2 Functioning as the first stage of the risk assessment process fo r Registration Review, this problem formulation provides an overview of wh at is currently known a bout the environmental fate and ecological effects associ ated with cymoxanil and its degr adates. It also describes the preliminary ecological risk hypothesi s and analysis plan for evaluating and characterizing risk to non-target species in support of the registration review of cym oxanil. This document also recommends studies that shoul d be included in a generic da ta call-in (DCI) to address uncertainties surrounding the environmental fate and potential ecological effects of cymoxanil.3 

# Problem Formulation for the Environmental Fate, Ecological Risk, Endangered Species, and Drinking Water Exposure Assessments in Support of the Registration Review of Cymoxanil

1-[(EZ)-2-Cyano-2-methoxyiminoacetyl]-3-ethylurea CAS Registry Number: 57966-95-7 PC Code: 129106

P

repared by: Cheryl Sutton, Ph. D., Environmental Scientist Elizabeth Bosecker, Biologist Scott Glaberman, Ph.D., Biologist U.S. Environmental Protection Agency Office of Pesticide Programs E nvironmental Fate and Effects Division E nvironmental Risk Branch I V 1200 Pennsylvania Ave., NW M

ail Code 7507P Washington, DC 20460 R eviewed by: Thomas Steeger, Ph.D, Senior Science Advisor Jim Carleton, Ph.D, Senior Fate Scientist Marietta Echeverria, Branch Chief, ERB IV

March 7, 2012 

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CN CH 34 Table of Contents

1. Purpose ................................................................................................................... .................... 5 2. Problem Fo rmulation ....................................................................................................... .......... 5 2.1. Nature of Regulatory Action ............................................................................................. .. 5 2.2. Previous Assessments .................................................................................................... ..... 6 2.2.1. Previous Ecological Risk Assessments ........................................................................ 6 2.2.2. Drinking Water Exposure Assessments ....................................................................... 8 3. Stressor Source and Distribution .......................................................................................... ..... 9 3.1. Mechanism of Action .......................................................................................................... 9 3.2. Overview of Pesticide Use and Usage ................................................................................ 9 3.3. Environmental Fate and Transport.................................................................................... 12 3.4. Degradates of Concern ...................................................................................................... 14 3.5. Water Quality ................................................................................................................. ... 16 4. Receptors.................................................................................................................. ................ 17 4.1. Effects to Aquatic Organisms ........................................................................................... 17 4.2. Effects to Terrestrial Organisms ....................................................................................... 20 4.3. Incident Databases Review ............................................................................................... 22 4.4. Ecosystems Potentially at Risk ......................................................................................... 22 5. Assessment Endpoints ...................................................................................................... ....... 23 6. Conceptual Model .......................................................................................................... .......... 23 6.1. Risk Hypothesis ......................................................................................................... ....... 24 6.2. Conceptual Diagram ...................................................................................................... ... 24 7. Analysis Plan ............................................................................................................. .............. 26 7.1. Stressors of Concern .................................................................................................... ..... 27 7.2. Measures of Exposure .................................................................................................... ... 31 7.3. Measures of Effect ...................................................................................................... ...... 33 7.4. Integration of Exposure and Effects ................................................................................. 34 7.5. Deterministic and Probabi listic Assessment Methods ...................................................... 36 7.6. Endangered Species Assessments ..................................................................................... 36 7.7. Drinking Water Assessment ............................................................................................. 3 7 7.8. Endocrine Disruptor Screening Program .......................................................................... 37 7.9. Preliminary Identifica tion of Data Gaps ........................................................................... 38 7.9.1. Environmental Fate .................................................................................................... 38 7.9.2. Effects Data .......................................................................................................... ...... 41 8. References ................................................................................................................ ................ 45 APPENDIX A: Registered Uses and Applicat ion Rates for Cymoxanil Based on Information from OPP/BEAD 1 . ........................................................................................................................ 57 APPENDIX B1: Names and Structures of Major Environmental Degradates of Cymoxanil. .... 60 APPENDIX B2: Environmental Fate Studies Details .................................................................. 65 APPENDIX C: Ecotox Open Litera ture Studies for Cymoxanil. ................................................ 67 APPENDIX D: Submitted Ecological Eff ects Toxicity Data for Cymoxanil ............................. 70 APPENDIX E: Output from ECOSAR for Cy moxanil and its Major Degradates ....................... 84 APPENDIX F: Screening Imbibition Program (SIP) v.1.0 and Screening Tool for Inhalation Risk (STIR) v.1.0 Description, Assumptions, Inputs and Outputs ............................................. 103 APPENDIX G. Data Call-In Justification Tables for Ecological Effects Studies ...................... 1075 1. Purpose

The purpose of this problem formulation is to pr ovide an understanding of what is known about the environmental fate and ecological effects of cymoxanil, considering its currently registered uses. Cymoxanil is a urea compound that was in itially developed for control of late blight ( Phytophthora infestans ) on potatoes throughout the U.S. and ha s been registered since the late 1970s for use throughout the world to control the fungal diseases late blight and downy mildew in a variety of crops. The ini tial registration in the United Stat es occurred in1998. There are no residential uses for cymoxanil nor are there formulat ions of the pesticide cl assified as “restricted use.” This document provides a plan for an alyzing data relevant to cymoxanil and for conducting environmental fate, ecological risk, endangered species, and drinking water exposure assessments for its registered uses. Additionally, this problem formulation identifies data gaps, uncertainties, and potential assumptions used to address those uncertainties relative to characterizing the potential ecological risk associat ed with the registered uses of cymoxanil on agricultural crops.

2. Problem Formulation

2.1. Nature of Regulatory Action

Under the Federal Insecticide, F ungicide, and Rodenticide Act (FIF RA), all pesticid es distributed or sold in the United States generally must be registered by the Environmental Protection Agency (Agency). In determining whether a pestic ide can be registered in the U.S., the Agency evaluates the safety of the chemical to non-target species based on a wide range of environmental and health effects studies. In 1996, FIFRA was amended by the Food Quality Protection Act (FQPA), and the Agency was mandated to implement a new program for the periodic review of pesticides, i.e ., Registration Review 1 . The Registration Review program is intended to ensure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to human health and the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the new Registration Review program, the Agency periodically reevaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely.

As part of the implementation of the Registratio n Review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide and Rodentic ide Act (FIFRA), the Agency is beginning its evaluation of cymoxanil to determine whether it continues to meet the FIFRA standard for registration. This problem formulation for the environmental fate, ecological risk, Federallylisted threatened and endangered species (hereafte r referred to as “listed”), and drinking water assessment chapter in support of th e registration review of cymoxanil will be posted in the initial docket which will open the public ph ase of the review process.

1 http://www.epa.gov/oppsrrd1/registration_review/6 2.2. Previous Assessments

EFED has assessed multiple uses of cymoxanil for Section 3, IR-4, and Section 18 registrations. The registrant, E. I. du Pont de Nemours and Company, was previously granted registration of cymoxanil on potatoes with the October 23, 1997 Section 3 New Chemical Environmental Risk Assessment (DP Barcode D233366). Additional us es (including fruiting vegetables, head lettuce, and cucurbits) were added and the appl ication rate on potatoes was increased with the January 29, 2003 updated drinking water and ecol ogical risk assessment (DP Barcode D261193); grapes (east of the Rocky M ountains) and hops with the September 20, 2006 Inter-Region 4 (IR4) tolerance petition (DP Barcode D323681); can eberries with the September 22, 2006 IR-4 tolerance petition (DP Barcode D332755) and the September 21, 2006 drinking water assessment (DP Barcode D331978); and leafy greens, bulb vegeta bles, caneberries, ci lantro leaves, onions, spinach and leaf lettuce with the May 6, 2008 IR-4 tolerance peti tion (DP barcode D348437 ) and the May 13, 2008 revised drinking water assessment (DP Barcode D347651).

Multiple Section 18 Emergency Exemption petiti ons under FIFRA Section 18 were reviewed for cymoxanil, mainly on potatoes, hops and tomato es. Curzate M-8 (8% ai) and Manex C-8, the end-use products associated with most of these requests, are no longer registered.

The major findings from the Section 3 and IR-4 assessments are summarized below. Following review of the previous risk a ssessments, conclusions were noted ; however, modifications to the previous risk conclusions ar e possible. These changes ( e.g., evaluating drinking water exposure to birds and mammals) are due to an evoluti on of Agency policy since cymoxanil was first registered. While non-target te rrestrial and aquatic plants were previously assessed, an assessment of listed species in these taxa was no t performed. Further, environmental fate and ecological toxicity data are re-e valuated as part of the Regist ration Review process and certain studies that previously met gui deline standards or registration requirements may no longer meet current guideline standards.

2.2.1. Previous Ecological Risk Assessments

Cymoxanil was first registered in 1997 by E. I. du Pont de Nemours and Company. According to the initial assessment (D233366; USEPA, 1997), risks to no n-target terre strial plants 2 , acute or chronic risks to non-target ins ects, or chronic risks from gr anular/bait formulations to mammalian or avian species were not assessed by EF ED at that time. In contrast, the Agency’s acute and chronic risk Le vels of Concern (LOCs) 3 for non-granular products were not exceeded for the maximum broadcast application rate of 0. 12 lb a.i./A for birds or mammals. Risk to nontarget aquatic plants were considered low fo llowing the assessed use pattern, and no aquatic acute or chronic risk LOCs were exceeded at the maximum application rate of 0.12 lbs a.i./A (0.84 lbs. a.i./year). No risk to listed or non-li sted species was identifi ed at the time of the

2 Non-target plants were not assessed because data have not been submitted for cymoxanil
3 LOC's are criteria used to indicate potential risk to nontar get organisms and the need for a regulatory decision. The criteria indicate that a chemical, when used as directed, has the potential to cause undesirable effects on nontarget organisms. In order to determine if an LOC has been exceeded, a risk quotient must be derived and compared to the LOC. A risk quotient is calculated by dividing an appropriat e exposure estimate by an appr opriate toxicity test effect level. Please see Section 7.4 for further description of the LOC approach.7 assessment. The formulated product Curzate ® M8, which is no longer registered, contained 64% mancozeb [known to be toxic to fish, highly toxic to freshwater i nvertebrates (daphnid EC 50 = 1.0 mg/L), and very highly toxic to estuarine invertebrates (mysid LC 50 = 0.011 mg/L)], and it was not known if the combination of cymoxanil and mancozeb was more toxic than either chemical was separately.

The IR-4 Tolerance Petition for Cymoxanil (Curzate ® 60 DF; 60% ai) use on hops completed in August of 2001 (D271572) was assessed at an application rate th at was less than previous Section 3 (D233366) use on potatoes, so no new ri sk assessment was conducted. However, the assessment recommended that the label language used in the previous assessment remain in effect due to the uncertainty pertaining to th e ecological effects of cymoxanil when used in combination with protectant fungicides (mancoze b, chlorthalonil, triphenyltin hydroxide, or metiram).

The Section 3 new use that was assessed in January of 2003 (D261193) incr eased the application rate on potatoes to 0.1875 lbs a.i. /acre (maximum 6 applications pe r year) and added the uses of fruiting vegetables, head lettuce, and cucurbits at the same application rate. In the screeninglevel assessment, EFED determined that the newl y proposed cymoxanil app lication rates resulted in exceedences of the chronic risk LOC for fres hwater fish, avian species, and wild mammals. The reported chronic risk quotients (RQs) for fi sh, birds, and wild mammals were 2.6, 2.1, and 2.1, respectively. Acute risks were expected to be substantially lower than OPP’s LOC. The calculated risks were found to be higher than those submitted in previous risk assessments primarily because of differences in model vers ions used and model inputs. GENEEC 2 was used, which contains improved estimates of sp ray drift that account fo r the likelihood that cymoxanil was applied using nozzles with a fine droplet si ze distribution.

The IR-4 Tolerance Petition for cymoxanil (Tanos ® ; 25% cynmoxanil, 25% famoxadone) use on grapes and hops completed in September of 2006 (D323681) had higher si ngle application rates (0.25 lbs ai/acre with a maximum of 10 applications per year for grapes and 6 applications per year for hops, with respective a nnual rates of 2.5 lb a.i./A/yr a nd 1.5 lbs a.i./A/yr) than those evaluated in the previous Sec tion 3 registration for the use of cymoxanil on potatoes (D233366) and for the initial IR-4 tolerance pe tition for use of cymoxanil (Curzate ® 60 DF) on hops (D271572). Based on the environmental fate and ecol ogical effects data cont ained in the original Section 3 and on estimates of terrestrial and aquatic exposure genera ted using the higher application rates, neither acute nor chronic ri sk LOCs were exceeded for aquatic animals. Additionally, acute risk quotient s for birds and mammals were also below LOCs. However, based on a default foliar dissipation half-life of 35 days for cymoxanil on avian and mammalian forage items, the chronic risk LOC was exceeded for terrestrial animals, but the default foliar dissipation value was considered conservative given that cymoxa nil degrades relatively quickly by hydrolysis and by aqueous photolysis under ideal conditions. In addition, uncertainty regarding the potential risks to non-target organisms from the formulated product Tanos ® was identified because of the increa sed toxicity associated with cy moxanil’s co-formulated product, famoxodone. No aquatic animal LOCs were exc eeded for listed or non-listed species. No aquatic plant toxicity data were submitted, so risk s to aquatic plants could not be determined. No acute risk LOCs were exceeded for listed birds or mammals; however the chronic risk LOC was exceeded for birds and mammals when a 35- day foliar dissipation half-life was used.8 The IR-4 Tolerance Petition for cymoxanil (Tanos ® ) use on caneberries in September 2006 (D332755) included lower applicatio n rates than those evaluated in the previous new use of cymoxanil on grapes and hops (D323681). The asse ssed rate was the maximum application rate for caneberries: 0.19 lbs a.i./acre with a maximum of 6 applications at 7-day intervals, with a maximum annual rate of 1.1 lbs a.i./acre. Base d on environmental fate and ecological effects data contained in the original Section 3 and on the estimates of terrestrial and aquatic exposure generated using the proposed lo wer application rate of cymoxanil, neither acute nor chronic LOCs were exceeded for aquatic animals. Again, uncertainty was identified in this assessment because of lack of data on foliar di ssipation rates. If the default foliar dissipation rate of 35 days was used for terrestrial assessments, the chronic risk LOC was exceeded for both birds and mammals, but the default foliar dissipation value was considered conservative given the limited persistence of cymoxan il in the environment.

Finally, an IR-4 Tolerance Peti tion for use of cymoxanil (Tanos ® ) on leafy greens, bulb vegetables, and caneberries was assessed in May of 2008 (D348437). The proposed single application rates were less than those evaluated in th e previous new use of cymoxanil on grapes and hops (D323681). The maximum application rate s assessed were: 0.16 lbs a.i./A with a maximum of 8 applications (5-day interval) for bulb vegetables per season, with a maximum annual rate of 1.3 lbs a.i./A. For spinach, which can have up to 2 seasons per year, the maximum annual application rate was assesse d at 2.6 lbs a.i./A/year. The acute and chronic LOCs were not exceeded for aquatic animals or plants. In additi on, if the default foliar dissipation half-life of 35 days is used for the terrestrial risk assessment, the chronic risk LOCs are exceeded for birds and both acute and chronic LOCs are exceeded for mammals. Again, the default foliar dissipation value was considered conservative given th e limited persistence of cymoxanil in the environment.

2.2.2. Drinking Water Exposure Assessments

The initial “water resources a ssessment” for cymoxanil was c onducted by EFED in 10/1997 for the Section 3 new use registration on potatoe s (D233366). The end-use product (Curzate M-8, no longer registered; 8% ai) also contained the fungicide mancozeb (64% a.i.). The assessment was essentially qualitative, and concluded that cymoxanil is not likely to persist in (most) surface waters, although it “ may be more persistent in deep er and/or unclear waters with low microbiological populations, long hydrologic residence times and acidic pH. ” The assessment also stated that the compound “ is expected to be degraded rapidly in the environment ,” and although it was “ mobile in four soils te sted, EFED believes that th e chemical does not pose a threat to ground water quality .”

A Tier 1 Drinking Water Assessment (DWA) was c onducted for the IR-4 registration for the use of cymoxanil on caneberries (9/21/2006). Th e DWA was performed using the FQPA Index Reservoir Screening Tool (FIRST; versi on 1.0) for surface water and the Screening Concentration in Ground Water (SciGRow; versi on 2.3) model for groundwater. The proposed application rate was less than the rates evaluate d in the previous new use of cymoxanil grapes and hops (DP D323681), so Estimated Drinking Wate r Concentrations (EDWCs) reported in the assessment were based on the use on grapes.9 Most recently, a revised Tier 1 DWA was conducte d for the use of cymoxanil on leafy greens, bulb vegetables, caneberries, cilantro leaves , onions, spinach and leaf lettuce (D347651; 5/13/08). The EDWCs determined in that asse ssment for spinach (0.0018 ppb for groundwater and 9.3 ppb and 0.05 ppb for acute and chronic surface water, respectively) were higher than previously reported values and currently re present the maximum EDWCs that have been recommended for use in the Health Effects Di vision’s (HED) human dietary risk assessment.

3. Stressor Source and Distribution

3.1. Mechanism of Action

Cymoxanil is a locally systemic fungicide that penetrates plant tissue rapidly after application. The systemic characteristic is intended to provide anti-fungal activity post-infection. Cymoxanil is in the chemical group cyanoacetamideoxime, wh ich is listed as a Group 27 fungicide by the Fungicide Resistance Action Committee (FRAC) 4 . It is the only fungicide in its FRAC chemical group. The fungicidal activity of cymoxanil is du e to the inhibition of a number of cellular processes which are critical to the growth and development of fungal pathogens, including nucleic acid, protein and lipid biosynthesis, resp iration and membrane permeability. In general, cymoxanil is active on fungi that belong to the order Peronosporales and is mainly used to control late blight and ot her Phytophthora diseases, a nd downy mildews (USEPA, 2011b).

3.2. Overview of Pesticide Use and Usage

Cymoxanil is a urea compound that was initiall y developed for control of late blight ( Phytophthora infestans ) on potatoes throughout the U.S. and ha s been registered since the late 1970s for use throughout the world, and since 1998 in the U.S., to control the fungal diseases late blight and downy mildew in a va riety of crops (USEPA, 2011b).

Cymoxanil is formulated as dry flowable and dust. One end-use product, Curzate ® 60 DF, is used as a tank-mix with a protect ant fungicide, such as a coppe r product. Another cymoxanil containing product is Tanos ® , which includes 25% cymoxanil and 25% femoxadone. The third registered product is Evolve ® , which is a potato seed-piece treat ment containing 1 % cymoxanil, 2.5% thiophanate-methyl, and 6% mancozeb. Cymoxa nil may be applied as a seed treatment to potato seed pieces and also to peas (as seeds fo r export only). Seed treatments may be made using slurry or mist seed treatment equipmen t. Foliar applications may be made using ground, aerial, and chemigation equipment (USEPA, 2011b).

Cymoxanil is registered for use on potatoes, to matoes, peppers, cucurb its, leafy vegetables (except Brassica group 4), bulb vegetables (bulb onion and green onion subgroup), grapes grown east of the Rocky mountains, caneberries (except in California), and hops (except in California). There are also FIFRA Section 24c Special Lo cal Need (SLN) registrations for use on the following crops: spinach, cabbage, Swiss chard, and table beets when they are grown for seed. In

4 FRAC is characterized as a specialist t echnical gropu of CropLife International http://www.frac.info/frac/index.htm10 addition, there is a SLN registration for use for commercial seed treatment for peas intended for export.

Maximum label rates for registered cymoxanil uses are presented in Table 3.1 . Rates are based on labels for the end-use products DuPontTM Tanos ® fungicide (dry flowable; 25% a.i.; coformulated with famoxadone at 25% ; Reg. No. 352-604); DuPontTM Curzate ® 60 DF fungicide (60% a.i.; Reg. No. 352-592); and EVOLVE ® Potato Seed-Piece Treatment Fungicide (1% a.i.; co-formulated with mancozeb, thiophanate-methyl, and ethylene bis -dithiocarbamate ion; Reg. No. 264-973).

Table 3.1. Summary of Cymoxanil Application Rates from Current Labels.

Use Max. Single Applic.Rate (lbs a.i./A) Max. No. Applic./Crop Cycle Max. Applic. Rate/Crop Cycle

(lbs a.i./A/cc) Max. No. Applic./Yr Max. Annual Applic. Rate (lbs a.i./A/yr) Min. Applic. Interval

(days)

Bulb Vegetables 0.156 NS 1 1.3 NS NS 5

Caneberries 0.156 NS 1.1 NS 1.1 5

Cucurbits 0.1875 NS NS NS 1.1 5

Grapes 0.125 9 1.1 NS NS 10 Hops 0.125 6 0.75 NS 0.75 6 Leafy Vegetables 0.156 NS 0.75 NS NS 5
Lettuce (Head

and Leafy) 0.1875 NS NS NS 1.1 5

Spinach 0.1875 NS NS NS 1.1 5 Peppers 0.156 NS 1.1 NS 1.1 5 Potatoes 0.125 6 0.75 NS 1.1 5 Tomatoes 0.1875 NS NS NS 1.1 5 Potato/Seed Treatment 0.0375 lb a.i./ lb seed NS NS NS NS NS

1 NS = Not specified on the label.
Based on information for the years 2001 – 2008 from the USDA-NASS (United States Department of Agriculture's Nati onal Agricultural Statistics Serv ice) and from private pesticide market research, the September 2011 Scr eening Level Usage Analysis (SLUA; Table 3.2 ) generated by OPP’s Biologic and Economic Analys is Division (BEAD) states that the main crops on which cymoxanil is used include potat oes, cucumbers, tomatoes, other vegetables, grapes and melons (USEPA, 2011a). Usage data fo r hops are not available. Use data collected by the California Department of Pesticide Regulation (CADPR; Table 3.3 ) for the years 2007 – 2009 indicate that the main usages of cymoxanil in California are for head lettuce, potatoes and tomatoes (USEPA, 2011a).

For the years 2008-2010, the main crops in terms of total pounds of activ e ingredient applied were potatoes (49%), cucumbers (22%), toma toes (8%), pumpkins (5%), and peppers (5%) (USEPA, 2011a). These crops were also the top in terms of the total acres treated. Over the broader timeframe of 1998-2010 timeframe, usag e on potatoes was highest in 1998 and 2000 and has generally leveled off ( Figure 3.1 ). Usage overall has increased since the addition of several11 new crops in 2004. For the most recent years of 2008-2010, cymoxanil usage in agriculture (excluding seed treatments) averaged a pproximately 50,000 pounds for 400,000 treated acres (USEPA, 2011a). Seed treatments were excluded th roughout this use analysis because usage data are only available for potatoes for 2009-2010. Howeve r, as a general estimate, seed treatments on potatoes accounted for less than 3% of the total acre treatmen ts to potatoes in 2009 and 2010.

Table 3.2. Screening Level Estimates of Agricultural Uses of Cymoxanil for 2003-2010 (BEAD, 9/13/2011) Percent Crop Treated Crop Lbs. A.I. Avg. Max.

Caneberries 1,000 10 15
Cantaloupes <500 <2.5 <2.5

Cucumbers 9,000 25 45
Grapes, wine <500 <2.5 <2.5

Lettuce 2,000 5 10

Onions 1,000 5 15
Peppers 2,000 10 15

Potatoes 20,000 10 20
Pumpkins 2,000 10 20
Spinach <500 <2.5 <2.5
Squash 1,000 10 25

Tomatoes 4,000 5 10

Watermelons <500 <2.5 5

Table 3.3. CADPR Cymoxanil Use Information for 2007 – 2009. Commodity 2007 Pounds Applied 2008 Pounds Applied 2009 Pounds Applied Celery, General 1 Lettuce, Head (All Or Unspec) 1197 1743 1709 Lettuce, Leaf (All Or Unspec) 28 N-Grnhs Grwn Trnsplnt/Prpgtv Mtrl 39 9 25
N-Outdr Grwn Trnsplnt/Prpgtv Mtrl 9 2
Peppers (Fruiting Vegetable), (Bell,Chili, Etc.) 16 15 5
Potato (White, Irish, Red, Russet) 308 1074 256
Spinach 7 Squash (All Or Unspec) 1 1 Tomato 171 898 206 Tomatoes, For Processing/Canning 60 276 93

Watermelons 1 Grand Total 1803 4015 233212 The states with the highest agricu ltural usage in terms of pounds AI applied are Michigan (19%), Washington (13%), Florida (11%), California (1 0%), Wisconsin (6%), and Idaho (5%) (USEPA, 2011a). These states were also the ones with the highest usage in terms of the total acre s treated.

3.3. Environmental Fate and Transport

Cymoxanil is a relatively nonvolatile, highly wate r soluble compound that is not expected to significantly persist in the aquatic environment when ne utral and alkaline conditions are prevalent. Its persistence in acidic aquatic enviro nments is uncertain. It hydrolyzes quickly in alkaline and neutral media, and photodegra des quickly in aqueous media under optimal conditions. Its persistence in soil is not well de fined due to limited data , although hydrolysis will also play a role in higher pH soils. It is su sceptible to aerobic biode gradation in soil, with mineralization to CO 2 , although additional data are needed to fully understand the fate of the parent and its numerous transformation products in aerobic soil. While most of the major hydrolytic and photolytic degradates were not observed in large amount s in the aerobic soil metabolism studies, only IN-KQ960 (see Appendix B1 ) and oxamic acid were detected in the aerobic soil metabolism studies, but not in the hydrolysis or aqueous photolysis studies. However, all soil metabolism degradates may not have been identified, as the extraction method used in these studies was questionable given th e large amount of nonextra ctced residues present in the soil samples from as early as day 1. While submitted data indicate that cymoxanil will degrade in water/sediment (aquatic ) systems, particularly at high pHs, the data are uncertain due to high levels of nonextracted re sidues throughout thes e studies as well. Also, the observed degradation was likely due to hydrolysis based on the high pHs of the study systems, which tended toward neutral or alkaline levels. Thus, it remains unclear how the compound will behave in more acidic environments where hydrol ysis will not be a major route of dissipation.

With organic carbon (oc) part itioning coefficients (K oc ; in mL/g oc) of 22-138 in four soils, cymoxanil has been shown to be mobile to highly mobile in soil based on the Food and Agriculture Organization (FAO) classification scheme. Alt hough a batch equilibrium study on the degradates was classified as not acceptabl e because only one concentration was studied, the results indicated that the cymoxanil degr adates IN-W3595, In-R3273 and In-KQ960 are all highly mobile in soil. The si ngle point measurements of K oc ranged from 0 to 50 mL/g oc. The degradate IN-U3204 was unstable in the test system.

Based on the measured vapor pressure (1.1x10 -6 Torr) and the estimated Henry’s Law Constant (3.3 x 10 -10 atm-m 3 /mol), cymoxanil is not expected to sign ificantly volatilize from water or soil. While no fish bioconcentration da ta are available, the ocatanol -water partition coefficient (K ow) values (3.9, 4.7) indicate that th e compound is not likely to be bi oconcentrated in fish tissue.

Additional details on the fate of cymoxan il and its degradates are presented in Appendix B2

.

Table 3.4 summarizes the general physical, chemical , and fate and tran sport properties of cymoxanil.13 Table 3.4. General Chemical Properties and En vironmental Fate Properties of Cymoxanil, (E)-2-cyano-N-[ethylamino)carbon yl]-2-(methoxyimino)acetamide.

Parameter Value Reference (MRIDs/ Classification) Comments

Selected Physical/Chemical Parameters

Molecular mass 198.2 g/mol Product chemistry Section 3 New Chemical Risk Assessment (D233366).

Vapor pressure (20°C) 1.1 x 10 -6 Torr Product chemistry Section 3 New Chemical Risk Assessment (D233366).

Water solubility (20°C) 780 mg/L (pH 7) 890 mg/L (pH 5) Product chemistry Section 3 New Chemical Risk Assessment (D233366).
Henry’s law constant (20°C, pH 7) 3.3 x 10 -10 atm-m 3 /mol Estimated 1

Octanol-water partition coefficient (K ow ) (20°C) 3.9 in pH 5 buffer, 4.7 in pH 7 buffer Product chemistry Section 3 New Chemical Risk Assessment (D233366).

Hydrolysis (t 1⁄2; days; @ 25°C) Stable @ pH 5 1.4 @ pH 7 0.022 @ pH 9 44180738 (Acceptable)

Aqueous Photolysis (t 1⁄2; days ) 3.6 44180739 & 44180740 (Acceptable) In pH 5 buffer. Half-life was corrected for continuous irradiation, so differs from that reported in past assessments.

Soil Photolysis (t 1⁄2; days ) 74 44180741 (Supplemental) Half-life was corrected for natural sunlight, so differs from that reported in past assessments. Not a significant fate pathway.

Aerobic Soil Metabolism (t 1⁄2; days ) No data 44180742 (Supplemental)

44180743 & 45357101 (Not

Acceptable)

AMR 1988-91 (Supplemental) No useable half-life data available. Submitted studies are classified not acceptableor supplemental, and halflives will not be used in risk assessments. Data are from foreign and/or volcanic ash soils and are of questionable validity (thus, not upgradeable) due to analytical method/residue extraction issues.

Anaerobic Soil Metabolism No data No data have been submitted.14 Parameter Value Reference (MRIDs/ Classification) Comments

Anaerobic Aquatic Metabolism No data 44180744 (Not Acceptable) AMR 2446-92 (Supplemental) No usable data available. Supplemental data are not representative of typical use conditions.

Aerobic Aquatic Metabolism No data 44180741 (Not Acceptable) Submitted data are classified not acceptable. Mobility Soil Adsorption Coefficient K d (mL/g) 0.3 (sandy loam, 1.3% om) 2.9 (clay loam, 4.5% om)

1.4 (silt loam, 1% om) 0.8 (silt loam, 1.3% om) 44180745 (Acceptable) Parent compound

44180746 (Not Acceptable) Deficient since only single concentration studied. For degradates W3595, R3273, KQ960 & JX915, all K f ‘s

were ≤ 1.5 and K oc ’s were 0- 50.

AMR 2724-93 (Acceptable) Leaching column study.

Organic Carbon Partitioning Coefficient K oc (mL/g oc) 22 (sandy loam, 1.3% om) 64 (clay loam, 4.5% om)

138 (silt loam, 1% om) 57 (silt loam, 1.3% om) 44180745 (Acceptable) K oc model is valid for this pesticide. FAO mobility classes are mobile (3 soils) to moderately mobile (1 soil). Field Dissipation Terrestrial Field Dissipation (t 1⁄2; days ) (top 15 cm of soil) 0.9 (Silt loam; pH 6.5; MD site) 8.7 (Loam; pH 7.8; CA site) 44180747 (Acceptable) Parent not detected below 15 cm. Degradates not monitored.

45294105
45294105
44946410 (All Supplemental) Studies were on famoxadone plus cymoxanil mixture. Cymoxanil was not monitored.

Bioaccumulation in Fish Fish Bioaccumulation (BCF) No data Data not needed based on low K ow values.
1 Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)

3.4. Degradates of Concern

Major degradates are compounds that form at greater than 10% of the applie d in at least one fate study, or are known to be toxicol ogically significant. The degrad ates reported in the abiotic15 laboratory fate studies (presented in Table 3.5 ), which are potentially degradates of concern, include 1-ethyldihydro-6-imino-2,3,5(3H) pyrimidinetrione-5-(O-methyloxime) ( IN-U3204); {[(ethylamino) carbonyl]} ethylam ino)carbonyl]amino}oxoacetic acid ( IN-KP533 ); cyano(methoxyimino)acetic acid ( IN-U3595 ); 3-ethyl-4-(methoxyamino)-2,5-dioxo-4- imidazolidinecarbonitriile ( IN-JX915 ); ethylimidazolidinetri one-5-(O-methyloxime) ( INR3273 ); 1-ethyldihydro-6-imino-2,4,5{3H}-pyr imidinetrione-5-(O-methyloxime) ( IN-U3204 ); ethylimidiazolidinetrione ( IN-T4226 ); and oxalic acid. All of th e degradates listed above are hydrolysis products and/or photodegr adates in soil and/or water ( Appendix B2 for additional details).

In the aerobic soil metabolism studies, th e compounds 3-ethyl-4-(methoxyamino)-2,5-dioxo-4- imidazolidinecarboxamide ( IN-KQ960 ), IN-W3595

, CO 2

, and IN-U3204 were present as major degradates in one or more soils (incl uding foreign and volcanic ash soils); while IN-18474 (oxamic acid), IN-R3273

, IN-KP533 , and IN-JX915 were present as minor degradates in all soils in which they were detected. Of these, only IN-KQ960 and oxamic acid were not detected in the hydrolysis and/or photolysis studies. Ho wever, as noted earlier, there remains a data gap for aerobic soil metabolism data and it is uncer tain whether all residues were adequately characterized in the submitted studies, as well as whether the soils used in the studies are representative of intended us e sites. There are no anaero bic soil metabolism data, and the submitted data for aerobic aquatic metabolism ar e not acceptable. In the one supplemental anaerobic aquatic metabolism study, degradates were likely due to hydrolysis and were not identified. None of the degradates were monito red in the terrestrial fi eld dissipation study.

In a batch equilibrium study, the degradat es IN-W3595, IN-R3273 and IN-KQ960 were all shown to be highly mobile in soil, and in an aged soil column leaching study, the degradates oxamic acid (IN-18474) and IN-KP533 we re detected in the leachate.

Degradates from the submitted environmental fate studies and their maximum detections are briefly summarized in Table 3.5 below, while Appendix B1 lists the major degradates, chemical structures, and chemical names.

Based on the available information the main degr adates of concern with respect to exposure include IN-3204, IN-KP533, IN-R 3273, IN-JX915, and IN-U3595. In addition, IN-KQ960 is of concern due to its toxicity. Potential exposure to IN-KQ960 is uncertain due to aerobic soil metabolism data gaps.

Table 3.5. Summary of cymoxanil degradates from the environmental fate studies.

Study/Data Source Metabolites Maximum Detection(s)

Soil Photolysis (44180741) IN-JX915
CO 2 11% (day 7)
14%

Hydrolysis (44180738) IN-U3204

IN-KP533

IN-U3595 53% (day 2, pH 7), 61% (0.2 days, pH 9) 57% (day 30, pH 7), 32% (day 10, pH 9) 39% (day 3, pH 9)16Oxalic acid and oxamic acid (IN18474) <10% each (pH 9)

Aquatic Photolysis (44180739 & 44180740) IN-JX915
IN-R3273
IN-KP533 IN-18474 (oxamic acid)
IN-U3204
IN-T4226 52% (day 4) 35% (day 15; end of study) 8% (day 15)
2.1%
≤ 1% 6.7% (day 15)
Aerobic Soil Metabolism 1 (44180742, AMR 1988-91) Volcanic Ash Soil (AMR 1988-91) IN-KQ960 IN-W3595 CO 2 IN-18474 (oxamic acid) IN-U3204 IN-R3273

4 Foreign Soils Including 1 Volcanic Ash Soil (44180742) IN-KQ960 IN-W3595 CO 2 IN-18474 (oxamic acid)

IN-U3204

IN-R3273 IN-KP533 IN-JX915 Volcanic Ash Soil (AMR 1988-91) 18.5% (day 7) 9.0-11.1% (day 1) 26.4-30.8% (day 365) Value not reported. 22.6-26.8% (8 hours) 5.9-6.3% (8 hours)

4 Foreign Soils Including 1 Volcanic Ash Soil (44180742) 5% (d 9) 8% (d 2), 18% (d 7) Values not reported. 5% (d 5), 5% (d 15), 5% (d 30), 8% (d 3) 22.5% (4 hr), 61% (8 hr), 5% (d 5), 8% (d 0) 2% 2% (d 2) <2%, 8% (d 0)

1 Data are from studies classified as supplemental for multiple r easons including the use of only foreign soils and/or volcanic a sh soils, which have not been shown to be representative of intended use areas in the U.S. There remains a data gap for this study type, and these s tudies are not upgradeable due to questionable validity resu lting from extraction method deficiencies. Information on degradates is included here only to indicate which degradates may potentially form in soil.

3.5. Water Quality

Cymoxanil is not identified as a cause of impairment for a ny water bodies under section 303(d) of the Clean Water Act 5 . In addition, no Total Maximum Daily Loads (TMDL) have been developed for this pesticide 6 and there are no aquatic life criteria for it 7 . More information on impaired water bodies and TMDLs can be found at http://www.epa.gov/owow/tmdl/

. The Agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to th e quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Im paired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Asse ssment and Management Process (see:

5 based on information provided at http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885 , accessed 9/13/2011
6 based on information provided at http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl _pollutant_detail?p_pollutant_group_id=885&p_pollutant_ group_name=PESTICIDES , accessed 9/13/2011
7 based on information provided at http://www.epa.gov/waterscien ce/criteria/aqlife/index.html , accessed 9/13/201117 http://www.epa.gov/oppfead1/cb/p pdc/2006/november06/session1-sop.pdf ), in order to ensure they can be used quantitatively or qual itatively in pesticide risk assessments.

No surface water monitoring data were available for cymoxanil. Neither the USGS’s National Water Quality Assessment (NAW QA) program nor the Californi a Department of Pesticide Regulation monitoring programs include d cymoxanil as an analyte.

Cymoxanil is not listed on the Title 3 Califor nia Code of Regulation’ s “Ground Water Protection List” (3CCR section 6800(b) http://www.cdpr.ca.gov/docs/legbills/calcode/040101.htm#a6800

4. Receptors

Consistent with the process described in th e Overview Document (USEPA, 2004), the risk assessment for cymoxanil relies on a surrogate species approach. Toxicological data generated from surrogate test species, which are intended to be representative of broad taxonomic groups, are used to extrapolate the pot ential effects on a variety of species (receptors) included under these taxonomic groupings.

Acute and chronic toxicity data from studies submitted by pesticide registrants along with the available open literature are used to evaluate the potential direct and indirect effects of cymoxanil to aquatic and terrestrial receptors. This includes toxicity of the technical grade active ingredient, degradates, and when available, formulated products ( e.g. , “Six-Pack” studies). The open literature studies are identified through EPA’s ECOTOXicology (ECOTOX; USEPA 2011 8 ) database, which employs a literature search e ngine for locating chemical toxicity data for aquatic life, terrestrial plants, and wildlife. The evaluation of both sources of data may also provide insight into the direct and indirect e ffects of cymoxanil on biotic communities from loss of species that are sensitive to the chemical and from changes in structure and functional characteristics of the affected communities . An ECOTOX run conducted in August 2011 for cymoxanil found that sixteen aquatic studies and six terrestrial studies are available; however, these studies have not been formally reviewed as part of this Problem Formulation. References to all ECOTOX studies are presented in Appendix C . Data from these studi es and data from an up-dated ECOTOX run for cymoxanil will be evaluated for possible quantitative and/or qualitative inclusion in the risk assess ment in support of Registration Review.

A summary of the most sensitiv e data representing non-target or ganisms exposed to cymoxanil in aquatic and terrestrial habita ts is provided in Sections 4.1 and 4.2. A summary of ecological incidents associated with cymoxanil and a desc ription of ecosystems pot entially at risk are provided in Section 4.3.

4.1. Effects to Aquatic Organisms

Based on the available data, cymoxanil is categori zed as slightly toxic to freshwater fish (LC 50 = 29,000 μg a.i./L) and estuarine/marine fish (LC 50 > 47,500 μg a.i./L) on an acute exposure basis ( Table 4.1 ). It is considered slightly toxic to both freshwater invertebrates (LC 50 = 28,000 μg

8 USEPA. 2011. ECOTOX Database. http://cfpub.epa.gov/ecotox/18 a.i./L) and estuarine/marine invertebrates (LC 50 > 44,400 μg a.i./L) on an acute basis. Additionally, chronic data on aquatic organisms fo r freshwater and estuarine/marine fish and freshwater invertebrates are also available. The most sens itive endpoint for chronic freshwater fish was based on total length (NOAEC = 0.98 μg a.i./L; MRID 443446-10), while the most sensitive endpoint for chronic estuarine/marine fi sh was based on survival at test termination (NOAEC = 94.2 μg a.i./L; MRID 441807-26). Th e most sensitive endpoint for chronic freshwater invertebrates was ba sed on survival at test termination (NOAEC = 67 μg a.i./L; MRID 441807-24). The most sensitive species fo r each taxa from submitted aquatic animal toxicity studies are presented in Table 4.1

. A summary of all submitted ecotoxicity data for cymoxanil and one degradate is provided in Appendix D

. Degradates toxicity data for cymoxanil ar e only available for the degradate 3-ethyl-4- (methoxyamino)-2,5-dioxo-4-imidazolidinecarboxamide (IN-KQ960) based on a study in the freshwater invertebrate Daphnia magna ( Table 4.1 ). The data indicate that this degradate is approximately 35 times more toxic to freshwater invertebrates than th e parent compound with a 48-hr EC 50 of 800 μg a.i./L (MRID 456892-01) versus 28,000 μg a.i./L (MRID 441807-19) for the parent. The parent and degradate are of similar mol ecular weight so the toxicity values are able to be directly compared without needing to correct for molecular weight.

Toxicity and risk from cymoxanil degradates is an area of uncertainty for aquatic organisms. As discussed in the environmental fate section, several degradates may form via hydrolysis, photolysis, and metabolism, yet ther e are little to no toxic ity data available for them. There is an exposure concern for several of these de gradates (IN-3204, IN-KP533, IN-R3273, IN-JX915, and IN-U3595) due to their mobility and magnitude of formation, as noted in Section 3.4

. Potential exposure to IN-KQ960 is uncertain due to aerobic soil metabolism data gaps.

A formulation containing 6.58% cymoxanil and 26.5% elemental copper was also tested under acute exposure conditions with D. magna (MRID 465038-03; Table 4.1 )

. When the concentration of cymoxanil in the formulation is corrected for percenta ge a.i., the 48-hour EC 50 (2.8 μg ai/L) is 4 orders of magnitude lower than when cymonil is tested under similar conditions as technical active ingredie nt alone (28,000 μg ai/L).

Table 4.1. Summary of the Most Sensitive Species by Taxon from Submitted Aquatic Animal Toxicity Studies for Cymoxanil.

TAXON SPECIES ENDPOINT CHEMICAL/ FORMULATION MRID STUDY CLASSIFICATION

Freshwater Fish (Acute) Bluegill Sunfish ( Lepomis macrochirus ) 96-hr LC 50 29,000 μg a.i./L Cymoxanil (97.8%) 441807-18 Acceptable

Estuarine/ Marine Fish

(Acute) Sheepshead Minnow ( Cyprinodon variegatus ) 96-hr LC 50 >47,500 μg a.i./L Cymoxanil (97.8%) 441807-20 Acceptable

Estuarine/

Marine Invertebrates (Acute) Mysid Shrimp ( Americamysis bahia ) 96-hr LC 50 >44,400 μg a.i./L Cymoxanil (97.8%) 441807-22 Acceptable

Freshwater Fish Rainbow Trout ( Oncorhynchus NOAEL: 0.98 μg a.i./L Cymoxanil (97.3%) 443646-10 Acceptable19 (Chronic) mykill ) LOAEL: 2.4 μg a.i./L Most Sensitive Endpoint (Total Length) Freshwater Invertebrates (Acute) Waterflea ( Daphnia
magna ) 48-hr EC 50 : 28,000 μg a.i./L Cymoxanil (97.8%) 441807-19 Acceptable

Freshwater Invertebrates (Acute) Waterflea ( Daphnia
magna ) 48-hr EC 50 : 2.8 μg a.i./L DPX-HYZ80 31 WG Cymoxanil

(6.58%) Metallic Copper (26.5%) 465038-03 Supplemental

Freshwater Invertebrates (Acute) Waterflea ( Daphnia
magna ) 48-hr EC50 = 800 μg a.i./L NOAEC = 560 μg a.i./L Cymoxanil Degradate 3-ethyl-4- (methoxyamino)-

2,5-dioxo-4- imidazolidinecarboxamide (INKQ960) (94.6%) 456892-01 Acceptable

Freshwater Invertebrates

(Chronic) Waterflea ( Daphnia
magna ) NOEC: 67 μg a.i./L LOEC: 150 μg a.i./L Most Sensitive Endpoint (Survival) Cymoxanil (97.8%) 441807-24 Acceptable

Estuarine/ Marine Fish

(Chronic) Sheepshead Minnow ( Cyprinodon variegatus ) NOEC: 94.2 μg a.i./L LOEC: 178 μg a.i./L Most Sensitive Endpoint (Survival) Cymoxanil (97.8%) 441807-26 Acceptable

Estuarine/

Marine Invertebrates

(Chronic) Mysid Shrimp ( Americamysis bahia ) NOEC: 1.700 μg a.i./L LOEC: 3,770 μg a.i./L Most Sensitive Endpoint (Number of young/female, male and female length, and female dry weight) Cymoxanil (97.8%) 441807-27 Acceptable

For non-vascular aquatic plants , several toxicity studies we re submitted for the cymoxanil technical active ingredient: Pseudokirchneriella subcapitata (green algae; MRIDs 441807-30, 441807-33); Navicula pelliculosa (freshwater diatom; MRID 441807-32); Skeletonema costatum (marine diatom; 441807-31); Anabaena flos-aquae (cyanobacteria; MRID441807-29). The most sensitive endpoint from among these studies is an EC 50 of 202 μg a.i./L based on average cell20 density in N. pelliculosa ( Table 4.2 ; see Appendix D for full list of studies and endpoints); this endpoint value will be used in risk assessmen t to quantify risk to non-vascular plants. A duckweed study was also submitted to represent vascular aquatic plants; the maximum application rate tested (793.8 μg a.i./L) result ed in no reduction in frond number over the 14-day test period.

Table 4.2. Summary of the Most Sensitiv e Endpoints from Submitted Aquatic Plant Toxicity Studies for Cymoxanil.

TAXON ENDPOINT CHEMICAL/ FORMULATION MRID STUDY CLASSIFICATION Aquatic Nonvascular Plants

Freshwater Diatom ( Navicula pelliculosa ) 120-hr EC 50 = 202 μg a.i./L NOAEC = 63.3 μg a.i./L (Based on algal cell density) DPX-T3217-113 (Cymoxanil; 97.3%) 441807-32 Acceptable

Aquatic Vascular Plants

Duckweed ( L. gibba ) 14-day EC 50 > 793.8 μg a.i./L NOAEC = 793.8 μg a.i./L (Based on frond growth) DPX-T3217-113 (Cymoxanil; 97.3%) 441807-28 Acceptable

4.2. Effects to Terrestrial Organisms

Table 4.3 summarizes the most sensitive terrestrial animal toxicity endpoints for cymoxanil based on an evaluation of submitted studies. Cym oxanil technical is categorized as practically nontoxic to birds on both an acute oral (LD 50 > 2250 mg ai/kg-bw; MRID 441807-11) and subacute dietary (LC 50 > 5620 mg ai/kg-diet; MRID 441807-13) exposure basis. Treatmentrelated mortalities were observed in acute oral st udies. Cymoxanil is slightly toxic to mammals on an acute oral exposure basis (LD 50 > 960 mg/kg-bw; MRID 436165-12)

Chronic toxicity studies of mallard duck ( Anas platyrhynchos ; MRID 441807-15) and laboratory rat ( Rattus norvegicus ) (MRID 436165-20 ) are included in the summary table below. The endpoint for the chronic bird study was based on significant reductions in egg production (eggs laid, eggs set, and viable embryos), while th e endpoint for the chronic mammal study was based upon decreased F 1 pup viability on postnatal days 0-4 and on significant F 1 pup viability on postnatal days 0-4 and on a significant reduction in F 2b pup weight.

Cymoxanil technical is practic ally nontoxic to young adult ho neybees on an acute contact exposure basis (LD 50 > 25 μg a.i./bee; MRID 441807-35) and exhibits low toxicity to honeybees on an acute oral exposure basis (LD 50 > 1,000 mg a.i./bee; MRID 441807-36).

Passerine bird toxicity data as well as terrestr ial plant toxicity studies for vegetative vigor or seedling emergence are not av ailable for cymoxanil.21 Table 4.3. Summary of the Most Sensitive E ndpoints from Submitted Terrestrial Toxicity Studies for Cymoxanil Technical.

TAXON ENDPOINT CHEMICAL/ FORMULATION MRID STUDY CLASSIFICATION BIRDS Acute Oral Mallard Duck ( Anas platyrhynchos ) 14-day LD 50 > 2250 mg a.i./kg-bw Cymoxanil (97.8%) 441807-11 Acceptable

Sub-Acute Dietary Bobwhite quail ( Colinus virginianus ) 8-day LC 50 > 5620 mg a.i./kg-diet Cymoxanil (97.8%) 441807-13 Acceptable

Chronic

Mallard Duck ( Anas platyrhynchos ) NOAEC:100 mg a.i./kg diet LOAEC: 300 mg a.i./kg diet (Based on significant reductions in egg production) Cymoxanil (97.8%) 441807-15 Acceptable

MAMMALS Acute

Laboratory Rat ( Rattus norvegicus ) LD 50 > 960 mg/kgbw Cymoxanil (97.8%) 436165-12 Acceptable

Chronic

Laboratory Rat ( Rattus norvegicus ) NOAEL: 6.5 mg a.i./kg-bw LOEAL:32.1 mg a.i./kg-bw (Based on reduction in mean bodyweight, overall body weight gain, and food consumption in parental (F 0 ) males; reduced mean bodyweight during gestation and lactation of F 1 females; decreased mean F 1 pup viability; reduced F 2 pup weight) Cymoxanil (97.8%) 436165-20 Acceptable

TERRESTRIAL INVERTEBRATES Honey Bee (contact) (Apis melifera) LD 50 > 25 μg a.i./bee Cymoxanil (97.8%) 441807-35 Acceptable

Honey Bee (oral)

(Apis melifera) LC 50 > 1000 mg a.i./bee Cymoxanil (97.8%) 441807-36 Acceptable

Earthworm ( Eisenia fetida ) 14-day LC 50 = 2109 mg a.i./ kg dw soil Cymoxanil (96.0%) 442007-02 Supplemental22 TAXON ENDPOINT CHEMICAL/ FORMULATION MRID STUDY CLASSIFICATION

Predatory Mite ( Typhlodromus pyri ) 7-days: No statistical difference seen at 9 g a.i./ha for growth or reproduction; however, statistical difference were seen at 120 g a.i./acre Cymoxanil (60%) 454754-01 Supplemental

4.3. Incident Databases Review

Preliminary reviews of the Ecological Incident Information System (EIIS, version 2.1) and the Avian Incident Monitoring System (AIMS) 9 were conducted on August 27, 2011. No incidents associated with cymoxanil use have been report ed in EIIS. In addi tion, no incidents involving birds were reported in the AI MS database for cymoxanil.

In addition to the major incidents recorded in EIIS, additional incidents may be reported to the Agency in aggregated incident re ports. Pesticide registrants repor t certain types of incidents to the Agency as aggregate counts of incidents occurring per product per quar ter. Ecological incidents reported in aggregate re ports include those categorized as ‘minor fish and wildlife’ (WB), ‘minor plant’ (P-B), and ‘other non-target ’ (ONT) incidents. ‘Oth er non-target’ incidents include reports of adverse effect s to insects and other terrestria l invertebrates. However, for cymoxanil, as of August 27, 2011, no aggregated incidents have been reported.

Actual incidents associated with the use of cymo xanil may be higher than what is reported to the Agency. Incidents may go unreported since effe cts may not be immediat ely apparent and/or readily attributed to the use of a chemical. As such, the absenc e of incident reports cannot be construed as the absence of incidents.

4.4. Ecosystems Potentially at Risk

The ecosystems at risk are often extensive in scop e; therefore, it may not be possible to identify specific ecosystems during the development of a nation-wide ecological risk assessment. However, in general terms, terrestrial ecosystem s potentially at risk could include the treated field and immediately adjacent areas that may r eceive drift or runoff. Areas adjacent to the treated field could include cultiv ated fields, fencerows and hedgero ws, meadows, fallow fields or grasslands, woodlands, wetlands and riparian habitats, and other unc ultivated areas.

Aquatic ecosystems potentially at risk include wa ter bodies adjacent to or downstream from, the treated field and could include impounded bodies such as ponds, lake s and reservoirs, or flowing waterways such as streams or rivers. For uses in coastal areas, aquati c habitat also includes marine ecosystems, including estuaries.

9 http://www.abcbirds.org/abcprograms/ policy/pesticides/aims/aims/index.cfm23 5. Assessment Endpoints

Assessment endpoints represent the ac tual environmental value that is to be protected, defined by an ecological entity (species, community, or othe r entity) and its attri bute or characteristics (USEPA, 1998). For cymoxanil, the ecological entities may include the following: birds, mammals, terrestrial-phase amphibian s, reptiles, freshwater fish a nd invertebrates, aquatic-phase amphibians, estuarine/marine fish and invertebrate s, terrestrial plants, terrestrial invertebrates, and aquatic plants. The attributes for each of these entities include growth, reproduction, and survival.

6. Conceptual Model

For a pesticide to pose an ecological risk, it mu st reach ecological receptors in biologically significant concentrations. An exposure pathway is the means by which a pesticide moves in the environment from a source to an ecological recepto r. For an ecological pathway to be complete, it must have a source, a release mechanism, an environmental transport medium, a point of exposure for ecological receptors, an d a feasible route of exposure.

The conceptual model for cymoxanil provides a wr itten description and visual representation of the predicted relationships between cymoxanil, potential routes of exposure, a nd the predicted effects for the assessment endpoint. A conceptual model consists of two major components: risk hypothesis and a conceptual diagram (USEPA, 1998).

Based on the submitted environmental fate data , cymoxanil is a highly water soluble compound that is not expected to volatili ze. It will degrade quickly in neutral and alkaline media, but may be persistent in acidic environments (water and soil), although the chemical photodegrades quickly in aqueous media under optimal ( i.e. clear) conditions. Cymoxa nil has been shown to be mobile to highly mobile in soil (FAO classifi cation scheme), and its degradates IN-W3595, INR3273 and IN-KQ960 are all expected to be high ly mobile in soil based on limited available data. Based on its very low K ow value, cymoxanil is not expected to bioaccumulate in aquatic or terrestrial food chains.

Based on submitted ecological effect data, cymoxanil is characterized as slightly toxic to fish [and aquatic-phase amphibians for which fish serv e as surrogates] and aq uatic invertebrates on an acute exposure basis. Chronic exposure resu lted in effects on growth and survival. The compound is characterized as slightly toxic to mammals on an acute oral exposure basis but is practically non-toxic to birds [a nd terrestrial-phase amphibians and reptiles for which birds serve as surrogates] on both an acute oral and subacu te dietary exposure basis. Chronic exposure resulted in decreased survival in mammals and in reductions in egg production in birds. The compound is practically nontoxic to honey bees on both an acute contact and oral exposure basis. Although there are no toxicity data currently available for terrestrial plants, aquatic plant toxicity data indicate that nonvascular plan ts are several orders of magnit ude more sensitive to cymoxanil than vascular plants. Available toxicity data also indicate that several fo rmulations of cymoxanil and the degradate IN-KQ960 are considerably more toxic to nontarget organisms than the technical grade active ingredient.24 Previous ecological risk assessments for cymoxan il highlighted possible risk to birds, mammals, and aquatic organisms due to cymoxanil use. As such, listed species in all taxa may potentially be affected indirectly due to alterations in th eir habitat and effects on primary productivity. It was previously determined that all other taxa we re not at direct risk from cymoxanil use. However, this determination was based on an incomp lete dataset. Risks to passerine bird species and terrestrial plants are uncertain.

6.1. Risk Hypothesis

A risk hypothesis describes the predicted re lationship among the stre ssor, exposure, and assessment endpoint response along with the rationa le for their selection. Because data are incomplete with which to assess effects to a ll taxa, the following ecological risk hypothesis is being employed for this ecological risk assessment:

Given the uses of cymoxanil as a fungicide, and its environmental fate properties, there is potential exposure from cymoxan il, its potential degradates ofconcern (i.e., IN-3204, INKP533, IN-R3273, IN-JX915, IN-U3595, and IN-KQ 960), and formulated products to non-target terrestrial and/or aquatic organism s. When used in accordance with the label, cymoxanil, its degradates, and formulated products may result in potential adverse effects upon the survival, growth, and reproduc tion of non-target terrestrial and/or aquatic organisms.

6.2. Conceptual Diagram

The environmental fate properties of cymoxanil i ndicate that runoff, spray drift and direct spray represent potential transport mechanisms to aquatic and terrestrial habitats where non-target organisms may be either directly or indir ectly exposed. These transport mechanisms ( i.e
., sources) are depicted in the conceptual diagrams below ( Figures 6.1 and 6.2 ) along with the receptors of concern and the potential attribute changes in the receptors due to exposures of cymoxanil. While not captured in Figure 6.2 , exposure of terrestrial vertebrates from drinking water containing cymoxanil and degradates of con cern is also a route of exposure that will be assessed.25 Figure 6.1. Conceptual Model for Cymoxan il and Degradate Effects on Aquatic Organisms. Dotted Lines Indicate Exposure Pathwa ys that Have a Low Likelihood of Contributing to Ecological Risk. Stressor

Source

Receptors

Attribute Change Cloransulam-methyl and Degradates of Concern applied to use site

Spray drift

Aquatic animals Invertebrates Vertebrates

Individual organisms Reduced survival Reduced growth Reduced reproduction Food chain Reduction in nonvascular and vascular plants Reduction in prey Modification of PCEs

related to prey availability Habitat integrity Reduction in primary productivity Reduced cover Community change Modification of PCEs related to

habitat Surface water/

Sediment Runoff

Aquatic Animals Invertebrates Vertebrates Exposure Media

Uptake/gills or integument

Ingestion Ingestion Atmospheric transport

Wet/dry deposition Soil Leaching to Groundwater

Uptake/gills or integument

Aquatic Plants Non-vascular Vascular Uptake/cell, roots, leaves Riparian plants terrestrial exposure pathways see

Figure 6.2 Cymoxanil and Degradates of Concern applied to the use site26 Figure 6.2. Conceptual Model for Cymoxan il and Degradate Effe cts on Terrestrial Organisms . Dotted Lines Indicate Exposure Path ways that Have a Low Likelihood of Contributing to Ecological Risk.

7. Analysis Plan

In order to address the risk hypot hesis, the potential for adverse effects on the environment will be estimated. The use, environmental fate, and ecological effects of cymoxanil will be characterized and integrated to assess the ri sks. Risk quotients (RQ) will be derived for cymoxanil by dividing estimated environmental concentrations (EEC) by the most sensitive endpoint from the relevant, availabl e toxicity data for cymoxanil.

This analysis plan will be re visited and may be revised dependi ng upon a full review of the data available in the open literature and the inform ation submitted by the public in response to the opening of the Registration Review docket. Stressor

Source

Attribute Change Cloransulam-methyl and Degradates of Concern applied to use site

Direct application Spray drift

Terrestrial vertebrates Terrestrial

inverts

Individual organisms Reduced survival Reduced growth Reduced reproduction Food chain Reduction in prey and food Modification of PCEs

related to prey availability Habitat integrity Reduction in primary productivity Reduced cover Community change Modification of PCEs related

to habitat Terrestrial plants grasses/forbs, fruit, seeds (trees, shrubs) Runoff

Terrestrial Vertebrates Exposure Media & Receptors Soil

Ingestion Ingestion Ingestion Dermal uptake/Ingestion Atmospheric transport

Root uptake/contact Wet/dry deposition

Ingestion Leaching to Groundwater Irrigation

water Cymoxanil and Degradates of Concern applied to the use site27 7.1. Stressors of Concern

The stressors or residues of concern in this assessment will include cymoxanil and any degradates for which there are both toxicological and exposure concerns. Based on the available information (presented in Table 3.5 ), the main degradates of concern with respect to exposure include IN-3204, IN-KP533, IN -R3273, IN-JX915, and IN-U3595. There is toxicological concern for IN-KQ960, but exposure is uncertain due to aerobic soil metabolism data gaps. All of the major degradates of cymoxanil were run through EPA’s ASTER (Assessment Tools for the Evaluation of Risk) 10 Program to check for a specific mo de of action; however, ASTER put all of the major degradates into a non-polar narcosis class and predicted less toxicity than the parent compound. The nonpolar narcosis QSAR is i nvoked only if the structural characteristics of a chemical do not suggest a more specific mode of action or if there is insufficient information in the ASTER training database for the specific chemical group under examination (i.e., a lack of mechanistic information on specific functional moieti es). Given that such a non-specific mode of action was used to estimate toxicity of degradat es in ASTER, it is not appropriate to use these results alone to assess the potential toxicity of cymoxanil degradates.

Empirical toxicity data are onl y available for one cymoxanil degradate, IN-KQ960, in the form of an acute freshwater invertebra te toxicity study (MRID 456892-01) with Daphnia magna

. Based on this study IN-KQ960 is 35 times more toxic than cymoxanil technical (MRID 443646- 10) to D. magna on an acute exposure basis. In addition, IN-KQ960 was determined to be more mobile than the parent compound. Based on this information, IN-KQ960 will be considered a stressor of concern at the time the risk assessm ent is carried out. Modeled exposure estimates resulting from cymoxanil use will reflect the pr edicted environmental fate of cymoxanil and INKQ960.

Since empirical toxicity data are only availabl e for the degradate IN-KQ960, the relevance of other major cymoxanil degradates for risk a ssessment was considered by estimating toxicity endpoints using EPA’s Ecological Structure Activity Relationships (ECOSAR) Program 11

. ECOSAR uses structure-activity re lationships (SARs) to predict th e aquatic toxicity of untested chemicals based on their structural similarity to chemicals for which aquatic studies are available. The toxicity data used to build th e SARs are collected from publicly available experimental studies and confidential submissi ons provided to the U.S. EPA New Chemicals Program. Although ECOSAR is maintained as a stand-alone program, the ECOSAR QSARs are also included in the EPA EPISuite program and the web-based PBT Profiler tool. The SARs in ECOSAR express correlations between a compound' s physicochemical propert ies and its toxicity within specific chemical classes. Table 7.1 shows all of the chemical classes into which the major degradates fit (see cymoxa nil and degradate structures in Appendix B ). Bolded values indicate that the ECOSAR-estimated toxicity en dpoint was lower (more sensitive) than that measured for the parent. These toxicity estimat es are only used to prio ritize which degradates are likely a risk concern and how they should be handled in the risk assessment. The estimated values may over- or underestimate actual toxicity of the compounds. Appendix E provides the output from ECOSAR. In Table 7.1 , similarly structured degrad ates are grouped together.

10 http://www.epa.gov/med/Prods_Pubs/aster.htm
11 http://www.epa.gov/oppt/newchems/tools/21ecosar.htm28 The degradate IN-KP533 is similarly structured to the parent and has similar ECOSAR results; thus, toxicity of this degradate will be assumed to be equivalent to the parent across aquatic organisms unless additional data t oxicity data becomes available.

For the degradate IN-W3595, acute toxicity endpoints estimated by ECOSAR were much lower (more sensitive) than what was measured fo r the parent. Because there are also exposure concerns for this degradate, additional acute t oxicity data for IN-W3595 is recommended for one freshwater fish (preferably bluegill sunfish [ Lepomis macrochirus ]; 850.1075), one invertebrate ( Daphnia ; 850.1010), and one nonvascular plant species (preferably green algae ( Pseudokirchnerie lla subcapitata ); 850.5400) to provide a basi c foundation for comparing toxicity of parent and degradate

The degradates IN-U3204, IN-R3273, IN-JX 915, IN-KQ960, and IN-T4226 all form in appreciable amounts and have expos ure concerns. Moreover, these degradates all have similar molecular structures and produce similar toxicity estimates in ECOSAR. Empirical toxicity data is only available for IN-KQ960, which showed that the degradate is 35 times more toxic than the parent in freshwater invertebra tes. It is worth noting that ECOSAR did not flag IN-KQ960’s toxicity to daphnids; thus, there is uncertainty in the use of ECOSAR for these chemicals. 12 ECOSAR results predict that toxic ity of this entire group of degr adates is higher relative to the parent for green algae, which may be associated with their carbonyl urea structure. Submission of additional effects data for IN- KQ960 would help determine if this particular degradate is more toxic than the parent to other aquatic organisms, given the avai lable empirical data. In addition, data on IN-KQ960 could also repres ent potential toxicity of the enti re degradate group to aquatic organisms so that experimental data on each degr adate is not necessary fo r evaluating risk. Since data on IN-KQ960 is already available for freshwat er invertebrates, two additional acute studies on freshwater fish (preferably bluegill sunfish ( Lepomis macrochirus ); 850.1075) and algae (preferably the freshwater diatom Navicula pelliculosa ; 850.5400) would provide a basic foundation for comparing toxicity of parent and degradates.

Oxalic acid is considered to have negligible toxicity when compared to the parent compound.

Table 7.1. Comparison of Measured Toxicity Endpoints for Cymoxanil with Estimated Aquatic Toxicity Endpoints for Major De gradates of Cymoxanil (Estimated Using ECOSAR v.1) and Resulting Structu re-Activity Relationships (SARs).* Compound (compounds class used by ECOSAR) Estimated Toxicity Endpoint (mg/L) 96-hr FW fish

EC 50 /LC 50 48-hr Daphnid

LC 50 96-hr EC 50 Green Algae Fish Chronic Value Daphnid Chronic

Value Cymoxanil Parent (measured) 29 28 4.1 0.01 0.07

Cymoxanil (Ecosar) Aliphatic Amines 284 29.0 32.5 26.5 2.1

Cymoxanil (Ecosar) Carbonyl Ureas 134 144 0.02 1.0 3.4

Cymoxanil (Ecosar) 2537 1043 960 215 88.3

12 More information about the uncertainties associated with ECOSAR can be found in the following documents: http://www.epa.gov/oppt/newchems/tools/ecosarusersguide.pdf http://www.epa.gov/oppt/newchems/tools/ecosartechfinal.pdf29 Compound (compounds class used by ECOSAR) Estimated Toxicity Endpoint (mg/L) 96-hr FW fish

EC 50 /LC 50 48-hr Daphnid

LC 50 96-hr EC 50 Green Algae Fish Chronic Value Daphnid Chronic

Value Neutral Organic SAR

IN-U3204 (Ecosar) Aliphatic Amines 433 42.8 51.1 44.5 2.9

IN-U3204 (Ecosar) Carbonyl Ureas 191 274 0.015 1.4 5.1

IN-U3204 (Ecosar) Neutral Organic SAR 4517 1762 1619 371 143

IN-KP533 (Ecosar) Carbonyl Ureas 1333 10592 0.012 9.7 51.5

IN-KP533 (Ecosar) Neutral Organic SAR 1.17e+005 33302 30308 8024 2063

IN-W3595 (Ecosar) Aliphatic Amines 0.79 0.12 0.06 0.02 0.01

IN-W3595 (Ecosar) Neutral Organic SAR 0.96 0.78 0.74 0.12 0.12

IN-R3273 (Ecosar) Aliphatic Amines 29 3.5 2.9 1.7 0.29

IN-R3273 (Ecosar) Carbonyl Ureas 19.1 4.9 0.013 0.14 0.36

IN-R3273 (Ecosar) Neutral Organic SAR 121 65 60 11.9 6.9

IN-JX915 (Ecosar) Aliphatic Amines 1364 123 176 184 7.8

IN-JX915 (Ecosar) Carbonyl Ureas 506 1575 0.015 3.7 16

IN-JX915 (Ecosar) Neutral Organic SAR 21692 7326 6703 1639 526

IN-KQ960 (Ecosar) Aliphatic Amines 10172 794 1513 2148 43.3

IN-KQ960 (Ecosar) Carbonyl Ureas 2824 32099 0.016 20.5 118

IN-KQ960 (Ecosar) Amides 25732 1.51e+005 369 5.08 769.6

IN-KQ960 (Ecosar) Neutral Organic SAR 3.28e+005 86912 78939 21543 5092

IN-T4226 (Ecosar) Carbonyl Ureas 184 334 0.011 1.3 5.2

IN-T4226 (Ecosar) Neutral Organic SAR 5219 1948 1788 418 15230 Compound (compounds class used by ECOSAR) Estimated Toxicity Endpoint (mg/L) 96-hr FW fish

EC 50 /LC 50 48-hr Daphnid

LC 50 96-hr EC 50 Green Algae Fish Chronic Value Daphnid Chronic

Value Oxalic Acid (Ecosar) Neutral Organics 1.68e+005 67877 39659 10918 2519

* Bolded values indicate that the ECOSAR-estimat ed toxicity endpoint was much lower (more sensitive) than that measured for the parent.
For degradates assumed to have similar toxicity to aquatic organisms relativ e to the parent due to structural similarities ( e.g. , IN-KP533), a total toxi c residue (TTR) approach will be used by summing the residues observed in fate studies a nd then estimating degrad ation rates based on the total summed residues. The TTR degradation rate s will then be used to estimate exposure in place of degradation rates for the parent al one. The modeled EECs for TTR will then be compared to toxicity end points for the parent.

For degradates that are potentially more highly toxic to aquatic organisms relative to the parent, available toxicity data will be compared to EECs for the particular degradate and will be used to derive degradate-specific RQ values that can be compared to agen cy LOCs. If toxicity data does not exist for a particular degr adate or group of structurally similar degradates, ECOSAR predictive toxicity data, as well as other availabl e toxicity information fr om the open-literature, will be used to characterize uncer tainties and pinpoint critical knowledge gaps. Toxicity studies that would help reduce degradate uncertainties in risk assessment are described in the preceding paragraphs, in Tables 7.5 and 7.6 , and in Appendix G.

The Agency does not routinely include an evalua tion of mixtures of act ive ingredients in its ecological risk assessments. This applies to mi xtures of multiple active ingredients in product formulations as well as those in the applicator’s tank. In the cas e of the product formulations of active ingredients (that is, a regi stered product containing more than one active ingr edient), each active ingredient is subject to an individual risk assessment for regulatory decision regarding the active ingredient on a particular use site. If effects data are available for a formulated product containing more than one active ingredient, the da ta may be used qualitatively or quantitatively in accordance with the Agency’s Overview Document and the Services’ Evaluation Memorandum (USEPA, 2004; USFWS/ NMFS, 2004). Available toxicity data for environmental mixtures of cymoxanil with other pesticides will be presented as part of the ecological risk assessment. It is expected that the toxic e ffect of cymoxanil, in combination with other pesticides used in the environment, is likely to be a function of many f actors including but not necessarily limited to: (1) the e xposed species, (2) the co-contaminants in the mixture, (3) the ratio of cymoxanil and co-contamin ant concentrations, (4) differen ces in the pattern and duration of exposure among contaminants, and (5) the di fferential effects of other physical/chemical characteristics of the receiving waters ( e.g. organic matter present in sediment and suspended water). Quantitatively predicting the combined e ffects of all these variables on mixture toxicity to any given taxa with confidence is beyond the ca pabilities of the available data and current methodologies; however some data does exist on mi xtures of cymoxanil with other chemicals indicating the possibility of increased toxicity of the co-for mulation relative to cymoxanil alone. Specifically, LC 50 values for a co-formulation of cy moxanil (6.58%) with copper hydroxide (26.5%) in freshwater crustaceans ( D. magna ), fish ( O. mykiss ), and algae ( P. subcapitata ) are31 2.78, 10.3, and 9.4 μg cymoxanil a.i./L (values corre cted for percent a.i. in formulation), respectively, while endpoint values for the sa me groups exposed to cymoxanil technical are 28,000, 61,000, and 4,110 μg a.i./L, indicating several orde rs of magnitude difference in all cases (see Table 1 in Appendix E for further study information). However, in order to demonstrate synergism between these active ingredients, the co -formulation must also increase toxicity of copper hydroxide. At the time of this problem fo rmulation, sufficient toxicity data on copper hydroxide is not readily availabl e in the EFED database to make this comparison. However, sufficient open-literatu re data (e.g. via EPA’s ECOTOX database) may exist and will be collected and examined at the time of the registra tion review risk assessment in order to evaluate potential synergistic effects with cymoxanil. Also, a qualitative di scussion of implications of the available pesticide mixture effects data on the confidence of risk assessment conclusions will be addressed as part of th e uncertainty analysis.

7.2. Measures of Exposure

In order to estimate risks of cy moxanil exposures in aquatic an d terrestrial environments, all exposure modeling and resulting risk conclusion s will be made based on maximum application rates for the currently registered uses as discussed in Secti on 3.2. Measures of exposure are based on aquatic and terrestrial models that esti mate environmental concentrations of cymoxanil using the maximum labeled application rate a nd application methods th at have the greatest potential for off-site transport of the chemical. The models used to generate aquatic estimated environmental concentrations ( EEC) are the Pesticide Root Zone Model (PRZM) coupled with the EXposure Analysis Model System (EXAMS). As discussed in the preceding section, the EECs will be based on the parent compound plus any other degradates that are determined to be of toxicological concern based on information available at the time of the assessment. Environmental inputs for the TTR in aquatic syst ems will be calculated using the total residue approach. The model used to produce terrestrial EECs on food items is T-REX. The model used to derive EECs relevant to terrestrial and we tland plants is TerrPlant. These models are parameterized using relevant reviewed registrant-submitted environmental fate data.

PRZM (v3.12.2, May 2005) and EXAMS (v2.98.4.6, Ap ril 2005) are screening simulation models coupled with the graphical user interf ace, PE (v5.0, November 2006) to generate daily exposures and 1-in-10-year EECs of cymoxanil (a nd residues of concern) that may occur in surface water bodies adjacent to application sites receiving cymoxanil through runoff and spray drift. PRZM simulates pesticide application, movement and transformation on an agricultural field and the resultant pesticide loadings to a receiving water body via runoff, erosion, and spray drift. EXAMS simulates the fate of the pesticide and resulting concentrati ons in the water body. The standard watershed geometry used for ecolo gical pesticide assessments assumes application to a 10-hectare agricu ltural field that drains into an adjace nt 1-hectare water body that is 2 meters deep (20,000 m 3 volume) with no outlet. The com posite model PRZM/EXAMS is used to estimate screening-level exposure of aquatic orga nisms to cymoxanil. The measure of exposure for aquatic species is the 1-in-1 0-year peak or rolling mean concentration. The 1-in-10-year peak is used for estimating acute exposures of di rect effects to aquatic organisms. The 1-in-10- year 60-day mean is used for assessing the eff ects to fish and aquatic-phase amphibians from chronic exposure. The 1-in-10-year 21-day mean is used for assessing the effects on aquatic invertebrates from chronic exposure.32 Exposure estimates for terrestrial an imals assumed to be in the target area or in an area exposed to spray drift are derived using the T-REX model (version 1.4.1, 10/08/2008). This model incorporates the Kenaga nomogr aph, as modified by Fletcher et al. (1994), which is based on a large set of actual field residue data. The upper limit values from the nomograph represent the 95 th percentile of residue values from actual field measurements (Hoerger and Kenaga 1972). The Fletcher et al. (1994) modifications to the Kenaga nomograph are based on measured field residues from 249 published research papers, incl uding information on 118 species of plants, 121 pesticides, and 17 chemical classes. For input into T-REX, the defa ult foliar dissip ation half-life of 35 days will be used due to insufficient foliar dissipation rate data on cymoxanil. The initial Section 3 assessment (DP Barcode D233366) relied on a foliar dissipation half-life of 2 days based on the upper 90 th percentile aerobic soil metabolis m half-life. However, without magnitude of residue data with which to esti mate foliar dissipation half-lives, the current approach is to utilize a default half-life of 35 da ys. Since cymoxanil appears to be susceptible to both biotic and abiotic degradation (aqueous photolysis t 1⁄2 =3.6 days; hydrolysis at pH 7 t 1⁄2 =1.4 days), the use of the 35-day default value is likely conservative. Therefore, estimated environmental concentrations on terrestrial forage items will be calculated based both on the 35- day default foliar dissipation ha lf-life and assuming a half-life roughly an order of magnitude lower. If terrestrial plant toxicity data are av ailable, EECs for terrestrial plants inhabiting dry and wetland areas are derived using TerrPlant (version 1.2.2, 12/26/2006). This model uses estimates of pesticides in runoff and in spra y drift to calculate EEC s. EECs are based upon solubility, application rate and minimum incorporation depth. If terrestrial plant data is not available at the time of the registration review ri sk assessment, risks of concern will be assumed for this group.

The AgDRIFT spray drift model (v2.01; May, 2001) is used to assess exposures of organisms to cymoxanil deposited on terrestrial habitats by spray drift.

The Screening Imbibition Program (SIP v.1.0, Released June 15, 2010) was used to calculate an upper-bound estimate of exposure of birds and mammals to cymoxanil through drinking water using the compounds solubility value, the most sensitive acute and chronic avian toxicity endpoints ( i.e ., bobwhite quail LD 50 >2250 mg a.i./kg-bw; NOAEC 300 mg a.i./kg-diet) and the most sensitive acute and chroni c mammalian toxicity endpoints ( i.e ., laboratory rat LD 50 >960 mg a.i./kg-bw and NOAEL = 100 mg a.i./kg-bw, respectively). Appendix F provides a description of the model and assumptions in deriving an upper-bound exposure estimate. Cymoxanil’s reported solubility in water at 20°C is 780 mg/L at pH 7 (and 890 mg/L at pH 5). Drinking water exposure alone was determined to be a potential concern for mammals on a chronic exposure basis (see Appendix F for model results). Although this model flags acute exposure to birds and mammals as a potenti al concern based on potential estimated environmental concentrations in drinking water at pH 8.5 and above, toxicity data demonstrate that acute/subacute effects from cymoxanil e xposure are not likely a concern for birds or mammals given that the compound is characterized as practically nontoxic to birds on both an acute oral and subacute dietary exposure basi s and the compound is only slightly toxic to mammals on an acute oral exposure basis. This exposure pathway though will be explored further with the development of SIP v.2.0 in the Ecological Risk Assessme nt for cymoxanil. Detailed information about the SIP v.1.0, as well as the tool, can be found on the EPA’s website
at http://www.epa.gov/pesticides/science/models_pg.htm#terrestrial

.33 The Screening Tool for Inhalation Risk (STIR v. 1.0, Released November 23, 2010) was used to assess the potential for risk to bird and mammals from inhalation exposure. Appendix F also provides a description of this model and assu mptions in deriving exposure estimates. The exposure pathways that are assessed by this tool include both droplet i nhalation and vapor phase inhalation. Allometric equations th at relate inhalation rate to body weight are used to derive an estimated inhalation dose of either droplets or vapor for a 0.020 kg bird and a 0.015 kg mammal (Mineau et al. 1996; Sample and Arenal 1999; USEPA 1993).

Results from acute inhalation toxicity studies fo r mammals from the "six-pack" that are routinely submitted to the Registration Division of the Office of Pesticide Programs can be directly compared with the estimated inhalation doses from vapor and droplets. In most cases however, avian inhalation data are lacking. STIR uses the avian oral toxicity data together with both the mammalian oral and inhalation toxicity data to de rive an estimate of avia n inhalation toxicity. Based on the findings of the 2004 Science Advisory Panel (USEPA, 2004), an adjustment factor is applied to these data to adjust the estimate of avian inhalation toxicity for differences in diffusion efficiency across th e avian lung membrane compared to the mammalian lung membrane.

STIR relies on the application ra te, application method, defined dr oplet spectra (if applicable), molecular weight, vapor pressure and the temperat ure associated with th e vapor pressure of a specific chemical to obtain an estimate of the dropl et and vapor concentrati on in the air. These concentrations are compared with an estimated inhalation LD 50 of a specific chemical as a ratio that is then compared with a th reshold of 0.1. If the ratio of th e exposure to the toxicity exceeds 0.1, then the screening tool indicates that a revi ewer is to "Proceed to Refinements", at which point the reviewer can request specific studies th at will help to address uncertainty related to inhalation risk. The user's guide contains info rmation for the specific studies that may be requested. However, if the screening tool indi cates "Exposure not Likely Significant", then the reviewer can assume that the i nhalation pathway is not expected to be a significant source of risk.

The results of STIR for cymoxanil indicated “Exposure not Likely Significant;” thus, no additional studies will be requested to address uncer tainties related to inhalation risk to birds (see Appendix F for model results).

7.3. Measures of Effect

Ecological effects data are used as measures of di rect and indirect effects to biological receptors. As discussed previously, data are obtained from registrant-submitted studies or from literature studies identified by ECOT OX (USEPA, 2007b). The ECOT OX database provides more ecological effects data in an attempt to brid ge existing data gaps. ECOTOX is a source for locating single chemical toxicity data and potenti al chemical mixture toxi city data for aquatic life, terrestrial plants, and wildlife. ECOTOX was created and is maintained by the USEPA, Office of Research and Devel opment, and the National Health and Environmental Effects Research Laboratory's Mid- Continent Ecology Division.34 Also as discussed previously, information on the potential eff ects of cymoxanil on non-target animals is also collected from the Ecologica l Incident Information System (EIIS; USEPA, 2007a). The EIIS is a database containing adve rse effect (typically mortality) reports on nontarget organisms where such effects have b een associated with the use of pesticides.

Incidents reported in the aggreg ate incident reports and the Av ian Incident Monitoring System (AIMS) will also be searched again. AIMS is a database administered by the American Bird Conservancy with partial funding from EPA). It contains public ly available data on reported avian incidents involving pesticides ( http://www.abcbirds.org/abcprograms/ policy/pesticides/aims/aims/index.cfm ).

Where available, sub-lethal effects observed in both registrant-submitted and open literature studies will be evaluated qualitatively. Such effects may include behavioral changes ( e.g. , lethargy and changes in colora tion). Quantitative assessments of risks, though, are limited to those endpoints that can be di rectly linked to the Agency’s assessment endpoints of impaired survival, growth and reproduction.

The assessment of risk for direct effects to non-target organisms makes the assumption that toxicity of cymoxanil to birds is similar to toxicity to terrestri al-phase amphibians and reptiles. The same assumption is made for fish and aquatic-phase amphibians.

The acute measures of effect used fo r animals in this assessment are the LD 50 , LC 50 and EC 50
. LD stands for "Lethal Dose", and LD 50 is the amount of a material, given all at once, that is estimated to cause the death of 50% of the test organisms. LC st ands for “Lethal Concentration” and LC 50 is the concentration of a chemical that is estimated to kill 50% of the test organisms. EC stands for “Effective Concentration” and the EC 50 is the concentration of a chemical that is estimated to produce a specific effect in 50% of the test organisms. Endpoints for chronic measures of exposure for listed and non-lis ted animals are the NOAEL/NOAEC and NOEC. NOAEL stands for “No Observed-Adverse-Effect-Level ” and refers to the hi ghest tested dose of a substance that has been reported to have no harm ful (adverse) effects on test organisms. The NOAEC ( i.e. , “No-Observed-Adverse-Effect-Concentration” ) is the highest test concentration at which none of the observed effects were statistically different fr om the control. The NOEC is the No-Observed-Effects-Concentration. Fo r non-listed plants, only acute exposures are assessed ( i.e. , EC 25 for terrestrial plants and EC 50 for aquatic plants); for listed plants either the NOAEC or EC 05 is used.

7.4. Integration of Exposure and Effects

Risk characterization is the inte gration of exposure and ecological effect characterizations to determine the potential ecological risk from the use of cymoxanil and the likelihood of direct and indirect effects to non-target organisms in aqua tic and terrestrial habitats. The exposure and effects data are integrated in order to evaluate pot ential adverse ecological effects on non-target species. For the assessment of cymoxanil risks, the risk quoti ent (RQ) method is used to compare estimated exposure and measured toxicity values. Acute and chronic EECs are divided by acute and chronic toxicity values. The resu lting RQs are then compared to the Agency’s Levels of Concern (LOC) (USEPA, 2004) ( Table 7.2 ). These criteria are used to indicate when35 cymoxanil’s use, as directed on the labels, has th e potential to cause adve rse direct or indirect effects to non-target organisms. In addition, inci dent data from EIIS, aggregate incident reports, and AIMS will be considered as pa rt of the risk characterization.

Table 7.2. Agency risk quotient (RQ) metrics and levels of concern (LOC) for Federallylisted (listed) threatened/endangered and non-listed species per risk class.

Risk Class Risk Description RQ LOC
Aquatic Animals (fish and invertebrates)

Acute Potential for effects to non-listed animals from acute exposures Peak EEC/LC 50 1 0.5

Acute Restricted Use Potential for effects to animals from acute
exposures Risks may be mitigated through restricted use classification Peak EEC/LC 50 1 0.1

Acute Listed Species Listed species may be potentially affected by acute exposures Peak EEC/LC 50 1 0.05

Chronic Potential for effects to non-listed and listed animals from chronic exposures 60-day EEC/NOEC (fish)

1 21-day EEC/NOEC (invertebrates)

Terrestrial Animals (mammals and birds)

Acute Potential for effects to non-listed animals from acute exposures EEC 2 /LC 50 (Dietary)
0.5 EEC/LD 50 (Dose)

Acute Restricted Use Potential for effects to animals from acute
exposures Risks may be mitigated through restricted use classification EEC 2 /LC 50 (Dietary)

0.2 EEC/LD 50 (Dose)

Acute Listed Species Listed species may be potentially affected by acute exposures EEC 2 /LC 50 (Dietary)
0.1 EEC/LD 50 (Dose)

Chronic Potential for effects to non-listed and listed animals from chronic exposures EEC 2 /NOAEC 1

Plants

Non-Listed Potential for effects to non-target, non-listed plants from exposures EEC/ EC 25 1

Listed Plant Potential for effects to non-target, listed plants from exposures EEC/ NOEC 1 EEC/ EC 0536 7.5. Deterministic and Probab ilistic Assessment Methods

The quantitative assessment of risk will primar ily depend upon the deterministic point estimatebased approach described in th e risk assessment. Depending on the risk manager’s need for additional information regarding risk, an effort will be made to further qualitatively describe risk using probabilistic tools that the Agency has developed. These tools have been reviewed by FIFRA Scientific Advisory Panels ( http://www.epa.gov/sc ipoly/sap/index.htm ) and have been deemed as appropriate means of refining asse ssments where deterministic approaches have identified risks.

7.6. Endangered Species Assessments

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA), the Agency will evaluate risks to Federally-listed th reatened and/or endangere d (listed) species from registered uses of cymoxanil. This assessm ent will be conducted in accordance with the Overview Document (USEPA, 2004), provisions of the ESA, and the Services’ Endangered Species Consultation Handbook (USFWS/NMFS, 1998).

The action area is used to identify all listed (t hreatened and endangered) species and designated critical habitat that could be affected by the Federal action. The Federal action is the authorization or registration of pesticide use or uses as descri bed on the label(s) of pesticide products containing a particular active ingredient. The action area is defined by the Endangered Species Act as, “all areas to be affected directly or indirec tly by the Federal action and not merely the immediate are involved in the action” (50 CFR §402.2). Based on an analysis of the Federal action, the action area is defined by the actual and pote ntial use of th e pesticide.

In the case of nationwide ecological risk a ssessment conducted for cymoxanil under Registration Review, the action area will encomp ass the entire United States and its territories. The purpose of defining the action area as the entire United States and its territories is to ensure that the initial area of consideration encompasses all areas where cymoxanil may be used now and in the future, including the potential for off-site trans port via spray drift and downstream dilution. Additionally, the concept of a na tionwide action area takes into acc ount the potential for direct and indirect effects and any poten tial modification to critical ha bitat based on ecological effect measures associated with reduction in survival, growth, and reproduction, as well as the full suite of sublethal effects available in the effects literatu re. It is important to note that the nationwide action area does not imply that dire ct and/or indirect e ffects and critical habitat modification are expected to or are likely to occur over the full ex tent of the action area, but rather to identify all listed species and critical habita t that may potentially be affected by the action. The Agency will use more rigorous analysis including consideratio n of available land cover data, toxicity data, and exposure information to determine areas wh ere individual listed species and designated critical habitat may be affected or modified via endpoints associated with reduced survival, growth, or reproduction.37 7.7. Drinking Water Assessment

A drinking water assessment (DWA) will be con ducted to support future human health dietary risk assessments of cymoxanil. The drinking water assessment will incorporate model estimates of cymoxanil residues of concern plus any degrad ates of toxicological concern in surface water and groundwater. Potential degradates of concern include IN-KP533, which was a maximum average of 57.0% of the applie d at the end of the hydrolysis study period at pH 7, and was a maximum average of 31.6% of the applied at day 10, after which it declined slowly to an average of 27.6% of the applied at day 30 at pH 9. A nother potential degradate of concern is IN-U3595, which was present at significant concentrations only at pH 9 in the hydrolysis study, in which it was a maximum average of 39.0% of the applied at day 3 and declined very slowly thereafter. Two aquatic photolysis degradates that may be of potential concern include IN-JX915, which was a maximum of 52% of the applied at day 4 and decreased slowly to 25% by 15 days, and INR3273, which was a maximum of 35.4% of the ap plied at the end of the 15 day irradiation period.

Past DWAs have been limited to the parent compound only and were conducted at the Tier I screening level. The final determ ination of the residues of con cern for the DWA for Registration Review will be made through consultation with the Health Effects Division (HED) and through any proceedings of the ROCKS (Residues of Concern Knowledge Subcommittee). Concentrations of cymoxanil and any identified residues of concern in surface water will be estimated using PRZM/EXAMS (see description in Section 7.2 ). Groundwater exposure estimates for cymoxanil and its residues of concern will be estimated using the Screening Concentration in Ground Water (SCI-GROW) m odel (v.2.3, July 2003) followed by a higher-tier model if necessary. The drinking water assessm ent will also include a summary of available surface and groundwater monitoring data.

7.8. Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include e ndpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its registration de cision, EPA reviews these data and selects the most sensitive endpoints for relevant risk as sessment scenarios from the existing hazard database. However, as required by FFDCA secti on 408(p), cymoxanil is subject to the endocrine screening part of the Endocrine Di sruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator38 may designate.” The EDSP employs a two-tiered approach to making th e statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects 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 pest icide active ingredients and 9 inert ingredients. Cymoxanil is not among the group of 58 pesticide active ingredient s on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issu e future EDSP orders/data callins, requiring the submission of EDSP screening assays for cymoxa nil. For further information on the status of the EDSP, the policies and procedur es, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screen ing battery, please visit our website: http://www.epa.gov/endo/.

7.9. Preliminary Identification of Data Gaps

7.9.1. Environmental Fate

The environmental fate database for cymoxanil is partially complete, with a few significant exceptions. For all of the soil and/or sediment laboratory degr adation studies, the extraction method was questionable given the high levels of nonextractables present from early sampling intervals onward in the studies. While two of the submitted aerobic soil metabolism studies are classified supplemental, none of the studies were conducted using domestic (U.S.) soils, and data were not presented showing that the soils used we re representative of in tended use sites in the U.S. Additionally, some soils were volcanic ash soils that are not repres entative of intended use areas. Aerobic soil metabolism data are needed for at least three soils obtained from intended use areas in the United States. While studies co nducted using foreign soils are allowable if the soils are shown to be representative of intended use sites in the U.S., the submitted studies remain of questionable use due to multiple proble ms such as inadequate extraction methods, high nonextractables from early on in th e studies, and high inter-replicat e data variability. Thus, the submitted aerobic soil metabolism studies are not upgradeable. Anaerobic soil metabolism data have not been submitted. Both anaerobic and aerobic aquatic metabolism data are still needed, as the submitted studies are either not acceptable or were conducted using a system not representative of intended use conditions. For bo th aquatic metabolism studies, it is necessary that data be submitted for at least two aquatic sedime nt systems, one of which is at an acidic pH.

The mobility study on the degradates IN-W 3595, IN-R3273 and IN-KQ960 is classified supplemental because only a single concentration was studied. However, additional mobility data on these compounds are not needed at this tim e, as the compounds were all determined to be very mobile and a new study would not likely prov ide additional useful in formation. Mobility data on the degradates IN-KP533 and IN-JX915 are not needed, as these degradates are either not detected or present as minor degradates ea rly on in the soil metabolism studies, or will be39 mainly associated with degradation in water. Similarly, while the photo degradation on soil study is classified supplemental, an additional st udy is not needed because the submitted study demonstrates that this will not be a significant environmental fate pathway.

While the terrestrial field dissipation study provided information on the parent compound, degradates were not monitored because in an ae robic soil metabolism study that was previously classified “acceptable,” CO 2 was the only major degradate. However, that metabolism study has since been classified “not acceptable” due to mu ltiple deficiencies including some associated with residue characterization. An additiona l terrestrial field dissipation study is not recommended because it is unlikely to provi de new useful information on cymoxanil.

Table 7.3 identifies studies by the master record iden tification (MRID) numb er that offer data for each guideline requirement, as well as study clas sifications and whether or not further data are needed in order to support risk assessment ( i.e. , whether there is a data gap).

Table 7.3. Environmental Fate Data Require ments for Cymoxanil Uses, Status, and Data Gaps.

OPPTS Guideline Data Requirement Submitted Studies (MRID) Classification Data Gap? Comment

835.1230 Adsorption/ desorption and leaching 44180745 Acceptable

No Batch equilibrium study on parent.

44180746 Not Acceptable Multiple degradates shown to be very mobile, so additional data are not needed.

No MRID Acceptable AMR 2724-93 Soil column leaching study.

835.2120 Hydrolysis 44180738 Acceptable

No −

No MRID Supplemental Lab. Proj. ID AMR-2018-91. Inadequate analytical method for separating degradates.

835.2240 Aqueous photolysis 44180739 44180740 Acceptable No

−

835.2410 Soil photolysis 44180741 Supplemental No Dark control results show a discrepancy with results of aerobic soil metabolism, but soil photodegradation is not a significant fate pathway for this chemical, so new data are not
necessary.

835.4100 Aerobic soil metabolism 44180742 Supplemental

Yes All foreign soils including Japanese volcanic ash; method deficiencies; incomplete data reported. Data will not be used in risk assessments.

44180743 45357101 Not Acceptable Only one soil studied. High nonextractables by day 2. Extraction method inadequate. High inter-replicate variability. Study was downgraded from “acceptable.”40 OPPTS Guideline Data Requirement Submitted Studies (MRID) Classification Data Gap? Comment

No MRID Supplemental Initial and supplement reports AMR 1988-91. Data obtained from a volcanic ash soil not representative of intended use sites. Data will not be used in risk
assessments.

835.4200 Anaerobic soil metabolism None Not Applicable No No data have been submitted. The study is not recommended unless useful data on the anaerobic aquatic metabolism of cymoxanil are not submitted.

835.4300 Aerobic aquatic metabolism 44180741 Not Acceptable Yes Inadequate extraction of residues. No data for an acidic pH system or sterile control, so degradation in both systems studied was only due to hydrolysis. Sediments had very little organic carbon (0.1 and 0.8%) so not likely representative of sediments near intended use sites. Data are needed for at least two aquatic sediment systems, one of which is at an acidic pH.

835.4400 Anaerobic aquatic metabolism 44180744 Not Acceptable

Yes Inadequate material balances; high nonextracted residues; conducted at pH with rapid hydrolysis. Data are needed for at least two aquatic sediment systems, one of which is at an acidic pH. Study was downgraded from “acceptable.”

No MRID Supplemental AMR 2446-92. Conditions not definitively aerobic or anaerobic throughout. Conducted at pH 9, so rapid hydrolysis and system not representative of intended use sites. Degradates not identified. Data will not be used in risk assessment.

835.6100 Terrestrial field dissipation 44180747 Acceptable

No − 45294105
45294105
44946410 Supplemental All three studies were on famoxadone plus cymoxanil mixture. Cymoxanil was not monitored in any of them.
Analytical method with

ILV– soil 44180749 44180752 Acceptable No

−

Analyticalmethod with ILVwater 44180750 44180751 Acceptable No

−

Analytical method with ILV - sediment None Not Applicable No

−

850.1730 Fish bioconcentration No Data Not Applicable No Based on very low K ow (4.7 @pH7), not likely to bioconcentrate in fish.41 7.9.2. Effects Data

Although many submissions have been made to pr ovide information on the effects of cymoxanil technical to aquatic and terrestria l organisms, data gaps remain ( Tables 7.4-7.6 ). The following studies are recommended to address ecological eff ects data gaps and uncertainties. Data call-in justification tables for non-guideline and degrade studies are provided in Appendix G.

Avian Acute Oral Toxicity (1 study)

Acute avian oral toxicity data were submitted for exposures of bobwhite quail and mallard duck to cymoxanil; however, data are not available for passerines, which are now required under the new 40 CFR Part 158 (Oct. 26, 2007) data requirement s for conventional pesticides. Therefore, an acute oral toxicity study (850.2100) with a passeriform species is recommended.

Honeybee Larval Toxicity Study (1 study)

Although cymoxanil is practically non-toxic to honeybees on an acu te contact and oral exposure basis, these studies are conduc ted with young adult honeybees and do not provide information on the potential toxicity of cymoxa nil to developing brood (larvae a nd pupae). In addition, since cymoxanil is a systemic fungicide, it may be tran sferred to pollen and nectar and subsequently brought back to hive where larvae and pupae ma y be exposed. Honeybee brood studies are not currently a data requirement in the U.S., howev er, there is uncertainty regarding the potential effects of cymoxanil on honeybee brood. Therefore, a non-guidelin e honeybee larval toxicity study is recommended as a special study.

Terrestrial Plant Studies (2 studies)

Terrestrial plant toxicity studies are required for regi stration of pesticides with outdoor uses (CFR Part 158). Tier II vegetative vigor (OSCPP 850.4100) and Tier II seedling emergence (OCSPP 850.4150) studies are required on a TEP to investigate the effects of the pesticide enduse product on the growth and survival of terrestrial plants if a test ed terrestrial species exhibits a 25% or greater detrimental eff ect in the Tier 1 study. The st udies should be conducted on the same species as Tier 1. In the absence of these data, risk to terrestrial plants will be assumed.

Degradate Studies (5 studies)

Several ecological effects studies on cym oxanil degradates IN-KQ960 and IN-W3595 are recommended to better assess the potential risk of cymoxanil exposure to non-target organisms. The studies listed below should be submitted to increase certainty in the risk estimation:

• Freshwater Fish-Acute Toxicity (850.1075) with IN-KQ960 and IN-W3595

• Freshwater Invertebrates-Acute Toxicity (850.1010) with IN-W3595

• Aquatic Plant Growth Algal Toxicity (850.5400) with IN-KQ960, and IN-W3595 (preferably with freshwater diatom, Navicula pelliculosa , since it is the most sensitive species tested with the parent compound)42 EFED recommends requesting data on the degrad ate IN-KQ960 because of an acceptable acute freshwater aquatic invertebrate study (850.1010) showing that this degradate is 35 times more toxic to Daphnia magna than the parent compound (MRID 45689201). IN-KQ960 has a similar chemical structure to the other majo r degradates: IN-R3273, IN-JX915, IN-T4226 and IN-U3204. Thus, studies carried out on IN-KQ960 could be used to interpret risk from the other three similarly structured major degradates listed above. Without th ese data, uncertainty as to the toxicity of these degradates will be highlighted as a critical uncer tainty in the risk assessment.

All of the acute toxicity endpoi nts for IN-W3595 predicted in ECOSAR are much lower (more toxic) than measured values for the parent; th erefore additional data is recommended on this degradate as well. Without additional data, toxicity of this degradate will be reported as a critical uncertainty in the risk assessment.

Table 7.4. Available Ecological Effects Data for Terrestrial Animals Exposed to Cymoxanil and Remaining Data Gaps.

Guideline Description MRID/ Accession Classification Data Gap? Comments

850.2100 Avian acute oral toxicity 441807-10 Acceptable Yes * *Avian acute oral toxicity data are not available for passerines, which are required under the new 40 CFR Part 158.

**EPA’s process related to terrestrial invertebrates and pollinators is changing, and honeybee acute oral data (already submitted for cymoxanil (MRID 44180736) will soon be used to support screening-level assessment.

*** Recommended since cymoxanil is a systemic fungicide and may be transferred to pollen and nectar and subsequently brought back to hive 441807-11 Acceptable

850.2200 Avian sub-acute dietary toxicity 441807-12 Acceptable No 441807-13 Acceptable

850.2300 Avian reproduction 441807-15 Acceptable No 441807-14 Acceptable No

850.3020 Honeybee acute contact toxicity 441807-35 Accep table No**

850.3030 Honeybee Toxicity of Residues on Foliage 463504-03 Acceptable No

Nonguideline Honeybee Larval Toxicity None Not Applicable Yes***43 Table 7.5. Available Ecological Effects Data for Aquatic Animals Exposed to Cymoxanil and Remaining Data Gaps.

Guideline Description MRID/ Accession Classification Data Gap? Comments

850.1075 Freshwater fish – Acute toxicity with TGAI 441807-17 Acceptable No * Freshwater acute invertebrate study (MRID 456892-01) showed degradate IN-KQ960 to be 35 times more toxic than the TGAI. Without additional data, risk to aquatic organisms will be assumed for IN-KQ960 and similarly structured degradates. ECOSAR results reported IN-W3595 to be much more toxic than the parent; if no additional data is available, uncertainty in the toxicity of this degradate will be reported in the risk
assessment

** Data is already available onIN-KQ960, but not on INW3595; thus, data on INW3595 is recommended. 441807-18 Acceptable

Freshwater fish – Acute toxicity with TEP 465038-02 Supplemental No

Freshwater fish – Acute toxicity with degradate IN-KQ960 and IN-W3595 None None available Yes*

850.1010 Freshwater invertebrates – Acute toxicity 441807-19 Acceptable No

Freshwater invertebrates – Acute toxicity with TEP 465038-03 Supplemental No

Freshwater invertebrates – Acute toxicity withdegradate INW3595** 456892-01 Acceptable Yes*

850.1075 Estuarine/Marine fishAcute toxicity with TGAI 441807-20 Acceptable No

850.1025/ 850.1035 Estuarine/Marine Organisms – Acute toxicity with TGAI 441807-21 Acceptable

No 441807-22 Acceptable

850.1300 Freshwater invertebrate – life cycle test 441807-24 Acceptable No

850.1350 Estuarine/marine invertebrates – life cycle test 441807-27 Acceptable No

850.1400 Freshwater fish – early life stage test 443646-10 Acceptable No

Saltwater fish – early life stage test 441807-26 Acceptable No44 Table 7.6. Available Ecological Effects Da ta for Plants Exposed to Cymoxanil and Remaining Data Gaps.

Guideline Description MRID Classification Data Gap? Comments

850.4100 Terrestrial Plant toxicity: Tier I seedling emergence with TEP None None available Yes

850.4225 Terrestrial Plant toxicity: Tier II seedling emergence with TEP or TGAI None None available Yes Conduct Tier 1 study first. Tier 2 required if a tested terrestrial species exhibits a 25% or greater detrimental effect in the Tier 1 study. Study should be conducted on the same species as Tier 1.

850.4150 Terrestrial Plant toxicity: Tier I vegetative vigor with TEP None None available Yes

850.4250 Terrestrial Plant toxicity: Tier II vegetative vigor with TEP or TGAI None None available Yes Conduct Tier 1 study first. Tier 2 required if a tested terrestrial species exhibits a 25% or greater detrimental effect in the Tier 1 study. Study should be conducted on the same species as Tier 1.

850.5400 Aquatic Plant Growth: algae with TGAI 441807-30 Acceptable

No 441807-32 Acceptable 441807-31 Acceptable 441807-29 Acceptable

Aquatic Plant Growth: algae with TEP 46503801 Supplemental No Contamination of copper hydroxide was seen in the controls of this study; thus, interpretation of results should be analyzed with caution

Aquatic Plant Growth:

algae with degradateIN-KQ960 and INW3595 None None available Yes Freshwater acute invertebrate study (MRID 456892-01) showed degradate IN-KQ960 to be 35 times more toxic than the TGAI and ECOSAR results reported IN-W3595 to be much more toxic than the parent; thus, without the data, the degradates will be assumed to be 35 times more toxic than the parent to all aquatic organisms.

850.4400 Aquatic Plant Growth: vascular plants with TGAI 44180728 Acceptable No45 8. References

Fletcher, J.S., J.E. Nellessen, and T.G. Pfleeger. 1994. Literature review and evaluation of the EPA food-chain (Kenaga) nomogram, an instru ment for estimating pesticide residues on plants. Environ. Tox. Chem. 13 :1383-1391.

Herbicide Resistance Action Committee (HRAC). 2009. Classification of Herbicides According to Mode of Action. Accessed on August 20, 2010. Online at http://www.hracglobal.com/Publications/Cla ssificationofHerbicideModeofAction/tabid/2 22/Default.aspx.

Hoerger, F. and E. E. Kenaga. 1972. Pe sticide Residues on Plants: Correlation of Representative Data as a Basis for Estimation of their Magnitude in the Environment. In F. Coulston and F. Korte, eds., Environmental Quality and Safety: Chemistry, Toxicology, and Technology, Georg Thieme Publ., Stuttgart, West Germany, pp. 9-28.

Mineau, P., B.T. Collins, and A. Baril. 1996. On the use of scaling factors to improve interspecies extr apolation to acute toxicity in birds. Reg. Toxicol. Pharmacol. 24: 24-29.

Sample, B.E. and C.A. Arenal. 1999. Allometric Models for Interspecies Extrapolation of Wildlife Toxicity Data. Bulleti n of Environmental Contamin ation and Toxicology. 62:653-663.

USDA. 1997. Usual Planting and Harvesting Dates fo r U.S. Field Crops. National Agricultural Statistics Service. United States Departme nt of Agriculture. Accessed August 9, 2010. Online at: http://usda.mannlib.corne ll.edu/usda/nass/planting/uph97.pdf

USEPA. 1997. EFED Section 3 Registration for Cymoxanil PC Code No. 129106; Case No. 061132. DP Barcode: D233366. U.S. Environmental Protection Agency, Office of Pesticide Programs. October 23,1997.

USEPA. 1998. Guidelines for Ecological Risk A ssessment. Risk Assessment Forum, Office of Research and Development, Washi ngton, D.C. EPA/630/R-95/002F. April 1998. http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=30759

USEPA. 2001. IR-4 Tolerance Petition for Cymoxa nil (Curzate 60 DF) us e on Hops. PC Code No. 129106; Case No. 061132. DP Barcode: D271572. U.S. Envi ronmental Protection Agency, Office of Pesticide Programs. October 13, 2001.

USEPA. 2003. EFED Amended Registration for Cymoxanil PC Code No. 129106; Case No. 061132. DP Barcode: D261193. U.S. Environmental Protection Agency, Office of Pesticide Programs. January 29, 2003.46 USEPA. 2004. Overview of the Ecological Risk Assessment Process in th e Office of Pesticide Programs. U.S. Environmental Protection Ag ency, Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, Washington DC. January 23, 2004.

USEPA. 2003. EFED Amended Registration for Cymoxanil PC Code No. 129106; Case No. 061132. DP Barcode: D261193. U.S. Environmental Protection Agency, Office of Pesticide Programs. January 29, 2003.

USEPA. 2006. EFED IR-4 Tolerance Petition for Cymoxanil (Tanos ® ) Use on Grapes and Hops. PC Code N o. 129106; Case No. 061132. DP Barcode: D261193. U.S. Environmental Protection Ag ency, Office of Pesticide Programs. September 20, 2006.

USEPA. 2006. EFED IR-4 Tolerance Petition for Cymoxanil (Tanos ® ) Use on Caneberries. . PC Code No. 129106; Case No. 061132. DP Barcode: D261193. U.S. Environmental Protection Agency, Office of Pesticide Programs. September 20, 2006.

USEPA. 2007a. Ecological In cident Information System. http://www.epa.gov/espp/consultation/ecorisk-overview.pdf

USEPA. 2007b. ECOTOXicology Da tabase. Office of Research and Development National Health and Environmental Effects Research Laboratory’s (NHEERL’s) Mid-Continent Ecology Division (MED). http://cfpub.epa.gov/ecotox/

.

USEPA. 2008. IR-4 Tolerance Petiti on for the use of cymoxanil (Tanos ® ) on leafy greens, bulb vegetables, caneberries, cilantro leaves, onions, spinach and leaf lettuce. May 6, 2008.

USEPA. 2008. Revised Drinking Water Assessment for the Proposed New Use of cymoxanil (Tanos ® ) on leafy greens, bulb vegeta bles, caneberries, cilantro leaves, onions, spinach and leaf lettuce. May 13, 2008.

USEPA. 2011a. Cymoxanil (12910 6): Screening Level Usage Analysis. U.S. Environmental Protection Agency, Office of Prevention, Pes ticides and Toxic Substances, Biological and Economic Analysis Division. Sept. 13, 2011.

USEPA. 2011b. BEAD Chemical Profile for Re gistration Review: Cymoxanil (129106). U.S. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Biological and Economic Analysis Division. Sept. 21, 2011.

U.S. Fish and Wildlife Service (USFWS) and Na tional Marine Fisheries Service (NMFS). 1998. Endangered Species Consultation Handbook: Procedures for Conducting Consultation and Conference Activities Under Section 7 of the Endangered Sp ecies Act. Final Draft. March 1998.

USFWS/NMFS/NOAA.2004. 50 CFR Part 402. Join t Counterpart Endangered Species Act Section 7 Consultation Regulations; Final Rule. Federal Register Volume 69. Number 20.Pages 47731-47762. August 5, 2004.47 U.S. Geological Survey (USGS). 2011. Pesticid e Use Maps. U.S. Geological Survey, National Water-Quality Assessment (NAWQA) Program, Pe sticide National Synt hesis Program. Accessed on September 2011. Online at: http://water.usgs.gov/nawqa/pnsp/ usage/maps/compound_listing.php?year=0248 SUBMITTED ENVIRONMENTAL FATE STUDIES:

MRID 44180738 Lawler, S. (1996) Hydrolysis of Cymoxanil (DPX-T3217) in Buffer Solutions of pH 5, 7, and 9: Lab Project Number: AMR 3677-95. Unpublished study prepared by DuPont Agricultural Products. 77 p.

No MRID Horne, P. (1992) HYDROLYS IS DF-[2-14C]DPX-T3217. Submitted, Sponsored and Performed by E.I. DuPont de Nemours and Company, DuPont Agricultural Products, Wilmington, DE under Laboratory Project ID AMR-2018-91, Study Completed on 19 August 1992, Received by EPA in 1995.

MRID 44180738 Proposed Hydroly tic Degradation Pathway.

MRID 46348602 Willems, I.; Slangen, P.; Hoiti nk, M. (2003) Aqueous Hydrolysis of Cymoxanil. Project Number: 308734. Unpublishe d study prepared by Notox V.O.F. 177 p.

MRID 44180739 Anderson, J.; Horne, P.; Lawler, S.; et al. (1993) Phot odegradation of (2- (carbon 14))DPX-T3217 (Cymoxanil) in Pond Wa ter and Sterile Buffer pH 5: Lab Project Number: AMR 1990-91. Unpublished study prepared by DuPont Agricultural Products. 63 p.

MRID 44180740 Anderson, J.; Lawler, S.; Swain, R. (1993) Quantum Yield Determination of DPX-T3217 (Cymoxanil) and LC/MS Confirmation of Unknown Degradates in Sterile Buffer pH 5: Supplement No. 1 to “Photodegradati on of (2-(carbon 14))DPX -T3217 (Cymoxanil) in Pond Water and Sterile Buffer pH 5”: La b Project Number: AMR 1990-91. Unpublished study prepared by DuPont Agricu ltural Products. 42 p.

MRID 45465101 Contract draft available. Trab ue, S.; Lydick, T. (2001) Degradation of Cymoxanil in Two Water/Sediment System s: Lab Project Number: 2695. Unpublished study prepared by DuPont Agricu ltural Products. 97 p.

MRID 44180741 Berg, D. (1996) Photodegradati on of Radiolabeled Cymoxanil on Soil Under Simulated Sunlight: Lab Project Number : AMR 3582-95. Unpublished study prepared by DuPont Agricultural Products. 51 p.

44180742 Boucher, C. (1994) Degradation Rate of (carbon 14)Cymoxanil on Four Soils: Lab Project Number: AMR 2869-93. Unpublished study pr epared by DuPont Agricultural Products. 57 p.

44180743 Boucher, C. (1996) Aerobic Metabo lism of (carbon 14)-Cymoxanil: Lab Project Number: AMR 3438-95. Unpublished study prepared by DuPont Agricultural Products. 48 p.

45357101 Anderson, J. (2001) Aerobic Soil Meta bolism of (carbon 14)-Cymoxanil: Revision No. 1: Lab Project Number: AMR 3438-95: 3438 -95. Unpublished study prepared by DuPont Agricultural Products. 42 p.49 No MRID Boucher, Caro line, R. (1993) Aerobic Soil Metabolism of [2-14C]DPX-T3217 (Cymoxanil). Performed and Submitted by E. I. du Pont Nemours and Company, DuPont Agricultural Products, Wi lmington, DE. Supplement Report Number AMR 1988-91.

No MRID Knoch, E. (1993) Degradation and Metabolism of Cymoxanil (DPX-T3217) in Water/Sediment Systems. Unpublished Study C onducted by RCC Unmweltchemie & Co., K.G. RoBdorf, Germany and Submitted by Dupont. Protocol AMR 2446-92.

44180744 Hausmann, S. (1996) Anaerobic Aquatic Metabolism of Cymoxanil: Lab Project Number: AMR 3407-95. Unpublished study prepared by DuPont Agricultural Products. 75 p.

No MRID Knoch, E. (1993) Degradation a nd Metabolism of Cymoxanil (DPX-T3217) in Water/Sediment Systems. Unpublished Study C onducted by RCC Unmweltchemie & Co., K.G. RoBdorf, Germany and Submitted by Dupont. Protocol AMR 2446-92.

44180745 Horne, P. (1992) Batch Equilibrium (A dsorption/Desorption) Studies of (carbon 14)DPX-T3217: Lab Project Number: AMR 2112-91. Unpublished study prepared by DuPont Agricultural Products. 34 p.

44180746 Hausmann, S.; Adams, G. (1996) So il Batch Equilibrium Study of Cymoxanil Degradates: Lab Project Nu mber: AMR 3722-95. Unpublished study prepared by DuPont Agricultural Products. 97 p.

No MRID Lawler, S.M. (1993) Soil Colu mn Leaching Study of 14C-Cymoxanil. Study Performed and Submitted by E.I. du Pont de Ne mours and Company, Wilmington, Delaware. Du Pont Report No. AMR 2724-93.

44180747 McClory, J.; Jones, W. (1996) Fiel d Soil Dissipation of Cymoxanil Following Application of Curzate M-8 Fungicide: Lab Project Number: AMR 3401-95: AMR 3595-95. Unpublished study prepared by DuPont Agricultural Products. 106 p.

44946410 McClory, J.; Holt, J. (1999) Field So il Dissipation of Famoxadone and Cymoxanil Following Application of DPX-KP481 Fungici de, USA: Lab Project Number: ML97-0705DUP: AMR 4329-97. Unpublished study prepared by DuP ont Agricultural Products and Morse Laboratories, Inc. 214 p.

45294105 McClory, J. (2000) Fiel d Soil Dissipation of Famoxadone and Cymoxanil Following Application of DPX-KP481 50 WG Fungicide, WG, USA, 1999: Lab Project Number: 2342: ML99-0780-DUP. Unpublished study prepared by E.I. du Pont de Nemours and Company and Morse Laboratories. 221 p.

45294106 McClory, J. (2000) Fiel d Soil Dissipation of Famoxadone and Cymoxanil Following Application of DPX-KP481 50 WG Fungicide, WG, USA, 1999: Lab Project Number: AMR 4329-97: ML97-0705-DUP. Unpublished study prepar ed by E.I. du Pont de Nemours and Company and Morse Laboratories. 205 p.50 44180749 McClory, J.; Jones, W.; DeLuke, P. (1996) Analytical Method for the Determination of Residues of Cymoxanil in Soil Using Liqui d Chromatography: Lab Project Number: AMR 3595-96. Unpublished study prepared by DuP ont Agricultural Products. 39 p.

44180750 Nathan, E.; Hill, S. (1995) Analytical Method for the Determination of Cymoxanil in Water Using Liquid Chromatography: Lab Project Number: AMR 3430-95. Unpublished study prepared by DuPont Agricu ltural Products. 62 p.

44180751 Nathan, E. (1996) Independent Laboratory Validation of the An alytical Method for the Determination of Residues of Cymoxanil in Water Using Liquid Chromatography: Lab Project Number: AMR 3683-95: ML96-0585-DUP. U npublished study prepared by Morse Labs, Inc. 144 p.

44180752 Lochhaas, C. (1996) Independent Laborato ry Validation of an Analytical Method for the Determination of Cymoxanil Residues in So il by High-Pressure Liquid Chromatography: Lab Project Number: AMR 4119-96: 43550: AMR 3595-95. Unpublished study prepared by ABC Labs, Inc. 53 p.

45317701 Hertl, J. (2001) Cymoxanil (DPX-T3217) Technical: Activated Sludge, Respiration Inhibition Test: Final Report: Lab Project Number: 8951171: 4483. Unpublished study prepared by Institut fur Biologische Analytik und Consulting IBACON GmbH. 26 p.51 SUBMITTED ECOLOGICAL EFFECTS STUDIES:

44180716 Baer, K. (1992) Static, Acute, 96-Hour LC50 of DPX-T3217-113 (Cymoxanil) to Common Carp, Cypr inus carpio: Lab Project Number: HLR 734-92: 9581-023: 734-92. Unpub lished study prepared by DuPont's Haskell Lab for Toxicol ogy and Industrial Medicine. 32 p.
44180717 Baer, K. (1993) Static, Acute, 96-Hour LC50 of DPX-T3217-113 (Cymoxanil) to Rainbow Trout, On corhynchus mykiss: Lab Project Number: HLR 735-92: 4581-936: 735- 92. Unpublished study prepared by DuPont's Haskell Lab for Toxicol ogy and Industrial Medicine. 28 p.
44180718 Baer, K. (1993) Static, Acute, 96-Hour LC50 of DPX-T3217-113 (Cymoxanil) to Bluegill Sunfish, Le pomis macrochirus: Lab Project Number: HLR 934-92: 4581-936: 834- 92. Unpublished study prepared by DuPont's Haskell Lab for Toxicol ogy and Industrial Medicine. 29 p.
44180719 Baer, K. (1993) Static, Acute, 48-Hour EC50 of DPX-T3217-113 (Cymoxanil) to Daphnia magna: Lab Project Number: HLR 736-92: 4581-936: 736-92. Unpublished study pr epared by DuPont's Haskell Lab for Toxicology and Industrial Medicine. 30 p.
45689201 Samel, A. (2002) IN-KQ960: Stat ic, Acute, 48-Hour EC(50) to Daphnia magna: Lab Project Number: 13219: 9559: DUPONT-9559. Unpublished study prepared by E.I. du Pont de Nemours and Company. 36 p.
46503803 Hoke, R. (2005) Metallic Coppe r (as Copper Hydroxide)/Cymoxanil (DPX-HYZ80) 31 WG (4.2:1): Acut e Toxicity to Daphnia magna. Project Number: DUPONT/14373, 15203. Unpublished study prepared by Dupont Haskell Laboratory and E.I. du Pont de Nemours and Company. 46 p.
43987601 Bowman, Jane and John Bucksath (1995) Acute Flow-Through Toxicity of S-1668 to Daphnia ma gna. ABC Laboratories, Inc., Columbia, MO. Sumitomo Chem ical Company, Ltd., Osaka 541, Japan
44180720 Boeri, R.; Kowalski, P.; Ward, T. (1996) Acute Toxicity of DPXT3217-113 (Cymoxanil) to the Sheepshead Minnow, Cyprinodon variegatus: (Final Report): Lab Project Number: HLO 634-96: 10372- 001: 808-DU. Unpublished study prepared by T. R. Wilbury Labs, Inc. 41 p.
44180721 Boeri, R.; Kowalski, P.; Wa rd, T. (1996) Acute Flow-Through Mollusc Shell Deposition Test w ith DPX-T3217-113 (Cymoxanil): (Final Report): Lab Project Number: HLO 633-96: 10372-001: 810- DU. Unpublished study prepared by T. R. Wilbury Labs, Inc. 38 p.52 44180722 Boeri, R.; Kowalski, P.; Ward, T. (1996) Acute Toxicity of DPXT3217-113 (Cymoxanil) to the Mysi d, Mysidopsis bahia: (Final Report): Lab Project Number: HLO 632-96: 10372-001: 809-DU. Unpublished study prepared by T. R. Wilbury Labs, Inc. 38 p.

44180723 Kreamer, G. (1996) DPX-T3217-113 (C ymoxanil): Early-Life Stage Toxicity to Rainbow Trout, Oncorh ynchus mykiss: Lab Project Number: HLR 411-96: 10495: 411-96. Unpublishe d study prepared by DuPont's Haskell Lab for Toxicology and Industrial Medicine. 469 p.
44180724 Baer, K. (1993) Chronic Toxicity of DPX-T3217-113 (Cymoxanil) to Daphnia magna: 24-Hour Renewal: Revised Report: Lab Project Number: HLR 354-93: 4581-936: 354- 93. Unpublished study prepared by DuPont's Haskell Lab for Toxicol ogy and Industrial Medicine. 493 p.
44180725 Baer, K. (1992) Flow-Through, 21- Day Toxicity of DPX-T3217-113 (Cymoxanil) to Rainbow Trout, On corhynchus mykiss: Lab Project Number: HLR 545-92: 9581-023: 545- 92. Unpublished study prepared by DuPont's Haskell Lab for Toxicol ogy and Industrial Medicine. 65 p.
44180726 Boeri, R.; Kowalski, P.; Ward, T. (1996) Early Life Stage Toxicity of DPX-T3217-113 (Cymoxanil) to the Sheepshead Minnow, Cyprinodon variegatus: (Final Report): Lab Project Number: HLO 913-96: 10372- 002: 812-DU. Unpublished study prepared by T. R. Wilbury Labs, Inc. 816 p.
44180727 Boeri, R.; Kowalski, P.; Ward, T. (1996) Chronic Toxicity of DPXT3217-113 (Cymoxanil) to the Mysid, Mysidopsis bahia: (Final Report): Lab Project Number: HLO 914- 96: 10372-002: 811-DU. Unpublished study prepared by T. R. Wilbury Labs, Inc. 742 p.
44364610 Boeri, R.; Magazu, J.; Ward, T. (1997) DPX-T3217-113 (Cymoxanil): Early Life-Stage Toxicity to Ra inbow Trout, Oncorhynchus mykiss: (Final Report): Lab Projec t Number: 1013-96: 11104: 1204-DU. Unpublished study prepared by T.R. W ilbury Laboratories, Inc. 540 p.
44180728 Leva, S.; Sloman, T. (1996) Cymoxanil: Influence on Growth and Reproduction of Lemna gibba G3: Lab Project Number: AMR 3775-96: MR 10615. Unpublished study prepared by DuPont Stine-Haskell Research Center. 39 p.
44180729 Hughes, J.; Williams, T.; C onder, L. (1996) DPX-T3217-113(Cymoxanil): Influence on Growth and Reproduction of Anabaena flosaquae: Lab Project Number: 19- 06-2: AMR 4109-96. Unpublished study prepared by Carolina Ecotox, Inc. 74 p.
44180730 Hughes, J.; Williams, T.; C onder, L. (1996) DPX-T3217-113 (Cymoxanil): Influence on Growth and Reproduction of Selenastrum capricornutum: Lab Project Number: 19-06-1: AMR 4110-96. Unpublished study prepared by Ca rolina Ecotox, Inc. 61 p.53 44180731 Hughes, J.; Williams, T.; C onder, L. (1996) DPX-T3217-113 (Cymoxanil): Influence on Growth and Reproduction of Skeletonema costatum: Lab Project Number: 19-06-4: AMR 4111-96. Unpublished study prepared by Carolina Ecotox, Inc. 61 p.
44180732 Hughes, J.; Williams, T.; C onder, L. (1996) DPX-T3217-113 (Cymoxanil): Influence on Growth and Reproduction of Navicula peliculosa: Lab Project Number : 19-06-3: AMR 4112-96. Unpublished study prepared by Carolina Ecotox, Inc. 72 p.
44180733 Douglas, M.; Handley, J. (1988) The Algistatic Activity of Cymoxanil Technical: (Final Report): Lab Project Number: DPT 171(Q)/88601. Unpublished study prepared by Hunti ngdon Research Centre Ltd. 20 p.
45039001 Hoke, R.; Sloman, T. (2000) Cymo xanil Aquatic Degradate Mixture Including RF1: Influence on Growth and Growth Rate of the BlueGreen Alga, Anabaena flos-aquae: Lab Project Number: 12453: 324: DUPONT-3529. Unpublished study prepar ed by E.I. Du Pont de Nemours and Company. 56 p.
44180729 Hughes, J.; Williams, T.; C onder, L. (1996) DPX-T3217-113 (Cymoxanil): Influence on Growth and Reproduction of Anabaena flos-aquae: Lab Project Number: 19-06-2: AMR 4109-96. Unpublished study prepared by Ca rolina Ecotox, Inc. 74 p.
44180732 Hughes, J.; Williams, T.; C onder, L. (1996) DPX-T3217-113 (Cymoxanil): Influence on Growth and Reproduction of Navicula peliculosa: Lab Project Number : 19-06-3: AMR 4112-96. Unpublished study prepared by Carolina Ecotox, Inc. 72 p.
45039001 Hoke, R.; Sloman, T. (2000) Cymo xanil Aquatic Degradate Mixture Including RF1: Influence on Growth and Growth Rate of the BlueGreen Alga, Anabaena flos-aquae: Lab Project Number: 12453: 324: DUPONT-3529. Unpublished study prepar ed by E.I. Du Pont de Nemours and Company. 56 p.
46503801 Sloman, T. (2005) Metallic Coppe r (as Copper Hydroxide)/Cymoxanil (DPX-HYZ80) 31 WG (4.2: 1): Influence on Growth and Growth Rate of Green Alga Pseudokirchneriella s ubcapitata: Trade Secret. Project Number: DUPONT/14371, 15203. Unpublished study prepared by Dupont Haskell Laboratory and E.I. du Pont de Nemours and Company. 49 p.
44180735 Hoxter, K.; Bernard, W.; Smit h, G. (1993) H #19,062-02: An Acute Contact Toxicity Study with the Hone y Bee: Final Report: Lab Project Number: 112-275: HLO 100-93: 100- 93. Unpublished study prepared by Wildlife International Ltd. 17 p.
44180736 Hoxter, K.; Bernard, W.; Smit h, G. (1993) H #19,062-02: A Dietary LC50 Toxicity Study with the Honey Bee: Final Report: Lab Project54 Number: 112-274: HLO 99-93: 99-9 3. Unpublished study prepared by Wildlife International Ltd. 16 p.
46477601 Bocksch, S. (2004) Metallic Copper (as Copper Hydroxide)/Cymoxanil (DPX-HYZ80 ) 31WG (4.2:1): Acute Oral and Contact Toxicity to the Honeybee, Apis Mellifera L.: Final Report. Project Number: DUPONT/14369, 20041156/01/BLEU, 15203. Unpublished study prepared by Arbeitsgemeinschaft GAB Biotechnologie. 32 p.
46350402 Candolfi, M.P. (1996) DPX-KX007- 5: Laboratory Acute Oral and Contact Toxicity Test with the Honeybee (Apis mellifera), Based on the EPPO Guideline 170 (1992) and FIFRA Gudieline 141-1. Laboratory: Springborn Laborator ies (Euroupe) AG, Health and Environmental Sciences, Seestr asse 21, 9326 Horn, Switzerland, Du Pont Agricultural Products, Expe rimental Station, BLDG. E402-5236, Wilmington, Delaware 18990-0402.

46350403 A.B. Sindermann, J.R. Porch and H.O. Krueger (2004) Cymoxanil/Famoxadone (DPX-KP481) 50 WG (1:): A Foliage Residue Toxicity Study with the Ho ney Bee. Laboratory: Wildlife International, Ltd. 8598 Commerce Drive, Easton, Maryland 21601. E.I. Dupont de Nemours and Co mpany, Wilmington, Delaware 19898.
44946327 Kuhner, C. (1997) DPX-KP481, a Wa ter Dispersible Granular (WG) Formulation Containing DPX-JE874 (254 g ai/kg) and Cymoxanil (266 g ai/kg): Acute Toxicity to the Staphylinid Beetle, Aleochara bilineata Gyll. (Coleoptera, Staphy linidae) in the Laboratory: Final Report: Lab Project Number : AMR 4235-96: 96259/01-NLAB. Unpublished study prepared by GAB Biotechnologie GmbH and IFU Umweltanalytik GmbH. 22 p. DPX-KP481 = Famoxadone + Cymoxonil
44946328 Kuhner, C. (1997) DPX-KP481, a Wa ter Dispersible Granular (WG) Formulation Containing DPX-JE874 (254 g ai/kg) and Cymoxanil (266 g ai/kg): Acute Toxicity to the Green Lacewing, Chrysoperla carnea steph. (Neuroptera, Chrys opidae) in the Laboratory: Final Report: Lab Project Number : AMR4234-96: 96259/01-NLCC. Unpublished study prepared by GAB Biotechnologie GmbH IFU Umweltanalytik GmbH. 25 p.
44946329 Kuhner, C. (1997) DPX-KP481, a Wa ter Dispersible Granular (WG) Formulation Containing DPX-JE874 (254 g ai/kg) and Cymoxanil (266 g ai/kg): Acute Toxicity to the Hoverfly, Episyrphus balteatus DEG. (Diptera; Syrphidae) in the Laboratory: Final Report: Lab Project Number: AMR4232-96: 96259/01-NLEB. Unpublished study prepared by GAB Biotechnologi e GmbH IFU Umweltanalytik GmbH. 30 p.55 44946330 Kuhner, C. (1997) DPX-KP481, a Wa ter Dispersible Granular (WG) Formulation Containing DPX-JE874 (254 g ai/kg) and Cymoxanil (266 g ai/kg): Acute Toxicity to the Ground Beetle, Poecilus cupreus L. (Coleoptera, Carabidae) in the Laboratory: Final Report: Lab Project Number: AMR4233-96: 96259/01-NLPC. Unpublished study prepared by GAB Biotechnologi e GmbH IFU Umweltanalytik GbmH. 29 p.
44946331 Thompson, B. (1999) Cymoxanil/Famoxadone (DPX-KP481) 50 WG (25%:25%). An Extended La boratory Study to Evaluate the Effects on the Green Lacewing, Ch rysoperla carnea: Lab Project Number: DP-97-8: AMR4540-97. Unpublished study prepared by Agrochemical Evaluation Unit Sc hool of Biological Sciences University of Southampton. 24 p.
44946332 Thompson, B. (1999) Cymoxanil/Famoxadone (DPX-KP481) 50 WG (25%:25%): an Extended La boratory Study to Evaluate the Effects on the Hoverfly, Episyrphus balteatus: Lab Project Number: DP-97-9: AMR4541-97. Unpublished study prepared by Agrochemical Evaluation Unit Sc hool of Biological Sciences University of Southampton. 32 p.
44946333 Beech, P.; Mead-Briggs, M. ( 1998) Cymoxanil/Famoxadone (DPXKP481) 50 WG (25%:25%). An Extended Laboratory Study to Evaluate the Effects on the Ground Beetle, Poecilus cupreus: Lab Project Number: DP-97-10: AMR4539-97. Unpublished study prepared by Agrochemical Eval uation Unit School of Biological Sciences University of Southampton. 22 p.
44946334 Thompson, B. (1999) Cymoxanil/Famoxadone (DPX-KP481) 50 WG (25%:25%). A Semi-field St udy to Evaluate the Effects on Aphid Parasitoids (Hymenoptera, A phidiinae) in a Potato Crop: Lab Project Number: DP-97-3: AMR4542-97. Unpublished study prepared by Agrochemical Eval uation Unit School of Biological Sciences University of Southampton. 35 p.
45475401 Gossmann, A. (2001) Cymoxanil (DPX-T3217) 60%WG: A Laboratory Test to Study the Effects on the Predatory Mite Typhlodromus pyri (Acari, Phytoseiidae): Lab Project Number: 1731: 4932063. Unpublished study prepared by Institut fur Biologische Analytik und Cons ulting IBACON GmbH. 41 p.
46430401 Warmers, C. (2004) Metallic Copper (as Copper Hydroxide)/Cymoxanil (DPX-HYZ 80) 31WG (4.2:1): A Multiple Rate Test to Study the Eff ects on the Predatory Mite Typhlodromus pyri (Acari, Phytos eiidae): Final Report. Project Number: 20041156/01/NLTP, DUPONT/14360, 15203. Unpublished study prepared by GAB Biotechnologie Gmbh. 34 p.56 44200702 Armstrong, K.; Caley, C.; Hall, B.; et al. (1991) Cymoxanil (Tech.) Determination of Acute Toxicity (LC50) Earthworms: Lab Project Number: 8548: 381499: IRI 8548. U npublished study prepared by Inveresk Research International. 33 p.
44967203 Caley, C.; Knight, B.; Boyle, J. (1994) DPX-JE874-221: Determination of Acute Toxicity (LC50) in Earthworms: Lab Project Number: 10206: 383475: IRI 383475. Unpublished study prepared by Inveresk Resear ch International. 33 p.
46464301 Muther-Paul, J. (2005) Metallic Copper (As Copper Hydroxide)/Cymoxanil (DPX-HYZ 80) 31WG (4.2:1): Sublethal Toxicity to the Earthworm Eisenia fetida in Artificial Soil: Final Report. Project Number: 20041156/01/NREF, DUPONT/14375, 15203. Unpublished study prepar ed by GAB Biotechnologie Gmbh. 31 p.
46785301 Luhrs, U. (2006) Metallic Copper (As Copper Oxychloride)/Cymoxanil (DPX- KK807) 44WG (9.5:1): Effects on Reproduction and Soil Growth of the Earthworm, Eisenia fetida, in Artificial Soil: Final Report. Project Number: DUPONT/17203, 15950, 1502. Unpublished study prepared by Institut fuer Biologische Analytik und Consulting IBACON. 42 p.57 APPENDIX A: Registered Us es and Application Rates for Cymoxanil Based on Information from OPP/BEAD 1

.

Use Max Single Applic. Rate (lb

ai/A) Max No. Applic./

Crop Cycle Max. Applic. Rate/Crop Cycle Max. No. Applic./Yr Max. Applic. Rate/Yr (lb

ai/A/yr) Min. Applic. Interval

Amaranth, Chinese 0.1563 NS 0.75 NS NS 5 d Beets (Unspecified) 00.12 NS NS 5/yr NS 5 d

Blackberry 0.1563 NS 1.1 NS NS 5 d

Cabbage 0.12 NS NS 5/yr NS 5 d

Caneberries 0.1563 NS 1.1 NS NS 5 d

Cardoon 0.1563 NS 0.75 NS NS 5 d

Celery 0.1563 NS 0.75 NS NS 5 d

Celtuce 0.1563 NS 0.75 NS NS 5 d

Chard, Swiss 0.1563 NS 0.75 NS NS 5 d

Chervil 0.1563 NS 0.75 NS NS 5 d

Chive 0.1563 NS 1.3 NS NS 5 d Chrysanthemu m, Garland 0.1563 NS 0.75 NS NS 5 d

Corn Salad 0.1563 NS 0.75 NS NS 5 d

Cress, Garden 0.1563 NS 0.75 NS NS 5 d

Cress, Upland 0.1563 NS 0.75 NS NS 5 d

Cucumber 0.1563 NS 0.5 NS 1.1 5 d Cucurbit Vegetables 0.1875 NS NS NS 1.1 5 d

Dandelion 0.1563 NS 0.75 NS NS 5 d

Dock (Sorrel) 0.1563 NS 0.75 NS NS 5 d Endive (Escarole) 0.1563 NS 0.75 NS NS 5 d

Fennel 0.1563 NS 0.75 NS NS 5 d

Garlic 0.1563 NS 1.3 NS NS 5 d

Grapes 0.125 9 1.1 NS NS 10 d58 Hops 0.125 6 0.75 NS .75 10 d || 6 d

Leafy Greens 0.1563 NS 0.75 NS NS 5 d Leafy Vegetables 0.1563 NS 0.75 NS NS 5 d

Leek 0.1563 NS 1.3 NS NS 5 d

Lettuce, Head 0.1875 NS NS NS 1.1 5 d Lettuce, Leaf (Black Seeded Simpson, Salad Bowl, Etc.) 0.1875 NS NS NS 1.1 5 d

Loganberry 0.1563 NS 1.1 NS NS 5 d Melons, Cantaloupe 0.1563 NS 0.5 NS 1.1 5 d Melons, Honeydew 0.1563 NS 0.5 NS 1.1 5 d

Melons, Musk 0.1563 NS 0.5 NS 1.1 5 d

Melons, Water 0.1563 NS 0.5 NS 1.1 5 d

Onion 0.1563 NS 1.3 NS NS 5 d Onions (Green) 0.1563 NS 1.3 NS NS 5 d Orach (Mountain Spinach) 0.1563 NS 0.75 NS NS 5 d

Parsley 0.1563 NS 0.75 NS NS 5 d Peas (Unspecified) 0.0199 lb / lb seed NS NS NS NS

Pepper 0.1563 NS 1.1 NS 1.1 5 d

Pimento 0.1563 NS 1.1 NS 1.1 5 d Potato, White/Irish 0.0075 lb / lb seed NS NS NS NS Potato, White/Irish 0.0375 lb / lb seed NS NS NS NS 5 d Potato, White/Irish 0.125 6 0.75 NS 1.1 5 d

Pumpkin 0.1563 NS 0.5 NS 1.1 5 d Purslane, Garden 0.1563 NS 0.75 NS NS 5 d Purslane, Winter 0.1563 NS 0.75 NS NS 5 d

Radicchio 0.1563 NS 0.75 NS NS 5 d59 Raspberry (Black, Red) 0.1563 NS 1.1 NS NS 5 d

Rhubarb 0.1563 NS 0.75 NS NS 5 d Roquette (Arrugula) 0.1563 NS 0.75 NS NS 5 d

Shallot 0.1563 NS 1.3 NS NS 5 d

Spinach 0.1875 NS NS NS 1.1 5 d Spinach, New Zealand 0.1563 NS 1.3 NS NS 5 d Squash (Summer) 0.1563 NS 0.5 NS 1.1 5 d Squash (Winter) (Hubbard) 0.1563 NS 0.5 NS 1.1 5 d

Tomato 0.1875 NS NS NS 1.1 5 d Vegetables (Unspecified) 0.1563 NS 1.3 NS NS 5 d Chrysanthemu

m 0.1563 NS 0.75 NS NS 5 d Peas (Unspecified) 0.02 lb / lb seed NS NS 1/yr NS

1 Information extracted from table: PRD Appe ndix A: Food/Feed & Non-Food/Non-Feed Uses Considered in Registration Review Work Planning; USEPA/OPP/BEAD 2/16/2011).60 APPENDIX B1: Names and Structures of Majo r Environmental Degrad ates of Cymoxanil.

Cymoxanil [DPX-T3217]

IUPAC Name: 1-[(EZ)-2-Cyano-2-methoxyiminoacetyl]-3-ethylurea. 1-(2-Cyano-2-methoxyiminoacetyl)-3-ethylurea. CAS Name: 2-Cyano-N-[(ethylamino)carbonyl]-2-(methoxyimino)acetamide. CAS Number: 57966-95-7. SMILES String: O=C(NCC)NC(=O)C(=NOC)C#N (EPI Suite, v3.12 SMILES).

“E” configuration

IN-U3204

IUPAC Name: 6-Imino-1-methyl-5-methylenedih ydropyrimidine-2,4(1H,3H)-dione (ISIS/Draw with ACD/Name add-in). CAS Name: 1-Ethyldihydro-6-imino-2,4,5(3H)-pyrim idinetrione 5-(O-methyloxime). CAS Number: 71342-66-0.

IN-W3595

IUPAC Name: (2E)-Cyano(methoxyimino)acetic acid (ISIS/Draw with ACD/Name addin). CAS Name: Cyano(methoxyimino)acetic acid. CAS Number: 78325-17-4. N H C H 3

O N H

O N O

CN CH 3

N NH O
NOCH 3

N H O
CH 2 CH 361 “E” configuration

IN-R3274

IUPAC Name: (2E)-Cyano(hydroximino)acetic acid (ISIS /Draw with ACD/Name add-in). CAS Name: Cyano(hydroxyimino)acetic acid. CAS Number: 78325-18-5; 38157-71-0 (E isome r); 95679-11-1 (Z isomer).

“E” configuration

IN-R3273

IUPAC Name: 1-Methyl-5-methyleneimidazolid ine-2,4-dione (ISIS/Draw with ACD/Name add-in). CAS Name: Ethylimidazolidinetrione 5-(O-methyloxime). CAS Number: 71342-67-1. O H

O N O

CN CH 3

O H

O N OH

CN

N NH

O

NOCH 3

C 2 H 5 O62 IN-KP533

IUPAC Name: {[(Ethylamino)carbonyl]amino}(oxo) acetic acid (ISIS/Draw with ACD/Name add-in). CAS Name: [[(Ethylamino)carbonyl]amino]oxoacetic acid. CAS Number: 105919-00-4.

IN-JX915

IUPAC Name: 3,4-Dimethyl-2,5-dioxoimidazolidine- 4-carbonitrile (ISIS/Draw with ACD/Name add-in). CAS Name: 3-Ethyl-4(methoxyamino)-2,5-dioxo-4 -imidazolidinecarbonitrile. CAS Number: Not reported.

IN-KQ960

IUPAC Name: 3,4-Dimethyl-2,5-dioxoimidazolidine- 4-carboxamide (ISIS/Draw with ACD/Name add-in). CAS Name: 3-Ethyl-4-(methoxyamino)-2,5-dioxo-4-imidazolidinecarboxamide. CAS Number: Not reported. N H C H 3

O N H

O O

OH

N N H O

O NHOCH 3 C 2 H 5
CN

N N H O

O NHOCH 3 C 2 H 5
CONH 263 IN-T4226

IUPAC Name: 1-Methylimidazolidine-2,4,5-trione (IS IS/Draw with ACD/Name add-in). CAS Name: Ethylimidazolidinetrione. CAS Number: 57012-86-9.

IN-18474 (Oxamic acid)

IUPAC Name: Amino(oxo)acetic acid (ISIS/Draw with ACD/Name add-in). CAS Name: Aminooxoacetic acid. CAS Number: 471-47-6.

Oxalic acid

IUPAC Name: Oxalic acid (ISIS/Draw with ACD/Name add-in). CAS Name: Ethanodioic acid. CAS Number: 144-62-7. N N H O

O C 2 H 5

O

O H

O O

NH 2

O H

O O

OH64 Carbon Dioxide

IUPAC Name: Carbon dioxide. CAS Name: Carbon dioxide. CAS Number: 124-38-9.

IN-Q8761

IUPAC Name: Not reported. CAS Name: 2-Cyano-N-[(ethylaminocar bonyl]-2-methoxyimino)acetamide. CAS Number: Not reported. C O O

N H C H 3

O N H

O N

CN -OCH 365 APPENDIX B2: Environmental Fate Studies Details

Abiotic Degradation

Hydrolysis is a significant fate pathway in some environments. Cymoxanil hydrolyzes with a pH dependent pattern, as it is relativ ely stable at pH 5, but hydrolyzes rapidly in neutral and alkaline media (t 1/2 of 1.4 days at pH 7, 0.022 days at pH 9; MRID 441807-38). The major hydrolytic degradates observed are: IN-U3204, IN-KP-533 (which appears to persist), and IN-U3595. Cymoxanil also photodegrades quickly in water (t 1/2 of 3.6 days at pH 5). The major photoproducts are IN-JX915 and IN-R3273. Cymoxa nil photodegrades slowly on soil, with a half-life of 74 days.

Metabolism in Soil and Aquatic Environments

In soils aged for 30 days under aerobic soil me tabolism conditions for a leaching column study (AMR 2724-93), approximately 40-42% of th e applied cymoxanil was recovered as 12 CO 2
. However, while cymoxanil clearly does degrade in aerobic soil, includi ng through mineralization to CO 2 , it is uncertain how quickly this will occur in soils at intended use sites in the U.S., or what transformation products may be produced and possibly persist, due to a lack of acceptable data. Submitted aerobic soil metabolism studies are classified as not acceptable (44180743 & 45357101) or supplemental (44180742; AMR 1988-91), a nd half-lives from such will not be used in risk assessments. All of the submitted data are from foreign and/or volcanic ash soils and the studies had multiple problems such as inad equate extraction methods, high nonextractables from early on in the studies, and high inter-repli cate data variability. Th ere are no anaerobic soil metabolism data available.

The submitted anaerobic aquatic metabolism studies do not provide usable data. One submitted study (MRID 44180744) is classified as not acceptable due to nume rous deficiencies, while the other study (AMR 2446-92) is classified as supp lemental, but was conducted at an alkaline pH (9) at which the observed degradation was likel y due to hydrolysis and is not considered representative of intended us e conditions. Similarly, in the single submitted aerobic aquatic metabolism study (MRID 44180741), extraction of resi dues was inadequate, there were no data for an acidic pH system, and degradation in bo th systems studied was only due to hydrolysis. Additionally, the sediments had very little organic carbon (0.1 and 0.8%), so are not likely representative of sediments near intended use sites.

New studies are needed to adequately understand the role of metabolism in the degradation of cymoxanil in aerobic soils. To understand th e fate of cymoxanil in anaerobic aquatic environments, new data are needed for at least two anaerobic aquatic sediment systems, one of which is at an acidic pH. Data are also needed for at least two aerobic aquatic sediment systems, one of which is at an acidic pH.

Degradates detected in the submitted aerobic soil metabolism studies included IN-KQ960, INW3595, CO 2, IN-U3204, IN-18474 (oxamic acid), IN-R 3273, IN-KP533, and IN-JX915. The first four of these were present as major degradat es in one or more soils, while the latter four were present as minor degradates in all soils in which they were detected. Of these, only IN-66 KQ960 and oxamic acid were not detected in the hydrolysis or aqueous photolysis studies. Degradates detected in the a quatic metabolism studies were li kely due only to hydrolysis. However, it is uncertain whether all residues were adequately characterized in the submitted soil and aquatic metabolism studies, as well as wh ether the soils/sediments and conditions ( e.g ., pH) used in the studies are representa tive of intended use sites.

In a terrestrial field dissipation study (MRI D 44180747) conducted at two sites, the parent dissipated with half-lives of 0.9 days (silt loam; pH 6.5; MD s ite) and 8.7 days (loam; pH 7.8; CA site). Degradates were not monitored in the study.

Transport and Soil Mobility

Cymoxanil is not expected to significantly vo latilize from soil or water based on its vapor pressure (1.1x10 -6 Torr) and estimated Henry’s Law Constant (3.3 x 10 -10 atm-m 3 /mol).

In four soils, cymoxanil has been shown to be mo bile to highly mobile in soil based on the FAO classification scheme and organic carbon partitioning coefficients (K oc ; in mL/g oc) of 22-138 (MRID 44180745). Based on a batch equilibriu m study, the degradat es W3595, R3273 and KQ960 are highly mobile in soil, with single point measurements of K oc ranging from 0 to 50. While the study was classified "not acceptable“ b ecause only one concentration was studied, the results did indicate that the cymoxanil degr adates are all highly mobile (44180746). The degradate U3204 was unstable in the test syst em. In an unaged leaching column study (no MRID; AMR 2724-93), parent cymoxanil, oxa mic acid (IN-18474) and IN-KP533 were all detected in leachate. In the aged leaching column from that study, oxamic acid was the only degradate detected in the leachate. The leaching of degradates was not determined in the field, as degradates were not monitored in the sing le acceptable terrestrial field dissipation study (MRID 44180747). Parent cymoxanil was not detect ed in field studies below the 0-15 cm soil depth at any of the sampling intervals.

Cymoxanil is not expected to bioconcentrate/bi oaccumulate in aquatic organisms based on the low measured Kow’s of 3.9 (pH 5) and 4.7 (pH 7). Bioconcentration in fish data have not been submitted.67 APPENDIX C: Ecotox Open Literature Studies for Cymoxanil.

Ecotox Aquatic Literature Cited

Office of Pesticide Programs. 2000. Anabaena flosaquae . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Navicula pelliculosa . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Pseudokirchneriella subcapitata. Pesticide Ecotoxicity Database (Formerly: Environmental Effects Data base (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Pseudokirchneriella subcapitata . Pesticide Ecotoxicity Database (Formerly: Environmental Effects Data base (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Skeletonema costatum . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Daphnia magna . Pesticide Ecotoxicity Database (Formerly: Environmental Effects Database (EEDB)). Envi ronmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Americamysis bahia . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Cyprinodon variegates . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Cyprinus carpio . Pesticide Ecotoxicity Database (Formerly: Environmental Effects Database (EEDB)). Envi ronmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Lepomis macrochirus . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.68 Office of Pesticide Programs. 2000. Oncorhynchus mykiss . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Oncorhynchus mykiss . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Lemna gibba . Pesticide Ecotoxicity Database (Formerly: Environmental Effects Database (EEDB)). Envi ronmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Crassostrea virginica . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Svobodova, Z., and M. Pecena. 1988. Cyprinus carpio . Changes in the Red and White Blood Picture of Carp After Acute Exposure to Toxi c Substances. Pr. Vyzk. Ustav Ryb. Hydrobiol. Vodnany17: 116-128

Svobodova, Z., and M. Pecena. 1988. Cyprinus carpio . Changes in the Red and White Blood Picture of Carp After Acute Exposure to Toxi c Substances. Pr. Vyzk. Ustav Ryb. Hydrobiol. Vodnany17: 116-128

Ecotox Terrestrial Literature Cited

Office of Pesticide Programs. 2000. Anas plat yrhynchos. Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Colinus virginianus . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Colinus virginianus . Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Anas plat yrhynchos. Pesticide Ecotoxicity Database (Formerly: Environmental Effect s Database (EEDB)). Environmental Fate and Effects Division, U.S.EPA, Washington, D.C.

Office of Pesticide Programs. 2000. Apis mellifera . Pesticide Ecotoxicity Database (Formerly: Environmental Effects Database (EEDB)). Envi ronmental Fate and Effects Division, U.S.EPA, Washington, D.C.69 Office of Pesticide Programs. 2000. Apis mellifera . Pesticide Ecotoxicity Database (Formerly: Environmental Effects Database (EEDB)). Envi ronmental Fate and Effects Division, U.S.EPA, Washington, D.C.70 APPENDIX D: Submitted Ecological Ef fects Toxicity Da ta for Cymoxanil

Data from acceptable acute 96-hour freshwater fi sh studies were submitted for rainbow trout, Oncorhynchus mykiss , (MRID 441807-17) and bluegill sunfish, Lepomis macrochirus (MRID 441807-18). For rainbow trout, sublethal effect s included dark coloration (MRID 441807-17); the resulting LC 50 value was 61 mg a.i./L with con centrations of 19, 32, 54, 90, and 150 mg a.i./L tested. The bluegill sunfish Lepomis macrochirus (most sensitive freshwater fish species tested) exhibited sublethal effects, including le thargy erratic swimming, irregulator respiration, and dark coloration; the LC 50 value was >29 mg a.i./L with concentrations measure of 19, 32, 54, 90, and 150 mg a.i./L tested. Two additional freshwater fish studies were submitted for cymoxanil technical. The first was a supp lemental acute 96-hour study carried out on the common carp ( Cyprinus carpio ) (MRID 441807-16). The resulting LC 50 value was 91 mg a.i./L when exposed at concentrations of 19, 32, 54, 90, and 150 mg a.i./L tested. Sublethal effects included fish surfacing and loss of equilibrium. The second freshwater fish study submitted on cymoxanil technical was a supplemental 21- day study carried out on rainbow trout (MRID 441807-25). Mortality was seen at the lowest treatment level (0.22 mg a.i./L) when exposed to concentrations of 0.26, 0.64, 1.6, 4.0, and 10 mg a.i/L; however, the reviewer of the study did not believe that this was treatment related. Mortality was also seen at the three highest treatment levels. In addition, sublethal effects were seen at the three highest treatment levels. These effects included, gasping, lying on the bottom, e rratic swimming, and partial loss of equilibrium. The 21-day LC 50 was determined to be 1.5 mg a.i./L.

In addition to the freshwater fish studies subm itted on cymoxanil techni cal, there were also a number of formulated product studies submitted. One supplemental study with rainbow trout was submitted on the formulated product DPX- HYZ80 31 G (26.5% metallic copper and 6.58% cymoxanil; MRID 46503802). The 96-hour LC 50 was 10 μg ai/L. Sub-lethal effects observed during the study included erratic swimming, lethargy, partial loss of equilibrium, and rapid respiration. Based on the absense of mortalit y or sub-lethal eff ectsthe NOAEC and LOAEC were 2.97 and 6.37 μg cymoxanil /L, respectively. Nevertheless, this study is confounded by the high levels of copper detected in the controls. Based on the results of this study a nd the toxicity value for cymoxanil, the formulated product is classi fied as very highly toxic to freshwater fish on an acute exposure basis. A supplemental non-guideline study was submitted on the formulated product DPX-KP481- 25 50 WG (26.6% cymoxanil and 25.4% famoxadone) using juvenile rainbow trout (MRID 461448-01). The 96-hour LC 50 for the formulated product was 9.3 μg ai/L (a.i. is cymoxanil), which categorizes the formulated product as very-highly toxic to juvenile rainbow trout on an acu te exposure basis. Sub-lethal effects included lethargy, dark coloration, and fish at the surface. No signs of to xicity were observed in either control group, or in the 8 or 14 μg/L test groups during the study. In addition, two 96-hour static acute sediment toxicitystudies of cymoxanil co-formulated wi th famoxadone were submitted for the rainbow trout. Both studies were clas sified as supplemental. One study was carried out on DPX-KP481- 25 which contained 25.63% cymoxanil and 25.0 6% famoxadone (MRID 449463-03). All test groups experienced >50% mortality; thus, an LC 50 could not be reliably calculated. The other study was carried out on the formulated pr oduct DPX-KX007-5, which contained 30.84% cymoxanil and 23.04% famoxadone (MRID 449463-02). The 96-hour LC 50 was determined to be >30 μg ai/L, with no mortalities observed at any of the treatment concentrations tested.71 Data are available for one estuarin e/marine fish, the sheepshead minnow, Cyprinodon variegatus (MRID 441807-20), resulting in a visually determined 96-hr LC 50 >47.5 mg a.i./L and a NOEC of 11.3 mg a.i./L with con centrations measured at 6.6, 11.3, 18.8, 29.0, and 47.5 mg a.i./L. Mortality and sublethal effects, including lethargy and surfacing, were observed at concentrations ≥ 18.8 mg a.i./L.

One acceptable chronic freshwater fish study on the rainbow trout ( Oncorhynchus mykiss ) (MRID 443646-10) was submitted for cymoxanil technical. The NOEC was found to be 0.98 μg a.i./L and the LOEC was 2.4 μg a. i./L, with the most sensitive e ndpoint being reduct ions in total length. In addition, another chronic study was submitted on the rainbow trout (MRID 441807- 23); however, this study was classified as supplemental because the NOEC could not be determined due to adverse effects detected at all of the treatment concentrations; effects at ≥ 0.11 mg a.i./L included erratic swimming, loss of e quilibrium, rapid respiration, lethargy, reductions in growthcompared to controls , and partial loss of equilibrium The LOEC was 0.031 mg a.i./L, which was the lowest concentration tested.

An acceptable chronic estuarine/marine fish study on the sheepshead minnow ( Cyprinodon variegatus ) (MRID 441807-26) was submitted. The NOE C was detemined to be 0.0942 mg a.i./L and the LOEC was 0.178 mg a.i./L based on reduced survival. Some of the fish observed at the two highest test concentr ations exhibited behavioral e ffects including lethargy, erratic swimming, and loss of equilibrium.

One acceptable toxicity study was submitted on fres hwater aquatic invertebrates for cymoxanil technical. The study was an acute toxicity study to the waterflea, Daphnia magna , (MRID 441807-19). The 48-hour EC 50 was 28 mg a.i./L, which classifies cymoxanil as slightly toxic to freshwater invertebrates on an acute exposure ba sis. A supplemental study was also submitted on the waterflea for the formulated product DPX-HYZ80 31 WG (6.58% cymoxanil and 26.5% copper hydroxide; MRID 465038-03) in which the 48-hour EC 50 was found to be 2.78 μg a.i./L classifying the formulated product as very highly toxic to freshwater in vertebrates on an acute exposure basis. The fact that th is endpoint is four orders of magnitude lower than for the parent may reveal that when cymoxanil is formulated w ith other compounds it increas es in toxicity. In addition, mortality or sublethal effects from cy moxanil exposure were reported for the mysid shrimp ( Americamysis bahia formerly Mysidopsis bahia ); the 96-hr LC 50 was >44.4 mg a.i./L (MRID 441807-22). This endpoint classifies cym oxanil as no more than slightly toxic to estuarine/marine invertebrates on an acute exposure basis. A study was also carried out on the Eastern oyster ( Crassostrea virginica ) (MRID 441807-21); the 96-hr EC 50 for Eastern oyster was >46.9 mg a.i./L tested. Mean shell depositi on was decreased 35% comp ared to the negative control at the highest concentra tion tested, and no additional adve rse effects were noted;he 96-hr NOAEC was 28.2 mg a.i./L based on mean shell deposition.

An acute study of waterfleas ( Daphnia magna ) was submitted on the degradate IN-KQ960 (MRID 456892-01). The 48-hour EC 50 was calculated at 0.8 mg a.i./L, which classifies INKQ960 as very highly toxic to freshwater invert ebrates on an acute exposure basis. Sub-lethal effects observed in surviving daphnia from all treatment levels including lethargy and pale coloration.72 Two acceptable chronic studies for freshwater aq uatic invertebrates have been submitted for cymoxanil technical (97.8%). One was done on the waterflea ( Daphnia magna ) (MRID 441807- 24), and resulted in a NOEC of 0.067 mg a.i./L and a LOEC of 0.15 mg a.i./L based on the survival endpoint. The other study was done on the mysid shrimp ( Mysidopsis bahia ) (MRID 441807-27) in which a NOEC of 1.70 mg a.i./L a nd a LOEC of 3.77 mg a.i./L was determined based on reduction in growth and reproduction. No chronic estuarine/marine chronic studies have been submitted.

A supplemental acute oral study on the bobwhite quail was submitted on the formulated product DPX-KX007-5 (30.4% cymoxanil; 22.7% famoxadone) resulting in an LD 50 of >684 mg a.i./L. This categorizes the formulated product, DPX-KX 007-5 as slightly toxic to birds on an acute exposure basis. Clinical signs of toxicity were seen in two males from the second to highest treatment level and one male and two female s from the highest concentration measured beginning on day 2 and day 1, respectively. Ef fects included ruffled appearance, lethargy, reduced reaction to sound and movement, wing droop, loss of coor dination, lower limb weakness, prostrate posture, loss of righting reflex, and/or coma.

An acceptable acute oral toxicity study on the la boratory rat was conducted for the registration of cymoxanil. In one study conducted on cymoxanil (96.5-97.8%) (MRID 436165-12), rats were given a single oral dose of cymoxanil technical an d were observed for 14 days. Sublethal effects in both sexes included lethargy a nd low posture, but clinical signs were resolved within one day of exposure. The combined oral 14-day LD 50 was determined to be 960 mg/kg-bw.

In a two-generation reproduction study (MRID 436165-20) rats were exposed to cymoxanil through their diet. Based on increase d pup deaths, the NOAEL and LOAEL for developmental/offspring systemic toxicity ar e 100 mg/kg-diet/day a nd 500 mg/kg-diet/day, respectively. The equivalent NOAEC for parental sy stemic toxicity is 6.5 mg/kg-bw/day. .

Cymoxanil technical is classi fied as practically non-toxi c to young adult honey bees ( Apis mellifera ) based on the one acute contact toxici ty study (MRID 441807-35). The resulting 48- hour LD 50 and NOAEL based on immobile/lethargic bees are >25 μg a.i./bee and 25 μg a.i./bee, respectively. In addition, an acceptable acute or al toxicity study was carried out on cymoxanil technical that also classified the chemical as practically non-toxic to young adult honeybees (MRID 441807-36). The resulting LC 50 and NOAEC based on immobile/lethargic bees are >1000 mg a.i./bee and 1000 mg a.i./bee, respectively.

A supplemental acute contact and acute oral study on the honeybee was submitted on the formulated product DPX-HYZ80 31 WG ( 6.58% cymoxanil and 25.5% copper hydroxide) (MRID 464776-01). This study resulted in an acute oral 72-hour LC 50 of 0.79 μg a.i./bee and 72-hour NOEL of 0.21 μg a.i./bee a nd an acute contact 72-hour LD 50 of 4.5 μg a.i./bee and 72- hour NOAEL of 0.82 μg a.i./bee. Thus, the formulated product DPX-HYZ80 31 WG is classified as very highly toxic to honeybees on an acute oral exposure basis and is moderately toxic to honeybees on an acute contact exposure basis.

An acceptable acute contact and supplemental acute oral honeybee study was submitted on the formulated product DPX-KX007-5 (30.4% cy moxanil and 22.7% famoxadone) (MRID 463504-73 02). Both the acute oral and the acute contact LD 50 was estimated at 61.4 μg a.i./bee, and as a result DPX-KX007-5 is classified as practically non-toxic to honeybees on an acute contact exposure basis.

An acceptable toxicity of residues on foliage test was submitted for the formulated product cymoxanil/famoxadone (DPX-KP481) 50 WG (1 :1) (MRID 463504-03). The study indicated that the RT 25 for cymoxanil technical was <1 hour wh en applied at a rate of 0.1875 lbs DPXKP481/acre. No sub-lethal effects were noted during the 24- hour exposure period.

A supplemental 14-day earthworm ( Eisenia fetida ) study was carried out on cymoxanil technical (MRID 442007-02). The LC 50 was 2109 mg a.i./kg dw soil and the NOAEC was 125 mg a.i./kg dw soil; however, more than 10% mortality was not ed in the control group, so results must be interpreted with caution.

A 28-day study of the formulated product DP X-HYZ80 31 WG (26.5% metallic copper and 6.58% cymoxanil) was conducted using E. fetida (MRID 464643-01). The 28-day LC 50 was determined to be >65.8 mg a.i./kg dw soil and the NOAEC was 149 mg a.i./kg dw soil.

A 7-day toxicity study of the predatory mite ( Typhlodromus pyri ) using cymoxanil technical (60%) (MRID 454754-01) found that under the conditions tested, predatory mite mortality (mean 39%) after 7 days was statistically different (p <0.05) than the contro ls (mean = 17%) following treatment at a rate equiva lent to 120 g a.i./ha.

No toxicity data have been submitted for terres trial plants. Although the cxymoxanil is used on a broad range of terrestrial plants and there are no incidents report ed involving terre strial plants, the Agency cannot be certain wit hout additional data th at terrestrial plants are not affected by cymoxanil.

TABLE 1. Ecological Effects Data for Terrestrial and Aquatic Animals

SPECIES ENDPOINT CHEMICAL/ FORMULATION MRID STUDYCLASSIFICATION COMMENTS

BIRDS Birds (Acute) Bobwhite quail (Colinus virginianus) 14-day LD 50 >2250 mg a.i./kg-bw Cymoxanil (97.8%) 441807-10 Acceptable

Mallard Duck (Anas platyrhynchos) 14-day LD 50 >2250 mg a.i./kg-bw Cymoxanil (97.8%) 441807-11 Acceptable

Bobwhite quail (Colinus virginianus) 14-day LD 50 >684 mg a.i./kg-bw DPX-KX007-5 Cymoxanil (30.4%) Famoxadone

(22.7%) 449463-18 Supplemental

Birds (Acute/Sub-Acute) Mallard Duck (Anas platyrhynchos) 8-day LC 50 >5620 mg a.i./kg-diet Cymoxanil (97.8%) 441807-12 Acceptable74 SPECIES ENDPOINT CHEMICAL/ FORMULATION MRID STUDYCLASSIFICATION COMMENTS

Bobwhite quail (Colinus virginianus) 8-day LC 50 >5620 mg a.i./kg-diet Cymoxanil (97.8%) 441807-13 Acceptable

Birds (Chronic)

Mallard Duck ( Anas platyrhynchos ) NOAEC: 100 mg a.i./kg diet LOAEC: 300 mg a.i./kg diet Cymoxanil (97.8%) 441807-15 Acceptable Endpoints based on eggs laid, eggs set, viable embryos,

live 3-week

embryos,

normal hatchlings, 14- day old survivors, and

hatchling

weight

Bobwhite quail ( Colinus virginianus ) NOAEC: 300 mg a.i./kg diet LOAEC: 1200 mg a.i./kg diet Cymoxanil (97.8%) 441807-14 Acceptable Live 3-week embryos,

normal hatchlings, 14- day survivors,

live 3-week embryos of eggs set, normal

hatchlings of

eggs laid,

normal hatchlings of eggs set, and 14-day survivors of

eggs set MAMMALS Mammals (Acute) Laboratory Rat (Rattus norvegicus) LD 50 > 960 mg a.i./kg-bw Cymoxanil (97.8%) 4 36165-12 Acceptable75 SPECIES ENDPOINT CHEMICAL/ FORMULATION MRID STUDYCLASSIFICATION COMMENTS

Mammals (Chronic)

Laboratory Rat ( Rattus norvegicus ) NOAEL: 100 mg a.i./kg-bw LOEAL:500 mg a.i./kg-bw Cymoxanil 4361 65-20 Acceptable Based on reduction in

mean bodyweight, overall body weight gain,

and food consumption in

parental (F 0 ) males; reduced

mean bodyweight during gestation and lactation of

F 1 females; decreased TERRESTRIAL INVERTEBRATES Honey Bee (oral) (Apis

melifera) LC 50 > 1000 mg a.i./bee Cymoxanil (97.8%) 441807-36 Acceptable

Honey Bee (contact) (Apis melifera) LD 50 >25 μg a.i./bee Cymoxanil (97.8%) 441807-35 Acceptable

Honey Bee (Apis melifera)

(Toxicity of Residues on Foliage Test) RT 25 : <1 hour (@0.1875 lbs DPX-Kp481/A

with a spray volume of 20 gal/A) Cymoxanil/ Famoxadone 50WG (1:1) Cymoxanil (25%)

Famoxadone (25%) 463504-03 Acceptable

Honey Bee (Apis melifera)

(acute oral/ acute contact) Acute oral: LD 50 > 61.4 μg cymoxanil/bee Acute contact: LD 50 > 61.4 μg cymoxanil/bee DPX-KX007-5 Cymoxanil (30.4%) Famoxadone

(22.7%) 463504-02 Acute Oral: Supplemental Acute Contact:

Acceptable

Honey Bee (Apis melifera) (acute oral/acute contact) Acute oral: LC 50 = 0.7896
μg cymoxanil/bee

NOAEL = 0.2118 μg cymoxanil/bee Acute contact: LD 50 = 4.474
μg cymoxanil/bee

NOAEL = 0.8225 μg cymoxanil/bee DPX-HYZ80 31 WG Cymoxanil (6.58%) Copper Hydroxide (25.5%) 464776-01 Acute Oral: Supplemental Acute Contact: Supplemental Study carried
out on Formulated Product, not AI, so does not fulfill guideline

requirement76 SPECIES ENDPOINT CHEMICAL/ FORMULATION MRID STUDYCLASSIFICATION COMMENTS

Earthworm ( Eisenia fetida ) 14-day LC 50 : 2109 mg a.i./L Cymoxanil (>96.0%) 442007-02 Supplemental >10% mortality in the controls

Earthworm ( Eisenia fetida ) 28-day LC 50 : >65.8 mg a.i./kg dw soil NOAEC: 149 mg a.i./kg dw soil DPX-HYZ80 31 WG Metallic Copper (26.5%) Cymoxanil (6.58%) 464643-01 Supplemental Study carried
out on Formulated Product, not AI, so does not fulfill guideline

requirement

Predatory Mite ( Typhlodromus pyri ) 7-days: No statistical difference seen at 9 g a.i./ha for growth or reproduction;

however, statistical difference were

seen at 120 g a.i./acre Cymoxanil (60%) 454754-01 Supplemental

FRESHWATER FISH Freshwater Fish (Acute) Common Carp

( Cyprinus

carpio ) 96-hr LC 50 : 91 mg a.i./L Cymoxanil (97.8%) 441807-16 Supplemental

Rainbow Trout (Oncorhynchus mykiss) 96-hr LC 50 : 61 mg a.i./L Cymoxanil (97.8%) 441807-17 Acceptable

Rainbow Trout (Oncorhynchus mykiss) 96-hr LC 50 : 10.3 μg a.i./L DPX-HYZ80 31 WG Metallic Copper (26.5%) Cymoxanil (6.58%) 465038-02 Supplemental Study carried
out on Formulated Product, not AI, so does not fulfill guideline

requirement Rainbow Trout (Oncorhynchus mykiss) 21-day LC 50 : 1.5 mg a.i./L Cymoxanil (97.8%) 441807-25 Supplemental

Bluegill Sunfish (Lepomis macrochirus) 96-hr LC 50 : 29 mg a.i./L Cymoxanil (97.8%) 441807-18 Acceptable

Rainbow Trout (Oncorhynchus mykiss) 96-hr LC 50 : 9.3 μg a.i./L DPX-KP481-25 50 WG Famoxadone DPX-JE874(25.4%); DPXT3217 Cymoxanil (26.6%) 461448-01 Acceptable Study carried
out on Formulated Product, not AI, so does not fulfill guideline

requirement Freshwater Fish (Chronic)77 SPECIES ENDPOINT CHEMICAL/ FORMULATION MRID STUDYCLASSIFICATION COMMENTS

Rainbow Trout ( Oncorhynchus mykiss ) NOEC: Not Determined LOEC: 0.031

mg a.i./L Cymoxanil (97.3%) 441807-23 Supplemental

Rainbow Trout ( Oncorhynchus mykiss ) NOEL: 0.98 μg a.i./L LOEL: 2.4 μg a.i./L Cymoxanil (97.3%) 443646-10 Acceptable Based on total length

ESTUARINE/MARINE FISH Estuarine/Marine Fish (Acute) Sheepshead

Minnow ( Cyprinodon variegatus ) 96-hr LC 50 > 47.5 mg a.i./L Cymoxanil (97.8%) 441807-20 Acceptable

Estuarine/Marine Fish (Chronic) Sheepshead

Minnow ( Cyprinodon variegatus ) NOEC: 0.0942 mg a.i./L Cymoxanil (97.8%) 441807-26 Acceptable Based on survival at test

termination

FRESHWATER INVERTEBRATES

Freshwater Invertebrates (Acute) Waterflea (Daphnia magna) 48-hr EC 50 : 28 mg a.i./L Cymoxanil (97.8%) 441807-19 Acceptable

Waterflea (Daphnia magna) 48-hr EC 50 : 2.78 μg a.i./L DPX-HYZ80 31 WG Cymoxanil (6.58%) Copper Hydroxide (26.5%) 465038-03 Supplemental Study carried
out on Formulated Product, not AI, so does not fulfill guideline

requirement Freshwater Invertebrates (Chronic)

Waterflea (Daphnia magna) NOEC: 0.067 mg a.i./L LOEC: 0.15 mg a.i./L Cymoxanil (97.8%) 441807-24 Acceptable Based on survival

ESTUARINE/MARINE INVERTEBRATES Estuarine/Marine Invertebrate (Acute) Eastern Oyster (Crassostrea

virginica) 96-hr EC 50 > 46.9 mg a.i./L Cymoxanil (97.8%) 441807-21 Acceptable

Mysid Shrimp (Americamysis bahia) 96-hr LC 50 > 44.4 mg a.i./L Cymoxanil (97.8%) 441807-22 Acceptable78 SPECIES ENDPOINT CHEMICAL/ FORMULATION MRID STUDYCLASSIFICATION COMMENTS

Estuarine/Marine Invertebrate (Chronic)

Mysid ( Mysidopsis bahia ) NOEC: 1.70 mg a.i./L LOEC: 3.77 mg a.i./L Cymoxanil (97.8%) 441807-27 Acceptable Based on number of young/female, male and female length, and female dry weight.

An acceptable Tier I toxicity study on the green alga, Psuedokirchneriella subcapitata (formerly Selenastrum capricornatum ; MRID 441807-30) was submitted for cymoxanil technical using DPX-T3217-113 Cymoxanil yielding an 120-hr IC 50 >1,050 μg a.i/L the maximum growth inhibition was 23.3%. In addition, an acceptable Ti er 1 toxicity study on the saltwater diatom ( Skeletonema costatum ) (MRID 441807-31) was submitted for cymoxanil technical again resulted in an IC 50 >920 μg a.i./L; the maximu m inhibition was 1.50%.

An acceptable Tier II toxicity study was submitted for cymoxanil technical on the cyanobacteria ( Anabaena flos-aquae ) (MRID 441807-29) with a 120-hour EC 50 of 230 μg a.i./L and a NOAEC of 65 μg a.i./L. In addition, an acceptable Tier II study with the freshwater diatom ( Navicula pelliculosa ) (MRID 441807-32) was submitted with a 120-hour EC 50 of 200 μg a.i./L and a NOAEC of 63 μg a.i./L (most sensitive e ndpoint for non-vascular aquatic plants).

A Tier II study of cymoxanil techni cal (MRID 441807-33) was conducted with P. subcapitata

. The study is classified as supplemental. The 120-hour EC 50 was 4,110 μg a.i./L and the NOAEC was 62.5 μg a.i./L.

Another Tier II study (MRID 465038- 01) that was carried out on P. subcapitata was submitted on the formulated product DPX- HYZ80 31 WG (6.58% cymoxanil a nd 26.5% metallic copper as copper hydroxide). The 120-hr IC 50 (9.4 μg ai/L) and NOAEC (5.13 μg a.i./L) are based on plant biomass. This study was confounded by coppe r in the controls; how ever, it is uncertain whether the contamination affected the power of the study to detect treatment effects.

A Tier 1 study on cymoxanil was conducted on the aquatic vascular plant duckweed, Lemna gibba , with the technical grade active ingredient (MRID 441807-28) . The study was classified as acceptable and resulted in an IC 50 >794 μg a.i./L.

TABLE 2. Ecological Effects Data for Plants

SPECIES ENDPOINT CHEMICAL/ FORMULATION (percent a.i.) MRID STUDYCLASSIFICATION COMMENTS

Aquatic Nonvascular Plants79 Green Alga ( Psuedokirchneriella subcapitata, reported as Selenastrum capricornutum Printz) 120 hr-23.3% growth inhibition at 1050 μg a.i./L (Tier 1) Cymoxanil (97.3%) 44180730 Acceptable

Green Alga ( Psuedokirchneriella subcapitata ) 72 hr-Cell Density: EC 05 : 5.2 μg a.i./L EC 50 : 9.5 μg a.i./L NOAEC: 5.13 μg a.i./L Biomass: EC 05 : <5.13 μg a.i./L EC 50 : 9.4 μg a.i./L NOAEC: 5.13 μg a.i./L Growth Rate: EC 05 : 6.9 μg a.i./L EC 50 : 16 μg a.i./L NOAEC: 7.88 μg a.i./L DPX-HYZ80 31 WG Cymoxanil

(6.58%) Metallic Copper (26.5%) 46503801 Supplemental Study carried
out on Formulated Product, not AI, so does not fulfill guideline

requirement

Freshwater Diatom ( Navicula pelliculosa ) 120-hr EC 50 = 202 μg a.i./L NOAEC = 63.3 μg a.i./L Cymoxanil (97.3%) 44180732 Acceptable

Saltwater Diatom

( Skeletonema

costatum ) 120 hr-1.50% growth inhibition at 916 μg a.i./L (Tier 1) Cymoxanil (97.3%) 44180731 Acceptable

Cyanobacteria (Anabaena flosaquae ) 120-hr EC 50 = 231 μg a.i./L NOAEC = 65.2 μg a.i./L Cymoxanil (97.3%) 44180729 Acceptable

Green Alga ( Psuedokirchneriella subcapitata, reported as Selenastrum capricornutum Printz) 120-hr EC 50 = 4.11 mg a.i./L

NOAEC = 0.625 mg a.i./L Cymoxanil (95%) 44180733 Supplemental80 Aquatic Vascular Plants

Duckweed ( L. gibba ) (Tier 1) 14 day- 0% frond growth inhibition when

compared to the control Cymoxanil (97.27%) 44180728 Acceptable

Cymoxanil Ecological Effects Data for Terrestrial Plants None Available

TABLE 3. Degradate Ecological Effects Data

SPECIES ENDPOINT CHEMICAL/ FORMULATI

ON (percent a.i.) MRID STUDYCLASSIFICATION COMMENTS

Freshwater Invertebrates (Acute) Waterflea (Daphnia magna) 48-hr EC 50 : 0.8 mg a.i./L IN-KQ960 Cymoxanil

(94.6%) 45689201 Acceptable Carried out on the Degradate

IN-KQ960

A supplemental non-guideline extended laborat ory two month study on the predatory mite ( Typhlodromus pyri ) was also carried out for the fo rmulated products DPX-KP007 (8.3% famoxadone and 12% cymoxanil) and DPX- KX007 WG (22.7% famoxadone and 30.4% cymoxanil) (MRID 449672-02). Juvenile mortality in treated groups was similar or higher than that seen in control groups; how ever, the majority of mites in the treated groups developed much slower than in the control group. Despite relatively low mortalit y in the first week, the total effect in all treatments was high. The eff ect on reproduction was caused by both failure to develop to the adult stage and by poor reprodu ctive performance in surviving females.

Two supplemental/non-guideline studies were carried out on the formulated product DPXKP481-25 (cymoxanil 26.6% and famoxadone 25.4%) on the ground beetle ( Poecilus cupreus ). The first, 15-day acute study, (MRID 449463-30) was carried out to determine the effect of the formulated product under worst case laborat ory conditions. The s econd, 3 month extended laboratory study (MRID 449463-33), was carriedout to determine the effects on Poecilus
cupreus when exposed on field grown potatoes. Both studies were carried out at an application rate that included 0.175 cymoxanil/ha. Both stud ies found no significant reduction in survival or feeding capacity when compared to the c ontrol survival and feeding rates.

In addition, two other supplemen tal/non-guideline studies were ca rried out on the formulated product DPX-KP481-25 (cymoxanil 26.6% and famoxadone 25.4%) on the hoverfly ( Ephisyrphus balteatus ). The first, an acute toxicity study (MRID 449463-29) lasted 6 weeks, and the second, an extended laboratory study (MRI D 449463-32) lasted 4 months . Both tested at an application rate that included 0.175 cym oxanil/ha. The first study found no significant reductions in survival; however, there was a si gnificant reducti on (33.5%) in reproduction rate (percent fertile eggs/female) when compared to the control. The second study found no significant reduction in survival when comp ared to control survival after the 3 rd or 6 th application. However, there was a reduction in fecundity rates (eggs/female/day and in egg viability), compared to the control, after the 3 rd and 6 th applications (10 day intervals for applications).81 A supplemental/non-guideline 8-week acute study was also carried out on the formulated product DPX-KP481-25 (25.4% famoxadone and 26.6% cymoxanil) for the green lacewing, ( Chrysoperla carnea ). Tested at an application rate that included 0.175 cymoxanil/ha, there was no significant reduction in surviv al or reproduction when compared to control survival or reproduction.

Finally, a supplemental/non-guidelin e 4.5 month semi-field study looki ng at the toxicity of DPXKP481-25 to aphid parasitoids ( Aphidius colmani ) was submitted. The purpose of the study was to determine the effects of DPX-KP481-25 on aphi d parasitoids when exposed to fresh residues in a potato crop. The crop was treated on nine 10 -day intervals, and statistical analysis was attempted by the reviewer for analysis. Howeve r, during the study, treatme nt applications and methods were altered because of the spread of potato blight. Thus, it was determined by the reviewer that the results of the study were inconclusive, and the effect of DPX-KP481-25 to aphid parasitoids ( Aphidius colmani ) could not be determined.

TABLE 4. Non-Guideline Ec ological Effects Data
Non-Guideline Studies Co-formulated with Famoxadone

SPECIES ENDPOINT CHEMICAL/ FORMULATION

(percent active

ingredient) MRID STUDY CLASSIFICATION

Ground Beetle ( Poecilus cuperus ) At an application rate of 0.16 lbs ai/acre or 0.175 kg ai/acre, no

significant reduction in survival or feeding rates when compared to control survival and feeding rates DPX-KP481-25 (TEP) Cymoxanil

(26.6%) Famoxadone

(25.4%) 44946330 Supplemental

Ground Beetle ( Poecilus cuperus ) At an application rate of 0.16 lbs ai/acre or 0.175 kg ai/acre, no

significant reduction in survival or feeding capacity when compared to control after the 1 st , 4 th , 6 th , or

9 th application. (10 day interval for applications) DPX-KP481-25 (TEP) Cymoxanil

(26.6%) Famoxadone

(25.4%) 44946333 Supplemental82 Green Lacewing

( Chrysoperla

carnea ) At an application rate of 0.16 lbs ai/acre or 0.175 kg ai/acre, no

significant reduction in survival or reproduction when compared to control survival and reproduction DPX-KP481-25 (TEP) Cymoxanil

(26.6%) Famoxadone

(25.4%) 44946328 Supplemental

Hoverfly ( Episyrphus

balteatus ) At an application rate of 0.16 lbs ai/acre or 0.175 kg ai/acre, no

significant reduction in

survival; however, significant reduction (33.5%) in reproduction rate

(percent fertile eggs/female) when compared to control existed DPX-KP481-25 (TEP) Cymoxanil

(26.6%) Famoxadone

(25.4%) 44946329 Supplemental

Hoverfly ( Episyrphus

balteatus ) At an application rate of 0.16 lbs ai/acre or 0.175 kg ai/acre, no

significant reduction in survival when compared to control survival after the 3 rd and 6 th application. However, there was a reduction

in fecundity rates, (eggs/female/day/

and in the egg

viability), compared to the control after the 3X and 6X application (10 day interval for applications). DPX-KP481-25 (TEP) Cymoxanil (25.50%) Famoxadone

(25.24%) 449463-32 Supplemental83 Predatory Mite ( Typhlordomus pyri ) Juvenile mortality in treated groups was similar or higher than in the

control group. The majority of

mites in the treatment group developed much slower than the control group. Low mortality in

the first week, but total effect on

all treatments was high. Effect on reproduction was seen in both failure to develop to adult stage and
poor reproduction performance of surviving females. DPX-KX007 SC (TEP) (12% cymoxanil; 8.3%

famoxadone)

DPX-KX007 WG

(TEP) (30.4% cymoxanil; 22.7% famoxadone) 44967202 Supplemental

Aphid Parasitoid ( Aphidius colmani ) Inconclusive Results DPX-KP481-25 (TEP) Cymoxanil (25.50%) Famoxadone

(25.24%) 44946334 Supplemental

Rainbow Trout ( Oncorhynchus mykiss ) 96-hour Static Acute Tox in Presence of Sediment. All test groups

experienced >50% mortality;

thus, no LC 50 could be reliably calculated DPX-KP481-25 (TEP) Cymoxanil (25.63%) Famoxadone

(25.08%) 44946303 Supplemental

Rainbow Trout ( Oncorhynchus mykiss ) 96-hour Static Acute Tox in Presence of Sediment: 96-hr

LC 50 > 30 μg a.i./L NOEL: 30 μg a.i./L DPX-KX007-5 (TEP) Cymoxanil (30.84%) Famoxadone

(23.04%) 44946302 Supplemental84 APPENDIX E: Output from ECOSAR for Cymoxanil and its Major Degradates

ECOSAR Version 1.10 Results Page Parent Cymoxanil SMILES : O=C(NCC)NC(=O)C(=NOC)C(#N) CHEM : Acetamide, 2-cyano-N- (ethylamino)carbonyl -2-(methoxyimino)- CAS Num: 057966-95-7 ChemID1: MOL FOR: C7 H10 N4 O3 MOL WT : 198.18 Log Kow: 4.244 (EPISuite Kowwin v1.68 Estimate) Log Kow: 0.672 (User Entered) Log Kow: 0.59 (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: 160.50 (deg C, PhysPr op DB exp value for Wat Sol est) Wat Sol: 2993 (mg/L, EPISuite WSKowwin v1.43 Estimate) Wat Sol: 780 (mg/L, User Entered) Wat Sol: 890 (mg/L, PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ---------- Log Kow: 0.672 (User Entered) Wat Sol: 780 (mg/L, User Entered)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

Measured CAS No Organism Durati on End Pt mg/L (ppm) Ecosar Class Reference

=========== ========== ========== ====== ==========

========================= == ========================= 057966-95-7 Daphnid ChV 0.1 Carbonyl Urea OPP Pesticide Ecotoxicity DB 057966-95-7 Daphnid 48-hr LC50 0.8 Carbonyl Urea OPP Pesticide Ecotoxicity DB 057966-95-7 Fish ChV 0.0015 Carbonyl Urea OPP Pesticide Ecotoxicity DB 057966-95-7 Fish 96-hr LC50 29 Carbonyl Urea OPP Pesticide Ecotoxicity DB; LC50>SH2 057966-95-7 Fish 96-hr LC50 61 Carbonyl Urea OPP Pesticide Ecotoxicity DB; LC50>SH285 057966-95-7 Fish (SW) ChV 0.12 Carbonyl Urea OPP Pesticide Ecotoxicity DB 057966-95-7 Mysid ChV 2.5 Carbonyl Urea OPP Pesticide Ecotoxicity DB

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Aliphatic Amines Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Aliphatic Amines : Fish 96-hr LC50 283.832 Aliphatic Amines : Daphnid 48-hr LC50 28.993 Aliphatic Amines : Green Algae 96-hr EC50 32.469 Aliphatic Amines : Fish ChV 26.457 Aliphatic Amines : Daphnid ChV 2.050 Aliphatic Amines : Green Algae ChV 9.643

Carbonyl Ureas : Fish 96-hr LC50 133.595 Carbonyl Ureas : Daphnid 48-hr LC50 144.144 Carbonyl Ureas : Green Algae 96-hr EC50 0.015 Carbonyl Ureas : Fish ChV 0.961 Carbonyl Ureas : Daphnid ChV 3.379 Carbonyl Ureas : Green Algae ChV 0.004 Carbonyl Ureas : Fish (SW) 96-hr LC50 116.724 Carbonyl Ureas : Mysid (SW) 96-hr LC50 496.004 Carbonyl Ureas : Fish (SW) ChV 3.503

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 2537.129 * (Baseline Toxicity) : Daphnid 48-hr LC50 1043.315 * : Green Algae 96-hr EC50 960.274 * : Fish ChV 214.599 : Daphnid ChV 88.346 : Green Algae ChV 113.951

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.86 ------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Aliphatic Amines:

---------------- Maximum LogKow: 6.0 (Fish, Mysid LC50) Maximum LogKow: 5.0 (Daphnid LC50) Maximum LogKow: 7.0 (Green Algae EC50) Maximum LogKow: 8.0 (Fish, Daphnid ChV) Maximum LogKow: 7.0 (Green Algae ChV)

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV) IN-U3204 SMILES : O=C1(C(C(N(C (=O)(N1))CC)=N)=NOC) CHEM : CAS Num: ChemID1: MOL FOR: C7 H10 N4 O3 MOL WT : 198.18 Log Kow: 0.393 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 2.063E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: (PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ----------87 Log Kow: 0.393 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 2.063E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Aliphatic Amines Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Aliphatic Amines : Fish 96-hr LC50 432.812 Aliphatic Amines : Daphnid 48-hr LC50 42.801 Aliphatic Amines : Green Algae 96-hr EC50 51.107 Aliphatic Amines : Fish ChV 44.535 Aliphatic Amines : Daphnid ChV 2.932 Aliphatic Amines : Green Algae ChV 14.828

Carbonyl Ureas : Fish 96-hr LC50 191.132 Carbonyl Ureas : Daphnid 48-hr LC50 274.088 Carbonyl Ureas : Green Algae 96-hr EC50 0.015 Carbonyl Ureas : Fish ChV 1.376 Carbonyl Ureas : Daphnid ChV 5.135 Carbonyl Ureas : Green Algae ChV 0.004 Carbonyl Ureas : Fish (SW) 96-hr LC50 166.983 Carbonyl Ureas : Mysid (SW) 96-hr LC50 1177.595 Carbonyl Ureas : Fish (SW) ChV 4.547

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 4516.715 (Baseline Toxicity) : Daphnid 48-hr LC50 1761.627 : Green Algae 96-hr EC50 1618.813 : Fish ChV 370.609 : Daphnid ChV 142.678 : Green Algae ChV 167.82988 Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.

------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Aliphatic Amines:

---------------- Maximum LogKow: 6.0 (Fish, Mysid LC50) Maximum LogKow: 5.0 (Daphnid LC50) Maximum LogKow: 7.0 (Green Algae EC50) Maximum LogKow: 8.0 (Fish, Daphnid ChV) Maximum LogKow: 7.0 (Green Algae ChV)

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV) IN-W3595 ECOSAR Version 1.10 Results Page

SMILES : C(C(=O)(O))(=NOC)C(#N) CHEM : CAS Num: ChemID1: MOL FOR: C4 H4 N2 O3 MOL WT : 128.09 Log Kow: 4.270 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 52.43 (mg/L, EPISuite WSKowwin v1.43 Estimate)89 Wat Sol: (User Entered) Wat Sol: (PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ---------- Log Kow: 4.270 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 52.43 (mg/L, EPISuite WSKowwin v1.43 Estimate)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Aliphatic Amines Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Aliphatic Amines : Fish 96-hr LC50 0.794 Aliphatic Amines : Daphnid 48-hr LC50 0.123 Aliphatic Amines : Green Algae 96-hr EC50 0.060 Aliphatic Amines : Fish ChV 0.021 Aliphatic Amines : Daphnid ChV 0.013 Aliphatic Amines : Green Algae ChV 0.024

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 0.963 (Baseline Toxicity) : Daphnid 48-hr LC50 0.784 : Green Algae 96-hr EC50 0.736 : Fish ChV 0.121 : Daphnid ChV 0.118 : Green Algae ChV 0.499

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.90 ------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Aliphatic Amines:

---------------- Maximum LogKow: 6.0 (Fish, Mysid LC50) Maximum LogKow: 5.0 (Daphnid LC50) Maximum LogKow: 7.0 (Green Algae EC50) Maximum LogKow: 8.0 (Fish, Daphnid ChV) Maximum LogKow: 7.0 (Green Algae ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV) IN-R3273 ECOSAR Version 1.10 Results Page

SMILES : O=C1(C(N(C(=O)(N1))CC)=NOC) CHEM : CAS Num: ChemID1: MOL FOR: C6 H9 N3 O3 MOL WT : 171.16 Log Kow: 2.072 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 1033 (mg/L, EPISuite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: (PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ---------- Log Kow: 2.072 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 1033 (mg/L, EPISuite WSKowwin v1.43 Estimate)91 ------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Aliphatic Amines Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Aliphatic Amines : Fish 96-hr LC50 29.493 Aliphatic Amines : Daphnid 48-hr LC50 3.545 Aliphatic Amines : Green Algae 96-hr EC50 2.877 Aliphatic Amines : Fish ChV 1.674 Aliphatic Amines : Daphnid ChV 0.294 Aliphatic Amines : Green Algae ChV 0.961

Carbonyl Ureas : Fish 96-hr LC50 19.118 Carbonyl Ureas : Daphnid 48-hr LC50 4.947 Carbonyl Ureas : Green Algae 96-hr EC50 0.013 Carbonyl Ureas : Fish ChV 0.137 Carbonyl Ureas : Daphnid ChV 0.357 Carbonyl Ureas : Green Algae ChV 0.003 Carbonyl Ureas : Fish (SW) 96-hr LC50 16.709 Carbonyl Ureas : Mysid (SW) 96-hr LC50 5.586 Carbonyl Ureas : Fish (SW) ChV 0.817

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 121.202 (Baseline Toxicity) : Daphnid 48-hr LC50 65.002 : Green Algae 96-hr EC50 60.312 : Fish ChV 11.940 : Daphnid ChV 6.882 : Green Algae ChV 14.096

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES)92 are reported.

------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Aliphatic Amines:

---------------- Maximum LogKow: 6.0 (Fish, Mysid LC50) Maximum LogKow: 5.0 (Daphnid LC50) Maximum LogKow: 7.0 (Green Algae EC50) Maximum LogKow: 8.0 (Fish, Daphnid ChV) Maximum LogKow: 7.0 (Green Algae ChV)

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV) IN-KP533 ECOSAR Version 1.10 Results Page

SMILES : C(N(C(=O)(N(C(=O)(C(=O)O)))))C CHEM : CAS Num: ChemID1: MOL FOR: C5 H8 N2 O4 MOL WT : 160.13 Log Kow: -1.285 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 4.192E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: (PhysProp DB exp value)93 --------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ---------- Log Kow: -1.285 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 4.192E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Carbonyl Ureas : Fish 96-hr LC50 1333.035 Carbonyl Ureas : Daphnid 48-hr LC50 10591.899 Carbonyl Ureas : Green Algae 96-hr EC50 0.012 Carbonyl Ureas : Fish ChV 9.653 Carbonyl Ureas : Daphnid ChV 51.480 Carbonyl Ureas : Green Algae ChV 0.003 Carbonyl Ureas : Fish (SW) 96-hr LC50 1164.161 Carbonyl Ureas : Mysid (SW) 96-hr LC50 1.73e+005 * Carbonyl Ureas : Fish (SW) ChV 17.666

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 1.17e+005 * (Baseline Toxicity) : Daphnid 48-hr LC50 33302.348 : Green Algae 96-hr EC50 30308.281 : Fish ChV 8024.026 : Daphnid ChV 2063.463 : Green Algae ChV 1393.932

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.94 ------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV) IN-JX915 ECOSAR Version 1.10 Results Page

SMILES : O=C1N(C(C(=O)N1)(C(#N))NOC)CC CHEM : CAS Num: ChemID1: MOL FOR: C7 H10 N4 O3 MOL WT : 198.18 Log Kow: -0.366 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 2441 (mg/L, EPISuite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: (PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ---------- Log Kow: -0.366 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 2441 (mg/L, EPISuite WSKowwin v1.43 Estimate)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set95 ------------------ ------------------ ------------

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Aliphatic Amines Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Aliphatic Amines : Fish 96-hr LC50 1364.051 Aliphatic Amines : Daphnid 48-hr LC50 123.499 Aliphatic Amines : Green Algae 96-hr EC50 175.589 Aliphatic Amines : Fish ChV 183.659 Aliphatic Amines : Daphnid ChV 7.764 Aliphatic Amines : Green Algae ChV 47.806

Carbonyl Ureas : Fish 96-hr LC50 506.427 Carbonyl Ureas : Daphnid 48-hr LC50 1574.787 Carbonyl Ureas : Green Algae 96-hr EC50 0.015 Carbonyl Ureas : Fish ChV 3.656 Carbonyl Ureas : Daphnid ChV 16.031 Carbonyl Ureas : Green Algae ChV 0.004 Carbonyl Ureas : Fish (SW) 96-hr LC50 442.364 Carbonyl Ureas : Mysid (SW) 96-hr LC50 12377.822 * Carbonyl Ureas : Fish (SW) ChV 9.248

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 21692.068 * (Baseline Toxicity) : Daphnid 48-hr LC50 7326.005 * : Green Algae 96-hr EC50 6702.749 * : Fish ChV 1638.714 : Daphnid ChV 525.683 : Green Algae ChV 481.223

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.96 ------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Aliphatic Amines:

---------------- Maximum LogKow: 6.0 (Fish, Mysid LC50) Maximum LogKow: 5.0 (Daphnid LC50) Maximum LogKow: 7.0 (Green Algae EC50) Maximum LogKow: 8.0 (Fish, Daphnid ChV) Maximum LogKow: 7.0 (Green Algae ChV)

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV) IN-KQ960 ECOSAR Version 1.10 Results Page

SMILES : O=C1(N(C(C(= O)(N1))(C(=O)N)NOC)CC) CHEM : CAS Num: ChemID1: IN-KQ960 MOL FOR: C7 H12 N4 O4 MOL WT : 216.20 Log Kow: -1.636 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 4.409E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: (PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile97 --------------- ------------- ---------- Log Kow: -1.636 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 4.409E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Aliphatic Amines Amides Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Aliphatic Amines : Fish 96-hr LC50 10171.875 Aliphatic Amines : Daphnid 48-hr LC50 794.452 Aliphatic Amines : Green Algae 96-hr EC50 1512.983 Aliphatic Amines : Fish ChV 2148.461 Aliphatic Amines : Daphnid ChV 43.264 Aliphatic Amines : Green Algae ChV 370.316

Amides : Fish 96-hr LC50 25731.789 Amides : Daphnid 48-hr LC50 1.51e+005 * Amides : Green Algae 96-hr EC50 369.274 Amides : Fish ChV 5.078 Amides : Daphnid ChV 769.602 Amides : Green Algae ChV 74.813 Amides : Fish (SW) 96-hr LC50 21906.361 Amides : Mysid (SW) 96-hr LC50 439.944

Carbonyl Ureas : Fish 96-hr LC50 2824.336 Carbonyl Ureas : Daphnid 48-hr LC50 32099.426 Carbonyl Ureas : Green Algae 96-hr EC50 0.016 Carbonyl Ureas : Fish ChV 20.477 Carbonyl Ureas : Daphnid ChV 117.670 Carbonyl Ureas : Green Algae ChV 0.004 Carbonyl Ureas : Fish (SW) 96-hr LC50 2466.339 Carbonyl Ureas : Mysid (SW) 96-hr LC50 6.94e+005 *98 Carbonyl Ureas : Fish (SW) ChV 33.119

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 3.28e+005 * (Baseline Toxicity) : Daphnid 48-hr LC50 86912.406 * : Green Algae 96-hr EC50 78938.883 * : Fish ChV 21543.480 : Daphnid ChV 5091.974 : Green Algae ChV 3063.213

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.

------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Aliphatic Amines:

---------------- Maximum LogKow: 6.0 (Fish, Mysid LC50) Maximum LogKow: 5.0 (Daphnid LC50) Maximum LogKow: 7.0 (Green Algae EC50) Maximum LogKow: 8.0 (Fish, Daphnid ChV) Maximum LogKow: 7.0 (Green Algae ChV)

Amides :

------- Maximum LogKow: >8.5 (LC50) Maximum LogKow: >8.0 (EC50,ChV)

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50)99 Maximum LogKow: 8.0 (ChV) IN-T4226 ECOSAR Version 1.10 Results Page

SMILES : O=C1(C(=O)(N(C(=O)(N1))CC)) CHEM : CAS Num: ChemID1: MOL FOR: C5 H6 N2 O3 MOL WT : 142.12 Log Kow: 0.162 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 5.961E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: (PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ---------- Log Kow: 0.162 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 5.961E+004 (mg/L, EPIS uite WSKowwin v1.43 Estimate)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Carbonyl Ureas : Fish 96-hr LC50 184.319 Carbonyl Ureas : Daphnid 48-hr LC50 334.446 Carbonyl Ureas : Green Algae 96-hr EC50 0.011 Carbonyl Ureas : Fish ChV 1.328100 Carbonyl Ureas : Daphnid ChV 5.205 Carbonyl Ureas : Green Algae ChV 0.003 Carbonyl Ureas : Fish (SW) 96-hr LC50 161.022 Carbonyl Ureas : Mysid (SW) 96-hr LC50 1726.573 Carbonyl Ureas : Fish (SW) ChV 4.046

========================= == ================== ======== ======

========== Neutral Organic SAR : Fish 96-hr LC50 5219.018 (Baseline Toxicity) : Daphnid 48-hr LC50 1948.366 : Green Algae 96-hr EC50 1788.037 : Fish ChV 417.609 : Daphnid ChV 152.098 : Green Algae ChV 165.779

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.

------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

------------------ --------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV)

Oxalic Acid ECOSAR Version 1.10 Results Page

SMILES : O=C(O)C(=O)O CHEM : Ethanedioic acid CAS Num: 000144-62-7 ChemID1:101 MOL FOR: C2 H2 O4 MOL WT : 90.04 Log Kow: -1.737 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value - for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: 189.50 (deg C, PhysProp DB exp value for Wat Sol est, 189.5 dec) Wat Sol: 1E+006 (mg/L, EPISuite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: 1350 (mg/L, PhysProp DB exp value)

--------------- ------------- ---------- Values used to Generate ECOSAR Profile

--------------- ------------- ---------- Log Kow: -1.737 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 1350 (mg/L, PhysProp DB exp value)

------------------ ------------------ ------------ Available Measured Data from ECOSAR Training Set

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

No Data Available

--------------- ------------- ---------- ECOSAR v1.1 Class-sp ecific Estimations

--------------- ------------- ---------- Neutral Organics Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

========================= == ================== ======== ======

========== Neutral Organics : Fish 96-hr LC50 1.68e+005 * Neutral Organics : Fish 14-day LC50 1.47e+005 * Neutral Organics : Daphnid 48-hr LC50 67876.813 * Neutral Organics : Green Alga e 96-hr EC50 39658.563 * Neutral Organics : Fish ChV 10917.655 * Neutral Organics : Daphnid ChV 2519.062 * Neutral Organics : Green Algae ChV 1466.058 * Neutral Organics : Fish (SW) 96-hr LC50 2.07e+005 * Neutral Organics : Mysid 96-hr LC50 1.93e+006 * Neutral Organics : Fish (SW) ChV 2289.450 * Neutral Organics : Mysid (SW) ChV 5.05e+005 * Neutral Organics : Earthworm 14-day LC50 382.024102 Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted e ffect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.

------------------ ------------ Class Specific LogKow Cut-Offs

------------------ ------------ If the log Kow of the chemical is grea ter than the endpoint specific cut-offs presented below, then no effects at sa turation are expected for those endpoints.

Neutral Organics:

---------------- Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50, Mysid LC50) Maximum LogKow: 6.0 (Fish 14-day LC50; Earthworm LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV)103 APPENDIX F: Screening Imbibition Program (SIP) v.1.0 and Screening Tool for Inhalation Risk (STIR) v.1.0 Descriptio n, Assumptions, Inputs and Outputs

SIP v.1.0

SIP v.1.0 provides an upper bound estimate of ex posure of birds and mammals to pesticides through drinking water alone. This model is intended for use in problem formulation to determine whether or not drinking water exposure alone is a po tential pathway of concern. This does not aggregate drinking water exposure with other exposure routes (i.e., diet, inhalation, dermal).

Assumptions:

SIP employs the following conservative assumptions to derive upper bound exposure estimates: 1) The chemical concentration in drinking wate r is at the solubility limit in water (at 25 o C). 2) The assessed animals obtain 100% of thei r daily water needs through drinking water. 3) The daily water need is equivalent to the da ily water flux rate as calculated by Nagy and Peterson (1988). 4) The body weight of the assessed bird is equiva lent to the smallest generic bird modeled in T-REX (i.e., 20 g). This assumpti on results in the highest ratio of exposure to toxicity for the 3 assessed avian body weights of T-REX (i.e., 20, 100, 1000 g). 5) The body weight of the assessed mammal is equivalent to the largest generic mammal modeled in T-REX (i.e., 1000 g). This results in the highest ratio of exposure to toxicity for the 3 assessed mammalian body weights of T-REX (i.e., 15, 35, 1000 g).

Table 1. Inputs

Parameter Value
Chemical name Cymoxanil Solubility (in water at 25 o C; mg/L) 890

Mammalian LD 50 (mg/kg-bw) 960 Mammalian test species laboratory rat Body weight (g) of "other" mammalian species

Mammalian NOAEL (mg/kg-bw) 100 Mammalian test species laboratory rat Body weight (g) of "other" mammalian species

Avian LD 50 (mg/kg-bw) 2250 Avian test species mallard duck Body weight (g) of "other" avian species Mineau scaling factor 1.15

Mallard NOAEC (mg/kg-diet) 100104Bobwhite quail NOAEC (mg/kgdiet) 300 NOAEC (mg/kg-diet) for other bird species Body weight (g) of other avian species NOAEC (mg/kg-diet) for 2nd other bird species

Table 2. Mammalian Results Parameter Acute ChronicUpper bound exposure (mg/kgbw) 153.0800 153.0800Adjusted toxicity value (mg/kgbw) 738.3941 76.9161 Ratio of exposure to toxicity 0.2073 1.9902

Conclusion* Exposure through drinking water alone is a potential concern for mammals Exposure through drinking water alone is a potential

concern for mammals

Table 3. Avian Results Parameter Acute ChronicUpper bound exposure (mg/kgbw) 720.9000 720.9000Adjusted toxicity value (mg/kgbw) 1168.2572 4.9613 Ratio of exposure to acute toxicity 0.6171 145.3059

Conclusion* Exposure through drinking water alone is a potential concern for birds Exposure through drinking water alone is a potential concern for birds

*Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when aggregated with other routes ( i.e ., diet, inhalation, dermal), pesticide exposure through drinking water may contribute to a total exposure that has potential for effects to non-target animals.

STIR v.1.0

Inhalation is a potentially important route of expos ure to pesticides for mammalian and avian wildlife (Driver et al. 1991; USEPA 2004a). STIR is a screening tool that can be used at the Problem Formulation phase to assess the potential for risk to bird and mammals from inhalation exposure. The exposure pathways that are assessed by this tool include both droplet inhalation and vapor phase inhalation. Allometric equations that relate inhalation rate to body weight are used to derive an estimated inhalation105 dose of either droplets or vapor for a 0.020 kg bi rd and a 0.015 kg mammal (Mineau et al. 1996; Sample and Arenal 1999; USEPA 1993).

Assumptions * The saturated air concentration is the theoretical maximum pure product air concentration at 25oC and 1 atm of pressure. * The height of the direct spray column is 3.3 m for aerial applications and 1 m for ground applications. * The duration of vapor inhalation is assumed to be 1 hour and the duration of direct spray inhalation is assumed to be 1.5 minutes for aerial and 3 seconds for ground applications. * The fraction of direct spray that can be inhaled is assumed to be 90%, unless a droplet spectra is specified on the label. * This model accounts for the difference in both avian and mammalian field active inhalation rate compared to the resting rate by mu ltiplying the resting inhalation ra te by 3 according to USEPA, 1993. * Both of the mammalian and avian inhalation LD50' s are adjusted for body weight using allometric equations based on work by Mineau et al. 1996. The av ian allometric equation uses the Mineau scaling factor to modify the equation based on chemical specific data. If chemic al-specific data are available the user can specify the avian scaling factor (see Minea u, et al.,1996). Otherwise, enter the EFED default value of 1.15. STIR will not run unless a Mineau sca ling factor is entered. However, 1 can be entered if the assessor believes that body weight does not influence the toxicity of the chemical being assessed. * The inhalation of droplets and the i nhalation of vapor phase pesticide are accounted for in this model as two separate routes of exposure. The corresponding dose estimations should not be combined to obtain a composite exposure value.

Table 1. EFED Screening Tool for Inhalation for Cymoxanil



## Input

Application and Chem ical Information
Enter Chemical Name Cymoxanil Enter Chemical Use Fungicide Is the Application a Spray? (enter y or n) y If Spray What Type (enter ground or air) ground Enter Chemical Molecu lar Weight (g/mole) 198.18 Enter Chemical Vapor Pressure (mmHg) 1.10E-05 Enter Application Rate (lb a.i./acre) 0.1875

Toxicity Properties

Bird Enter Lowest Bird Oral LD 50 (mg/kg bw) 2250 Enter Mineau Scaling Factor 1.15 Enter Tested Bird Weight (kg) 0.178 Mammal Enter Lowest Rat Oral LD 50 (mg/kg bw) 960
Enter Lowest Rat Inhalation LC 50 (mg/L) 5.06 Duration of Rat Inhalation Study (hrs) 4 Enter Rat Weight (kg) 0.35


## Output106 Results Avian (0.020 kg ) Maximum Vapor Concentration in Air at Saturation (mg/m 3 ) 1.17E-01 Maximum 1-hour Vapor Inhalation Dose (mg/kg) 1.47E-02 Adjusted Inhalation LD 50 6.61E+01 Ratio of Vapor Dose to Adjusted Inhalation LD 50 2.23E-04 Exposure not Likely Significant Maximum Post-treatment Spray Inhalation Dose (mg/kg) 1.98E-02 Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD 50 3.00E-04 Exposure not Likely Significant

Results Mammalian (0.015 kg ) Maximum Vapor Concentration in Air at Saturation (mg/m 3 ) 1.17E-01 Maximum 1-hour Vapor Inhalation Dose (mg/kg) 1.85E-02 Adjusted Inhalation LD 50 3.01E+02 Ratio of Vapor Dose to Adjusted Inhalation LD 50 6.15E-05 Exposure not Likely Significant Maximum Post-treatment Spray Inhalation Dose (mg/kg) 2.49E-02 Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD 50 8.27E-05 Exposure not Likely Significant107 APPENDIX G. Data Call-In Justification Tables for Ecological Effects Studies

Study Title: Pollinator Larval Toxicity Study Guideline Number: Non-guideline Test Substance: Cymoxanil Rationale for Requiring the Data Although cymoxanil is practically non-toxic to young adult ho neybees on an acute contact exposure basis, these studies do not provide information on the potenti al toxicity of cymoxanil to developing honeybee brood (larvae and pupae). Since cymoxanil is a sy stemic pesticide, there is the potential for pollen and nectar to be contam inated with the product and subsequently brought back to the hive where larvae may be exposed. Th erefore, a non-guideline honeybee larval toxicity study is recommended. The registra nt should submit a proposed protocol for review and approval by EFED prior to init iation of the study. Practical Utility of the Data How will the data be used? Data will be used to assess risk to non-target lis ted and non-listed terrestrial invertebrate species. This study would allow the Agency to refine the screening-level hazard a ssessment for beneficial terrestrial invertebrates. The effects data will be used to determine the potential for adverse effects on beneficial terrestrial i nvertebrates through direct effects on larval bees.

How could the data impact the Agency’s future decision-making? EPA is required by section 7(a)(2) of the Endangered Species Act (E SA) to ensure that any action it authorizes or takes “... is not likely to jeopardize the con tinued existence of any endangered or threatened species or result in th e destruction or adverse modificati on of critical habitat” and “to use the best scientific data ava ilable” in carrying out this obliga tion. The data EPA intends to call in are necessary to inform the determination requ ired by ESA as to whether continued registration of a pesticide is or is not likely to jeopardize the species or its critical habitat. The lack of these data will limit the flexibility th at the Agency and registrants have in coming into compliance with ESA and could result in use restricti ons that are unnecessarily severe.

Study Title: Freshwater Fish Acute Toxicity Test Guideline Number: 850.1075 Test Substance: Degradates IN-KQ960 and IN-W3595 Rationale for Requiring the Data Acute freshwater fish toxicity data are being recommended for two degradates of cymoxanil: IN-KQ960 and IN-W3595.

For cymoxanil degradate IN-KQ960, a freshwater aquatic invertebrate study (850.1010) showed that this degradate is 35 times more toxic to Daphnia magna than the parent compound, indicating that this degradate is potentially more toxic to other aquatic organisms as well. Additional data are recommended to reduce uncertainty in the po tential effects of IN-KQ960 on fish. Moreover, IN-KQ960 has a similar chemical structure to several other major degradates: IN-R3273, INJX915, IN-T4226, and IN-U3204. Thus, studies carried out on IN-KQ960 could be used to interpret potential risk from the other three simila rly structured major degradates listed above.108 For cymoxanil degradate IN-W3595, all acute toxi city endpoints predicte d by ECOSAR are much lower (more toxic) than measured for the pare nt; therefore additional data are recommended on this degradate for freshwater fish. Practical Utility of the Data How will the data be used? These data will be used to assess risk to non-targ et listed and non-listed fres hwater fish species for the major cymoxanil degradates IN-KQ 960, IN-R3273, IN-JX915, IN-T4226, IN-U3204, and INW3595. Since few data are av ailable on the toxicity of these degr adates to particular aquatic taxa, information on acute effects of these degradates to freshwater fish would help reduce uncertainty as to the effects of cymoxanil degradates on aq uatic organisms in general and determine whether further testing with other species is warranted.

How could the data impact the Agency’s future decision-making? Submission of additional data on cymoxanil degrade toxicity may eliminate the need of having to presume risk of degradates to aquatic orga nisms in the ecological risk assessment.

Study Title: Freshwater Invertebrate ( Daphnia ) Acute Toxicity Test Guideline Number: 850.1010 Test Substance: Degradate IN-W3595 Rationale for Requiring the Data Acute toxicity endpoints predic ted by ECOSAR for cymoxanil degradate IN-W3595 are much lower (more toxic) than measured for the parent; therefore additional data is recommended on this degradate for freshwater invertebrates. Practical Utility of the Data How will the data be used? These data will be used to asse ss potential risks to non-target listed and non-listed freshwater invertebrate species for cymoxanil degradat e IN-W3595. Since no data are available on the toxicity of this degradate to aquatic taxa, information on acute effects of IN-W3595 to Daphnia would help determine if they are of potential ec ological concern to aquatic organisms in general and perhaps warrant further te sting with other species. How could the data impact the Agency’s future decision-making? Submission of additional data on IN-W3595 toxicity may eliminate the need of having to presume risk of this degradate to aquatic orga nisms in the ecological risk assessment.

Study Title: Nonvascular Aquatic Plant Toxici ty Test (preferably with freshwater diatom, Navicula pelliculosa ) Guideline Number: 850.5400 Test Substance: Degradates IN-KQ960 and IN-W3595 Rationale for Requiring the Data Nonvascular aquatic plant toxi city data (preferably with N. pelliculosa ) are being recommended for two degradates of cymoxanil: IN-KQ960 and IN-W3595.

For cymoxanil degradate IN-KQ960, a freshwater aquatic invertebrate study (850.1010) showed that this degradate is 35 times more toxic to D. magna than the parent compound, indicating that this degradate is potentially more toxic to othe r aquatic organisms as well. Additional data are109 recommended to reduce uncertainty in effect s of IN-KQ960 to aquatic plants. Moreover, IN-KQ960 has a similar chemical structure to several other major degradates: IN-R3273, IN-JX915, IN-T4226, and IN-U3204. Thus, studies car ried out on IN-KQ960 could be used to interpret potential risk from the other three simila rly structured major degradates listed above.

For IN-W3595, all acute toxicity endpoints predicted by ECOSAR are much lower (more toxic) than measured for the parent; therefore additi onal data are recommende d on this degradate for nonvascular aquatic plants.

N. pelliculosa is the recommended test species because it is the most sensitive to the parent compound. Practical Utility of the Data How will the data be used? These data will be used to asse ss potential risks to non-target listed and non-listed aquatic plants for degradates IN-KQ960, IN-R3273, IN-JX 915, IN-T4226, IN-U3204, and IN-W3595. Since few data are available on the toxicity of these degradates to particular groups of aquatic organisms, information on acute effects of these degradates to at least one aquatic pl ant species could help determine if they are of potential ecological conc ern to aquatic organisms in general and perhaps warrant further testing with other species. Therefore, these data would reduce uncertainty as to the effects of cymoxanil degradates on aquatic organisms in general.

How could the data impact the Agency’s future decision-making? Submission of additional data on cymoxanil degrade toxicity could eliminate the need of having to presume risk of degradates to aquatic orga nisms in the ecological risk assessment.