of target organ toxicity or neurotoxicity, and the lack of developmental or reproductive toxicity in the absence of parental effects which we re looked for in the dermal toxicity. Inhalation Short - Term (1 - 30 days) NOAEL= 9.1

mg/kg/day UF A= 10 X

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

for MOE = 100 **28 -**  **Day oral toxicity study in rats:**

LOAEL = 90.5 mg/kg/day based on decreased body weight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F). Inhalation Intermediate Term (1 - 6 mo nths) NOAEL= 6.4

mg/kg/day UF A= 10 X

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

for MOE = 100 **90 -**  **Day oral toxicity study in rats:**

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

of t oxicological d oses and endpoints for m etconazole for u se in o ccupational human h ealth risk a ssessments is presented below: **Table 5**  **. Summary of Toxicological Doses and Endpoints for Metconazole for Use in Occupational Hum an**  **Health Risk Assessments Exposure/**  **Scenario Poin**  **t of**

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short - ( 1 - 30 days) & Intermediate Term (1 - 6 mo nths) Quantification of dermal risk is not required due to lack of systemic or dermal toxicity at the Limit

Dose in a 21 - day

dermal toxicity study in the rat, the lack of target organ toxicity or neurotoxicity, and the lack of developmental or reproductive toxicity in the absence of parental effects which we re looked for in the dermal toxicity. Inhalation Short - Term

(1 - 30 days) NOAEL=9.1

mg/kg/day UF A=10 X

UF H =10 X Occupational LOC

for MOE = 100 **28 -**  **Day oral toxicity study in rats:**

LOAEL = 90.5 mg/kg/day based on decreased body weight (M), increased liver and kidney weight and hepatocellular hypertrophy and vacuolation (M/F). Inhalation Intermediate term (1 - 6 mo nths) NOAEL=6.4

mg/kg/day UF A=10 X

UF H =10 X Occupational LOC

for MOE = 100 **90 -**  **Day oral toxicity study in rats:**

LOAEL = 19.2 mg/kg/day based on increased spleen wt (F) and hepatic vacuolation (M).Page 19 of 44

**Table 5**  **. Summary of Toxicological Doses and Endpoints for Metconazole for Use in Occupational Hum an**  **Health Risk Assessments Exposure/**  **Scenario Poin**  **t of**

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Cancer (oral, dermal, inhalation) Classification: “Not Likely to be Carcinogenic to Humans” Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (int erspecies). UF H = potential variation in sensitivity among members of the human population (intra species). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term risk assessment. UF DB = to account for the absence of key date (i.e., l ack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Based on the available toxicity database and the Agency's current practices, the inhalation risk for metconazole was assessed using an oral toxicity study . The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advi sory

Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency

is in the process of evaluating the SAP report and may , as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for metconazole and/or a reexamination of the inhalation toxicity risk assessment. **4.5.1 Recommendation for combining routes of exposure for risk assessment**  For short - and intermediate - term risk assessments, the oral and inhalation routes can be combined due to the common endpoint (liver toxicity) via the oral and inhalation (oral equivalent) routes. Quantification of dermal risk is not required. There are no potential long term dermal or inhalation exposures to metconazole. **4 .6**  **Endocrine D**  **isruption** As required b y FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity , neurotoxicity, developmental, reproductive, and general or sy stemic toxicity . These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology , organ weights, estrus cyclicity , sexual maturation, fertility , pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk asses sment scenarios from the existing hazard database. However, as required b y FFDCA section 408(p), Metconazole is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).Page 20 of 44

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify any adverse endocrine - related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Metconazole is not among the gro up of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly , as part of registration review, EPA will issue future EDSP orders/data call ins, requiring the submission of EDSP screening assay s for metconazole. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/en do/ . **5 .0**  **Dietary Exposure/Risk Characterization Reference:**  Metconazole. Petition for Establishment of Permanent Tolerances on Sugarcane and Waiver Request for Additional Sweet Corn Stover Field Trial. Summary of Analytical Chemistry and Residue Data . A. Acierto, DP38 6784, 7

/2 7 /11. **5 .1**  **Pesticide Metabolism and Environmental Degradation 5**  **.1.1 Metabolism in Primary Crops**  No new metabolism data were submitted with the subject petition. Metabolism studies with banana, canola, mandarin, pea, and wheat were previously submitted. The metabolism of metconazole was found to be similar in all crops investigated . The main metabolic route of metconazole in crops is via oxidative hydroxylation of the methylene groups, the methyl groups on the cyclopentylring, and possibly the cyclopentyl ring. In addition, monohydrox yl ation may occur at the various pro - chiral carbons of metconazole, giving rise to chromatographicall y distinguishable stereoisomeric structures. The detection of TA and triazole conjugates in the canola, pea, and wheat studies indicates that the methylene group between the triazole and cyc lopentylrings is susceptible to oxidative hydroxylation. HED has determined that metconazole (parent) is the residue of concern for both the tolerance expression and risk assessment purposes in plants except for cereal grains; the residues of concern for risk assessment in cereal grains are metconazole and the metabolite M11. For the purpose of th e subject petition, the nature of the residue in plants is adequatel y understood. **5 .1.**  **2 Metabolism in Livestock** Page 21 of 44

No new metabolism data were submitted with the subject petition. Adequate ruminant and poultry metabolism studies are available, and the data indicate that t he metabolism of metconazole in ruminants and poultry is generall y similar. The major routes of metabol ism involve oxidation and/or oxidative hydrox yl ation of the methyl group at position 2 of the cyclopentylring and oxidative hydroxylation of the phenyl ring. Glucuronic acid conjugates were observed in the goat metabolism studies, and sulfate ester conju gates were observed in the hen metabolism study . In addition, in the hen metabolism study with triazole - labeled metconazole, C -N bond cleavage releasing 1,2,4 - T was observed. Based on the available data, HED has determined that the residue of concern for the tolerance expression in livestock commodities is metconazole (parent) . The residues of concern in livestock for purposes of the risk assessment are metconazole and metabolites M1 (free and conjugated), M12, and M31 (free and conjugated) . For the pur pose of th e subject petition, the nature of the residue in livestock is adequatel y understood. **5 .1.**  **3 Drinking Water Residue Profile**  **Reference:** Drinking Water Exposure Assessment to Establish Tolerances of Pa rent Metconazole for Sugarcane . DP38 7533 , F

. Khan, 5 /1 2/ 1 1 . A drinking water assessment for the proposed use on sugarcane w as performed using PRZM/EXAMS modeling. Estimated drinking water concentrations (EDWCs) of metconazole in drinking water from use o n the existing crops and sugarcane were provided by EFED . The EDWCs are based on the maximum proposed rates specified on the existing label s and on the proposed label . For surface water, the EDWCs for the proposed crop modeled in the assessment (highest concentration of 9.9 6 μg/L for aerial application to sugarcane in LA scenario) did not exceed the acute EDWC of 45.48 μ g/L for turf reported in a previous drinking water assessment (D P 340378, 2007). Since the highest EDWC for the crop modeled in the current assessment is lower than the acute EDWC for turf reported in the previous drinking water assessment, EFED recommended the use of the previous EDWC . Additionally, the surface water annual mean (chronic) EDWCs for the proposed crop modeled in the assessm ent (highest co ncentration of 3.6 μ g/L for aerial application to sugarcane in LA scenario) did not exceed the chronic EDWC of 38.16 μ g/L for the cranberry scenario (DP380513, 2010). Since the highest EDWC for the crop modeled in the current assessment is lower than the chronic EDWC for cranberry reported in the previous drinking water assessment, EFED recommended the use of the previous EDWC . EFED calculated screening level ground water estimates for metconazole using the SCI - GROW model. An acute and chr onic ground water EDWC of 0.04 31 μg/L was estimated for the currentl y proposed uses. This EDWC is less than the 0.38 μg/L EDWC from non - agricultural uses generated from the maximum application rate for turf in a previous assessment (D P 340378, 2007) . Drinking Water Data for Free Triazoles Residues of 1,2,4 - triazole in drinking water were provided to HED b y the EFED (I. Maher, DP320682, 28 Feb 2006). Due to the inter- conversion between 1,2,4 - triazole, triazole alanine, and triazole acetic acid that may oc cur in the environment, the residue estimates used in thesePage 22 of 44

assessments are a summation of all three residues and, therefore, represent an overestimate of actual concentrations of the common triazole metabolites in drinking water. The Tier II PRZM/EXAMS ( surface water) and SCIGROW (ground water) residue estimates are summarized in Table 5 . HED notes that there were no detects of 1,2,4 - triazole in any of the 271 water samples anal yz ed by PDP, with a limit of quantification of 730 parts - per - trillion (0.73 p pb). The surface water estimates are significantly greater than those for ground water, and were used in the assessments for free triazole as well as the conjugated metabolites. EFED stated that the new metconazole uses are covered b y the previous drinking water assessment for 1,2,4 - triazole (DP320682, I . Maher, 2/28/06). **Table 6**  **. Summary of Estimated Drinking Water Concentrations of 1,2,4 -**  **Triazole. Exposure Duration**  **Surface Water Concentration, ppm Ground**  **W ater Concentration, ppm**  Ac ute 0.041 0.001 C hronic 0.011 0.001 **5 .1.**  **4 Food Residue Profile**  **Residues of Concern Reference:**  Metconazole: FQPA Human Health Risk Assessment for Proposed New Uses on Small Grains, Stone Fruits, Tree Nuts, Peanuts, Soybeans, and Sugar Beets. PP#6F7094 and PP#6F7095. PC Code: 125619, DP331937 and D P331926. Y

. Donovan, 3/12/08. A summary

of the metabolites and degradates to be included in the risk assessment and tolerance expression are presented below in Table 7 . Detailed rationale for these conclusions were presented in a previous risk assessment document (DP331926, Y . Donovan, 03/12/08). **Table 7**  **. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression**  **.** Matrix Residues Included In Risk Assessment Residues Included In Tolerance Expression Plants Primary and Rotational

Crops, except Cereal Grains Metconazole Metconazole Primary and Rotational Crops, Cereal Grains only Metconazole and M11 Metconazole Livestock Metconazole; M1 and it s glucuronic acid conjugate; M12; M31 and its glucuronic acid conjugate Metconazole Drinking Water Metconazole Not Applicable Note: For all triazole - containing pesticides, the triazole - containing metabolites 1,2,4 - T, TA, and TAA should also be included as residues of concern for risk assessment purposes only for plant and livestock commodities. Since these metabolites are common to the entire class of triazole - derivative fungicides and because of differential toxicity between the metabolites and the various parent compounds, risks associated with exposure to 1,2,4 - T and to TA/TAA are addressed in separate risk assessment documents.Page 23 of 44

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

- 1,2,4 - triazol - 1 - yl)propanoic acid. **Crop Field Trials** BASF submitted field trial data for metconazole on sugarcane (MRID 48237401). The se data are adequate and support the use of metconazole on sugarcane . These data reflect the use of metconazole as four foliar broadcast applications at a 1x rate targeting 0.328 lb ai/A/season and a 5x (exaggerated) rate targeting 1.64 lb ai/A/season to sugarcane beginning at the vegetative or blooming stage with 14 - day intervals . The field trials support a PHI of 14 or 28 day s. From samples treated at 1x rate and harvested at a 14 - day PHI , the maximum total residues of parent metconazole (sum of cis - and trans - isomers) were 0.036 ppm in/on sugarcane RAC samples; residues of metabolites M11, M21, and M 30 were <LOQ (<0.01 ppm) . From 1x - treated RAC samples harvested at 27 - 28 day PHI s, the total residues of parent metconazole (sum of cis - and trans - isomers) were <0.01 - <0.022 ppm; residues of metabolites M11, M21, an d M30 were <LOQ (<0 . 01 ppm) in all samples. From the 5x - treated samples harvested at a 14 - day PHI , the maximum total residues of parent metconazole (sum of cis - and trans - isomers) were <0.017 - 0.139 ppm in/on sugarcane RAC samples ; metabolites M11, M21, an d M30 were <LOQ (<0.01 ppm) in all samples . From samples harvested at 27 - 28 day PHI s, the total parent metconazole residues (sum of cis - and trans - isomers) were <0.011 - 0.131 ppm; residues of metabolites M11, M21, and M30 were <LOQ (<0.01 ppm) in all sampl es . Residues of 1,2,4 - T and TA were <LOQ (<0.01 ppm) and <0.05 ppm for TAA in the sugarcane RAC samples collected from all field trials. The data support the use of metonazole SL on sugarcane for up to four broadcast foliar applications during bloom stag e at the rate of 0.33 lb ai/A/application/season. The data support a minimum retreatment interval ( RTI ) of 14 day s and a minimum PHIof 14 day s. The results of the sugarcane field trials are summarized in Table s 8 and 9 .Page 24 of 44

**Table 8**  **. Summary of Residue D**  **ata from Sugarcane Field Trials with Metconazole at 1X Application Rate.**  **Commodity Total** 

**Applic. Rate**  **lb ai/A Analyte**  **PHI (days)**  **Residue Levels 1**  **(ppm )**  **n Min.**  **Ma x.**  **HAFT 2**  **Median 3**  **(STMdR) Mean**  **4**

**(STMR) Std. Dev.**  **1x Rate** Sugarcane RAC 0.33 Cis - metconaz ole

13 - 14 16 <0.005 0.0304 0.0303 0.0162 0.0160 0.0087

Trans - metconazole <0.005 0.0054 0.0052 0.005 0.005 0.0001 metconazole <0.01 0.0359 0.0355 0.0212 0.0212 0.0088 M11 <0.01 <0.01 0.01 0.01 0.01 0.00 M21 <0.01 <0.01 0.01 0.01 0.01 0.0 0 M30 <0.01 <0.01 0.01 0.01 0.01 0.00 1,2,4 - T <0.01 <0.01 0.01 0.01 0.01 0.00 TA <0.05 <0.01 0.05 0.05 0.05 0.00 TAA <0.01 <0.01 0.01 0.01 0.01 0.00 Sugarcane RAC 0.33 Cis - metconazole

27 - 28 16 <0.005 0.0173 0.0150 0.0113 0.0106 0.0043

Trans - metconazole <0.005 <0.005 0.005 0.005 0.005 0.00 metconazole <0.01 <0.0223 0.0200 0.0163 0.0156 0.0043 M11 <0.01 <0.01 0.01 0.01 0.01 0.00 M21 <0.01 <0.01 0.01 0.01 0.01 0.00 M30 <0.01 <0.01 0.01 0.01 0.01 0.01 1,2,4 - T < 0.01 <0.01 0.01 0.01 0.01 0.00 TA <0.05 <0.05 0.05 0.05 0.05 0.00 TAA <0.01 <0.01 0.01 0.01 0.01 0.00 1 Includes residues of metconazole and metabolites. No conversion factors were applied. 2 HAFT = highest average field trial. 3 STMdR = Supervise d Trial Median Residue. 4 STMR = Supervised Total Mean Residue **Table 9**  **. Summary of Residue Data from Sugarcane Field Trials with Metconazole**  **at 5X Application Rate. Commodity**  **Total Applic.**

**Rate (lb ai/A)**  **Analyte PHI**  **(days) Residue Levels**  **1 (ppm)** 

**n M**  **in. Max.**  **HAFT 2**  **Median 3**  **(STMdR) Mean**  **4**

**(STMR) Std. Dev.**  **5x Rate**

Sugarcane RAC 1.64 Cis metconazole

14 4 0.0120 0.1169 0.1048 0.0528 0.0587 0.0542 Trans metconazole <0.005 0.0218 0.0198 0.0114 0.0124 0.0087 metconazole <0.0170 0.1387 0.1246 0.0642 0.0711 0.0629 M11 <0.01 <0.01 0.01 0.01 0.01 0.00 M21 <0.01 <0.01 0.01 0.01 0.01 0.00 M30 <0.01 <0.01 0.01 0.01 0.01 0.00 1,2,4 - T <0.01 <0.01 0.01 0.01 0.01 0.00 TA <0.05 <0.05 0.05 0.05 0.05 0.00 TAA <0.01 <0.01 0.01 0.01 0. 01 0.00

Sugarcane RAC 1.64 Cis metconazole

28 4 <0.0061 0.1091 0.0837 0.0322 0.0449 0.0494 Trans metconazole <0.005 0.0217 0.0162 0.0079 0.0106 0.0079 metconazole <0.0111 0.1308 0.0999 0.0401 0.0555 0.0571 M11 <0.01 <0.01 0.01 0.01 0.01 0.0 0 M21 <0.01 <0.01 0.01 0.01 0.01 0.00 M30 <0.01 <0.01 0.01 0.01 0.01 0.00 1,2,4 - T <0.01 <0.01 0.01 0.01 0.01 0.00 TA <0.05 <0.05 0.05 0.05 0.05 0.00 TAA <0.01 <0.01 0.01 0.01 0.01 0.00 1 Includes residues of metconazole and metabol ites M11, M21, and M3 0 . No conversion factors were applied. 2 HAFT = highest average field trial. 3 STMdR = Supervised Trial Median Residue. 4 STMR = Supervised Total Mean Residue **Processed Food and Feed**Page 25 of 44

BASF submitted a processing study for metconazole o n sugarcane. The processing data for sugarcane indicate that residues of metconazole and triazole metabolites do not concentrate in the sugarcane processed commodities except for TAA, which concentrated by a factor of 4.3x in molasses and for metconazole which concentrated slightly by a factor of 1.2x in blackstap molasses. This conclusion for TAA is based on the data provided in the BASF data tables but must be verified since the information provided in the BASF Summary text indicates that residues of th e triazole - related metabolites were <LOQ in refined sugar and blackstrap molasses except for TA residues which concentrated in blackstrap molasses b y a factor of 4.3x. An acceptable method was used for quantitation of residues in sugarcane RAC and process ed commodities. The residue data from the processing study is summarized in Table 10 for metconazole residues and Table 1 1 for the residues of the triazole - related processed fractions. **Table 10**  **. Metconazole Residues in Sugarcane Processed Fractions. St**  **udy Location**  **(City, State/Year**  **Processed**

**Commodity Total** 

**R ate**  **lb ai/A PHI** 

**(days) Metconazole Residue (ppm)**  **Processing Factor**  **1 Parent Metconazole**  **Metabolites trans**  **cis Total**  **M11 M21**  **M30** 08 - TX24 Weslaco, TX 2008 Sugarcane

RAC 1.65 14 0.0168 0.08 13 0.0981 <0.01 <0.01 <0.01 N/A Refined Sugar 0.005 <0.005 <0.01 <0.01 <0.01 <0.01 <0.1 Blackstrap molasses 0.0226 0.1021 0.1247 <0.01 <0.01 <0.01 1.3 1 The processing factor was calculated by dividing the metconazole residue in the processed commo dity by the metconazole residue in the cane RAC sample , e.g., 0.1247 / 0.0981 = 1.3 . The validated LOQ is 0.01 each for parent metconazole (sum of cis - and trans - metconazole) i n/on sugarcane RAC and processed commodities. For calculations, values <LOQ were considered to be 0.005 ppm for each parent . NA = not applicable. **Table 1**  **1 . Residues of Triazole**  **- related Compounds in Sugarcane Processed Fractions**  **Study Location (City, State/Year**  **Processed**

**Commodity Total** 

**Rate lb**  **ai/A PHI**  **(days) Residue of Triazole**  **Related Compounds (ppm)**

**T Processing**  **Factor 1**  **TA Processing**  **Factor 1**  **TAA Processing**  **Factor 1**  0 8 - TX24 Weslaco, TX 2008 Sugarcane

RAC 1.65 14 <0.01 NA <0.05 NA <0.01 NA Refined Sugar <0.01 1.0x <0.05 1.0x <0.01 1.0x Blackstrap molasses <0.01 1.0x <0.05 1.0x 0.043 4.3x 1 The processing factor was calculated by dividing the residue in the processed commodity by the residue in the cane RAC sample . The validated LOQ is 0.01 ppm each for T and TAA and 0.05 ppm for TA in/on sugarcane RAC and processed c ommodities. For calculations, values <LOQ were considered to be 0.01 ppm for T and TAA and 0.05 ppm for TA. NA = not applicable. **Meat, Milk, Poultry, and Eggs** Adequate cattle and poultry feeding studies are available . The onl y livestock feed item asso ciated with the proposed use on sugarcane is molasses. Molasses was previously considered in developing the livestock diet, and a metconazole concentration of 3.2 ppm was utilized (D P 350367, N. Dodd, 09/18/08). Therefore, the established livestock tolera nces are adequate to cover residues resulting from the proposed use.Page 26 of 44

**Field Accumulation in**  **Rotational Crops** No new field studies have been submitted. The earlier reviews required that end - use labels include plant - back restrictions of 30 day s for leafy vegetables and Brassica leafy vegetables and 120 day s for all remaining crops other than those with labeled uses. This requirement has been fulfilled and the statement now appears in the master label. **5 .2**  **Dietary Exposure and Risk Reference:**  **Metconazole:** Acute and Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for Residues in/on Vegetables, Tuberous &Corm, Subgroup 1C and Bushberry Subgroup 13 - 07B. A. Acierto, DP387504.drs, 3/28/11. A new dietary

assessment is not needed for the proposed Section 3 use on sugarcane because a previous dietary

assessment for an existing Section 18 use on sugarcane was conducted using residues of metconazole in/on sugarcane, cane at a tolerance level of 1.6 ppm and sugarcane, molasses at a tolerance of 3.2 ppm, which resulted in exposure and risk estimates well below HED’s level of concern ( D P 350663 N. Dodd, 9/23/20 0 8 ) . The proposed Section 3 use on sugarcane results in a tolerance residue of 0.06 ppm for sugarcane, cane, and a separate tolerance for sugarcane, molasses is no longer needed. Therefore, the dietary risk estimates from the most recent dietary assessment (DP387504, A. Acierto, 3/28/11) should still be used to estimate aggregate risks ; see Table 1 2 . **Table 1**  **2 . Summary of Dietary (Food and Drinking Water) Exposure Risk for Metconazolet**  **1 .**  **Population Subgroup Acute Dietary**  **(95 th**  **Percentile) Chronic Dietary**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD Dietary**  **Exposure (m**  **g/kg/day) % cPAD**  General U.S. Populati on

NA NA 0.002434 6 All Infants (<1 year old) 0.004831 12.1 Children 1 - 2 years old **0.005026 12.6**  Children 3 - 5 years old 0..004800 12 Children 6 - 12 years old 0.003289 8.2 Youth 13 - 19 years old 0.001961 4.9 Adults 20 - 49 years old 0.002158 5.4 Adults 50+ years old 0.001868 4.7 Females 13 - 49 years old **0.004578 3.8**  0.001874 4.7 1 The values fo r the highest exposed population for each type of risk assessment are bolded.Page 27 of 44

Dietary Assessment of Free Triazole and its Conjugates **Reference:** Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to Address The Ame nded Metconazole Section 3 Registration to Add Uses on Tuberous and Corm Vegetables (Group 1C) and Bushberry Subgroup 13 - 07B. T. Morton, DP388469.drs, 4/27/11. The p roposed S ection 3 use of metconazole on sugarcane did not result in an increase in dietary exposure estimates for free triazole or conjugated triazoles. Therefore, the last dietary exposure anal ys es for the triazole metabolites ( DP388469, T. Morton, 4/27/11 ) did not need to be updated. **6 .0**  **Residential (Non -**  **Occupational) Exposure/Risk Charac terization**  No new residential uses are being requested at this time. However, adults, adolescents , and children may

be exposed to metconazole from its currentl y registered use s o n turf and ornamentals. These risks have been previousl y assessed (DP341832, J. Arthur, 8/3/07) . Because dermal toxicity

endpoints for the appropriate duration of exposure (short - and intermediate - term) were not identified up to the limit dose , only resi dential handler inhalation exposures/risks for adults, and residential post - application incidental oral exposures/risks for children have been assessed. Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. Th is is particularly

the case with aerial application (a method proposed to be employed for metconazole ) , but, to a lesser extent, could also be a potential source of exposure from the ground application method also employed for metconazole . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices , and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted b y the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developi ng a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast , and ground h ydraulic methods. After the policy is in place, the Agency

may impose further refinement s in spray

drift management practices to reduce off - target drift with specific products with significant risks associated with drift. **6.1 Residential Handler Exposure and Risk Characterization**  Residential handler exposures are expected to be short - term in duration. An MOE  100 is adequate to protect residential pesticide handlers. All metconazole residential handler MOEs are estimated to be >100 for the established residential uses, an d therefore, do not cause concern for HED. A summary

of these exposures and risks is presented in Table 1 3 . Although a point of departue from an oral study was used to assess residential handler inhalation risks for metconazole, HED does not believe this assessment is under - protective of adult handlers. MOEs calculated for residential handlers were all >71,000, thus providing an amplePage 28 of 44

margin of safety

to account for any

uncertainties in route - to - route extrapolation. Short - term inhalation risks were not of concern to HED. **Table 1 3**  **. Residential Handler Short**  **- term** **Inhalation Exposures and Risks.** Scenario Exposure

Route Max. Rate

Application Unit

Exposure Amount

Treated/Day Daily Dose

(mg/kg/day) 1 Inhalation

MOE 2 1) mixer/loader/applicator w/ hose - end sprayer (ornamentals) Inhalation 0. 0025 lb ai/g al 0.017

mg/lb ai 100 Gal. 0.000061 150,000 2) mixer/loader/applicator w/ low - pressure hand wand sprayer (ornamentals) Inhalation 0.0025 lb ai/g al 0.03 mg/lb

ai 5 Gal. 0.0000054 1,700,000 3) mixer/loader/app licator w/ hose - end sprayer (turf) Inhalation 0.6 lb ai/A 0.017 mg/lb ai 0.023 Acre =

1000 ft2 0.0000034 2,700,000 4) mixer/loader/applicator w/ low - pressure hand wand sprayer (turf) Inhalation 0.6 lb ai/A 0.03 mg/lb ai 0.5 Acre 0.00013 71,000 1. Daily D ose = Application Rate * Unit Exposure * Amount Treated * Absorption factor (100% for inhalation)/Body Weight (70 kg). 2. Inhalation MOE = Inhalation short - term NOAEL (9.1 mg/kg/day) ÷ Daily Dose **6.2 Residential Post** **- A** **pplication Exposure and Risk Charact erization**  Adults, adolescents , and children may be exposed to metconazole from its proposed residential uses. Adults and adolescents may experience short - and intermediate - term dermal exposure from golfing and other activities on treated turf, as well as from tending treated ornamentals. Children age 3 to <6 ye ars old may experience short - and intermediate - term dermal and incidental oral exposure from activities on treated turf. However, because dermal toxicity endpoints for the appropriate durations of exposure were not identified up to the limit dose , and because inhalation exposure is considered to be insignificant for post - application exposures, only c hildren age 3 to <6 ye ars old incidental oral post - application exposures have been assessed. P ost - application risks to children following the application of metconazole to home lawns were calculated for short - and intermediate - term incidental oral exposures . A summary of th e estimated exposures and risks, along with the algorithms used for each small child exposure scenario are presented below in Tables 1 4 through 1 6 . All MOEs for toddler lawn exposure scenarios were > 100 and , therefore, are not of concern to HED . In addition, the total MOEs for combined toddler exposures (i.e., short - term and intermediate - term hand - to - mouth, object - to mouth, and incidental ingestion of soil) are >100 (see Table 1 7 ), and therefore, do not concern HED.Page 29 of 44

**Table 1**  **4 .**  **Oral Hand -**  **to -**  **mouth Short -**  **( ST) and Intermediate**  **- term (IT) Exposures and Risks for Children from**  **Treated Lawns .**  **Application Rate (lb**  **ai/A) Fraction** 

**of ai Available**  **Turf**

**Transferrable Residue at Day**  **“0" ( μ**  **g/cm 2**  **) 1**  **Exposure**

**Tim e**  **(hrs/day) Extraction** 

**by saliva Hand** 

**Surface Area (cm** **2 /eve**  **nt) Frequency** 

**(events/ hr) Body** 

**Weight (k**  **g) Daily Dose**  **2 (m**  **g/k g/day)**  **MOE 3** 

0.6 0.05 0.34 2 0.5 20 20 (ST) 15 0.009 1 (ST) 1000 (ST) 9.5 (IT) 0.004 3 (IT) 1500 (IT) 1 Turf Transferrable Residue ( μ g/cm2 ) = Application rate (lb ai/A) x Fraction of ai Available x 4.54E+8 μg/lb x 2.47E - 8 A/cm2 2 Daily Dose = (Turf Transferrable Residue x Extraction by Saliva x Hand Surface Area x Frequency x 1E - 3 mg/ μg x Exposure Time) / (Body Weight) 3 MOE = Short - term Oral NOAEL (9.1 mg/kg/day) or I ntermediate - Term Oral NOAEL (6.4 mg/kg/day) /Daily Dose. **Table 1**  **5** . **Oral Object -**  **to -**  **mouth (Turfgrass) Short -**  **(ST) and Intermediate -**  **term (IT) Exposures and Risks for Children**  **from Treated Lawns .**  **Application Rate (lb ai/A)**  **Fraction of**

**ai Available Grass Residue at Day** 

**“0" ( μ**  **g/cm 2**  **) 1**  **Surface Area**

**Mouthed (cm 2**  **/day) Body Weight**  **(k g)**  **Daily Dose 2** 

**(m g/k**  **g/day) MOE**  **3** 0.6 0.20 1.3 25 15 0.0022 4100 (ST) 2900 (IT) 1 Grass Residue ( μ g/cm2 ) = = Application rate (lb ai/A) x Fraction of ai Available x 4.54E+8 μ g/lb x 2.47E - 8 A/cm2 2 Dai ly Dose = [Grass residue ( μ g/cm2) x Surface Area Mouthed (cm2/day) x 1E - 3 mg/ μ g] / [Body Weight (kg)] 3 MOE = Short - term Oral NOAEL (9.1 mg/kg/day) or Intermediate - Term Oral NOAEL ( 6.4 mg/kg/day) /Daily Dose **Table 1**  **6** . **Short -**  **(ST) and Intermediate -**  **term ( IT) Exposure and Risk for Children from Ingestion of Soil from Treated**  **Law ns**  **. Application Rate**  **(lb ai/A) Fraction of ai** 

**Available Soil Residue at Day** 

**“0"(μg/g) 1**  **Ingestion Rate (m**  **g/day) Body** 

**Weight (k**

**g) Daily Dose**  **2 (m**  **g/k g/day)**  **MOE 3**  0.6 1 4.51 100 15 0.00 003 300,000 (ST) 210,000 (IT) 1 Soil residue ( μ g/g) = [Application Rate (lbs ai/A) x Fraction of ai Available x 4.54E+8 μ g/lb x 2.47E - 8 A/cm2 x 0.67 cm3 /g soil] 2 Daily Dose = [Soil residue ( μ g/g) x Ingestion rate (mg/day) x 1E - 6 g/ μ g] / [Body We ight (kg)] 3 MOE = Short - term Oral NOAEL (9.1 mg/kg/day) or Intermediate - Term Oral NOAEL ( 6.4 mg/kg/day) /Daily Dose **Table 1**  **7 . Children’s Residential Combined Short**  **- and Intermediate**  **- term Risk from Treated Turf**  **. Route**  **Daily Dose (mg/k g/day)**  **MOE Total ST**  **MOE 1**  **Total IT MOE 2**  Hand - to - Mouth 0.009 1 (ST) 1000 (ST) 810 1000 0.004 3 (IT) 1500 (IT) Object -to - Mouth 0.0022 4100 (ST) 2900 (IT) Soil I ngestion 0.00003 310,000 (ST) 220,000 (IT) 1. Total ST MOE = 1 ÷ [ (1/ST Hand - to - Mouth MOE ) + ( 1/ST Obj ect - to - Mouth MOE ) + ( 1/ST Soil Ingestion MOE) ] 2. Total I T MOE = 1 ÷ [ (1/I T Hand - to - Mouth MOE ) + ( 1/I T Object - to - Mouth MOE ) + ( 1/I T Soil Ingestion MOE) ] **7 .0**  **Aggregate Risk Assessments and Risk Characterization** In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e.g. , a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.Page 30 of 44

**7 .1**  **Acut e**  **& Chronic Aggregate Risk**  Acute and chronic aggregate exposures include food plus drinking water exposures. As demonstrated under Section 5.2 , a cute and chronic aggregate risks are not of concern. **7.2 Short**  **- and Intermediate**  **- Term Aggregate Risk**  The short - and intermediate - term aggregate risk assessments consider average (chronic) exposure estimates from dietary

consumption of metconazole (food and drinking water) and non occupational/residential use on turf (dermal and inhalation exposures for adults, and dermal plus incidental oral exposures for children). For adults appl yi ng metconazole to turf, short - and intermediate - term exposures were aggregate d. The exposure scenario with the highest daily dose and lowest MOE was used; i.e., mixer/loader/applicator with a low pressure handwand sprayer. The short - and intermediate - term aggregate MOEs from dietary exposure (food + drinking water) and non - occup ational/residential handler exposure (inhalation) for adults are 1 ,7 00 and 1 ,7 00, respectivel y; which are not of concern to HED (see Table 1 8 below), since they are greater than the level of concern MOE of 100. **Table 1**  **8 . Short**  **- and Intermediate**  **- Term** **Agg regate Risk Calculations for Adult Handlers**  Population/ Exposure Duration Inhalation Exposure Dietary Exposure Short - or Intermediate Term Aggregate MOE 2 NOAEL (mg/kg/day) Exposure

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

(mg/kg/day) MOE 1 Adult ST 9.1 0.00013 70,000 4.3 0.002 434 1, 8 00 1, 7 00 ST Adult IT 6.4 0.00013 49,000 4.3 0.002 434 1, 8 00 1, 7 00 ST 1 MOE = NOAEL / Exposure; The Level of Concern MOE is 100. 2 Aggregate MOE = 1/ [(1/MOE Inhalation) + (1/MOE Food + Drinking Water)] Post - application e xposures from the use on turf are considered predominantly short - term (1 - 30 day s) . Although exposures are expected via the dermal route, quantification of dermal risk is not required, since a dermal endpoint was not identified for short - , or intermediate - term exposures. Therefore, short - and intermediate - term post - application aggregate risk assessments were conducted onl y for average dietary and incidental oral exposures to toddlers. The short - and intermediate - term aggregate MOEs from dietary exposure (f

ood + drinking water) and non occupational/residential exposure (incidental oral) for children 1 - 2 years old are 42 0 and 4 6 0, respectivel y; these MOEs are not of concern to HED (see Table 1 9 below), since they are greater than the level of concern MOE of 1 00.Page 31 of 44

**Table 1**  **9 . Short**  **- and Intermediate**  **- Term** **Aggregate Risk Calculations for Postapplication Exposures** Population/ Exposure Duration Incidental Oral Exposure Dietary Exposure Short - or Intermediate Term Aggregate MOE 2 NOAEL (mg/kg/day) Exposure

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

(mg/kg/day) MOE 1 Kids 1 - 2 y

rs/ST 9.1 0.01123 810 4.3 0.00 5026 860 4 2 0 ST Kids 1 - 2 y

rs/IT 6.4 0.00643 1000 4.3 0.00 5026 860 4 6 0 IT 1 MOE = NOAEL / Exposure; The Level of Concern MOE is 100. 2 Aggregate MOE = 1/ [(1/M OE Incidental Oral ) + (1/MOE Food + Drinking Water)] These aggregate exposure assessments are considered conservative estimates, that should not underestimate risks, for the following reasons : 1) the dietary inputs used tolerance - level residues, 100% crop treated, and crop specific (turf) screening level drinking water modeling data (i.e., surface water model ing); 2) maximum application rates and minimum application intervals were used; and 3) conservative SOPs and upper level estimates of exposure were empl oyed. Updated Aggregate Assessment of Free Triazole & its Conjugates **Reference:** Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address Tolerance Petitions for Metconazole. DP389080, T. Morton, 4/27/11. The addition of the new proposed use on sugarcane does not increase the aggregate exposure to free triazoles and its conjugates. Therefore, the recently updated aggregate human health risk assessment for free triazoles and its conjugates remains unchanged and the aggregat e estimates are below HED’s level of concern ( DP389080, T. Morton, 4/27/11 ). **8 .0**  **Cumulative Risk Characterization/Assessment** Metc onazole is a member of the triazole - containing class of pesticides. Although conazoles act similarly in plants (fungi) by

inhibiting ergosterol biosy nthesis, there is not necessarily a relationship between their pesticidal activity and their mechanism of toxicity in mammals. Structural similarities do not constitute a c ommon mechanism of toxicity . Evidence is needed to establish that the chemicals operate b y the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxicological responses is found ; s ome are hepatotoxic and hepatocarcinogenic in mice. Some induce thy roid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation. It is not clearl y understood whether these biochemical events are directly connected to their toxicological outcomes. Thus, there is currentl y no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s procedures for cumulating effects from substances found to have a common me chanism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative .Page 32 of 44

Met conazole is a triazole - derived pesticide. This class of compounds can form the common metabolite 1,2,4 - triazole and two triazole conjugates (triazolylalanine and triaz olylacetic acid). To support existing tolerances and to establish new tolerances for triazole - derivative pesticides, including met conazole, U.S. EPA conducted a human health risk assessment for exposure to 1,2,4 - triazole, triazolylalanine, and triazolylac etic acid resulting from the use of all current and pending uses of any triazole - derived fungicide. The risk assessment is a highl y conservative, screening - level evaluation in terms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary and non - dietary

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

exposures). In addition, the Agency retained the additional 10X FQPA safety factor for the protection of infants and children. The assessment includes evaluations of risks for various subgroups, including those comprised of infants and children. The Agency ’s complete risk assessment is found in the propiconazole reregistration docket at http://www.regulations.gov , Doc ket Identification (ID) Number EPA HQ - OPP - 2005 - 0497. **9 .0**  **Occupational Exposure/Risk Pathway Reference:**  The occupational exposure and risk assessment was reviewed by the Exposure Science Advisory Council, the information provided in this Section comes from: . Metconazole. Occupational and Residential Exposure Assessment for Proposed New Foliar Use on Sugarcane. DP38 6786 , N. Tsaur, 6

/ 8 /11. Occupational handler exposure to metconazole is expected for individuals involved in foliar applications to sugarcane (mixing, loading, and applying) . Agricultural workers performing ty pical post - application activities may receive exposure to metconazole residues. **9 .1**  **Short -**  **and Intermediate**  **- Term Handler Risk**  CarambaTM Fungicide can be applied to sugarcane for foliar disease control via groundboom, aircraft, or chemigation. The proposed use pattern is summarized in Table 2 . Handler exposure is expected to be short - or intermediate - term based on information pro vided on the proposed label. The label states that all handlers must wear the proper personal protective equipment (PPE): a long - sleeved shirt, long pants, chemical resistant gloves, shoes, and socks. The quantitative exposure/risk assessment developed f or occupational handlers is based on the following exposure scenarios: Mixer/L oaders 1. Mixing/loading liquid to support groundboom applications , 2. Mixing/loading liquid to support aerial and chemigation applications , Flaggers 3. Flagging to support aerial app lication, Applicators 4. Applying spray s with groundboom equipment , 5. Applying spray s with aerial equipment ,Page 33 of 44

Unit Exposures Chemical - specific data for assessing exposure during pesticide handling activities (mixing/loading, appl yi ng, and mixing/loading/applying) were not submitted to the Agency in support of this petition . To assess handler exposures for regulatory actions when chemical specific monitoring data are not available, HED relies on the most scientifically- reliable surrogate data currentl y availab le from various sources such as the Pesticide Handler Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF). Some of these data, such as the industry task force data, are co mpensatory , subject to the data protection provisions of FIFRA. HED policy on use of surrogate data is described in more detail on the Agency's website (http://www.epa.gov/pesticides/science/handler- exposure - data.html). Scenario - specific surrogate exposure data, including their sources, are presented in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/pesticides/science/handler- exposure - table.pdf). Summaries of the short - and intermediate - term risks for occupational handlers are included in Table 2 0 . The maximum application rate for each exposure scenario is presented as the worst case scenario. All handler scenarios (mixer/loader, applicator, and flagger) resulted in short - and intermediate - term inhalatio n MOEs greater than the level of concern (MOEs ranged from 63,000 to 440,000 for short - term exposure and 45,000 to 310,000 for intermediate - term exposure ) at some level of risk mitigation and therefore do not exceed HED’s level of concern. **Table 2 0**  **. Met conazole Short**  **- and Interm**  **ediate -**  **Term Occupational Inhalation Exposures and Risks.**

**Exposure Scenario Application**  **Rate** a **Area**

**Treated Daily**  b **Inhalation**

**Unit Exposures**  c **Inhalation**

**Dose** d **Short -**  **Term**

**Inhalation MOE**  e **Int -**  **Term**

**Inhalation MOE**  e **lb ai/A acre** **s μg/lb ai**  **mg/kg/day LOC = 100**  **LOC = 100**

**Mi xer/Loader**  Mixing/Loading Liquids for Groundboom Applications 0.082 80 0.219 0.0000205 440,000 310,000 Mixing/Loading Liquids for Aerial and Chemigation Applications 0.082 350 0.219 0.0000898 100,000 71,000 **Fl agger**  Flagging for Aerial Application 0.082 350 0.35 0.000144 63,000 45,000 **Applicator** Applying Sprays via Groundboom Equipment 0.082 80 0.34 0.0000319 290,000 200,000 Applying Sprays via Aerial Equipment 0.082 350 0.068 0.0000279 330,000 230,000 a Ap plication Rates based on proposed uses for met conazole (CarambaTM Fungicide, EPA Reg. No. 7969 - 246) . b Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1. c Unit Exposures based on PHED Version 1.1 or AHETF data. Baseline = no respirator. d Inhalation Dose (mg/kg/day) = daily unit exposure (μg/lb ai) x application rate ( lb ai/acre ) x amount handled /day ( acres/day) x conversion factor (1 mg/1,000 μg) x absorptio n factor (100%) / body weight (7 0 kg). e MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day). ST NOAEL = 9.1 mg/kg/day. IT NOAEL = 6.4 mg/kg/day. **9 .2**  **Short -**  **and Intermediate**  **- Term Post** **- A** **pplication Risk**Page 34 of 44

Agricultural workers performing typical post - application activities may receive exposure to metconazole residues. However, since there is no dermal endpoint identified up to the limit dose , a dermal post - application assessment is not needed. Occupational Post - Application Inhalation Exposure Based on the A gency's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for metconazole at this time because the chemical has low vapor pressure (9.23 x 10 - 8 mmHg), is applied at a low rate (0.082 lb ai/A), and is not applied using airblast . However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ) and is in the proces s of evaluating the SAP report as well as available post - application inhalation exposure data generated by the Agricultural Reentry Task Force. The Agency may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for metconazole. Restricted Entry

Interval RE I s are typicall y based on the acute toxicity of technical chemical material . Under WPS , a ctive ingredients classified as acute T oxici ty Category III or IV for Acute Dermal and Primary Skin Irritation are assigned a 12 - hour REI. Thus, the 12 - hour REI on the label is acceptable.Page 35 of 44

**Appendix A: Toxicology Assessment A.1**  **Toxicology Data Requirements Table A.1.**  **Metconazole Toxicology Data Requirements Test**  **Technical Required**  **Satisfied** 870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irrit ation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... ye s yes yes yes yes yes

yes yes yes yes 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox. (hen) ................................ ..... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotox. Screening Battery (rat) ....................... 870.6200b 90 - Day

Neuro. Screening Battery (rat) .......................... 870.6300 Develop. Neuro ................................ .............................. no no yes yes no no

no n o yes no 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes no yes yes

yes yes Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no no no no

no noPage 36 of 44

**A.2 Toxicity Profiles Table A.2**  **Acute Toxicity Profile –**  **Metconazole Technical Guideline No.**  **Study Type MRID(s)**  **Results Toxicity Category**  870.1100 Ac ute oral [mouse] 44721512 LD 50 = >566 mg/kg III 870.1100 Ac ute oral [rat] 44721512 LD 50 = >566 mg/kg III 870.1100 Ac ute oral [rat] 44721513 LD 50 = >1459 mg/kg III 870.1100 Ac ute oral [rat] 447215 14 LD 50 = >5000 mg/kg IV 870.1200 Ac ute dermal [rat] 44721512 Dermal LD 50 > 2000 III 870.1200 Ac ute dermal [rabbit] 44721512 Dermal LD 50 > 2000 III 870.1200 Ac ute inhalation [ rat] 44721512 LD 50 = >5 .6 mg/L IV 870.2400 Ac ute eye irrit ation [rat] 44721513 mo derate irritant III 870.2500 Ac ute dermal irritation [rabbit] 44721513 mild irritant IV 870.2600 Skin sensitization [guinea pig] 44721513 neg. - **Table A.3 Subchronic, Chronic and Other Toxicity Profile**  **for Metconazole Tec hnical**  **1 Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3100 28 - Day

oral toxicity rodents (rat) 44721515 (1990)

M/F: 0, 30, 100, 1000, 3000 ppm M: 0, 2.7, 9.1, 90.5, 261.1 mg/kg/day F: 0, 3.1, 10.1, 97, 287.4 mg/kg/day Acc eptable/guideline NOAEL (M/F) = 9.1/10.1 mg/kg/day LOAEL (M/F) = 90.5/97 mg/kg/day based on depression of body weight in M, liver and kidney weight increases with associated histopathological effects (hypertrophy and fatty vacuolation) in liver only. 870. 3100 90 - Day

oral toxicity rodents (rat) 44721517 (1991)

M/F: 0, 30, 100, 300, 1000, 3000 ppm M: 0, 1.94, 6.4, 19.2, 64.3, 192.7 mg/kg/day F: 0, 2.1, 7.2, 22.1, 71.4, 208.0 mg/kg/day Acceptable/guideline NOAEL (M/F) = 6.4/7.2 mg/kg/day LOAEL (M/F) = 19.2/2 2.1 mg/kg/day based on increased spleen weight in females and hepatic vacuolation in males.

870.3100 90 - Day

oral toxicity rodents (mouse) 44721519 (1991)

M/F: 0, 30, 300, 3000 (wk 1)/2000(wk 2 - 13) ppm M: 0, 9.58, 50.5, 341.1 mg/kg/day F: 0, 6.94, 60.7, 4 38.5 mg/kg/day Acceptable/guideline NOAEL (M/F) = 9.58/6.94 mg/kg/day LOAEL (M/F) = 50.5/60.7 mg/kg/day based on increase in absolute and relative liver weights, hepatocellular hypertrophy and vacuolation, and increase in relative spleen weight (F), elevat ed AST and ALT activity.Page 37 of 44

**Table A.3 Subchronic, Chronic and Other Toxicity Profile**  **for Metconazole Tec hnical**  **1 Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3150 28 - Day

oral toxicity non - rodents (dog) 44721520 (1991)

M/F: 0, 100, 1000, and 7000 - 10000 ppm in diet Unacceptable/non - guideline (some preliminary test data provided) NOAEL (M/F) = 100 ppm in diet LOAEL (M/F) = 1000 ppm i n diet (increase in relative and absolute thyroid wt. in one/two females) Deficiencies: low

n (2M/2F per dose); decrease in food consumption means low exposure to test compound; actual dose received per dose group not provided. 870.3150 90 - Day

oral toxici ty non - rodents (dog) 44721521 (1991)

M/F: 0, 60, 600, 6000 ppm in diet M: 0, 2.5, 24.4, 225.2 mg/kg/day F: 0, 2.6, 24.3, 206.6 mg/kg/day Acceptable/guideline NOAEL (M/F) = 2.5/2.6 mg/kg/day LOAEL (M/F) = 24.4/24.3 mg/kg/day based on decreased food consum ption and body weight gain in females and elevated platelets and reticulocytes in males. 870.3200 21 - day Dermal

Toxicity 46808439 (2006)

0, 250, 500, 1000 mg/kg/day Acceptable/guideline **NOAEL** : 1000 mg/kg **LOAEL** : > 1000 mg/kg No evidence of dermal toxici ty 870.6200 Subchronic (13 -

week) Oral Neurotoxicity - rat 46808440 (2002) 0, 50, 170, 500 ppm M: 0, 4.84, 15.69, 47.08 mg/kg/day F: 0, 5.10, 17.62, 49.82 mg/kg/day Acceptable/Non - guideline **Systemic** NOAEL (M/F) = 4.84/5.10 mg/kg/ **Systemic** LOAEL (M/F) = 15 .69/ 17.62 mg/kg/ based on decreases in body weight and food consumption. **Neurotoxicity** NOAEL (M/F)  47.08/49.82 mg/kg/day 870.3700 Prenatal development

in rodents (rat) 44721522 (1991)

0, 12, 30, 75 mg/kg/day Gavage Acceptable/Guideline **Maternal** NOAEL = 12 mg/kg/day LOAEL = 30 mg/kg/day based on decrease in body weight gain. **Developm ental**  NOAEL = 12 mg/kg/day LOAEL = 30 mg/kg/day based on increased incidence of skeletal variations (predominantly lumbar ribs).Page 38 of 44

**Table A.3 Subchronic, Chronic and Other Toxicity Profile**  **for Metconazole Tec hnical**  **1 Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3700 Prenatal development

in rodent s (rat) 46808443 (2002)

0, 1, 4, 16, 64 mg/kg/day Gavage Acceptable/Guideline **Maternal** NOAEL= 16 mg/kg/day LOAEL= 64 mg/kg/day based on decreased body weight and food consumption, increased placental weight and increased incidence of swollen placenta . **Dev elopm**  **ental** NOAEL= 16 mg/kg/day LOAEL= 64 mg/kg/day based on based on an increase in early and late resorptions, decreased fetal body weight and increased incidence of incomplete ossification of sternebrae. 870.3700 Prenatal

developmental in non - rodents ( rabbit) Definitive Study 44721602 (1997)

0, 5, 10, 20, 40 mg/kg/day gavage Acceptable/Guideline **Materna** l NOAEL = 20 mg/kg/day LOAEL = 40 mg/kg/day based on reductions in body weight gain, food consumption, and changes in various hematology parameters (reductions in hematocrit, hemoglobin, mean corpuscular volume and increases in platelet counts and alkaline phosphatase activity). **Developm enta**  l NOAEL = 20 mg/kg/day LOAEL = 40 mg/kg/day based on increases in post - im plantation losses. 870.3700 Prenatal

deve lopmental in non - rodents (rabbit) 44721603 (1991) 0, 4, 10, 25, 62.5 mg/kg/day (Exp. #1) 0, 2, 4, 10 mg/kg/day (Exp. #2) Acceptable/Guideline **Materna** l NOAEL = 25 mg/kg/day LOAEL = 62.5 mg/kg/day based on body weight changes and slight clinical signs (anore xia/reduced or altered fecal output, cold ears). **Developm enta**  l NOAEL = 4 mg/kg/day LOAEL = 10 mg/kg/day based on examining data from the two experiments. Effects at 62.5 mg/kg/day show total litter loss, decreased live fetuses, increased early and late r esorptions. Effects at 25 mg/kg/day show some malformations: hydrocephaly (4 fetuses from 4 different litters, but NOT seen at 62.5 mg/kg/day) and limb effects (2 fetuses from 2 different litters, with one fetus with same effect at 62.5 mg/kg/d). Hydrocephaly and limb effects were observed at 10 mg/kg/day in Experiment #2, but not at that same dose in Experiment #1.Page 39 of 44

**Table A.3 Subchronic, Chronic and Other Toxicity Profile**  **for Metconazole Tec hnical**  **1 Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3800 Reproduction and

fertility effects 2 - generation - rat 46808447 (2002)

0, 30, 150 and 750 ppm M/F: 0/0, 2/2, 10.8/10.6, 53.2/53.0 mg/kg/day Acceptable/Guideline **Parental/System ic**  NOAEL (M/F) = 9.8/10.8 mg/kg/day LOAEL (M/F) = 49.4/53.2 mg/kg/day based on: decreased body weight and decreased weight gain in male and female parental animals, increased incidence of fatty hepatocyte change in male parental animals, and increased incidence of spleen cong estion in F1 parental females. **Reproductive** NOAEL (M/F) =  49.4/ 10.8 mg/kg/day LOAEL (M/F) = 53.2 mg/kg/day based on increased gestation length and decreased gestation index driven by dyst ocia (difficult labor). **Offspring** NOAEL (M/F) = 9.8/10.8 mg/kg/day LOAEL (M/F) = 49.4/53.2 mg/kg/day based decreased viability on lactation day 0 and decreased body weight in F2 offspring. 870.4100a Chronic toxicity

rodents (rat) 4472109 (1992) 0, 10, 1 00, 300, 1000 ppm M: 0, 0.44, 4.3, 13.1, 43.9 mg/kg/day F: 0, 0.52, 5.3, 16.0, 53.8 mg/kg/day Acceptable/Guideline NOAEL = (M/F) = 4.3/16.0 mg/kg/day LOAEL = (M/F) = 13.1/ 53.8 mg/kg/day based on an increase in mean adjusted liver weights at 12 months (M) and 24 months (F), increase in spleen weights at 24 months (F), and increased hepatocellular lipid vacuolation (M/F) and centrilobular hypertrophy (M/F). 870.4100b Chronic toxicity - dog 44721610 0, 30, 300, 1000, 3000 ppm in diet M: 0, 1.1, 12.0, 38.5, 1 10.0 mg/kg/day F: 0, 1.1, 10.3, 36.8, 113.7 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 12.0/10.3 mg/kg/day LOAEL (M/F) = 38.5/36.8 mg/kg/day based on decreased body weight gain weeks 1 - 13 (males), increased alkaline phosphatase activity (both sexes) and increased incidence of Kupffer cell pigmentation (females). 870.4200 a Carcinogenicity -

rat 44721611 (1992) 0, 100, 300, 1000 ppm M: 0, 4.6, 13.8, 46.5 mg/kg/day F: 0, 5.5, 16.6, 56.2 mg/kg/day Acceptable/Guideline Non - neoplastic findings at (M/F) 13.8/5 6.2 mg/kg/day: increased incidence of hepatocellular lipid vacuolation (M/F), centrilobular hypertrophy (M/F), liver pigment deposition (M), histiocytic foci in the spleen (M/F),and increase in severity of chronic renal nephropathy (M). Evidence of mo non uclear cell leukemia (F).Page 40 of 44

**Table A.3 Subchronic, Chronic and Other Toxicity Profile**  **for Metconazole Tec hnical**  **1 Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.42 00b Carcinogenicity mo use 44721612 (1992) 0, 30, 300, 1000 ppm M: 0, 4.5, 39.5, 166.9 mg/kg/day F: 0, 5.9, 58.1, 195.5 mg/kg/day Acceptable/Guideline Non - neoplastic findings at (M/F) 166.9/58.1 mg/kg/day: increase in vacuolation, hypertrophy, splenic atrophy and adrenal corticomedullary pigmentation, sinusoidal hypercellularity/single cell necrosis. Neoplastic findings: increase in liver cell tumors at high dose (M/F): Increased incidence of hepatocellular adenomas in male s and hepatocellular carcinomas in females. 870.5100 Salmonella

typhimurium and Escherichia coli Reverse Mutation Assay 44721613 (1990)

Up to limit dose of 5000 μg/ plate ( S. typhimurium ) and (E. coli) in the presence and absence of metabolic activatio n ( + S9) Acceptable/Guideline Test material was not cytotoxic with or without S9 activation in five S. typhimurium strains and one strain of E. coli , and did not induce a genotoxic response in any strain.

870.5300 In vitro Mouse

Lymphoma Mutagenesis Assay WL136184* *cis only isomer 44721615 (1991)

Six doses up to 125 μg/ml (toxicity was observed above that dose) in the presence and absence of metabolic activation ( + S9) Acceptable/Guideline There was no evidence of biologically significant induction of mutant colonies.

870.5375 I

n vitro Cy

togene tics Test 44721616 (1991)

From 6.25 to 400 g/ml, with and without metabolic activation ( + S9) Acceptable/Guideline Weakly positive (induced chromosome aberrations in Chinese hamster ovary cells) in the presence of S9 activation, negative without S9 activation. 870.5395 In vivo Mammalian

Erythrocyte Micronucleus Test: Mouse 44721618 (1995)

Up to the limit dose of 2000 mg/kg Acceptable/Guideline There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mo use bone marrow at any dose or collection time. 870.5550 I

n vivo / in vitro Mammalian UDS test Rat 44721620 (1995)

Up to the limit dose of 2000 mg/kg Acceptable/Guideline Negative for unscheduled DNA synthesis. 870.6200b Subchronic

Neurotoxicity - rat 46 808440 (2002) 0, 50, 170, 500 ppm M: 0, 4.84, 15.69, 47.08 mg/kg/day F: 0, 5.10, 17.62, 49.82 mg/kg/day Acceptable/Non - guideline **Systemic** NOAEL (M/F) = 4.84/5.10 mg/kg/ **Systemic** LOAEL (M/F) = 15.69/ 17.62 mg/kg/ based on decreases in body weight and food consumption. **Neurotoxicity** NOAEL (M/F)  47.08/49.82 mg/kg/dayPage 41 of 44

**Table A.3 Subchronic, Chronic and Other Toxicity Profile**  **for Metconazole Tec hnical**  **1 Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.7485 Metabolism and

pharmacokinetics: rat 44721622 (1992) single high dose: 164 mg/kg Radiolabel: (cyclopentyl 14 C ) Acceptable/Guideline Approximately 94% of radioactivity in excreta after five days: feces (males - 81.3%, females

- 65.5%) and urine (males - 13.6%, females - 28.4%) 870.7485 Metabolism and

pharmacokinetics: rat 44721623 (1991) single low dose: 2 mg/kg Radiolabel: (cyclopentyl 14 C) Acceptable/Guideline Approximately 94 % of radioactivity in excreta after 72 hrs: feces (males - 80%, females - 67%) and urine (males - 14.8%, females - 26%). Metabolite information presented. 870.7485 Metabolism and

pharmacokinetics: rat WL136184* *cis only isomer 44721624 (1991)

single high dose: 200 mg/kg (males only) Radiolabel: (Triazole - 14 C) Acceptable/Guideline Approximately 96% of radioactivity in excreta after seven days: feces (76%) and urine (20%). Metabolite information presented. 870.7485 Metabolism and

pharmacokinetics: rat WL136184* *cis only isomer 44721625 (1991)

single low dose: 2 mg/kg Radiolabel: (Cyclopentyl - 14 C) Acceptable/Guideline Excretion/retention in bile - duct cannulated rats. Approximately 80% of radioactivity was excreted in the bile after 48 hrs: males (7 8.7%) and females (83.3%). 870.7485 Metabolism and

pharmacokinetics: rat 46808449 (2002)

male/female rat single low dose: 2 mg/kg single high dose: 200 mg/kg repeated dose: 2 mg/kg Acceptable/Non - guideline Lo w potential for bioaccumulation following sing le or multiple dosing regimen. The time to maximum plasma concentration for male and female rats treated with either 2 mg/kg or 200 mg/kg was the earliest sampling interval, 0.25 hours and 4 hours, respectively The plasma half

- life of low - and high - dose r ats wa s slightly shorter in males than females, ~20 - 25 hours and ~34 hours, respectively. 870.7600 In Vivo Dermal

Penetration Study 46808450 (1990)

Acceptable/Non - guideline Dermal absorption= 16% (72 hrs) 870.7800 Immunotoxicity

Study: male rat 4810730 1 (2010)

0, 70, 210, 6300 ppm 0, 5.4, 17, 52 mg/kg/day Acceptable/Guideline Sy stemic NOAEL: 17 mg/kg/day. LOAEL: 52 mg/kg/day based on reduced body weight gain at day 7 and 14 of the study. I mmunotoxicity NOAEL: 52 mg/kg/day. LOAEL: > 52 mg/kg/day Effects on rat/mice liver enzymes WL136184* *cis only isomer 44721626 (1991)

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

Non - guideline Increased liver weight, cytochrome P450,

ethoxycoumarin O - deethyla se, ethylmorphine N - demethylase, and lauric acid 11 - hydroxylase in both rats and mice. No effect on ethoxyresorufin O - deethylase, palmitoyl CoA oxidation, or peroxisome proliferation (in term s of peroxisome number or morphology).Page 42 of 44

**Table A.3 Subchronic, Chronic and Other Toxicity Profile**  **for Metconazole Tec hnical**  **1 Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 14 - day Mechanistic Study 46665403 (2004)

0, 30, 300, 1000 ppm in diet (mice) for 14 days. F: 4.5, 48, 151 mg/kg/day Acceptable/

Non -guideline Increased liver weight (300 and 1000 ppm);

increased hepatic drug metabolizing enzymes (300 and 1000 ppm) after 7 days; enlarged livers ( 1000 ppm) at days 3, 7 and 14; hepatic hypertrophy and vacuolation (300 and 1000 ppm) at day 14; increased ALT and AST activities at 1000 ppm (day 14); increased lipid peroxide (300 and 1000) at day 14; increased PCNA labeling at 1000 ppm at day 3 and 7. 1 cis/trans ratio is 85:15. All studies used cis/trans mixture unless otherwise noted. **Appendix B : EPA Review of Human Research**  **This risk assessment relies in part on data from studies in which ad ult human subjects**  **were intentionally exposed to a pesticide or other chemical. These studies were determined to require a review of their ethical conduct, have received that review and have been**  **determined to be ethical. The PHED Task Force, 1995. The**  **Pesticide Handlers Exposure Database, Version 1.1. Task Force me** **mbers Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.**  **The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit**  **Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011. Appendix C**  **: Physical and Chemical Properties**  **of Metconazole Table C.**  **Physicochemical Properties of Metconazole** Parameter Value Reference s* (MRID) Melting point/range 100.0 - 108.4 ° C (using Electrothermal Digital Melting Point Apparatus) ( AC900,768 technical grade) 44721505 pH 5.81 at 25oC (1% aqueous suspension) 46808402 Relative d ensity (20°C) 1.14 (relative density to water at 4 ° C , using capillary stoppered, density - specific gravity bottle) (Lot No. AC 8879 - 140B) 44721505 Water solubility ( 20oC) Us ing shake - flask method: 18.7 ± 1.0 mg/L ( cis - isomer , WL148271, KNF - S - 474m) 13.6 ± 1.7 mg/L ( trans - isomer , WL148271, KNF - S 474m) 44721505Page 43 of 44

**Table C. Physicochemical Properties of Metconazole**  Parameter Value Reference s* (MRID) Solvent solubility ( g/L ) at 2 0oC Solvent Metconazole cis trans 44721505 acetone 363 251 117 methanol 403 294 117 dichloromethane 481 343 141 ethyl acetate 260 173 90.0 propanol 132 86.6 46.7 toluene 103 66.2 38.0 Hexane 1.40 0.929 0.483 Vapor pressure ( 20°C) Using gas - saturation method: < 1.23x10 - 5 Pa or 9. 23 x 10 - 8 mm Hg (metconazole) < 1.04x10 - 5 Pa or 7.80 x 10 - 8 mm Hg ( cis - isomer) < 1.96x10 - 6 Pa or 1.47 x 10 - 8 mm Hg ( trans - isomer) 44721505

Dissociation constant (pKa) 11.38±0.03 and 1.06±0.03 (in water at 29.1°C using spectrophotometric method; Lot No. AC 8879 - 140B) 44721505 Octanol/water partition coefficient, Log(KOW) At 20 oC (using flask shaking method) : Kow (log Kow) = 7090±989 (3.85) (Lot No. AC 8879 - 140B) (TGAI) Kow (log Kow) = 7 150±803 (3.85) ( cis - isomer , CL 354,801 ) Kow (log Kow) = 6800±1700 (3.8) ( trans - isomer , CL 354,802 ) 44721505

UV/visible absorption spectrum pH λ A log ε 46808403 cis - isomer 2.0 221.4 0.828 4.03 6.8 0.8452 4.04 7.0 0.9126 4.08 10.3 0.7226 3.98 trans - isomer 2.0 221.4 0.9053 4.07 7.0 0.9547 4.10 10.1 0.9893 4.11 * Product Chemistry Reviews : DP #256877, Shyam Mathur, Ph. D . , 9/12/2000 and DP #329168, Shyam Mathur, Ph.D., 7/13/07 .Page 44 of 44

**Appendix D**  **: International Residue Limit Status** 



### Metconazole (PC Code 125619 ; 07/27/ 11) Summary of US and International Tolerances an d Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 40 CFR 180.6 17 : Plant s/Livestock : Metconazole [5 - [(4 - chlorophenyl )meth yl ] - 2,2 - dimethyl - 1 - (1H - 1,2,4 - triazol - 1 - yl methyl)cyclopentanol] as the sum of its cis - and trans - isomers None N one

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Sugarcane, cane 0.06 Completed: M. Negussie; 07/27/2011 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.