## NEW CHEMICAL REGISTRATION
(Section 3) 

## ECOLOGICAL RISK ASSESSMENT Cyflufenamid; fungicide

US EPA PC # 555550

N H N O O F

F

CF 3

Chemical Name(s) : (Z)-N-[ α -(Cyclopropylmethoxyimino)-2,3-di fluoro-6-(trifluoromethyl) benzyl]-2-phenylacetamide (IUPAC), (Z)-N -[[(Cyclopropylmethoxy) amino][2,3-difluoro-6- (trifluoromethyl)phenyl]methylen e] benzeneacetamide (CAS)

Chemical Family : amidoxime
Pesticidal Mode of Action : unknown Proposed End-use Product : MILTREX ® 10 SC FUNGICIDE (EPA Reg. No.8033-xxx); 10% Suspension Concen tration (0.85 lb ai/gallon)

CYFLUFENAMID 10 SC FUNGICI DE (EPA Reg. No.8033-xxx); 10% Suspension Concentrati on (0.85 lb ai/gallon) Target Pest(s) : Powdery Mildew Proposed Target Crop(s) : Terrestrial Food and Non-food

Risk Assessors : Michael B. Lowit, Ph.D., Ecologist Rochelle F. H. Bohaty, Ph.D., Chemist
Environmental Risk Branch III
Environmental Fate and Effects Division

Rebecca Daiss, Biologist
Risk Assessment Branch IV
Health Effects Division

Secondary Reviewers : James A. Hetrick, Ph.D., Senior Scientist Pamela Hurley, Ph.D., Toxicologist
Environmental Risk Branch III
Environmental Fate and Effects Division

Approved By: Dana Spatz, Branch Chief
Environmental Risk Branch III
Environmental Fate and Effects Division2 

### Table of Contents

I. EXECUTIVE SUMMARY ..................................................................................................5
A. Nature of the Chemical Stressor ......................................................................................... 5 B. Potential Risks to Non-Target Organisms .......................................................................... 5 C. Environmental Fate and Exposure Summary ..................................................................... 7 D. Ecological Effects Summary ............................................................................................. 10 E. Uncertainties and Data Gaps ............................................................................................. 11 1. Environmental Fate and Exposure ................................................................................ 11 2. Ecological Effects ......................................................................................................... 12
a. Assessment of Uncertainties in the Aquatic Risk Assessment ................................. 14
b. Assessment of Uncertainties in th e Terrestrial Risk Assessment ............................. 15 F. Endangered Species Considerations ................................................................................ 16

II. PROBLEM FORMULATION ..........................................................................................17 A. Nature of Regulatory Action ............................................................................................. 18
B. Stressor Source and Distribution ...................................................................................... 18
1. Nature of the Chemical Stressor ................................................................................... 21 a. Mode of Action (MoA) of Cyflufenamid ................................................................. 21 2. Overview of Pesticide Usage ........................................................................................ 21 C. Receptors................................................................................................................... ........ 21 1. Aquatic and Terrestrial Effects ..................................................................................... 21 2. Ecosystems Potentially at Risk ..................................................................................... 23 D. Assessment Endpoints ...................................................................................................... 23 E. Conceptual Model ........................................................................................................... .. 23 1. Risk Hypothesis ............................................................................................................ 23 2. Conceptual Diagram ..................................................................................................... 24 F. Analysis Plan .............................................................................................................. ...... 26
1. Conclusions from Previous Risk Assessments ............................................................. 26 2. Measures of Exposure and Effects ................................................................................ 26 a. Aquatic Exposure Models ......................................................................................... 28 (1) PRZM-EXAMS ................................................................................................ 28 (2) KABAM ............................................................................................................ 28 b. Terrestrial Exposure Models ..................................................................................... 29 (1) T-REX Model ................................................................................................... 29 (2) TERRPLANT Model ........................................................................................ 30

III. ANALYSIS ...................................................................................................................... ....31
A. Use Characterization ....................................................................................................... .. 31 1. Label Uncertainty.......................................................................................................... ... 31 B. Exposure Characterization ................................................................................................ 3 3 1. Environmental Fate and Transport................................................................................ 33 a. Summary ................................................................................................................... 33 2. Measures of Aquatic Exposure ..................................................................................... 38 a. Aquatic Exposure Modeling ..................................................................................... 38 (1) Cucurbit Vegetables .......................................................................................... 43 (2) Low Growing Berries Except Cranberries ........................................................ 44 (3) Outdoor Landscape and Ornamentals ............................................................... 443 (4) Pome Fruit ......................................................................................................... 44 (5) Small Fruit Vine Climbing Except Fuzzy Kiwi Fruit ....................................... 45 b. Aquatic Exposure Monitoring and Field Data .......................................................... 45 c. Aquatic Bioaccumu lation Assessment ...................................................................... 45 3. Measures of Terrestrial Exposure ................................................................................. 46 a. Terrestrial Exposure Modeling ................................................................................. 46 (1) T-REX ............................................................................................................... 46 (2) TERRPLANT ................................................................................................... 50 (3) KABAM ............................................................................................................ 50
b. Residue Studies ......................................................................................................... 51 C. Ecological Effects Characterization .................................................................................. 52 1. Aquatic Effects Characterization .................................................................................. 52 a. Aquatic Animals ....................................................................................................... 52 (1) Acute Effects .................................................................................................... 52 (2) Chronic Effects ................................................................................................. 58 b. Aquatic Plants ........................................................................................................... 5 9
2. Terrestrial Effects Characterization .............................................................................. 62
a. Terrestrial Animals ................................................................................................... 62 (1) Acute Effects ..................................................................................................... 62 (2) Chronic Effects ................................................................................................. 67 (3) Field Studies...................................................................................................... 68
b. Terrestrial Plants ....................................................................................................... 6 8

IV. RISK CHARACTERIZATION .........................................................................................70 A. Risk Estimation - Integration of Exposure and Effects Data ............................................ 70 1. Risk to Aquatic Animals and Plants ............................................................................. 70 a. Aquatic Animals ....................................................................................................... 70 (1) Risk Following Acute Exposure ....................................................................... 70 (2) Risk Following Chronic Exposure .................................................................... 71 b. Aquatic Plants ........................................................................................................... 7 2
2. Risk to Terrestrial Animals and Plants ......................................................................... 73
a. Terrestrial Animals ................................................................................................... 73 (1) Risk Following Acute Exposure ....................................................................... 73 (2) Risk Following Chronic Exposure .................................................................... 74
b. Terrestrial Plants ....................................................................................................... 7 5 B. Risk Description............................................................................................................ .... 75 1. Risk to Aquatic Animals and Plants ............................................................................. 76 a. Aquatic Animals ....................................................................................................... 76 (1) Risk Following Acute Exposure ....................................................................... 76 (2) Risk Following Chronic Exposure .................................................................... 77 b. Aquatic Plants ........................................................................................................... 7 8
2. Risk to Terrestrial Animals and Plants ......................................................................... 79
a. Terrestrial Animals ................................................................................................... 79 (1) Risk Following Acute Exposure ....................................................................... 79 (2) Risk Following Chronic Exposure .................................................................... 81
b. Terrestrial Plants ....................................................................................................... 8 3
3. Review of Incident Data ............................................................................................... 834 4. Endocrine Effects .......................................................................................................... 83 5. Federally Threatened and Endangere d (Listed) Species Concerns ............................... 84
a. Action Area ............................................................................................................... 85 b. Taxonomic Groups Potentially at Risk ..................................................................... 86 (1) Discussion of Risk Quotients ............................................................................ 87 (2) Probit Dose Response Relationship .................................................................. 88 (3) Data Related to Under-represented Taxa .......................................................... 89 (4) Implications of Sublethal Effects ...................................................................... 89 c. Indirect Effects Analysis ........................................................................................... 91
d. Critical Habitat .......................................................................................................... 92 e. Co-occurrence Analysis ............................................................................................ 93 C. Description of Assumptions, Limitations, Un certainties, Strengths, and Data Gaps ....... 94 1. Assumptions, Limitations, and Uncertaintie s Related to Exposur e For All Taxa ........ 94
a. Maximum Use Scenario ............................................................................................ 94 2. Assumptions, Limitations, and Uncertainties Related to Exposure For Aquatic Species

94 a. Aquatic Exposure Model .......................................................................................... 94 3. Assumptions, Limitations, and Uncertaintie s Related to Exposure for Terrestrial Species ....................................................................................................................... ........... 95 a. Location of Wildlife Species .................................................................................... 95 b. Routes of Exposure ................................................................................................... 95 c. Dietary Intake and Other Limitations of Oral Studies in Terrestrial Species ........... 96
d. Incidental Releases Associated With Use ................................................................. 98
e. Residue Levels Selection .......................................................................................... 98 f. Terrestrial Exposure Model ...................................................................................... 98 4. Assumptions, Limitations and Uncertainti es Related to Effects Assessment ............... 99 a. Data Gaps of Requirements for Regist ration in the United States under FIFRA ..... 99
b. Sublethal Effects ..................................................................................................... 100 c. Age Class and Sensitivity of Effects Thresholds .................................................... 100 d. Use of Most Sensitive Species Tested .................................................................... 100 5. Assumptions, Limitations, Uncertainties, St rengths and Data Gaps Related to the
Acute and Chronic LOC’s .................................................................................................. 100

V. LITERATURE CITED ....................................................................................................102

VI. APPENDICES ...................................................................................................................1 035 I. Executive Summary

A. Nature of the Chemical Stressor

Cyflufenamid [(Z)-N-[ α -(Cyclopropylmethoxyimino)-2,3-difluor o-6-(trifluoromethyl) benzyl]-2- phenylacetamide; CAS Reg. No 180409-60-3] is a ne w pesticide active ingredient submitted for registration in the United States. Cyflufenamid is a fungicide that belongs to the amidoxime
class of chemicals. The biochemical mode of action is unknown, however the registrant suggests
that the mechanism is different from that of existing fungicides and that cyflufenamid may exhibit inhibitory effects at multiple life-cyc le stages (Nisso, 2009 and Sano et al., 2007).

The proposed registration of cyflufenamid include s foliar applications on cucurbit vegetables (crop group 9), low growing berry (crop subgroup 13-07G) except cranberries, pome fruit (crop subgroup 11), outdoor landscape and outdoor nursery ornamentals, and small fruit vine climbing except fuzzy kiwifruit (crop subgr oup 13-07F) for the treatment of powdery mildew. There are two end-use products, MILTREX ® 10 SC FUNGICIDE a nd CYFLUFENAMID 10 SC

FUNGICIDE. MILTREX ® 10 SC FUNGICIDE is la beled for agricultural use only (crop groups listed above) while CYFLUFENAMID 10 SC FUNGICIDE is only labeled for outdoor landscape and outdoor nursery ornamentals. For ag ricultural uses, cyflufenamid can be applied
at a rate of 0.022 lb ai/A twi ce per growing season while the cy flufenamid application rate for outdoor landscape and outdoor nursery ornamentals is 0.023 lb ai/A twice per year. Both labels permit aerial and ground applications methods. No enforceable spray drift reduction strategies are listed on the proposed label.

B. Potential Risks to Non-Target Organisms

The results of this screening-level assessment i ndicate no direct adverse e ffects are expected to any taxonomic group ( Tables 1 and 2 ) for which a complete dataset (all required species) of acceptable or supplemental data are available. However, studies were either not submitted or
were deemed invalid for freshwater inverteb rates (chronic), estuarine/marine fish and invertebrates (chronic), and aqua tic nonvascular plants (cyanobacter ia and green algae), so risk cannot be precluded for these taxonomic groups (liste d or non-listed species). Furthermore, risk to listed terrestrial plants cannot be precluded due to observed eff ects (> 5%) at the lowest test concentration for four (1 monocot and 3 dicots ) of the ten tested species in the seedling emergence study. Consequently, indirect effect s cannot be precluded for species dependent on freshwater invertebrates, estuar ine/marine fish and invertebrate s, aquatic nonvascular plants, and terrestrial plants (listed).

Risk to aquatic species was assessed based on total toxic cyflufenamid residues because data were not available on the toxicity of the four environmental degradation products (149-F, 149- F1, 149-F6, and 149-F11) to estuarine/marine or ganisms and vascular aquatic plants. In addition, data were not available on chronic de gradate toxicity to any taxa. Studies on
freshwater fish and invertebra tes indicate that the four de gradates are less toxic than cyflufenamid to those taxa. Studies were also submitted for nonvascular plants (green algae); however, it is not clear if the de gradates are less toxic than cyfl ufenamid because an acceptable study with the technical grade active ingredient (TGAI) was not submitted on the same species.6 Nonetheless, the four degradates did not show toxicity at or below the reported aqueous solubility limit of cyflufenam id within the range of 10 to 30°C. Although the environmental degradates appear less toxic than cyflufenamid to freshwater fish and i nvertebrates, the risk assessment is based on total toxic cyflufenamid re sidues for all aquatic ta xa since assessing risk for “cyflufenamid only” would not alter th e risk results for the proposed uses.

Risk was assessed assuming that one growing seas on is equivalent to one year; therefore, two cyflufenamid applications per season as stated on the labels is assumed to be equivalent to the maximum number of applications per year.

Table 1. Summary of Environmental Risk Conclusi ons for Terrestrial Animals and Plants from the Proposed New Uses of Cyflufenamid 1

Taxonomic

Group Risk Endpoint Summarized Risk Characterization and Important Uncertainties

Birds, Reptiles
and Terrestrial
Phase Amphibians Acute Risk Dose-based LD 50 s and dietary-based LC 50 s are greater than the highest
concentrations tested in four avian studies. There were no mortalities in any of the acute avian studies an d sublethal effects were transitory and/or slight. Acute risk to birds is not expected. 2

Acute risk to piscivorous birds is not expected. 2

Chronic Risk Risk quotients (RQs) cannot be calcula ted. Based on effects seen at the lowest administered dose, a NOAEC could not be identified for one test species (mallard duck), however, chronic risk to birds is unlikely. 2

Chronic risk to piscivorous birds is not expected. 2

Mammals Acute Risk Dietary-based LC 50 s are greater than the highest concentration tested in studies with cyflufenamid and the tested formulation. There were no mortalities in either study. Mortality was observed in studies on the four environmental degradation products. One or more of the four degradates may be more toxic than the tested formulation (on an ai basis). None of the acute levels of concern (LOCs) are exceeded for the four degradates. Acute risk to mammals is not expected. 2

Acute risk to piscivorous mammals is not expected. 2

Chronic Risk The chronic LOC is not exceeded on a dietary-basis or dose-basis for any food category.

The chronic LOC for piscivorous mammals is not exceeded.

Non-target
Invertebrates Acute Risk Cyflufenamid is classified as practically nontoxic to bees.

Terrestrial Plants Acute Risk The LOC for non-listed plants is not exceeded, thus risk is not expected.

The LOC for listed plants is not exceeded for three monocots and three dicots. However, RQs could not be estimated for one monocot and
three dicots due to effects at the lowe st test concentration. Therefore, risk to listed plants cannot be precluded.

1 Conclusions are based on a maximum yearly application rate of 0.046 lbs ai/A; two applications per year
at 0.023 lbs ai/A.

2 For further details consult the risk description section.7 Table 2. Summary of Environmental Risk Co nclusions for Aquatic Animals and Plants from the Proposed New Uses of Cyflufenamid 1

Taxonomic

Group Risk Endpoint Summarized Risk Characterization and Important Uncertainties

Freshwater Fish and Aquatic
Phase Amphibians Acute Risk None of the acute LOCs are ex ceeded, thus acute risk is not expected.

Chronic Risk Chronic risk is not expected. 2

Freshwater
Invertebrates Acute Risk Acute risk is not expected. 2

Chronic Risk No acceptable studies ar e available, thus chronic risk cannot be precluded.

Marine/
Estuarine Fish Acute Risk Acute risk is not expected. 2

Chronic Risk No studies were submitted, thus chronic risk cannot be precluded.

Marine/
Estuarine
Invertebrates Acute Risk None of the acute LOCs are exceeded (oyster). There is uncertainty in the actual exposure for the mysid st udy; however, acute risk is not expected. 2

Chronic Risk No studies were submitted, thus chronic risk cannot be precluded.

Aquatic Plants Acute Risk The LOC for listed species is not exceeded for vascular plants, thus risk is not expected for vascular plants.

Although there were no effects to Navicula or Skeletonema and no risk to those species expected, there is uncertainty with the estimated risk to non-vascular plants because it is based on the results from two algal species rather than the four species which fulfill guideline requirements.
In addition there is no available information on the mode of action for this pesticide which could be used to make inferences about toxicity to other algal species from the Navicula and Skeletonema results. Given the incomplete dataset, risk to non-vascular plants cannot be precluded.

1 Conclusion are based on a maximum yearly application rate of 0.046 lbs ai/A; two applications per year
at 0.023 lbs ai/A.

2 For further details consult the risk description section.

C. Environmental Fate and Exposure Summary

Technical grade cyflufenamid contains a mi xture of configurational isomers—NF-149 ( Z

isomer) and 149-( E )-FB. The mixture contains more of the Z -isomer than the E -isomer; only 0.3% w/w of the technical product is 149-( E )-FB. The formulated product contains <0.3% 149- ( E )-FB. NF-149 is present in hi gher concentrations than 149-( E )-FB under all study conditions [149-( E )-FB ≤ 12.6% applied radio activity].

In the environment, the major route of dissipation for cyfl ufenamid is through aerobic soil
metabolism or runoff of soil to wh ich cyflufenamid is adsorbed. Cyflufenamid is moderately persistent to persistent in terrestrial and aquati c environments. It is not susceptible to abiotic degradation under typical environm ental conditions. Aerobic so il and aquatic metabolism halflives range from one week to more than a year. It has a high soil partition coefficient (K
oc ) and will adsorb strongly to soils and sediments. However, cyflufenamid adsorbed to soil particles can move off-site by soil erosion to adjacent habitats including water bodies. Its low vapor pressure and Henry’s Law Constant suggests that volatilization of cyflufenam id from soil and water is not likely. Cyflufenamid has the potential to bi oaccumulate in aquatic organisms. A fish8 bioaccumulation study shows that cyflufenamid accumulates and is transformed in vivo ; however, most depurates in approximately five days.

All submitted studies used in this assessment are listed in Appendix A and the names and chemical structures of the reported transformation products are shown in Appendix B

.

Persistence

Cyflufenamid does not break down by abiotic pro cesses, such as hydrolysis and photolysis.
Aerobic soil metabolism studies indi cate that cyflufenamid is moderately persistent to persistent with half-lives ranging from 7 to 408 days (74 ± 130 days). Aerobic aquatic metabolism halflives are 50 and 128 days.

Transport

It is possible for cyflufenamid to reach surface wa ter through spray drift. However, its low vapor pressure (3.54 x 10 -5 Pa at 20°C) and Henry’s Law Constant (2.8 x 10 -7 atm-m 3 /mol at 20°C) suggest that volatilizat ion of cyflufenamid from soil and water are not likely dissipation routes.

Cyflufenamid adsorbs to soils wi th a soil partition coefficient (K
oc ) ranging from 1934 to 3087 mL/g. It may reach surface water by penetra ting the foliar canopy during application and foliar washoff to the soil followed by runoff of soil particles to which cyflufenamid is adsorbed.

Bioaccumulation

The Log K
ow of cyflufenamid is 4.7, therefore, it ha s the potential to bioaccumulate in aquatic organisms. BCF factors are betw een 250 and 1000 in both low-dose (1.0 μ g ai/L) and high-dose (10.0 μ g ai/L) BCF studies. Ninety pe rcent depuration occurs in approximately five days. Five cyflufenamid-based transformation products ar e reported in the BCF study—one environmental degradation product, N-Cyclopropylmethoxy-2,3-di fluoro-6-trifluoromethyl benzamidine (149- F), and four metabolites including 149- F-4-OH-B, 149-F4B, 149-F-3-OH-B, and 149-F- α -OHB. The names and chemical structures of th e reported transformation products are shown in Appendix B . A small percentage of unextractable residues are reported in the BCF study.

Degradates

There are at least six environmental tran sformation products of cyflufenamid: its E -isomer, carbon dioxide, 149-F, 149-F1 ( 2,3-Difluoro-6-trifluoromethylbe nzamidine), 149-F11 [(Z)-N-( α

Cyclopropylmethoxyimino-2,3-difluoro-6-trifluorome thylbenzyl)carbamoyl acetic acid], 149-F6 (2,3-Difluoro-6-trifluor omethyl-benzamide), and a major uni dentified volatile compound. 149-F, 149-F1, 149-F11, and 149-F6 are referenced to as the four environmenta l degradation products through out this assessment. The identified degr adation products are mobile to very mobile compounds and have short to very long half-lives.9 Aquatic Exposure

Based on the environmental fate properties of cyflufenamid and the proposed application methods, cyflufenamid use may lead to surface and ground water contamination. It is possible for cyflufenamid to reach surface water through sp ray drift. Furthermore, cyflufenamid may penetrate the foliar canopy duri ng application or may wash of f plant surfaces following application to the soil surface and adsorb to soil particulates. These particles can move off-site by soil erosion to adjacent water bodi es. The environmental degradat ion products of cyflufenamid may also reach surface water following runoff of cyflufenamid-adsorbed soil particulates or runoff of the degradation products in the dissolved phase. Some of the degradation products are also highly mobile in soil and are likely to l each into ground water and may recharge to surface

water.

Toxicity data show cyflufenamid is more acutely toxic to freshwater fish and invertebrates than four environmental degradation products ( 149-F, 149-F1, 149-F11, and 149-F6). Acceptable data was also available for toxicity of the f our degradation products to nonvascular plants, however, it is unknown if they ar e less toxic than cyflufenamid because an acceptable study for cyflufenamid on the same species was not submitte d. There are no degradate toxicity data for estuarine/marine organisms or aquatic vascular pl ants. In addition, no chr onic toxicity data for the four degradates are available for any aquatic ta xa. Given the lack of data for some taxa, as a conservative approach, aquatic exposure mode ling was based on total toxic cyflufenamid residues. This includes cyflufenamid, its is omer, and the four environmental degradation products. Total toxic residues are considered to be highly mobile, highly soluble, and persistent under all environmental conditions. Using th e Tier II PRZM-EXAMS modeling scenario for North Carolina apples, the maximum estimated en vironmental concentrations (EECs) for total toxic cyflufenamid residues in surface water is 0.85 μ g/L for the peak 1 in 10 year peak concentration. The calculated EECs are driven by th e relatively long half-lif e values used for the total toxic cyflufenamid residue s. Assessing risk for “cyflufen amid only” would not alter the risk results for the proposed uses.

Terrestrial Exposure

It is possible for cyflufenamid to reach a wide variety of terrestrial environments through direct spray, spray drift, and soil erosion. Cyflufenamid is moderately persistent on plant surfaces and may also be very persistent in soil. Microbial- mediated degradation of cyflufenamid in soil is expected to lead to terrestrial exposure to it s degradation products. The environmental fate properties of these compounds indicate that so me are more persistent and mobile than cyflufenamid. The degradation products may be transported to other terrestrial environments through runoff. These compounds are also expe cted leach into the sub-soil reducing the exposure potential.

Using the T-REX model 1.4.1 with th e default foliar dissipation ha lf-life of 35 days, the highest terrestrial EEC for cyflufenamid is 9.88 ppm on a dietary basis and 11.25 mg/kg on a dose basis. Crop-specific decline data for cyflufenamid residues from submitted crop field trial studies are available for several commodities (ranging from 5 to 52 days, see measures of terrestrial exposure for details); however, the default hal f-life was used for risk assessment since the10 refined approach would not have altered the overa ll risk results for the proposed uses. Data is available for each proposed crop group excep t outdoor landscape and outdoor nursery ornamentals. For landscape/ornamentals, use of a 52 day-half life (maximum observed in tested crops) instead of the default 35 days would result in the highest terrestrial EECs for any of the proposed crops and corresponding a pplication rates (2% higher maximum EEC for birds than maximum EEC based on 35 day half-life and 4% higher maximum EEC for mammals).

Toxicity data show that one or more of the four environmental degrad ation products (149-F, 149- F1, 149-F6, and 149-F11) may be more acutely toxi c to mammals than the tested formulation (on an ai basis); however it is not certain due to the non-definiti ve endpoint from the formulation study. Given the uncertainty, risk was assessed for the four environmental degradates. Terrestrial degradate EECs were calculated by multiplying the terrestrial cyflufenamid EECs by the molecular weight ratio (molecular weight of the degradate/molecular weight of cyflufenamid) and then normalizing for the maximu m percentage of degradation product formed
in the environment.

D. Ecological Effects Summary

All submitted studies used in this assessment are listed in Appendix A

.

Aquatic Organisms

Acute toxicity testing indi cates that technical cyflufenamid is moderately toxic to freshwater fish and highly toxic to estuarine/marine invertebrates (mollusks). Actual acute toxicity of the TGAI
to other taxa is uncertain because either non- definitive endpoints were reported, toxicity was based on total cyflufenamid (both dissolved a nd undissolved) concentrations, or both. Those taxa are freshwater invertebrates (immobility obs erved) and estuarine/marine fish (no effects observed) and invertebrates (saltwater mysid; mortality and sublethal effects observed).

No effects on fathead minnow growth were obser ved following chronic exposure; however other
sublethal effects were observed and no fish surviv ed at the highest test concentration. Toxicity was based on total cyflufenamid so actual t oxicity may have been lower than reported.

No effects on growth were observed in a vascul ar aquatic plant study and two nonvascular plant studies (freshwater and marine di atoms). Toxicity was based on total cyflufenamid in the marine diatom study.

Ecological effects are unknown for some taxa becau se studies were either not submitted or were deemed invalid for freshwater invertebrates (chronic), estuarine/marine fish and invertebrates (chronic), and aquatic nonvascular plan ts (cyanobacteria and green algae).

Terrestrial Organisms

Cyflufenamid is classified as practically nontoxic to birds, mammals, and terrestrial insects on an acute basis (toxicity cannot be categorized on a dose basis fo r the bobwhite quail; however it11 would be no more than slightly toxic). One of the environmental degradation products, 149-F1, was classified as moderately toxic to mammals.

A reproduction study in rats showed no fra nk reproduction effects from exposure to cyflufenamid; however, increased liver and thyr oid weights were observed in the parents and reduced body weight gain was observed in the F1 and F2 offspring.

Reproductive effects were observed in both th e mallard duck and bobwhite quail following chronic exposure to cyflufenamid. Growth e ffects were observed in the mallard duck study at the lowest concentration tested (14-day survivor weight) so a no effect concentration was not
determined.

Adverse effects to both monocots and dicots were observed in a vegetative vigor and a seedling emergence study. Effects to vegetative vigor were observed in onion (survival) and effects to seedling emergence were observed in oat (height ), cabbage (emergence), soybean (height), and tomato (dry weight).

E. Uncertainties and Data Gaps

1. Environmental Fate and Exposure

• MILTREX ® 10 SC FUNGICIDE, the ag ricultural use only label, states that a maximum of two applications per growing season ma y be applied to the proposed crops. In modeling both the aquatic and terrestrial EECs, it is assumed that the registrant intended for one growing season to be equivalent to one year; therefore, two cyflufenamid applications per season is assumed to be equivalent to the maximum number of applications per year. If the label is inte nded to allow multiple growing seasons per year, further assessment is necessary because the calculated EECs may under estimate the actual exposure for crops that have multiple growing seasons per year.

• The EECs in surface water are estimated usi ng a total toxic residue approach which requires input parameter assumptions. This approach should provide conservative exposure concentrations for th e proposed cyflufenamid uses . The assumptions are listed
below.

o Degradation product 149-F6 was not observed to be greater than 10% of applied radioactivity; however, it is included in this risk assessment. This was done for several reasons: 1) in some studies the concentrations of 149-F6 approaches 10%; 2) not all study durations are long en ough to see clear formation and decline patterns for 149-F6; and 3) toxicity of 149- F6 compared to cyflufenamid and the other major degradates is unknown for taxa for which there are no toxicity data.

o When no data are available for the identif ied degradates, input values are assumed to be equivalent to the value for cyfl ufenamid. If data are available for cyflufenamid as well as its degradation products and the data cannot be combined, the most conservative plausible values are used.12 • In one aerobic soil metabolism study (MRID 47620715), an unidentified volatile compound (VOC-2) is approaching 10% at stud y termination. This degradation product
is not assessed.

• The registrant indicates in a literature report that there is vapor phase activity despite the low vapor pressure of cyflufenamid (Sano, et al., 2007). The regist rant indicates that vapor phase activity observed is from cyfluf enamid and not one of the environmental degradation products 1 however, EPA has yet to review data to support this conclusion. Vapor phase activity of cyflufenamid and its degradation products were not assessed.

Based on the proposed use pattern and the uncer tainties in the exposure assessment, the following information and additional studies would help to refine the risk assessment and reduce
some of the aforementioned uncertainties:

• Identification of VO C-2 from MRID 47620715.

2. Ecological Effects

The available ecotoxicity database is incomplete . For aquatic species, no toxicity studies have been submitted for chronic exposure to estuarine/ marine fish or invertebrates. In addition, toxicity studies submitted for exposure to two species of aquatic nonvascular plants (cyanobacteria and green algae) an d chronic exposure to freshwat er invertebrates were found to be scientifically invalid (see Appendix C for details). In addition, th e results from the available Tier I seedling emergence study i ndicate the need for Tier II te sting on four species (tomato, cabbage, oat, and soybean). Finally, physical pr operties of cyflufenamid indicate that it may partition to soil and persist, thus chronic invertebrate whole se diment studies are needed to
address risk to benthic invert ebrates. The following studies are considered data needs:

• Aquatic invertebrate life- cycle (freshwater) (850.1300)

A new aquatic invertebra te life-cycle study ( Daphnia magna ) is needed to address uncertainties regarding risk to freshwater invertebrates. The submitted study with Daphnia magna had excessive parental mortality ( 30%) in the negative control group. High mortality is suggestive of issues with the health of the test organisms and compromises interpretation of treatment related effects.

• Aquatic invertebrate life- cycle (saltwater) (850.1350)

A chronic study with estuarine/marine inverteb rates is not available. Cyflufenamid is highly acutely toxic to estuarine/marine i nvertebrates. As use sites may include

1 Email to Samantha Hulkower (U.S. EPA) from John Wrubel (Nisso America) dated Aug. 10, 2010; “Small quantities of vaporizing cyflufenamid may be effective for control, because cyflufenamid has strong preventive activity at low concentrations.”13 marine/estuarine areas, a chroni c study with estuarine/marine invertebrates is needed to address this uncertainty.

• Fish early-life stage (saltwater) (850.1400) A chronic study with estuarine/marine fish is not available. Cyflufenamid is moderately toxic to freshwater fish, while to xicity to estuarine/marine fish is uncertain but is at most highly toxic. There is potential risk to estuarine/marine fish because use sites may include marine/estuarine areas. A chronic study with an estuarine/marine fish is needed to address uncertainty regarding chronic toxic ity. If an acceptable ra inbow trout chronic study is submitted, there will be sufficient da ta to estimate the chronic toxicity to estuarine/marine fish. Alternatively, the es timate can be made if an acceptable acute fathead minnow study is submitted in addi tion to redoing the chronic fathead minnow study (see below). The estimate would be ba sed on an acute to chronic ratio comparison using the acute and chronic freshwater fi sh studies (same species) and the acceptable acute study with sheepshead minnow. A va lid comparison is contingent upon having definitive endpoints for the acute and ch ronic freshwater fish studies.

• Aquatic plant growth (cyanobacter ia and green algae) (850.5400)

New toxicity studies with cyanobacteria and green algae are needed to address uncertainties regarding risk to nonvascular pl ants. Existing data (freshwater and marine diatoms) suggest that risk to aquatic nonvasc ular plants is low; however, any adverse effects of cyflufenamid may have been masked due to a solvent effect in the submitted cyanobacteria and green algae studies. In a ddition there is no av ailable information on
the mode of action for this pesticide which could be used to make inferences about toxicity to other algal species from the Navicula and Skeletonema studies. Given the incomplete dataset and narrow taxonomic re presentation of the available data (only diatoms), risk to nonvascular plants cannot be precluded.

• Seedling emergence – Tier II (850.4100)

In the available Tier 1 seedling emergence study, > 25% effect was observed for tomato and cabbage. Typically Tier II testing is required when > 25% effect is observed in a Tier I study at an application rate equivalent to the maximu m proposed application rate. On this alone, a Tier II would not be needed at this time given that the observed effects were close to 25% (26% to 27%) at a tested a pplication rate 1.6 to 2 times higher than the maximum proposed application rate. Howeve r, a Tier II seedling emergence study is needed for four plants (tomato, cabbage, oa t, and soybean) to address uncertainties regarding listed species due to a lack of establishing a NOAEC or EC 05 for all four plants.

• Chronic invertebrate whole sediment study us ing the TGAI (two freshwater species: a midge and an amphipod; one estuarine species: an amphipod)

The whole sediment study is requested because cyflufenamid has a high log K
ow value ( ≥ 3), a high K
oc ( ≥ 1000), one K d value ≥ 50 mL/g, and is persistent in sediment (aerobic soil and aquatic sediment metabolism half-lif e > 10 days). See environmental fate and14 transport summary for details. These data indicate that the co mpound may partition to sediment and persist. Use sites may include freshwater and marine/e stuarine areas, thus tests on freshwater and estuarine species ar e requested to address this uncertainty.

A protocol should be submitted for approva l prior to study initiation (if a study has already been conducted then the protocol will be reviewed for acceptability). Consult agency-wide guidance: EPA Test Method 100.5 [Life-cycle Test for Measuring the
Effects of Sediment Associated Contaminants on Chironomus dilutus (formerly
Chironomus tentans )], EPA Test Method 100.4 ( Hyalella azteca 42-d Test for Measuring the Effects of Sediment Associat ed Contaminants on Survival, Growth, and Reproduction), and EPA 600/R-01/020 ( Leptocheirus plumulosus in USEPA 2001 Method for Assessing the Chronic Toxicityof Marine and Estuarine SedimentAssociated Contaminan ts with the Amphipod Leptocheirus plumulosus ). The protocol should include spiked, formulated sediment (OECD Guideline 218 Sediment-Water Chironomid Toxicity Test Using Spiked Sediment).

a. Assessment of Uncertainties in the Aquatic Risk Assessment

Uncertainty exists from several aquatic studie s because toxicity endpoints were based on total cyflufenamid (both dissolved and undissolved) con centrations due to a failure to centrifuge or filter samples prior to analysis wh en concentrations were near or above the limit of solubility. As such, toxicity may be underestimated. Nonethel ess, risk is not expected for the proposed uses (see risk description se ction for details).

Although risk is not expected for the proposed uses and additional studies ar e not needed at this time, the following studies may be needed if hi gher EECs are anticipated (e.g., from a proposed new use). If additional studies are requested then special em phasis should be given to centrifugation or filtration to re duce uncertainty in the study resu lts. Several assumptions were made regarding actual toxicity in the submitted studies , thus the need to repeat one or all of these studies will depend not solely on EE Cs but also on other information if it becomes available, for instance, information on cyflufenamid solubility under test conditions (see risk description for further details).

• Chronic freshwater fish (850.1400)

The actual toxicity is uncertain for the eff ects observed in the chr onic freshwater fish study because endpoints are based on total cyflufenamid (both dissolved and undissolved).

There is additional uncertainty about chronic risk because an acute toxicity study on the
fathead minnow is not available. An acute LD 50 for the fathead minnow would indicate
whether or not the fathead minnow was the mo st sensitive species tested. Having an acute and chronic study on the same species re duces uncertainty about chronic toxicity.
This is because data from the two studies a llows for calculation of an acute to chronic
ratio which can be used to estimate chronic toxicity in cases wher e the chronic study was not conducted on the most acutely sensitive spec ies. It cannot be determined from the15 available data if fathead minnow is more se nsitive than the test species used in the available acute studies (rainbow trout and blue gill sunfish) and theref ore chronic risk may be underestimated. However, th e relative importance of this uncertainty can be assessed by comparing chronic toxicity of the fathead minnow (based on total cyflufenamid), the EECs for the proposed uses, and the chronic LOC. Based on that comparison, the
rainbow trout would need to be a minimum of 913 times more sensit ive than the fathead
minnow on a chronic basis to exceed the LOC for the proposed uses. Therefore, this uncertainty is likely a minor issue for the proposed uses.

The rainbow trout acute study is acceptable and shows greater se nsitivity than the bluegill on an acute basis. Given this, submission of a chronic rainbow trout study on the TGAI would negate the need to redo the chr onic fathead minnow study and run a matching acute fathead minnow study. No matter wh ich study is conducted ; there should be special emphasis on centrifugation or filtra tion prior to analytical measurement of cyflufenamid.

• Acute freshwater invertebrates (850.1010)

The actual toxicity is uncertain for the effects observed in the acute freshwater invertebrate study because endpoints are based on total cyflufenamid (both dissolved and undissolved).

• Acute estuarine/marine inverteb rates (saltwater mysid) (850.1035)

Although the mysid appears less sensitive than the oyster to the TGAI there is the possibility that it is more sensitive. This is because toxicity in the mysid study is based on total cyflufenamid and so toxicity may be underestim ated. Thus, there is the possibility that the mysid LC 50 based on dissolved cyflufenamid is lower than the oyster

EC 50 based on dissolved cyflufenamid.

b. Assessment of Uncertainties in the Terrestrial Risk Assessment

Uncertainty exists in the assessm ent of chronic risk to birds b ecause a treatment related effect
was observed at the lowest test concentra tion in the mallard duck study (5% reduction in survivor body weight), thus a NOAEC was not identified. However, the avian reproduction study is not needed at this time because the uncerta inty is assumed to be low given the nature of the observed effect, the conservative nature of the EEC, and the proposed uses (see risk description for details).

In contrast to aquatic organisms, studies on mammals indicate that all four environmental degradation products are more acute ly toxic than technical cyfluf enamid. Given this, there is uncertainty about toxicity of the four degradates to birds since no studies were available. The degradation product 149-F would need to be at le ast 107 times more acutely toxic than technical cyflufenamid on a dose basis and more than 286 times more toxic on a dietary basis to exceed the LOC. The other three degr adation products (149-F1, 149-F6, a nd 149-F11) would need to be16 even more toxic than 149-F. The current a ssessment assumes that it is unlikely that the degradation products would be 100 times or mo re toxic than technical cyflufenamid.

F. Endangered Species Considerations

Table 3 summarizes the federally listed species (endange red and/or threatened) at risk associated with either direct or indirect effects following ap plication of cyflufenamid for the proposed uses.

Table 3. Listed Species Risks Associated With Direct or Indirect Effects from Cyflufenamid Use on Cucurbit Vegetabl es, Low Growing Berries, Pome Fruits, Ornamentals, and Small Climbing Fruit Vines 1

Listed Taxon Direct Effects Indirect Effects
Terrestrial and semi-aquatic plants - monocots Yes 2 No

Terrestrial and semi-aquatic plants – dicots Yes 3 No

Terrestrial invertebrates No 4 No

Birds

No Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates and aquatic non-vascular plants 2,3,6,8
Terrestrial-phase amphibians

No 5 Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 2,3,6,8
Reptiles

No 5 Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates and aquatic non-vascular plants 2,3,6,8

Mammals

No Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates and aquatic non-vascular plants 2,3,6,8
Aquatic non-vascular plants Yes 6 Yes from effects to freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 6,8
Aquatic vascular plants

No Yes from effects to freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 6,8

Freshwater fish No Yes from effects to freshwater invertebrates and aquatic non-vascular plants 6,8
Aquatic-phase amphibians

No 7 Yes from effects to freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 6,8

Freshwater invertebrates No for acute, Yes for chronic 8 Yes from effects to freshwater invertebrates and aquatic non-vascular plants 6,8

Marine/estuarine fish No for acute, Yes for chronic 8 Yes for marine/estuarine fi sh and invertebrates and aquatic non-vascular plants 6,8

Marine/estuarine invertebrates No for acute, Yes for chronic 8 Yes for marine/estuarine fi sh and invertebrates and aquatic non-vascular plants 6,8

1 Maximum application rate is two applications per year at 0.023 lbs ai/A; yearly application rate of 0.046 lbs ai/A.17 2 In tier 1 seedling emergence and vegetative vigor studies, no direct effects are expected for three monocots, however, effects greater than 5% were observed at the lowest test concentration in 1 of the 4 test species considered to fulfill guideline requirements, thus risk cannot be precluded.

3 In tier 1 seedling emergence and vegetative vigor studies, no direct effects are expected for three dicots, however, effects greater than 5% were observed at the lowest test co ncentration in 3 of the 6 test species considered to fulfill guideline requirements, thus risk cannot be precluded.

4 Quantitative risk to terrestrial invertebrates not normally conducted. Direct effects to beneficial terrestrial invertebrates are not expected because cyflufenamid is pr actically non-toxic to bees.

5 Results from avian species used as surrogate for assessing risk to terr estrial-phase amphibians and reptiles.

6 Acceptable/supplemental studi es were available for two of the four al gal species considered to fulfill guideline requirements. No direct effects are expected for the two species with acceptable/supplement al studies; however, risk to nonvascular plants cannot be precluded without acceptable data on the two other species.

7 Results from freshwater fish used as surrogate for assessing risk to aquatic-phase amphibians

8 Studies were not submitted or invalid, thus risk cannot be precluded.

II. Problem Formulation

The purpose of this problem formulation is to provide the foundation for the ecological risk assessment being conducted for the new fungicide, cyflufenamid [Z)-N-[ α -(Cyclopropylmethoxy imino)-2,3-difluoro-6-(trifluoromet hyl)benzyl]-2-phenylacetamide]. The chemical structure of cyflufenamid is shown in Figure 1 . Chemical identification of cyflufenamid is provided in

Table 4 . As such, the problem formulation articulates the purpose and objectives of this risk assessment, evaluates the nature of the problem, and provides a plan for analyzing the data and characterizing the risk.

N H N O O F

F

CF 3

Figure 1. Chemical Structure of Cyflufenamid

Table 4. Chemical Identifi cation of Cyflufenamid Chemical Name(s) (Z)-N-[ α -(Cyclopropylmethoxyimino)-2,3-difluoro-6-(trifluoromethyl)benzyl]-2- phenylacetamid e (IUPAC) (Z)-N-( α -Cyclopropylmethoxyimino-2,3-difluoro-6-trifluoromethylbenzyl)-2- phenylacetamid e (IUPAC) (Z)-N-( α -Cyclopropyl-methoxyimino-2,3-difluoro-6-trifluoromethylbenzyl)-2- phenylacetamid e (IUPAC) (Z)-N-[[(Cyclopropylmethoxy)amino][2,3-difluoro-6- (trifluoromethyl)phenyl]meth ylene]benzeneacetamide (CAS) N-[(Z)-[(Cyclopropylmethoxy)amino][2,3-difluoro-6- (trifluoromethyl)phenyl]methyl ene]benzeneacetamide (CAS)

Chemical Abstracts Service (CAS) Registry Number 180409-60-3

Company Code(s) NF-149, NS-0036, 149-(Z)-FB18 Empirical Formula C 20 H 17 F 5 N 2 O 2

USEPA Pesticide Code (PC #) 555550

Molecular Mass 412.36 g/mol Smiles Notation O=C(Cclccccc1)NC(= NOCC2CC2)c3c(F)c(F )ccc3C(F)(F)F

Proposed End-use
Product MILTREX® 10 SC FUNGICIDE (EPA Reg.No.8033-xxx); 10% Suspension Concentration (0.85 lb ai/gallon) CYFLUFENAMID 10 SC FUNGICIDE (EPA Reg.No.8033-xxx); 10% Suspension Concentration (0.85 lb ai/gallon)

A. Nature of Regulatory Action

Cyflufenamid is a new pesticide active ingredie nt being proposed as a fungicide to control powdery mildew in a variety of outdoor non-food and food use crops. As a new active ingredient submitted for registration, there ar e no previously prepared ecological risk assessments by the Agency for cyflufenamid uses.

B. Stressor Source and Distribution

The stressor is the chemical cyflufenamid wh en applied to terrestrial non-food and food use crops to control powdery mildew. The proposed uses include cucurb it vegetables (crop subgroups 9a and 9b), low growing berry (crop su bgroup 13-07G) except cranberries, pome fruit (crop group 11), outdoor landscape and outdoor nurs ery ornamentals, and small fruit vine climbing except fuzzy kiwifruit (crop subgroup 13-07F ). The geographic extent of the proposed uses of cyflufenamid in the United States is widespread according to USDA National Agriculture Statistics Service. For example, a significant amount of cucumbers (cucurbit vegetable) were planted in Michigan last year while strawberries (low growing berry) were primarily planted in California. Majority of apple (pome fruit) bearing acreage is found in Washington according to 2009 statistics. Cucumbers, strawberries, and ap ples can also be found in a number of other states including Michigan, New Yo rk, Ohio, and Wisconsin, in additi on to several other states as represented in Figures 2

, 3 , and 4 . Cyflufenamid use on landscape and outdoor ornamentals is also expected to be widespread. There are a number of possible applicat ion sites as shown in

Table 5 including nurseries, residentia l proprieties, commercial, in stitutional, and recreational areas such as outdoor malls, educational campuses , campgrounds, golf courses, and parks. These three crops underscore the potential widespread use of cyflufenam id in the United States. The proposed cyflufenamid applications by cr op group or subgroup are provided in Table 5

.19 0 12500 25000 37500 50000

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No

rt h Caro l i n a Ohio South Carolin a T e x a s Wisconsin All Other R e ported S tates

StateTotal Acreage Planted in 2009

Figure 2. Total Acreage of Cucumbers Planted in 2009 by State ; Fresh and processing cucumbers are represented in this figure.

0 12500 25000 37500 50000

Ca

lif

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M i chig a n

New Y ork

N

orth Car o lina Oh i o Oregon Pennsyl v ania

Washington Wisco n sin

StateTotal Acreage Planted in 2009

Figure 3. Total Acreage of Strawberries Planted in 2009 by State ; Fresh and processing strawberries are included in this figure.20 0 50000 100000 150000 200000

California Idaho Ma

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se t t s
M

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s h i ngt

o n West Virg i ni

a
Wi

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t ates

StateTotal Bearing Acreage in 2009

Figure 4. Total Acreage Bearing Apples in 2009 by State

Table 5. Proposed Crops and Use Sites for Cyflufenamid Crop Possible Sites Grown 1

Cucurbit Vegetables (9a and 9b) Field Nursery Low Growing Berries (13-07G) Field Nursery Outdoor Landscape and Outdoor Nursery Ornamentals 2 Abelia, acalypha (copper-leaf), achillea (y arrow), ageratum, amelanchier (juneberry shadbush), amorpha (false indigo), aster, azalea, ba rberry, begonia, bellflower, bittersweet, buckeye, buttonbush, California poppy, catalpa, flowering cherry, horse chestnut, cosmos, flowering crabapple, crepe-myrtle, dahlia, delphinium, dogwood, elm, euonymus, fleabane, gaillardia, gardenia, geranium, gerbera daisy, ornamental gourd, grape leaf ivy, hackberry, hawthorn, hibiscus, holly, hollyhock, honeysuckle, lilac, locust, maple (not for sugar production), mock-orange, mountain laurel, oak, pansy, flowering pear, petunia, phlox, photinia, privet, rhododendron, rose, salvia, sedum, snapdragon, spirea, su nflower (seeds from treated plants may not be used for food or feed), sycamore, trumpet creeper, viburnum, walnut (nuts from treated trees may not be used for food pu rposes), willow, and zinnia. Nursery
Fields Residential properties
Public areas
Commercial areas
Institutional areas
Recreational areas such as: Campgrounds
Golf courses
Parks

Pome Fruit (11) Field/Orchards Nursery Small fruit Vine Climbing Subgroup Except Fuzzy Kiwifruit (13-07D) Field Nursery

1 Examples are intended to be representative of possible application sites and may not include all possible locations.

2 CYFLUFENAMID 10 SC FUNGICIDE label excludes homeo wner application; however, it does not restrict application sites.21 1. Nature of the Chemical Stressor

Cyflufenamid [(Z)-N-[ α -(Cyclopropylmethoxyimino)-2,3-difluor o-6-(trifluoromethyl) benzyl]-2- phenylacetamide; CAS Reg. No 180409-60-3] is a ne w pesticide active ingredient submitted for registration in the United Stat es. Technical grade cyflufen amid contains a mixture of configurational isomers—NF-149 ( Z -isomer) and 149-( E )-FB. The mixture contains more of the

Z

-isomer than the E -isomer; only 0.3% w/w of th e technical product is 149-( E )-FB.

a. Mode of Action (MoA) of Cyflufenamid

The biochemical mode of acti on of cyflufenamid is unknown, however, the registrant suggests
that the mechanism is different from that of existing fungicides and that cyflufenamid may exhibit inhibitory effects at multiple life-cycle stages (Nisso, 2009 and Sano et al., 2007). Since the mode of action of cyflufenamid is unknown it is uncertain if ther e are other chemicals registered as pesticides that share the same mode of action as cyflufenamid.

2. Overview of Pesticide Usage

Since cyflufenamid is a new pesticide active ingr edient the actual usage is not known. There are two end-use products, MILTREX ® 10 SC FUNGICIDE a nd CYFLUFENAMID 10 SC
FUNGICIDE. Both of these form ulations contains <0.3% 149-( E )-FB. MILTREX ® 10 SC FUNGICIDE is proposed for use on a variety of te rrestrial food uses (agriculture only) while

CYFLUFENAMID 10 SC FUNGICI DE is proposed for use only on terrestrial non-food use crops (i.e., ornamentals). More details on the proposed crop uses, as well as possible use areas are provided in Table 5 and II. B. Stressor Source and Distribution of this document.

Both aerial and ground foliar application methods are proposed on the labels. No enforceable spray drift reduction strategies are li sted on the label. Both labels state, “do not apply directly to water, or to areas where surface wa ter is present or to intertidal areas below the mean high water
mark.” Use of MILTREX ® 10 SC FUNGICIDE is recommended at the “first sign of disease development” while no such recommendation is provided on the CYFLUFENAMID 10 SC
FUNGICIDE label. CYFLUFENAMID 10 SC FUNG ICIDE can be applied twice per year at a maximum cyflufenamid application rate of 0.023 lb ai/A (outdoor landscape and ornamentals).

MILTREX ® 10 SC FUNGICIDE can be applied twi ce per growing season at a maximum cyflufenamid application rate of 0.022 lb ai/A.

C. Receptors

1. Aquatic and Terrestrial Effects

The receptor is the biological entity th at is exposed to the stressor (EPA, 1998)

. Based on the proposed uses for cyflufenamid, it is expected that the aquatic and terrestrial receptors will
include freshwater fish a nd invertebrates, marine/estuarine fish and invertebrates, aquatic plants, terrestrial plants, birds, mammals, and terrestrial invertebrates.22 Consistent with the process described in th e Overview Document (EPA, 2004a), this risk assessment uses a surrogate species approach in its evaluation of cyfluf enamid. Toxicological data generated from surrogate test species, wh ich are intended to be representative of broad taxonomic groups, are used to extrapolate to poten tial effects on a variety of species (receptors)
included under these ta xonomic groupings.

Acute and chronic toxicity data from studies submitted by pesticide registrants are used to evaluate the potential direct effects of cyfluf enamid to the aquatic and terrestrial receptors
identified in this section. This includes toxicity data on the tec hnical grade active ingredient, any major transformation products, and when available, formulated products.

Table 6 provides a summary of the taxonomic groups and surrogate species tested to help understand potential acute ecologica l effects of cyflufenamid to these non-targ et taxonomic groups. In addition, the table provides a prelimin ary overview of the poten tial acute toxicity of cyflufenamid by providing the acute toxicity classificati on of the tested species.

Chronic toxicity data are available from an acceptable mammalian reproduction study, one acceptable and one supplemental avian reproduction study, and a supplemental freshwater fish early life-stage study. In the mammalian reprodu ction study, no significant effects relating to survival or reproduction were reported; however , increased liver and thyroid weights were observed in the parents and reduced body weight gain was observed in the F1 and F2 offspring. For the avian reproduction studies, reproductive effects were observed in mallard duck and bobwhite quail at higher test con centrations while treatment relate d growth effects were observed only in mallard duck (14-day survivor weight at a ll test concentrations). In the fish study there was no effect on growth; however other sublet hal effects were obser ved (internal bleeding, swollen abdomen, pink feces, and deformed mouth) and no fish survived at the highest test
concentration.

Table 6. Summary of the Taxonomic Gro ups and the Surrogate Species Tested to Understand Potential Acute Ecological Effect s of Cyflufenamid to These Non-Target Taxonomic Groups
Taxonomic Group Surrogate Species Acute Toxicity Classification 1

Birds 2 Mallard Duck ( Anas platyrhynchos ) Bobwhite Quail ( Colinus virginianus ) Zebra finch ( Poephila guttata ) Practically non-toxic Practically non-toxic 5 Practically non-toxic Mammals Laboratory rat ( Rattus norvegicus ) Practically non-toxic Insects Honey bee ( Apis mellifera ) Practically non-toxic

Freshwater fish 3 Bluegill sunfish ( Lepomis macrochirus ) Rainbow trout ( Oncorhynchus mykiss ) Not classified 6 Moderately toxic Freshwater invertebrates Water flea ( Daphnia magna ) Not classified 6, 7

Estuarine/marine fish Sheepshead minnow (Cyprinodon variegatus) Not classified 6

Estuarine/marine
invertebrates Mysid shrimp (Americamysis bahia) Eastern oyster ( Crassostrea virginica) Not classified 7 Highly toxic

Terrestrial plants Monocots 4

Dicots 4 Not applicable

Aquatic plants and algae Duckweed ( Lemna gibba ) Cyanobacteria ( Anabaena flos-aquae ) Marine diatom ( Skeletonema costatum ) Not applicable23 Taxonomic Group Surrogate Species Acute Toxicity Classification 1
Freshwater diatom ( Navicula pelliculosa ) Green Algae ( Selenastrum capricornutum)

1 Based on toxicity to cyflufenamid.

2 Birds represent surrogates for terrest rial-phase amphibians and reptiles.

3 Freshwater fish may be surroga tes for aquatic-phase amphibians.

4 Four species of monocots (onion, ryegra ss, oat, and corn) and six species of di cots (sugarbeet, cabba ge, soybean, lettuce, tomato, and radish).

5 Classified as practically nontoxic on a di etary basis but not classified on a dos e basis due to a non-definitive endpoint.

6 Not classified due to non-definitive endpoint.

7 Not classified because toxicity is based on total cyflufenamid concentrations; toxicity could be lower based on dissolved
concentrations.

2. Ecosystems Potentially at Risk

The ecosystems potentially at risk are often extensive in scope; therefore, it may not be possible to identify specific ecosystems during the deve lopment of a nation-wide ecological risk assessment. Terrestrial ecosystems potentially at risk include the treated field and adjacent areas (e.g. cultivated fields, fencerows and hedgero ws, meadows, fallow fi elds or grasslands, woodlands, riparian habitats, and other uncultivated areas) that may receive drift, eroded soil, or runoff. Aquatic ecosystems at risk are water bod ies adjacent to or down stream from the treated site including impounded bodies such as ponds, lakes, and reservoirs, or flowing waterways such as streams or rivers as well as adjacent off-channel habitats that are permanently or intermittently connected to flowing waters. For uses in coas tal areas, aquatic habita t also includes marine ecosystems including estuaries, embaymen t’s, and near shore environments.

D. 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 (EPA, 1998). For cyflufenamid, the ecological entities may include the following: birds, mammals, freshwater fish and invertebrates, estuar ine/marine fish and invertebrates, terrestrial insects, terrestrial plants, and a quatic plants and algae. The attr ibutes for each of these entities may include growth, reproduction, and survival.

E. Conceptual Model

A conceptual model provides a written descriptio n and visual representation of the predicted relationships between cyflufenamid and its enviro nmental degradation products, potential routes of exposure, and the predicted effects for the assessment endpoint. A conceptual model consists of two major components: risk hypothesis and a conceptual diagram (EPA, 1998).

1. Risk Hypothesis

For a pesticide to pose an ecological risk, it must reach non-target organisms (receptors) at biologically significant c oncentrations. An exposure pathway is the means by which a pesticide moves in the environment from the application si te to non-target organisms. The evaluation of24 the ecological exposure pathways in this assessment includes an examination of the source and potential transport pathways for cyflufenamid and the determination of exposure routes of nontarget species.

For cyflufenamid, the following ecological risk hypothesis is being employed for this risk

assessment:

Given the proposed uses of cyflufenamid and its environmental fate properties, there is a likelihood of exposure to non-target terrestri al and aquatic organisms. When used in accordance with the proposed l abel, cyflufenamid can result in potential adverse effects upon the survival, growth, and reproduction of non-ta rget terrestrial and aquatic organisms.

2. Conceptual Diagram

The conceptual model diagram is a generic graphi c depiction of the risk hypotheses identified in the previous section. It is assumed that cyfluf enamid and its environmental degradation products are capable of affecting expos ed terrestrial and aquatic organisms if environmental concentrations are sufficiently elevated as a resu lt of proposed label uses. Through a preliminary process of examining fate and effects data, the risk hypotheses and conceptual model have been refined to reflect possible expos ure pathways and the organisms that are most relevant and applicable to this assessment as shown in Figure 5 . If exposed at sufficient levels, mortality may occur, as well as sublethal effects. Direct effects on a taxonomic group ma y result in indirect effects (i.e., loss of habitat and food resources) to other taxonomic groups. This assessment will examine the potential for these effects to occur within the surrogate taxa with the intent to extrapolate to actual effects within the environment.

In order for a chemical to pose an ecological risk, it must reach ecological receptors in biologically significant concen trations. An exposure pathway is the means by which a
contaminant moves in the environment from a sour ce to an ecological recept or. For this pathway to be complete, it must have a source, a releas e mechanism, an environmental transport medium for cyflufenamid and/or its transformation products , a point of exposure for ecological receptors, and a feasible route of exposure. The asse ssment of these pathways thus includes an examination of the sources and potential migr ation pathways for constituents, and the determination of potential exposur e routes. The conceptual model for both potential aquatic and
terrestrial risk is shown in Figure 5 . Exposure routes shown in dashed lines are not quantitatively considered because the resulting exposures are expected to be very low when compared to the major routes of exposure.

Exposure is expected to be dominated by runoff and spray drift. Cyflufenamid exposure may also result from off-site movement of cyflufen amid-bearing soil particulates to adjacent fields (soil erosion) or deposition of cyflufenamid-bearing soil particulates from wind erosion. The high K
oc s (>1900) of cyflufenamid suggest that leachi ng to ground water and recharge to surface water would not be a route of exposure. Ho wever, cyflufenamid degradation products are25Figure 5. Conceptual Diagram for Aquatic and Terrestrial Risk.Cyflufenamid (black lines); cyflufenamid transformationproducts (gray lines); major concern (solidlines); and minor concern (dashed lines).26 mobile to very mobile compounds and have short to very long half-lives suggesting that these compounds may leach into ground water and could r echarge to surface water, as well as reach surface water through runoff. Typi cally, surface water EECs provide a conservative estimate for ecological exposure since there are limited habitats within ground water supplies. Furthermore, ground water recharge to surface water is not exp ected to increase surfac e water EECs because it may take several years for the chemicals in gr ound water supplies to re ach surface water and such chemicals will likely be diluted when they reach surface water. Although there is potential for ground water contamination by cyflufenamid de gradation products, it is expected that the total toxic residue approach used in this a ssessment will provide surface water EECs that are protective for all aquatic environments. In the fu ture, if monitoring data does not support this assumption then this approach should be reexamin ed. Long-range transport of cyflufenamid and its degradation products was not assessed. Additiona l data are required in order to conduct such

an assessment.

This screening-level assessment fo r spray applications of cyfluf enamid only considers dietary exposure. Other routes of exposure that were not considered in the assessment are incidental soil ingestion exposure, inhalation exposure, dermal exposure, and drinking water exposure. These routes are not represented in the diagram. Furthe r discussion of these routes can be found in the Assumptions, Limitations and Uncertainties Relate d to Exposure for Terrestrial Species section (IV.C.3.b).

F. Analysis Plan

The structure of this risk assessment is based on guidance contained in U.S. EPA’s Guidance for Ecological Risk Assessment (U.S. EPA, 1998) and is cons istent with procedures and methodology outlined in the Overview Document (U.S. EPA, 2004a).

1. Conclusions from Previous Risk Assessments

There are no previous ecological risk assessments for cyflufenamid because this is the first registration petition for its us e in the United States.

2. Measures of Exposure and Effects

Measures of exposure are based on aquatic and terrestrial models that predict estimated environmental concentrations (EECs) using maxi mum labeled application rates and methods of application. Measures of effects data are obta ined from registrant submitted studies or from literature studies identified by ECOTOX in order to determine the direct a nd indirect effects to all taxa. The public ECOTOXicology database (E COTOX) was searched in order to provide more ecological effects data and in an attempt to bridge existing data gaps, however, no studies
were available at the time of this assessment. ECOTOX is a source for locating single chemical toxicity data for aquatic life, terrestrial plan ts, and wildlife. ECOT OX was created and is maintained by the USEPA, Office of Research and Development, and the National Health and
Environmental Effects Research Laborato ry's Mid-Continent Ecology Division.27 Table 7 summarizes the measures of ecological eff ects and exposure used to assess ecological risk following exposure to cyfluf enamid with the proposed uses.

Table 7. Measures of Ecological Eff ects and Exposure for Cyflufenamid Assessment Endpoint Surrogate Species and Measures of Ecological

Effect 1,2 Measures of Exposure

Birds 3 Survival Bobwhite quail and Zebra finch acute
oral LD 50 Bobwhite quail and Mallard duck subacute dietary LC 50 Maximum residues on food items (foliar) Reproduction and growth Mallard duck LOAEC and Bobwhite Quail reproduction NOAEC 6
Mammals Survival Laboratory rat acute oral LD 50 Reproduction and growth Laboratory rat reproduction
NOAEL/LOAEL

Freshwater fish 4 Survival Rainbow trout 96-hr LC 50 Peak EEC 8
Reproduction and growth Fathead minnow NOAEC/LOAEC 60-day average EEC 8

Freshwater
invertebrates Survival Water flea 48-hr EC 50 Peak EEC 8
Reproduction and growth No acceptable study available 21-day average EEC 8

Estuarine/marine fish Survival Sheepshead minnow 96-hr LC 50 Peak EEC 8
Reproduction and growth No study available 60-day average EEC 8

Estuarine/marine
invertebrates Survival Eastern oyster 96-hr EC 50 Saltwater mysid 96-hr EC 50 Peak EEC 8

Reproduction and growth No study available 21-day average EEC 8
Terrestrial plants 5 Survival and growth Mono cot seedling emergence EC 25 and NOAEC 7

Monocot vegetative vigor EC 25 and

NOAEC
Dicot seedling emergence EC 25 and

NOAEC 7

Dicot vegetative vigor EC 25 and

NOAEC Estimates of runoff and spray drift to non-target areas

Insects Survival (not quantitatively assessed) Honey bee acute contact LD 50 Maximum application rate

Aquatic plants and algae Survival and growth Duckweed 7-day EC50 and NOAEC

Freshwater diatom 96-hr EC 50 and

NOAEC

Marine diatom 96-hr EC 50 and

NOAEC Peak EEC 8

1 LD 50 = Lethal dose to 50% of the test population; NOAEC = No observed adverse effect concentration; LOAEC =
Lowest observed adverse effect concentration; LC 50 = Lethal concentration to 50% of the test population; EC 50 /EC 25 = Effect concentration to 50%/ 25% of the test population.

2 The most sensitive species tested within a taxonomic group are used for risk assessments.

3 Birds represent surrogates for amphibians (terrestrial phase) and reptiles.

4 Freshwater fish represent surrogates for amphibians (aquatic phase).

5 Four species of monocots and six species of dicots were tested.

6 Typically a NOAEC is used for assessment; however, a NOAEC was not defined in the mallard duck study and it would be lower than the NOAEC for the bobwhite quail.

7 A NOAEC was not defined for one species of monocot and three species of dicots.

8 One in 10-year return frequency.28 a. Aquatic Exposure Models

(1) PRZM-EXAMS

Tier II total toxic cyflufenamid residues EECs in surface water resulting from the proposed uses of cyflufenamid on cucurbit vegetables, low grow ing berries, pome fruit, outdoor landscape and outdoor nursery ornamentals, and small fr uit vines are calculated using PRZM (P esticide R oot
Z one M odel, version 3.12.3, June 2006; Carsel et al ., 1997) and EXAMS (EX posure A nalysis

M odeling S ystem, version 2.98.04.06, April 2005; Burns et al ., 2002) models in the PE5 shell. PRZM and EXAMS are screening simulation models that are linked using the input shell PE5 to generate daily exposures and 1-in-10 year EECs of total toxic cyflufenamid residues that may occur in surface water bodies adjacent to applic ation sites receiving total toxic cyflufenamid residues through runoff, erosion, and spray drif t for specific scenarios. PRZM simulates pesticide application, movement, and transforma tion on an agricultural field and the resultant pesticide loadings to a recei ving water body via runoff, erosion, and spray drift. EXAMS simulates the fate of the pestic ide and resulting concentrations in the water body. The standard scenario used for ecological pesticide asse ssments assumes application to a 10-hectare agricultural field that drains into an adj acent 1-hectare water body, 2-meters deep (20,000 m 3
volume) with no outlet (farm pond). PRZM-EXA MS was used to estimate screening-level exposure of aquatic organisms to total toxic cyfl ufenamid residues. The measure of exposure for aquatic species is the 1-in-10 year return peak or rolling mean concentration. The 1-in-10 year peak is used for estimating acute exposures of direct effects to aquatic organisms as well as indirect effects. The 1-in-10-year 60-day mean concentration is used for assessing chronic exposure. The 1-in-10 year 21-day mean concentr ation is used for assessing chronic exposures to aquatic invertebrates.

(2) KABAM

KABAM (K OW (based) A quatic B ioA ccumulation M odel) v.1.0 is used to estimate potential bioaccumulation of hydrophobic organic pesticides su ch as cyflufenamid in freshwater aquatic food webs and subsequent risks to mammals and birds via consumption of contaminated aquatic prey. This tool can also be used to estimate pe sticide concentrations in fish tissues consumed by humans (i.e., filets). The bioaccumulation por tion of KABAM is based upon work by Arnot and Gobas (2004) who parameterized a bioaccumulati on model based on PCBs and some pesticides (e.g., lindane, DDT) in freshwater aquatic ecosyst ems. KABAM relies on a chemical's octanolwater partition coefficient (K OW ) to estimate uptake and elim ination constants through respiration and diet of organisms in different trophic levels. Pesticide tissue residues are calculated for different levels of an aquatic food web. The model then uses pesticide tissue concentrations in aquatic animals to estimate dos e- and dietary-based e xposures and associated risks to mammals and birds consuming aquatic orga nisms, using an approach that is similar to the T-REX model (USEPA 2008).

KABAM incorporates 7 trophic levels to descri be bioaccumulation of a pesticide in a model aquatic food web: phytoplankton, zooplankton (e.g., Daphnia sp. ), benthic invertebrates (e.g., Chironomus sp ., crayfish), filter feeders (e.g., mussels, clams), small fish (e.g., young of the29 year), medium sized fish (e.g., adult bluegi ll), and larger upper-tr ophic level fish (e.g., largemouth bass).

Cyflufenamid concentrations in organisms of the aquatic trophic levels lis ted above were used to estimate acute and chronic expos ures of piscivorous mammals and birds consuming fish. For mammals, available chronic toxicity data on cyfl ufenamid was used to calculate risk quotients (RQs) for estimated exposures due to bioaccumulati on of cyflufenamid in an aquatic ecosystem. Acute (birds and mammals) and chronic (birds ) RQs were not calculated because definitive endpoints were not identified from the subm itted studies. Instead, a comparison was made between the EECs and toxicity data.

b. Terrestrial Exposure Models

(1) T-REX Model

The focus of terrestrial wildlife exposure estima tes is for birds (also acting as surrogate for reptiles and terrestrial-phase amphibians) a nd mammals with an exposure route emphasis on uptake through the diet. The cyflufenamid re sidues in or on potential dietary sources for mammals and birds (e.g., vegetation, insects, and seeds) were estimated using the Tier I model T-REX, version 1.4.1 (USEPA, 2008). In this Tier I assessment, it was assumed that organisms are exposed to one active ingred ient in a given exposure scenar io. In all screening-level assessments, the organisms are assumed to consume 100% of their diet as one food type.

The approach used to estimate exposure of te rrestrial animals to cyflufenamid was based on potential foliar applications of cyflufenami d. Upper-bound exposure levels were calculated for spray applications of cyflufenamid using maximum proposed application rates for two applications for the proposed uses. The exposure estimates are based on a database of pesticide
residues on wildlife food sources associated with specified a pplication rates (Hoerger and Kenaga, 1972; Fletcher et al ., 1994). Essentially, for a single application, there is a linear relationship between the amount of pesticide appl ied and the amount of pe sticide residue present on a given food item. Food item residue levels ar e then linearly adjusted based on application rate. The upper-bound estimates are used to estima te risks since these values represent the highend exposure that may be encountered for terrestr ial species that consume food items that have received label-specified pest icide application. Although these represent higher-end estimates, they do not represent the highest possible exposure estimates.

T-REX is a simulation model that, in additi on to incorporating the relationship between application rate and food item re sidue concentrations, accounts fo r pesticide degradation in the
estimation of terrestrial EECs. T-REX calculates pesticide residue s on each type of food item on a daily interval for one year. A first-order de cay function is used to calculate the residue concentration at each day based on the concentrations present from both initial and all subsequent applications. The decay rate is depe ndent on the foliar dissipa tion half-life. The food item concentration on any given day is the sum of all concentrations up to that day, taking into account the first-order degradati on. The initial applica tion occurs on day 0 (t=0) and the model runs for 365 days. Over the 365-day run, the high est residue concentration is the measure of exposure (EEC) used to calculate RQs.30 Foliar dissipation and residue decline studies can be important in estimating exposure because they essentially determine how l ong the pesticide remains in or on food items after application. In many cases, neither empirically determined fo liar dissipation nor residue decline half-life (with a day 0 residue) values are available, in which case the default value of 35 days is used (Willis and McDowell, 1987). Crop-specific decline data for cyflufenamid residues are available from submitted crop field trial studies for several commodities (ranging from 5 to 52 days, see measures of terrestrial exposure for details); however, the default foliar dissipation half-life (35 days) was used for risk assessment since the refi ned approach would not have altered the overall risk results for the proposed uses. Data is available for each proposed crop group except outdoor landscape and outdoor nursery ornamentals. For la ndscape/ornamentals, use of a 52 day-half life (maximum observed in tested crops ) instead of the default 35 days would result in the highest terrestrial EECs for any of the proposed crops and corresponding applic ation rates (2% higher maximum EEC for birds than maximum EEC based on 35 day half-life and 4% higher maximum EEC for mammals).

(2) TERRPLANT Model

The TerrPlant (Ver.1.2.2) model is us ed to predict EECs from terrestr ial uses for terrestrial plants located in dry and semi-aquatic areas adjacent to the treated field or treated water body. TerrPlant assumes 100% efficiency in ground and aerial applications. A semi-aquatic area (wetland) is defined as a low-lyi ng area of terrestrial habitat that is wet but may dry up at times throughout the year. TerrPlant inco rporates two similar conceptual models for depicting dry and semi-aquatic areas of terrestrial habitats. For bot h models, a non-target area is adjacent to the target area. Pesticide exposures to plants in th e non-target area are estimated to receive runoff and spray drift from the target area.

For a dry area adjacent to the treatment area, runo ff exposure is estimated as sheet runoff. Sheet runoff is the amount of pesticide in water that runs off of the soil surface of a target area of land which is equal in size to the non-target area (1:1 ratio of areas). In the sheet runoff scenario, the treated area generating runoff is assumed to dr ain into an area with equal size containing seedlings, resulting in 1, 2, or 5% of the appli cation rate being deposited. For semi-aquatic areas, runoff exposure is estimated as channel runo ff. Channel runoff is the amount of pesticide that runs off of a target area 10 times the size of the non-target area (10:1 ratio of areas). In the channel runoff scenario, a ten-to-one ratio of watershed area to receiv ing area results in 10, 20, or 50% of the application rate being deposited on soil with emer ging or emerged seedlings. With pesticides which are ground incorporated, the ru noff EEC is decreased because the application rate is divided by the incorporation depth be fore being multiplied by the runoff value. The magnitude of runoff is assumed to be dependent on the water solubility of the pesticide active ingredient. For pesticides with a solubility of <10, 10 to 100, or >100 ppm, runoff fractions of 0.01, 0.02 or 0.05 respectively are se lected by the model user.

Exposures through runoff and spray drift are then co mpared to measures of survival and growth (e.g. effects to seedling emergence and vege tative vigor) to deve lop RQ values. The model compares the combined deposition esti mates from runoff and spray drift to adverse effect levels measured in seedling emergence st udies. In addition, RQs are derived for plants31 with consideration for spray drif t exposures. For monocots and for dicots, TerrPlant compares estimated spray drift deposition, without a runoff exposure component, to the more sensitive measure of effect, either seedling emer gence or vegetative vigor (USEPA, 2005).

III. Analysis

A. Use Characterization

There are two proposed end-use product, MILTREX ® 10 SC FUNGICIDE (EPA Reg. No. 8033- XXX) and CYFLUFENAMID 10 SC FUNGICIDE (EPA Reg. No. 8033-XXX). Both products are a suspension concentrat e containing 10% (Z)-N-[ α -(Cyclopropylmethoxyimino)-2,3- difluoro-6-(trifluoromethyl)benzyl] -2-phenylacetamide (cyflufenamid) at a concentration of 0.85 pounds cyflufenamid per gallon. The product claims to control powdery mildew. The product is
intended for use on terrestrial f ood and non-food crops. Proposed cr ops and possible sites treated with cyflufenamid are listed in Table 5 . Proposed applicati on rates are shown in Table 8 . There are no rotational crop plant back restric tions for either of these products.

1. Label Uncertainty

There are two end-use products, MILTREX ® 10 SC FUNGICIDE for outdoor landscape and outdoor nursery ornamentals use only a nd CYFLUFENAMID 10 SC FUNGICIDE for agricultural use only (cucurbit vege tables, low growing berries, pom e fruit, and small fruit vine climbing subgroup except fuzzy kiwifruit) . The label for CYFLUFENAMID 10 SC FUNGICIDE does not define whether “per season” means that only one crop may be grown in a given field per year or if more than one crop cy cle per year is possible inferring multiple seasons per year. If the label is intended to allow multiple growing seasons per year, further assessment is necessary because it is possible that more than two cyflufenamid applications per year may be made for some crops such as strawberries. Ther efore, the calculated EECs may under estimate the actual exposure for crops that have multiple growing seasons per year.

Both labels state that the number of sprays of MILTREX ® 10 SC FUNGICIDE or

CYFLUFENAMID 10 SC FUNGICIDE per crop is not to exceed 50% of the total number of sprays for powdery mildew. It is recommended that MILTREX ® 10 SC FUNGICIDE application be alternated with ot her mode of action fungi cides.” Since the m ode of cyflufenamid
action is unknown it is unclear wh at alternatives exist.

The CYFLUFENAMID 10 SC FUNG ICIDE label excludes homeowner applications; however, it does not restrict applica tion sites. Therefore, applications to residential property are implied.32Table 8. Proposed Application Rates for Cyflufenamid Use on Cucurbit Vegetables, Low Growing Berries, OutdoorLandscape and Nursery Ornamentals,Pome Fruit, and Small Fruit VinesCropApplicationRate Range(lbs ai/A)Maximum SingleApplication Rate(lbs ai/A)MaximumApplicationRate PerGrowingSeason(lbs ai/A)MaximumNumber ofApplicationsMinimumIntervalApplication TechniqueCucurbitVegetables(9a and 9b)not applicable 0.011 0.022 27 days Aerial/GroundLow GrowingBerries (13-07G) ExceptCranberries0.011-0.022 0.022 0.044 2 14 days Aerial/GroundOutdoorLandscapeand OutdoorNurseryOrnamentalsup to 0.023 0.023 0.046 2 14 day Aerial/GroundPome Fruit(11)not applicable 0.022 0.044 2 14 day Aerial/GroundSmall fruitVineClimbingSubgroup(13-07D)Except FuzzyKiwifruit0.011-0.022 0.022 0.044 2 7 days1Aerial/Ground1Minimum interval 7 days (low rate) and 14 days (high rate)33 B. Exposure Characterization

1. Environmental Fate and Transport

a. Summary

Technical grade cyflufenamid contains a mi xture of configurational isomers—NF-149 ( Z

isomer) and 149-( E )-FB. The Z-isomer is always presen t in higher concentrations than the E

isomer; only 0.27% w/w of the technical product is 149-( E )-FB. The Z-isomer is favored under all study conditions; 149-( E )-FB ≤ 12.6% applied radio activity. Cyflufenamid is moderately persistent to persistent in soil and aquatic e nvironments. It is not susceptible to abiotic degradation under typical environm ental conditions. Aerobic so il and aquatic metabolism halflives range from one week to more than a year. It has a high soil partition coefficient (K
oc ) and will adsorb strongly to soils and sediments. However, particulates adsorbed to soil could move off-site by soil erosion to adjacent water bodie s. Its low vapor pressure and Henry’s Law Constant suggests that volatili zation from soil and water is not likely. Based on the Log K
ow , cyflufenamid has the potential to bioaccumulate in aquatic organisms. A fish bioaccumulation study shows that cyflufenamid accumulates a nd depurates readily within five days.

Table 9 presents physical, chemical, and environmenta l fate characteristics of cyflufenamid and its known environmental degradation products. The proposed environmental degradation pathway is provided in Figure 6

, along with key environmenta l fate characteristics of cyflufenamid and each of the identified degradates.

Persistence

Abiotic Conditions : Hydrolysis and Direct Photolysis is Water

In general, cyflufenamid is stable to abiotic pr ocesses in the environmen t. The persistence of cyflufenamid in abiotic water depends on the pH of the water (MRID 47620712). Cyflufenamid is stable at pHs 4, 5, and 7 at 50 °C. At pH 9, cyflufenamid estimated half-lives are 7 days (50 °C), 61 days (35 °C), and 630 days (20 °C).

Cyflufenamid irradiated in aque ous solutions at pH 7 was stab le to direct photolysis (MRID 47620713). The estimated photolysis half-life of cyflufenamid is 220 days, which is significantly longer than th e duration of the study.34Table 9. Environmental Fate and Transport Characteristicsfor Cyflufenamid and its Environmental Degradation Products1ParameterCyflufenamid149-F11149-F149-F1149-F6Total ResidueMolecular Weightg/mol412.36MRID 47620712a380.27MRID 47620721s294.22MRID 47620722s224.13MRID 47620723s225.12MRID 47620724snot applicableWater Solubility20°C0.52 mg/LMRID 47620416s0.842 g/LMRID 47620721s0.925 g/LMRID 47620722s60.89 g/LMRID 47620723s9.013 g/LMRID 47620724snot applicableVapor Pressure20°C3.54 x 10-5PaMRID 47620417snot reported not reported not reported Not Reported not applicableHenry’s LawConstant20 °C2.8 x 10-7atm-m3/ molcalculatednot reported not reported not reported not reported not applicableLog Kow(Lognoctanol/waterpartition coefficient)20 °C, pH 6.754.70MRID 47620415snot reported not reported not reported not reported not reportedHydrolysis Half-life(t1/2) pH 7StableMRID 47620712snot reported not reported not reported not reported not applicableAquatic PhotolysisHalf-life (t1/2) pH 7StableMRID 47620713snot reported not reported not reported not reported not applicableAdsorptionCoefficient (Kd)38, 17, 74,and 32 mL/gMRID 47620728s0.25, 0.25, 0.36,and 0.13 mL/gMRID 47620729s0.64, 0.13, 1.17,and 0.85 mL/gMRID 47620730s1.32, 0.58, 1.50,and 2.85 mL/gMRID 47620802s0.21, 0.09, 0.29,and 0.30 mL/gMRID 47638208snot applicableSoil PartitionCoefficient (Koc)2202, 2199, 3087,and 1934 mL/gMRID 47620728not applicable51, 33, 70,and 66 mL/gMRID 47620730s91, 88, 77, and213 mL/gMRID 47620802s9, 9, 12, and16 mL/gMRID 47638208snot applicableBinding Correlation organic contentnot to organiccontentorganic content organic content organic content not applicableAerobic SoilMetabolism Halflife (t1/2)21 and 19 daysMRID 47620715s7 days, MRID 47620716s9, 122, and 19MRID 47620717s19 and 408 daysMRID 47620718s41 days, MRID 47620719s3, 3, and 4 daysMRID 47620721s11, 6, and 14 daysMRID 47620722s161, 330,and 118 daysMRID 47620723s2310, 866, and1386 daysMRID 47620724s182 and 495 daysMRID 47620715s15 days, MRID 47620716s45, 50, and 182 daysMRID 47620717s58 and 693 daysMRID 47620718s122 days, MRID 47620719sAerobic AquaticMetabolismHalf-life (t1/2)128 and 50 days(total system)MRID 47620726snot calculated not calculated not calculated not calculated347 and 122(total system)MRID 47620726sAnaerobic AquaticMetabolismHalf-lifeStableMRID 47620725sand 47620727anot reported not reported not reported not reported not applicable1Registrant submitted studies listed above are classified as either a. acceptable or s.supplemental. Half-life values are based on best fit analysis.35 N H N O O F

F

CF 3

N H N O O F

F

CF 3 O

OH NH 2 N O F

F

CF 3

NH 2 NH F

F

CF 3 NH 2 O F

F

CF 3 Cyflufenamid, NF-149

t 1/2 = 7->365 days

K oc = 1934-3087 mL/g soil Water Solubility = 0.5 mg/L Field Dissipation = 365 days 149-F11

t 1/2 = 3-4 days

K d = 0.13-0.36 mL/g soil Water Solubility = 0.8 g/L Field Dissipation = 3 days Reduction

Deamination Mineralization CO 2 149-F

t 1/2 = 6-14 days

K oc = 33-70 mL/g soil Water Solubility = 0.9 g/L Field Dissipation = 120 days

149-F1

t 1/2 > 120 days

K oc = 77-213 mL/g soil Water Solubility = 60.9 g/L Field Dissipation = 457 days* 149-F6

t 1/2 >> 120 days

K oc = 9-16 mL/g soil Water Solubility = 9.0 g/L Field Dissipation = 60 days O

HO

Phenyl-acetic acid N H N O F

F

CF 3 O

149-(E)-FB

O x

i d

a

t i o

n H y d

r o l y s i s

* stud y te r mination CO 2 Hydrolysis

Figure 6. Degradation Pathway for Cyflufenamid ; A summary of the important
environmental fate characterist ics of cyflufenamid and its de gradation products are provided
under each relevant chemical structure. Bold font indicates major cyflufenamid degradates ( ≥ 10% observed). Half-life values presented are based on aerobic soil metabolism study results. Field dissipation data indicate the last sampli ng point when residue was identified. No abiotic degradation of cyflufenamid is expected. Note that, the terrestrial field dissipation study (MRID 47638209) is classified as upgradable.36 Biotic Conditions: Aerobic Soil Metabolism; Aquatic metabolism

Cyflufenamid degrades under aerobic conditi ons. The calculated non- linear half-lives for cyflufenamid correlate well with the observed DT 50 while the calculated lin ear half-lives do not. This supports a biphasic transformation. Severa l of the aerobic soil metabolism studies where conducted using foreign soils. These soils may repr esent potential use site s in the United States and are used to complement data collected from studies conducted with soils from the United States (email from registrant). 2

In several aerobic soil metabolism st udies, the nonlinear half-lives for cyflufenamid range from 7 to 408 days (74 ± 130 days) depe nding on the soil (MRIDs 47620715, 47620716, 47620717, 47620718, and 47620719). In seven of the eight soils te sted (one soil was studied twice), data collection extends long enough to establish an accurate half-life a nd to observe the DT 50 . In six of those seven soils, the observed DT 50 was between 8 and 30 days while the calculated nonlinear half-lives range from 7 to 40 days. In the other aerobic soil metabo lism study, the calculated linear half-life is higher (408 da ys) than the other experiment s (MRID 47620718). The registrant does not provide an explanation for this discrepa ncy. In one of the aforementioned aerobic soil metabolism studies, CO 2 was approximately 52% of the AR at the end of the study (373 days).
In another aerobic soil metabo lism study, the accumulation of an unidentified volatile compound was observed to steadily increase to approxi mately 10% at study termination (MRID 47620715).

Cyflufenamid was shown to be stable under anaer obic conditions. Cyflufenamid did not degrade in the anaerobic soil metabolism study (MRID 47620725 and 47620727).

In aquatic environments, cyflufenamid degrad es under aerobic conditions . In two different water:soil test systems cyflufen amid has linear half-lives of approximately 128 and 43 days and

DT 50 of 100 and between 30 and 59 days, respectively (MRID 47620726). In one of the aerobic aquatic metabolism study, the observed DT 50 for cyflufenamid is approximately 100 days for the entire system (water and sediment). In severa l aerobic aquatic metabolis m studies including this aerobic aquatic metabolism study, the applied radio activity remains >15% in the water layer at study termination (100 days).

Field Dissipation

Field dissipation studies were c onducted in three different U.S. locations—California, Georgia, and New York. These studies showed that cyfl ufenamid dissipates with half-lives between approximately 2 and 11 days (5.3 ± 4.8 days). In th e terrestrial field studie s, all four degradation products are observed in soil samples taken from the top 0-15 cm of the test sites at some point during the studies. 149-F was the only degradati on product observed in soil samples taken at depths >15 cm. At the Georgia site, 149-F was obs erved in soil samples collected as deep as 15- 30 cm. 149-F1 was the only degradation product observed in soil samples collected at study termination for any of the studies and identifi cation was only in soil samples taken from the Georgia site.

2 Email to Samantha Hulkower (U.S. EPA) from John Wrubel (Nisso America; on behalf of the registrant) dated Feb. 16, 2010; EU soils: Evesham 3 is an inceptisol; Arro w and Broomsgrove are either an alfisol or an inceptisol; and Speyer 2.2 is a mollisol.37 Bioaccumulation

The log of the n -octanol/water partition coefficient (K
ow ) for cyflufenamid is 4.7. The BCF factors for cyflufenamid range from 250 to 1000, depending upon the exposure level. Ninety percent depuration occurs within five days. Bioaccumulation was measured for both a low exposure level (1.0 μ g ai/L) and a high exposure level (10.0 μ g ai/L). Cyflufenamid exposure lasted for 28 days followed by a 14-day depuration phase. Five cyflufenamid-based transformation products are known from the fish study. The only environmental degradation product observed in the study is 149-F. The four cyflufenamid -based transformation products are metabolites and include N-( α -cyclopropylmethoxyi mino-2,3-difluoro-6- trifluoromethylbenzyl)-2-(4-hyd roxyphenyl)acetamide (149-F-4- OH-B), N-phenylacetyl-2,3- difluoro-6-trifluoromethylbe namidoxime (149-F4B), N-( α -cyclopropylmethoxyimino-2,3- difluoro-6-trifluoromethylbe nzyl)-2-(3-hydroxyphenyl)acetamid e (149-F-3-OH-B), and N-( α

Cyclopropylmethoxyimino-2,3-difluoro-6-trifluo romethylbenzyl)-2-hydroxy-2-phenylacetamide (149-F- α -OH-B). The chemical structures of these metabolites are shown in Appendix B . A
small amount of unextractable residu es was observed in the BCF studies.

Transformation

Although cyflufenamid ( Z -isomer) is present in higher quant ities it can be converted to 149-( E )- FB. Under all study conditions the Z -isomer was present in highe r concentrations that the E

isomer. In all submitted studies 149-( E )-FB was not observed to be ≤ 12.6% applied radio activity, which means that it is a major transf ormation product that is not formed in large amounts. The highest concentration of E -isomer was observed in one aerobic aquatic metabolism study (47620726). No data are available for 149-( E )-FB. It was assumed to behave like cyflufenamid in the environment. The registrant’s proposed degradation pathway of cyflufenamid is shown in Figure 6 . Three degradation produ cts, 149-F [N-Cyclopropyl methoxy-2,3-difluoro-6-trifluoro- methylbenzamidine], 149-F1 [ 2,3-Difluoro-6-trifluoromethyl benzamidine], and 149-F11 [(Z)-N-( α -Cyclopropylmethoxyimino-2,3-difl uoro-6-trifluoromethyl benzyl)carbamoylacetic acid] accumulate to >1 0% in a number of the submitted laboratory studies. One other degradation product, 149-F6 [2,3-Difluoro-6-trifl uoromethyl benzamide], was identified in a number of the submitted studies, but it does not accumulate to >10%. Although 149-F6 is not observed in any of the e xperiment to reach quantities >10% [presumable due to the relatively long half -life of 149-F1 under aerobic conditions and the short experimental durations (120 days)], it ha s the potential to persis t in the environment due to its long half-life.

The observed DT 50 for 149-F is 6 to 16 days (MRID 47620722) . The calculated non-linear halflives range from 6 to 14 days (10 ± 4 days) a nd the calculated linear ha lf-lives range from 14 days to 22 days (17 ± 4 days). For 149-F1, a DT 50 of >120 days was observed (MRID 47620723). The calculated linear half-lives range from 136 to 347 days (222 ±111 days). The
observed DT 50 for 149-F11 was 2 to 3 days (MRID 47620721) . The calculated linear half-lives range from 3 to 4 days (3 ± 0.6 days). For 149-F6, the DT 50 was not observed during the course of the experiments, therefore, it is assume d to be >120 days (MRID 47620724). The calculated
linear and nonlinear half-life va lues for 149-F6 range from 866 to 2311 days (1521 ± 731 days)
for three different soils.38 Transport

Batch equilibrium data for cyflufenamid sugge st that the compound adsorbs to soil and is “slightly mobile” according to the FAO classifica tion [organic carbon partition coefficients (K
oc ) range from 1934 to 3087 mL/g soil]. These values reasonably correlate with the organic content of the soil. The solubility of cyflufenamid in water is low (0.52 mg/L at 20 °C).

149-F11 is highly mobile or mobile and soil pa rtitioning does not correl ate with the organic content of the soil (MRID 47620729). Adsorption coefficients (K d ) range from 0.13-0.36 mg/L. 149-F11 is soluble in water (0.842 g/L).

149-F is also “mobile” according to the FAO classification (MRID 47620730). The soil partition coefficient correlates with the organi c carbon content of the test soil. K
oc s range from 33 to 70 mL/g soil. 149-F is also so luble in water (0.925 g/L).

149-F6 does adsorb to organic surfaces and is co nsidered “highly mobile or mobile” according to the FAO classification (MRID 47638208). K
oc s range 9 to 16 mL/g soil. 149-F6 is highly soluble in water (9.013 g/L).

149-F1 is considered “mobile to moderately m obile” according to the FAO classification. The soil partition coefficient correla tes with the organic carbon content of the test soil. K
oc s range from 77 to 213 mL/g soil. 149-F1 is highly soluble in water (60.89 g/L).

In aquatic systems, partitioning of cyflufenamid to sediment occurs rapidly. In batch equilibrium studies, adsorption-desorption reaches stead y-state within 24 hours. In several water:soil/sediment test systems, more than half of the applied ra dioactivity is found in
sediment/soil within one week of cyflufenamid application.

Laboratory studies i ndicate that cyflufenamid is not volatil e (<2% volatilizatio n). These results are consistent with its vapor pressure of 3.54 x 10 -5 Pa (2.66 x 10 -7 mmHg).

2. Measures of Aquatic Exposure

a. Aquatic Exposure Modeling

Tier II total toxic cyflufenamid residues EECs in surface water resulting from the proposed uses of cyflufenamid on cucurbit vegetables, low grow ing berries, pome fruit, outdoor landscape and outdoor nursery ornamentals, and small fruit vi nes are calculated using PRZM (version 3.12.3, June 2006) and EXAMS (version 2.98.04.06, April 2005) models in the PE5 shell.39 Input Parameters

The input parameters used in this risk assessmen t are selected from the environmental fate data submitted by the registrant in accordance with US EPA-OPP EFED water model input parameter guidance. This assessment is based on total toxic cyflufenamid residues. Note that, uncertainties exist in choosing input parameters. For this reas on, this assessment incorpor ates all scientifically available data to conservatively estimate total toxic cyflufenamid residue levels resulting from the proposed uses of cyflufenamid. To account for total toxic cyflufenamid residues, each relevant environmental fate study (hydrolysis, aq ueous photolysis, aerobic soil metabolism, etc.) are used to calculate the amount of cyflufen amid, 149-F11, 149-F, 149-F1, and 149-F6 present in each study at each sampling interval. The total con centrations are used to recalculate the rate constant and the corresponding half-life value for each study. These data are used to calculate modeling input parameters accord ing to the input parameter guida nce. When there are no data available for the identified degradates, input values are assumed to be equivalent to the value for cyflufenamid. If data are available for cyflufen amid as well as its degradation products and the data cannot be combined, the most conservative pl ausible values are used. This is based on the assessor’s best judgment. Rational for choosi ng each input parameter is discussed in the subsections below. Input values used in the model runs are summarized in Tables 10 and 11

.

Water Solubility

The registrant provided solubility information for cyflufenamid, as well as all degradates of toxicological concern at 20 °C. These values are provided in Table 9

.

Degradate 149-F1 is the most water soluble of th e five compounds consider ed in this assessment. Therefore, according to guidance 60.89 g/L is used for PRZM-EXAMS modeling.

Soil Partition Coefficient

The registrant provided data necessary to determ ine if soil binding is co rrelated with organic carbon content (i.e. the coefficient of variation for K
oc values is less than that for K d values) for cyflufenamid and its four degradates. Bindi ng correlation for each compound is provided in

Table 9 . When binding is correlated with organi c carbon content the partition coefficient (K
oc )
is also listed in Table 9

.

Studies indicate that degradate 149-F6 is not only highly mobile in so il, it is also persistent in the environment thus it likely to impact surface and groundwater. The average value of 11.5 mL/g is used in PRZM-EXAM modeling.

Aerobic Soil Metabolism Half-life

The rate constant for disappearance of total to xic cyflufenamid residues was calculated and the corresponding half-life value fo r each study is reported. Th ese values are reported in Table 9

. The 90 th percentile confidence bound on the mean tota l toxic cyflufenamid half-life value is 205 + [(1.392 x 234)/ √ 9)] = 314 days. This value is used in PRZM-EXAM modeling.40 Aerobic Aquatic Metabolism Half-life

The rate constant for disappearance of total to xic cyflufenamid residues was calculated and the corresponding half-life value de termined for each study. These values are reported in Table 9

. The 90 th percentile confidence bound on the mean tota l toxic cyflufenamid half-life value is 235 + [(3.078 x 159)/ √ 2)] = 581 days.

Model Scenario

When more than one standard scenario exis ts for a given crop group or subgroup all are modeled. Standard scenarios, th e scenario locations, and first application dates used in PRZMEXAMS modeling are provided in Table 10 and 11 . The CYFLUFENAMID 10 SC
FUNGICIDE label did not recommended an initia l application date. Meteorological data corresponding to the location of the standard scenario was us ed to indentify dates when conditions are conducive for powdery mildew a nd the runoff potential is high. These dates
where used in the mode runs. The MILTREX ® 10 SC FUNGICIDE label recommend to “begin application at first sign of dis ease development.” This implies that cyflufenamid may be applied at anytime during the growing season. Again, me teorological data was re ferenced to identify dates when pest pressure may be high and runo ff potential is high for eac h standard scenario location. This information was used in conjuncti on with crop profiles to choose the dates that
are used in the mode runs. EECs for aerial applications are reported.41Table 10. Chemical Specific Input Parameters Used in PRZM-EXAM Modeling to Estimate Total Toxic CyflufenamidResidue Concentrations Resulting From the Proposed Useson Cucurbit Vegetables, Low Growing Berries, Pome Fruit,Outdoor Landscape and Nursery Ornamentals, and Small Fruit VinesInput Parameter (Symbol; Unit)Value forCyflufenamidValue for TotalToxic CyflufenamidResiduesBasis for Total ToxicCyflufenamid ResidueInput SelectionReferenceMolecular Weight (g/mole) 412.36 412.36 value for cyflufenamid MRID 47620712Henry’s constant (atm-m3/molat 20oC) 2.8 x 10-42.8 x 10-4value for cyflufenamidcalculated using vaporpressure, molecular weight,and solubilityVapor Pressure (torr at 20oC) 2.7 x 10-72.7 x 10-7value for cyflufenamidSano. S., Kasahara, I.,Yamanaka, H.J. Pestic. Sci.2007,32, 137-138.Solubility in Water (at 20oC) 0.52 mg/L 60890 mg/Lmost conservative value;value for 149-F1MRID 47620723Hydrolysis Half-life (t1/2at pH 7) 00value for cyflufenamid MRID 47620712Aquatic Photolysis Half-life (t1/2at pH 7) 00value for cyflufenamid MRID 47620713Aerobic Soil Metabolism [upper 90thpercentile confidence bound on the meanhalf-life value (t1/2; days)]134 314recalculated for total toxicresidues using original data1MRID 47620715, 47620716,47620717, 47620718, and47620719Aerobic Aquatic Metabolism Half-life[water column; upper 90thpercentileconfidence bound onthe mean half-lifevalue (t1/2; days)]209 581recalculated for total toxicresidues using original data1MRID 47620726Anaerobic Aquatic Metabolism Half-life[benthic; upper 90thpercentile confidencebound on the meanhalf-life value (t1/2;days)]0 0value for cyflufenamidMRID 47620725 and47620727Average Soil Partition Coefficient (Koc;mL/g)2355.5 11.5most conservative value;value for 149-F6MRID 476207281Half-lives are recalculated according to half-life guidance for a new set of datathat combine all stressors (total toxic residues) so that calculated half-livesrepresent the decline of the all total toxic residues (i.e. cyflufenamid, 149-F11, 149-F, 149-F1, and 149-F6).42 Table 11. Management Specific Input Para meters Used in PRZM-EXAM Modeling to Estimate Total Toxic Cyflufenamid Residue Co ncentrations Resulting From the Proposed Uses on Cucurbit Vegetables, Low Growing Berries, Pome Fruit, Outdoor Landscape and Nursery Ornamentals, and Small Fruit Vines Input Parameter

(Symbol; Unit) Value Used Reference

CAM 2 aerial foliar application EFED Guidance

Application Type and Depth of Incorporation 0 Aerial application EFED Guidance

Spray Drift Fraction 0.05 Aerial application EFED Guidance

Application Efficiency 0.95 Aerial application EFED Guidance

Number of Applications/Application

Rate 2 Cucurbit Vegetables 2/0.012 kg ai/ha

Proposed Label Low Growing Berry 2/0.025 kg ai/ha

Ornamentals 2/0.026 kg ai/ha

Pome Fruit 2/0.025 kg ai/ha

Small Fruit Vine 2/0.025 kg ai/ha

Interval Between Applications Cucurbit Vegetables 7 days

Proposed Label Low Growing Berry, Ornamentals, Pome

Fruit, and Small
Fruit Vine 14 days

Location Specific Crop Scenarios and Application

Date Cucurbit Vegetables FL Cucumber
01/10

Proposed Label, Crop Specific Profiles, 1 PRZM-EXAM Scenario Profiles, and Meteorological

Data. MI Melon

01/07

MO Melon
15/07

NJ Melon

15/06

Low Growing Berry CA Fruit
15/03 CA Grapes
15/03 FL Strawberry
15/10 NY Grapes
15/07

Outdoor Landscape
and Ornamentals CA Nursery
01/01 FL Nursery
01/10 MI Nursery
01/0543 NJ Nursery
01/07 OR Nursery
01/07 TN Nursery
01/05

Pome Fruit CA Fruit
15/10 NC Apple

01/08 OR Apple

01/08 PA Apple

01/06

Small Fruit Vine CA Fruit
15/10 CA Grapes
15/03 NY Grapes
15/07

1 National Information System for the Regional IPM Centers, http://www.ipmcenters.org/cropprofiles/

2 Application rates used are based on maximum single application rates.

Estimated Environmental Concentrations in Surface Water

Tier II cyflufenamid EECs for the proposed us es on cucurbit vegetabl es, low growing berries, pome fruits, outdoor landscape and nursery, a nd small climbing fruit vines are listed in Tables

12 thru 16 , respectively. The model out put files are provided in Appendix D . Cyflufenamid applications to North Carolina apples provide th e most conservative Tier II EECs for total toxic residues. Tier II EECs for total toxic cyflufen amid residues are not expected to exceed 0.85 μ g/L for the 1-in-10 year return peak (used in acute assessments), 0.75 μ g/L for the 1-in-10 year 96- hour, 0.46 for the 21-day mean concentration (used in chronic assessments), and 0.22 μ g/L for the 1-in-10 year 60-day mean concentra tion (used in chronic assessments).

(1) Cucurbit Vegetables

Four cucurbit vegetable scenarios were selected to represent th e crop group including cucumber
and melons. Three different melon scenarios ex ist. The estimated environmental exposure
concentrations in surface water as a result of these uses are shown in Table 12

.

Table 12. Estimated Environmental Exposure Concentrations in Surface Water for Cucurbit Vegetable Scenarios

Scenario 1-in-10 year annual exceedance probability for EECs

Peak

μ g/L (ppb) 96-hour

μ g/L (ppb) 21-day

μ g/L (ppb) 60-day

μ g/L (ppb)

FL Cucumber 0.49 0.40 0.21 0.086

MI Melon 0.26 0.22 0.12 0.055

MO Melon 0.23 0.19 0.11 0.048

NJ Melon 0.18 0.15 0.082 0.04144 (2) Low Growing Berries Except Cranberries

Four Tier II model scenarios exist for low gr owing berries. The New York grape scenario provides the most conservative Tier II EECs. Ti er II surface water EECs as a result of these uses
are shown in Table 13

.

Table 13. Estimated Environmental Expo sure Concentrations of Total Toxic Cyflufenamid Residues in Surface Wat er from Cyflufenamid Use on Low Growing Berries

Scenario 1-in-10 year annual exceedance probability for EECs

Peak

μ g/L (ppb) 96-hour

μ g/L (ppb) 21-day

μ g/L (ppb) 60-day

μ g/L (ppb)

CA Fruit 0.12 0.11 0.075 0.047

CA Grapes 0.14 0.12 0.083 0.048
FL Strawberry 0.43 0.36 0.19 0.095

NY Grapes 0.53 0.44 0.24 0.11

(3) Outdoor Landscape and Ornamentals

Several nursery scenarios were used as su rrogates for outdoor landscape and ornamental landscape. Uses on ornamental trees and sh rubs beyond nurseries may include residential property, public areas, commercial areas, institutional areas, indus trial areas, industrial areas, rights-of-way and other easements, and recreationa l sites such campgrounds, golf courses, parks,
and athletic fields. The most conservative EECs are calculated using the California nursery
scenario as shown in Table 14

.

Table 14. Estimated Environmental Expo sure Concentrations of Total Toxic Cyflufenamid Residues in Surface Water from Cyflufenamid Use on Outdoor Landscape and Ornamentals

Scenario 1-in-10 year annual exceedance probability for EECs

Peak

μ g/L (ppb) 96-hour

μ g/L (ppb) 21-day

μ g/L (ppb) 60-day

μ g/L (ppb)
CA Nursery 0.29 0.25 0.15 0.075

FL Nursery 0.28 0.24 0.16 0.094

MI Nursery 0.26 0.22 0.15 0.077

NJ Nursery 0.36 0.30 0.20 0.11

OR Nursery 0.16 0.14 0.091 0.053

TN Nursery 0.47 0.40 0.24 0.12

(4) Pome Fruit

Four Tier II model scenarios ex ist for pome fruit. The North Carolina apple scenario gives the most conservative EECs not only for pome fruit but also all of the proposed uses. The estimated environmental exposure concentratio ns in surface water as a resu lt of these uses are shown in

Table 15

.45 Table 15. Estimated Environmental Exposure Concentrations of Total Toxic Cyflufenamid Residues in Surface Water from Cyflufenamid Use on Pome
Fruit

Scenario 1-in-10 year annual exceedance probability for EECs

Peak

μ g/L (ppb) 96-hour

μ g/L (ppb) 21-day

μ g/L (ppb) 60-day

μ g/L (ppb)

CA Fruit 0.13 0.11 0.08 0.05

NC Apples 0.85 0.75 0.46 0.22
OR Apples 0.15 0.13 0.09 0.05
PA Apples 0.44 0.37 0.21 0.12

(5) Small Fruit Vine Climbing Except Fuzzy Kiwi Fruit

There are three Tier II standard model scenario s for small vine climbing fruit. These are the same scenarios used to model low growing berr ies and based on the maximum application rate the results are the same for both crop subgroups. The EECs in surface water as a result of these
uses are shown in Table 16

.

Table 16. Estimated Environmental Exposure Concentr ations of Total Toxic Cyflufenamid Residues in Surface Water from Cyflufenamid Use on Small Fruit Vine Climbing Except Fuzzy Kiwi Fruit

Crop Scenario 1-in-10 year annual exceedance probability for EECs

Peak

μ g/L (ppb) 96-hour

μ g/L (ppb) 21-day

μ g/L (ppb) 60-day

μ g/L (ppb)

Small Fruit
Vine CA Fruit 0.12 0.11 0.075 0.047

CA Grapes 0.14 0.12 0.083 0.048

NY Grapes 0.53 0.44 0.24 0.11

b. Aquatic Exposure Monitoring and Field Data

Cyflufenamid is not registered in the United St ates. Therefore, aquatic exposure monitoring and
field data are not available.

c. Aquatic Bioaccumulation Assessment

Available data on the octanol-w ater partition coefficient (K
ow ) for cyflufenamid indicates that this pesticide may accumulate in aquatic food webs. Because the Log K
ow is > 4.0, KABAM v.1.0 was used to estimate concentrations of cy flufenamid residues in tissues of aquatic organisms resulting from bioaccumulation. Input parameters are provided in Table 17 and estimated concentrations of total toxic cyfl ufenamid residues in fish are provided in Table 18

. Output files from KABAM are provided in Appendix E

.46 Table 17. Input parameters for Cyfl ufenamid Residues Used in KABAM

Characteristic Total Toxic

Residue

Value Comments

Log K OW 4.7 Value for cyflufenamid was used (MRID 47620415). Data is not available for the environmental degradates.

K OW 50118.7 Calculated

K OC (L/kg oc) 11.3 Input value for degradate 149-F6 was used (lowest Koc). MRID

47620728 Time to steady state (T S ; days) 16 days This value is calculated automatically from the Log K OW value entered
above.

Pore water EEC (μg/L) 0.1294 a Value generated by PRZM/EXAMS benthic file for North Carolina apples (Pome Fruit at 0.022 lbs a i/A with 2 application/year). PRZM/EXAMS EEC represents the freely dissolved concentration of the pesticide in the pore water of the sediment. The appropriate averaging period of the EEC is dependent on the specific pesticide being modeled and is based on the time it takes for the chemical to reach steady state. 21-day EEC was used as averaging period closest to the time to steady state calculated above.

Water Column

EEC (μg/L) 0.4635 a Value generated by PRZM/EXAMS water column file for North Carolina apples (Pome Fruit at 0.022 lbs ai/A with 2 application/year). PRZM/EXAMS EEC represents the freely dissolved concentration of the pesticide in the water column. 21-day EEC was used as averaging period closest to the time to steady state calculated above (as discussed above for pore water).

a PRZM-EXAMS input values are calculated using to tal toxic cyflufenamid fate characteristics.

Table 18. Estimated Concentratio ns of Cyflufenamid in Fish

Ecosystem Component Total
concentration

(μg/kg-ww) Lipid

normalized

concentration (μg/kg-lipid) Contribution

due to diet (μg/kg-ww) Contribution

due to respiration (μg/kg-ww)

Small Fish 1,194 29842 139.24 1,054.43

Medium Fish 1,303 32586 267.31 1,036.15 Large Fish 1,572 39300 523.86 1,048.15

3. Measures of Terrestrial Exposure

a. Terrestrial Exposure Modeling

(1) T-REX

Exposure of free-ranging terrestrial animals is a function of the timing a nd extent of pesticide application with respect to the location and behavior of those sp ecies. OPP’s terrestrial exposure model generates exposure estimates assuming that the animal is present on the use site at the time that pesticide levels ar e highest. The upper-bound pesticid e residue concentration on food items is calculated from both initial applications and any additional app lications, taking into account pesticide degradation betwee n applications. Although this appr oach is conservative, it is reasonable, particularly when cons idering acute risks. For acute ri sks, the assumption is that the47 duration of exposure is a single day and, again, occurs when resi due levels are highest. In evaluating chronic risks, longer- term exposure estimates are also based on the assumption that the animal is present on the use site when resi due levels are highest and furthermore that it repeatedly forages on the use site although the fr equency and duration of foraging events on the use site are not explicitly considered or specified.

The current screening-level approa ch does not directly relate timi ng of exposure to critical or sensitive population, community, or ecosystem processes. Given that the application timing and location is crop-dependent, it is difficult to a ddress the temporal and spatial co-occurrence of cyflufenamid use and sensitive ecological processes. However, pesticides are frequently used from spring through fall; crop cultivation freque ntly starts in the spring, hence uses of cyflufenamid are likely to occur in spring and perhaps summer. Spring and early summer are typically seasons of active migrating, feeding, and reproduction for many w ildlife species. The increased energy demands associated with th ese activities (as opposed to hibernation, for example) can increase the potential for exposur e to pesticide-contamin ated food items since agricultural areas can represent a concentrated source of rela tively easily obtained, high-energy food items. In this assessment, the spatial extent of exposure for terrestrial animal species is limited to the use area only and the ar ea immediately surrounding the use area.

Currently, the Agency does not re quire toxicity studies on reptiles and amphi bians in support of pesticide registrations. To accommodate this data gap, birds are used as surrogates for terrestrialphase amphibians and reptiles. It is assumed that , given the usually lower metabolic demands of reptiles and amphibians compared to birds, expos ure to birds would be greater due to higher relative food consumption. While this assu mption is likely true, there are no supported relationships regarding the relativ e toxicity of a compound to birds and herpetofauna. The lack of toxicity data on reptiles and amphi bians represents a source of uncertainty in this assessment.

Tables 19 and 20 list selected predicted cyflufenamid EECs for birds, reptiles, terrestrial amphibians, and mammals obtained from T-RE X simulations for the proposed uses of cyflufenamid at the maximum label rates provided in Table 8

.48 Table 19. Terrestrial Food-Item Residue Estima tes for Birds with Cyflufenamid Proposed

Uses

Crop Food Item Maximum Dose-Based EECs (mg/kg) 1,2 Dietary-Based

EECs 1,3

Cucurbit Vegetables Short grass 5.62 4.94 Tall grass 2.58 2.26 Broadleaf plants/ small insects 3.16 2.78 Fruits, pods, seeds, lg. insects 0.35 0.31

Low-growing Berries Short grass 9.88 9.88 Tall grass 4.53 4.53 Broadleaf plants/ small insects 5.56 5.56 Fruits, pods, seeds, lg. insects 0.62 0.62

Small Fruit Vine Climbing Subgroup Short grass 11.25 9.88 Tall grass 5.16 4.53 Broadleaf plants/ small insects 6.33 5.56 Fruits, pods, seeds, lg. insects 0.70 0.62

Pome Fruit Short grass 10.57 9.28 Tall grass 4.84 4.25 Broadleaf plants/ small insects 5.95 5.22 Fruits, pods, seeds, lg. insects 0.66 0.58

Outdoor Landscape and
Ornamentals Short grass 11.05 9.70 Tall grass 5.07 4.45 Broadleaf plants/ small insects 6.22 5.46 Fruits, pods, seeds, lg. insects 0.69 0.61

1 Based on default foliar dissipation half-life of 35 days

2 Based on 20 gram birds (acute)

3 Size Class not used for dietary EECs49 Table 20. Terrestrial Food-Item Residue Esti mates for Mammals with Cyflufenamid Proposed Uses

Size Class

(grams) Dietary and Dose-Based EECs 1

Short Grass Tall Grass Broadleaf Plants/

Small Insects Fruits/Pods/

Seeds/ Large Insects Granivore

Cucurbit Vegetables

Dose-Based EECs

15 4.81 2.20 2.71 0.30 0.07

35 3.32 1.52 1.87 0.21 0.05

1000 0.77 0.35 0.43 0.05 0.01 Dietary-Based EECs 2

NA 5.04 2.31 2.84 0.32 NA Low Growing Berries

Dose-Based EECs

15 6.94 3.18 3.90 0.43 0.10

35 4.80 2.20 2.70 0.30 0.07

1000 1.11 0.51 0.63 0.07 0.02 Dietary-Based EECs 2

NA 7.28 3.34 4.10 0.46 NA Small Fruit Vine Climbing Subgroup

Dose-Based EECs

15 8.13 3.73 4.57 0.51 0.11

35 5.62 2.58 3.16 0.35 0.08

1000 1.30 0.60 0.73 0.08 0.02 Dietary-Based EECs 2

NA 8.53 3.91 4.80 0.53 NA

Pome Fruit

Dose-Based EECs

15 9.15 4.19 5.15 0.57 0.13

35 6.32 2.90 3.56 0.40 0.09

1000 1.47 0.67 0.82 0.09 0.02 Dietary-Based EECs 2

NA 9.59 4.40 5.40 0.60 NA
Outdoor Landscape and Ornamentals

Dose-Based EECs

15 9.25 4.24 5.20 0.58 0.13

35 6.39 2.93 3.60 0.40 0.09

1000 1.48 0.68 0.83 0.09 0.02 Dietary-Based EECs 2

NA 9.70 4.45 5.46 0.61 NA

1 Based on default foliar dissipation half-life of 35 days

2 Size Class not used for dietary EECs50 (2) TERRPLANT

Effects on non-target terrestrial plan ts are most likely to occur as a result of spray drift and/or runoff from ground applications. TerrPlant is ty pically used by EFED as a Tier 1 model for screening level assessments of pe sticides. TerrPlant derives pe sticide EECs in runoff and in
drift. Table 21 lists predicted EECs for non-target te rrestrial plants ba sed on the maximum proposed application ra te for cyflufenamid.

Table 21. Estimated Environmental Concentrat ions for Terrestrial Plants Based on the Proposed Uses of Cyflufenamid 1

Description EEC
Runoff to dry areas 0.00023 Runoff to semi-aquatic areas 0.0023 Spray drift 0.00115 Total for dry areas 0.00138
Total for semi-aquatic areas 0.00345

1 Maximum proposed single application rate of 0.023 lb ai/A.

( 

### 3 ) 

### KABAM

KABAM is used to estimate potential bioa ccumulation of hydrophobic organic pesticides in freshwater aquatic ecosystems and risks to ma mmals and birds consuming aquatic organisms which have bioaccumulated these pesticides. This tool can also be used to estimate pesticide concentrations in fish tissues consumed by hum ans (i.e., filets). The bioaccumulation portion of KABAM is based upon work by Arnot and Gobas (2004) who parameterized a bioaccumulation model based on PCBs and some pesticides (e.g., lindane, DDT) in freshwater aquatic ecosystems. KABAM relies on a chemical's octanol-water partition coefficient (K OW ) to estimate uptake and elimination constants through respiration and diet of organisms in different trophic
levels. Pesticide tissue residues ar e calculated for different levels of an aquatic food web. The model then uses pesticide tissue concentrations inaquatic animals to estimate dose- and dietarybased exposures and associated risks to mammals and birds consuming aquatic organisms, using an approach that is similar to the T-REX model (USEPA, 2008). Table 22 lists predicted EECs in cyflufenamid contaminated fish based the us e scenario resulting in th e highest peak aquatic EEC (NC pome fruits).51 Table 22. EECs for Mammals and Birds Consumin g Fish Contaminated by Cyflufenamid

Wildlife Species Biological Parameters EECs (pesticide intake)
Body Weight

(kg) Dry Food Ingestion Rate (kg/kg-bw/day) Wet Food Ingestion Rate (kg/kg-bw/day) Drinking

Water Intake (L/d) Dose Based (mg/kg-w/d) Dietary

Based (ppm)

Mammalian fog/water shrew 0.02 0.140 0.585 0.003 0.505 0.86

rice rat/star-nosed mole 0.1 0.107 0.484 0.011 0.423 0.87

small mink 0.5 0.079 0.293 0.048 0.382 1.30
large mink 1.8 0.062 0.229 0.168 0.299 1.30

small river otter 5.0 0.052 0.191 0.421 0.249 1.30
large river otter 15.0 0.042 0.157 1.133 0.247 1.57

Avian Sandpipers 0.0 0.228 1.034 0.004 0.9071 0.88

Cranes 6.7 0.030 0.136 0.211 0.1243 0.91

Rails 0.1 0.147 0.577 0.010 0.5935 1.03

Herons 2.9 0.040 0.157 0.120 0.1705 1.08
small osprey 1.3 0.054 0.199 0.069 0.2599 1.30
white pelican 7.5 0.029 0.107 0.228 0.1677 1.57

b. Residue Studies

Crop-specific decline data for residues of cyflufenamid are available from submitted crop field trial studies for cucumber, grape, st rawberry and apple crops (MRID 47620811, 42620809, 42620810, 47638213). Half-life values for repres entative commodities calculated using available magnitude of residue crop field trial data are as follows: cucurbit vegetables (52 days based on cucumber data), low-growing berries (5 days based on strawberry data), vine climbing small fruit (10 days based on grape data), and pome fruit (48 days based on apple data).

Although crop-specific decline data for residues of cyflufenamid are available from submitted crop field trial studies for each proposed crop group except outdoor landscape and outdoor nursery ornamentals commodities, the default foliar dissipation half-life (35 days) was used for risk assessment since the refined approach would not have altered the overa ll risk results for the proposed uses. For landscape/ornamentals, us e of a 52 day-half life (maximum observed in tested crops) instead of the default 35 days would result in the highest te rrestrial EECs for any of the proposed crops and corresponding application rates (2% higher maximu m EEC for birds than maximum EEC based on 35 day half-life and 4% higher maximum EEC for mammals).52 C. Ecological Effects Characterization

1. Aquatic Effects Characterization

a. Aquatic Animals

(1) Acute Effects

Freshwater Fish and A quatic-Phase Amphibians

Acute toxicity testing in dicates that technical cyflufenamid is moderately toxic to freshwater
fish. Available data on the four environmen tal degradation products (149-F, 149-F1, 149-F6, and 149-F11) indicate that they are less toxic than cyflufenamid. The tested formulation (NF149 10SC) does not appear to be more toxic than technical cyflufenamid. Table 23 summarizes
the effects from the available studies.

The freshwater fish study on rainbow trout for the formulation is classified as supplemental because the water samples were not centrifuged or filtered prior to anal ytical determination. Without centrifugation or filtration, the amount of chemical that is freely dissolved and
bioavailable cannot be determined. This is especially a problem as all of the testing concentrations were conducted above the water solubility limit of the technical grade active ingredient (0.52 mg ai/L at 20 o C). Therefore, the concentrations are reported as mg ‘total’ ai/L.

Table 23. Freshwater Fish Acut e Toxicity to Cyflufenamid

Common Name %AI Study parameters LC 50 /NOAEC/LOAEC MRID Classification/
Category

Technical (NF-149)

Rainbow trout
Oncorhynchus mykiss 95.2 96 hour study

7 fish/vessel

Mean measured concentrations: 0, 0 (solvent), 0.274, 0.524, 0.651, 0.872, and 1.43 mg ai/L
Static renewal study 96 HR LC 50 = 1.04 (0.651-1.43) mg ai/L 2,3

NOAEC = 0.274 mg ai/L
LOAEC = 0.524 mg ai/L (based
on sublethal effects: hyperventilation, coughing, darkened pigmentation, lethargy, nervous/erratic behavior, and loss of coordination) 47620626 Acceptable/
Moderately toxic 153 Common Name %AI Study parameters LC 50 /NOAEC/LOAEC MRID Classification/
Category

Bluegill Sunfish

Lepomis
macrochirus 95.2 96 hour study

7 fish/vessel

Mean measured concentrations: 0, 0(solvent), 0.274, 0.513, 0.915, 1.20, and 1.07 mg ai/L
Static renewal study 96 HR LC 50 >1.20 mg ai/L
NOAEC = 0.513 mg ai/L
LOAEC = 0.915 mg ai/L (based
on sublethal effects: hyperventilation, coughing, and darkened pigmentation) 47620625 Supplemental/
Not applicable

Poor analytical recovery resulted
in a shift in the
order of the two highest test
concentrations
relative to their respective
nominal
concentrations. However, the study is sufficient enough to
indicate that bluegill sunfish is
less sensitive than
the rainbow trout.

Environmental Degradates of Cyflufenamid (149-F, 149-F1, 149-F6, 149-F11)

Rainbow trout
Oncorhynchus mykiss >99.9 149-F
96 hour study

7 fish/vessel

Mean measured concentrations: 0, 1.16, 2.56, 5.48, 11.9, 24.3, and 55.7 mg ai/L
Static renewal study 96 HR LC 50 = 41.3 (24.3 to +infinity) mg ai/L 3

NOAEC = 2.56 mg ai/L
LOAEC = 5.48 mg ai/L (based
on sublethal effects: hyperventilation, darkened pigmentation, lethargy, nervous/erratic swimming behavior, and loss of coordination) 47825901 Acceptable/
Slightly toxic 1

Rainbow trout
Oncorhynchus mykiss 99.1 149-F1
96 hour study

10 fish/vessel

Mean measured
concentrations: 0 and 103 mg ai/L
Static renewal study 96 HR LC 50 >103 mg ai/L
NOAEC = 103 mg ai/L

No effects observed 47825902 Supplemental/
Practically nontoxic 1

Rainbow trout
Oncorhynchus mykiss >99.9 149-F6
96 hour study

10 fish/vessel

Mean measured
concentrations: 0 and 98.5 mg ai/L
Static renewal study 96 HR LC 50 >98.5 mg ai/L
NOAEC = 98.5 mg ai/L

No effects observed 47825903 Supplemental/
Not applicable54 Common Name %AI Study parameters LC 50 /NOAEC/LOAEC MRID Classification/
Category

Rainbow trout
Oncorhynchus mykiss 98.2 149-F11
96 hour study

10 fish/vessel

Mean measured
concentrations: 0 and 97.1 mg ai/L
Static renewal study 96 HR LC 50 >97.1 mg ai/L
NOAEC = 97.1 mg ai/L

No effects observed 47825904 Supplemental/
Not applicable

Cyflufenamid formulations

Rainbow trout
Oncorhynchus mykiss 112 g/L NF-149 10SC
96 hour study

7 fish/vessel

Mean measured concentrations: 0, 1.64, 3.41, 8.16, 17.6, 44.0, and 96.0 mg total ai/L
Static renewal study 96 HR LC 50 >96.0 mg total ai/L
NOAEC = 96.0 mg total ai/L

No effects observed 47620627 Supplemental (not to be used in risk estimation)/
Not applicable

1 Based on LC 50 (mg/L): < 0.1 very highly toxic; 0.1-1 highly toxic; >1-10 moderately toxic; >10-100 slightly toxic; >100 practically nontoxic

2 Bold value is the value that will be used to calculate risk quotients

3 Range is 95% confidence interval for endpoint

Freshwater Invertebrates

Acute toxicity testing indicates that technical cyflufenam id caused immobility (15%) to
freshwater invertebrates between 1.73 mg total ai/L and the limit of aqueous solubility (0.52 mg ai/L at 20°C); there is uncertainty about the co ncentration because toxicity was based on total cyflufenamid and it is assumed that the dissolved fraction of cyflufenamid may have been as low as the limit of aqueous solubility. Available da ta on the four environmental degradation products (149-F, 149-F1, 149-F6, and 149-F11) indicate that they are less toxic than cyflufenamid. The study on the tested formulation (NF-149 10SC) indi cates that it is not more toxic than the technical grade active ingredient (TGAI) up to the limit of the aqueous solubility of cyflufenamid; however there is un certainty above the li mit of solubility. The dissolved fraction of cyflufenamid was not measured for either the formulation or the TGAI, thus there is not enough information to determine which is more toxic based on the submitted studies. Nonetheless, it appears that the formulation is no more toxic than the TGAI based on total cyflufenamid concentrations (TGAI: 15% immobili ty at 1.73 mg total ai/L; Formulation: 0% immobility at 5.19 mg total ai/L) an d the assumption that cyflufenamid in the formulation was at
least as soluble as when tested as the TGAI. Table 24 summarizes the effects from the available
studies.

The freshwater invertebrate studies on Daphnia magna for the TGAI (MRID 47620628) and formulation (MRID 47620629) are cla ssified as supplemental because the water samples were not centrifuged or filtered prio r to analytical determination. W ithout centrifugation or filtration,
the amount of chemical that is freely dissolved and bioavailable cannot be determined. This is especially a problem as some or all of the testing concentrations were above the aqueous55 solubility limit of the t echnical grade active ingred ient (0.52 mg ai/L at 20 o C). Therefore, the concentrations are reported as mg ‘total’ ai/L and are not useful for risk quotient (RQ) calculations, but can contribu te to risk description.

Table 24. Freshwater Invertebrate Acute Toxicity to Cyflufenamid

Common Name %AI Study parameters EC 50 /NOAEC/LOAEC MRID Classification/
Category

Technical (NF-149)

Water flea
Daphnia magna 95.2 48 hour study
4 replicates; 5
inverts/conc. level

Mean measured concentrations: 0, 0(solvent), 0.106, 0.209, 0.403, 0.831, and 1.73 mg total ai/L
Static study 48 HR EC 50 >1.73 mg total ai/L
NOAEC = 0.831 mg total ai/L
LOAEC = 1.73 mg total ai/L based on immobility. 47620628 Supplemental (not to be used in risk estimation)/
Not applicable

Environmental Degradates of Cyflufenamid (149-F, 149-F1, 149-F6, 149-F11)

Water flea
Daphnia magna >99.9 149-F
48 hour study
4 replicates; 5
inverts/conc. level

Mean measured concentrations: 0, 4.09, 8.81, 19.4, 44.2, and 97.0 mg ai/L
Static study 48 HR EC 50 = 55.6 (46.2-67.4) mg ai/L 2

Probit Slope = 6.9 (3.8-10.0) 2

NOAEC = 19.4 mg ai/L
LOAEC = 44.2 mg ai/L based on immobility 47825905 Acceptable/
Slightly toxic 1

Water flea
Daphnia magna 99.1 149-F1
48 hour study
4 replicates; 5
inverts/conc. level

Mean measured concentrations: 0, 0.273, 0.577, 1.31, 2.80, 6.13, 13.7, and 29.8 mg ai/L
Static study 48 HR EC 50 = 14.4 (11.2-18.9) mg ai/L 2

Probit Slope = 3.5 (2.2-4.8) 2

NOAEC = 6.13 mg ai/L
LOAEC = 13.7 mg ai/L based on immobility 47825906 Acceptable/
Slightly toxic 1

Water flea
Daphnia magna >99.9 149-F6
48 hour study
4 replicates; 5
inverts/conc. level

Mean measured
concentrations: 0 and 103 mg ai/L
Static study 48 HR EC 50 >103 mg ai/L
Probit Slope = N/A
NOAEC = 103 mg ai/L

No effects observed 47825907 Acceptable/
Practically nontoxic 156 Common Name %AI Study parameters EC 50 /NOAEC/LOAEC MRID Classification/
Category

Water flea
Daphnia magna 98.2 149-F11
48 hour study
4 replicates; 5
inverts/conc. level

Mean measured
concentrations: 0 and 99.6 mg ai/L
Static study 48 HR EC 50 >99.6 mg ai/L
Probit Slope = N/A
NOAEC = 99.6 mg ai/L

No effects observed 47825908 Acceptable/
Not applicable

Cyflufenamid formulations

Water flea
Daphnia magna 112 g/L NF-149 10SC
48 hour study
4 replicates; 5
inverts/conc. level

Mean measured concentrations: 0, 0.780, 1.48, 2.62, 5.19, 11.0, 23.0, and 47.3 mg
total ai/L
Static study 48 HR EC 50 = 46.9 (27.5-134) mg total ai/L 2

Probit Slope = 1.45 (0.84-2.06) 2

NOAEC = 5.19 mg total ai/L
LOAEC = 11.0 mg total ai/L based on immobility 47620629 Supplemental (not to be used in risk estimation)/
Slightly toxic 1

1 Based on EC 50 (mg/L): < 0.1 very highly toxic; 0.1-1 highly toxic; >1-10 moderately toxic; >10-100 slightly toxic; >100 practically nontoxic

2 Range is 95% confidence interval for endpoint

Marine/Estuarine Fish

Acute toxicity testing in dicates that technical cyflufenamid is at most highly toxic to estuarinemarine fish. Data was not available for any of the four environmen tal degradation products (149-F, 149-F1, 149-F6, and 149-F11) or any formulations. Table 25 summarizes the effects from the available study.57 Table 25. Estuarine/Marine Fish Acute Toxicity to Cyflufenamid

Common Name %AI Study parameters LC 50 /NOAEC/LOAEC MRID Classification/
Category

Technical (NF-149)

Sheepshead
minnow
Cyprinodon variegatus 96.2 96-hour study
2 replicates; 20
fish/conc. level

TWA concentrations: 0, 0(solvent), 0.0443, 0.0929, 0.193, 0.320, and 0.307 mg total ai/L
Highest two nominal test concentrations (1.0 and 0.50 mg ai/L) were
at or above limit of aqueous solubility. Only the highest test level was centrifuged prior to analysis; the TWA was 0.20 mg ai/L (0.307 mg total ai/L).
Static study 96 HR LC 50 >0.20 mg ai/L
NOAEC = 0.20 mg ai/L

No effects observed 47620702 Acceptable/
Not applicable

Marine/Estuarine Invertebrates

Acute toxicity testing in dicates that technical cyflufenamid is highly toxic to estuarine-marine invertebrates. Data was not available for any of the four environmental degradation products (149-F, 149-F1, 149-F6, and 149-F11) or any formulations. Table 26 summarizes the effects
from the available studies.

The study on mysid is classified as supplemental because the water samples were not centrifuged or filtered prior to an alytical determination. Without centr ifugation or filtration, the amount of chemical that is freely dissolved and bioavail able cannot be determined. This is a problem because at minimum, the two highest test concentr ations were likely above the aqueous solubility limit of cyflufenamid and some of the lower tr eatment levels potentially exceeded the aqueous solubility limit as well. The number of test concentrations and how much they exceeded solubility is uncertain because the study was conducted at 25 o C and aqueous solubility (freshwater) was reported as 0.52 mg ai/L at 20 o C and 0.047 mg ai/L at 30 o C. Furthermore, solubility in saltwater was not re ported and is expected to differ from that in freshwater (likely lower). Without centrifugation or filtration, the am ount of chemical that is freely dissolved and bioavailable cannot be determined. Therefore, the concentrations are reported as mg ‘total’ ai/L and are not useful for RQ calculations, but can contribu te to risk description.58 Table 26. Estuarine/Marine Invertebra te Acute Toxicity to Cyflufenamid

Common Name %AI Study parameters EC 50 /LC 50 /NOAEC/LOAEC MRID Classification/
Category

Technical (NF-149)

Eastern oyster

Crassostrea virginica 96.2 96-hour study
20 oysters/conc. level

TWA concentration: 0, 0(solvent), 0.015, 0.031, 0.07, 0.09, and 0.24 mg ai/L
Flow-through study 96 HR EC 50 = 0.16 (0.12-0.21) mg ai/L 2,3

Slope = 4.77± 1.37 4

NOAEC = 0.09 mg ai/L
LOAEC = 0.24 mg ai/L based on reduction in shell growth. No
mortalities. 47620630 Acceptable/ Highly toxic 1

Saltwater mysid

Americamysis
bahia 96.2 96-hour study
Two replicates; 20 mysid/conc. level

Mean-measured concentration: 0, 0(solvent), 0.14, 0.24, 0.38, 0.61, and 0.69 mg total ai/L
Static study 96 HR LC 50 = 0.64 (0.56-0.70) mg total ai/L 3

Slope = 17.1 (2.4-31.8) 3

NOAEC = 0.24 mg total ai/L
LOAEC = 0.38 mg total ai/L
based on sublethal effects: surfacing, lethargy, and erratic swimming 47620701 Supplemental (not to be used in risk estimation)/
Not applicable

1 Based on LC 50 /EC 50 (mg/L): < 0.1 very highly toxic; 0.1-1 highly toxic; >1-10 moderately toxic; >10-100 slightly toxic; >100 practically nontoxic

2 Bold value is the value that will be used to calculate risk quotients.

3 Range is 95% confidence interval for endpoint.

4 Range is ± the standard error.

(2) Chronic Effects

Freshwater Fish

The freshwater fish study on fathead minnow (MRID 47620705) is classified as supplemental because the test samples were not centrifuged or fi ltered prior to analytical determination. This is a problem because at minimum, the highest nomin al test concentration was at or above the aqueous solubility limit of cyflufenamid and some of the lower treatment levels potentially exceeded the aqueous solubility limit as well. Th e number of test concentrations and how much they exceeded solubility is uncerta in because the study was conducted at 25 o C and aqueous solubility was reported as 0.52 mg ai/L at 20 o C and 0.047 mg ai/L at 30 o C. Without centrifugation or filtration, the am ount of chemical that is fr eely dissolved and bioavailable cannot be determined. Therefore, the concentrati ons are reported as mg ‘total’ ai/L and are not useful for RQ calculations, but can contribute to risk description.59 Table 27. Freshwater Fish Chronic Toxicity to Cyflufenamid

Common Name %AI Study Parameters NOAEC/LOAEC MRID Classification

Technical (NF-149)

Fathead minnow
Pimephales promelas 95.2 31-day Early Life Cycle (28-day post hatch)

Aerated continuous
flow. 60 embryos/concentration
level.

TWA concentrations: 0, 0 (solvent), 0.022, 0.042, 0.090, 0.20, and 0.45 mg total ai/L NOAEC = 0.20 mg total ai/L
LOAEC = 0.45 mg total ai/L

No fish survived at 0.45 mg total
ai/L and NOAEC is based on
survival. At test termination
there was no eff ect on growth.
The overall NOAEC was 0.09 mg total ai/L based on internal bleeding, swollen abdomen, pink feces, and deformed mouth. 47620705 Supplemental (not to be used in risk estimation)

Freshwater Invertebrates

No acceptable chronic studies on freshwater invertebrates are available.

Estuarine/Marine Fish

No chronic studies on estuarine/marine fish are available for review.

Estuarine/Marine Invertebrates

No chronic studies on estuarine/marine invertebrates are available for review.

b. Aquatic Plants

Vascular

The 7 day static renewal study with the TGAI on Duckweed did not indicate any effects on growth at concentrations up to 0.247 mg ai/L. Data was not available for any of the four environmental degradation products (149-F, 149-F 1, 149-F6, and 149-F11) or any formulations.

Table 28 summarizes the study.

Although the Duckweed study was performed as a Tier II study, it is acceptable only as a Tier I study. The two highest concentrations are approxim ately at or distinctly above the solubility limit (0.52 mg ai/L) reported in the study. However, the two concentrations were not centrifuged prior to analytical determination. The necessity to centrifuge the lower test concentrations is void assuming that the concentrations were not serially diluted from the secondary stock solution as the study reports (i.e., each con centration was made directly fr om the secondary stock solution
after serial dilution of the primary stock solution). In addi tion, the limit concentration (0.017 and 0.035 mg ai/L) calculated from a single applicat ion rate (0.023 lbs ai /A) and maximum annual application rate (0.046 lbs ai/A ), respectively, for outdoor la ndscape and outdoor nursery ornamentals, is far below the concentrations te sted in this study. Given the uncertainty in the60 bioavailability of the compound in the highest two concentrations and that no dose-response effects were observed, the NOAEC and EC 50 values are determined to be 0.247 and >0.247 mg ai/L, respectively.

Table 28. Vascular Aquatic Plan t Toxicity to Cyflufenamid

Species %AI Study parameters EC 50 /NOAEC MRID Classification

Technical (NF-149)

Duckweed Lemna gibba G3 96.2 Tier II study
7 day static renewal study

Mean measured concentrations: 0, 0 (solvent), 0.062, 0.125, 0.247 mg ai/L and 0.483 and 0.592 mg
total ai/L EC 50 > 0.247 mg ai/L

NOAEC = 0.247 mg ai/L 1

No effects on any endpoints (frond number, biomass, growth rate of frond number, and growth rate of biomass) 47620711 Acceptable as a Tier I study (limit test)

1 Bold value is the value that will be used to calculate risk quotients

Nonvascular

A 96 hour study with Navicul a did not show any effects at concentrations up to 0.269 mg ai/L. A 96 hour study with Skeletonema did not show any effects at concentrations up to 0.273 mg total ai/L; however samples were not centrifuged or filtered and solubility was not reported so
the dissolved concentration is uncertain. No other acceptable studies are available for nonvascular plants with the TGAI. Although there were studies submitted on the four environmental degradation products (149-F, 149-F 1, 149-F6, and 149-F11), it is not clear if they are less toxic than cyflufenamid because an acceptable study with the TGAI was not submitted on the same species. However, the four environmental degrad ates did not show toxicity at or below the reported aqueous solubility limit of cyflufenamid within the range of 10 to 30°C. Data was not available for any formulations. Table 29 summarizes the studies.

Although the Navicula study was performed as a Tier II st udy, it is acceptable only as a Tier I study. The highest nominal concen trations tested (500 and 1000 μ g ai/L) are approximately at or distinctly above the solubility limit (520 μ g ai/L) reported in the study. However, the two concentrations were not centrifuge d prior to analytical determina tion. The necessity to centrifuge the remaining concentrations is void assuming that the concentrations were not serially diluted from the secondary stock solution as the study reports (i.e., each c oncentration was made directly from the secondary stock solution after serial dilution of the prim ary stock solution). In addition, the limit concentration (17 and 35 μ g ai/L) calculated from a singl e application rate (0.023 lbs ai/A) and maximum annual application rate (0.04 6 lbs ai/A), respectively, for outdoor landscape and outdoor nursery ornamentals, is far below the concentrations tested in this study. Given the uncertainty in the bioavailability of the compoun d in the highest two conc entrations and that no dose-response effects were observed, the NOAEC and EC 50 values are determined to be 0.269 and >0.269 mg ai/L.61 Table 29. Non-Vascular Aquatic Pl ant Toxicity to Cyflufenamid

Species %AI Study parameters EC 50 /NOAEC MRID Classification

Technical (NF-149)

Freshwater

Diatom
Navicula pelliculosa 96.2 Tier II study
96 hour static study
4 replicates

Initial measured concentrations: 0, 0 (solvent), 0.074, 0.150, 0.269 mg ai/L and 0.417 and 0.580 mg
total ai/L EC 50 > 0.269 mg ai/L

NOAEC = 0.269 mg ai/L 1

No effects on any endpoints (cell density, yield, and growth rate) 47974503 Acceptable as a Tier I study (limit test)

Marine Diatom

Skeletonema

costatum 96.2 Tier II study
96 hour static study
3 replicates

Initial measured concentrations: 0, 0 (solvent), 0.035, 0.073, 0.141, 0.273, and 0.231 mg total ai/L EC 50 > 0.273 mg total ai/L NOAEC = 0.273 mg total ai/L

No effects on any endpoints (cell density, yield, and growth rate) 47974504 Supplemental (not to be used in risk estimation)

Environmental Degradates of Cyflufenamid (149-F, 149-F1, 149-F6, 149-F11)

Green Algae
Selenastrum capricornutum >99.9 149-F
Tier II study
72 hour static study
3 replicates (treatments), 6 replicates (control)

Mean measured concentrations: 0, 6.04, 12.5, 24.2, 49.0, and 93.6 mg ai/L Cell density

EC 50 = 55 (52-57) mg ai/L 2
Probit Slope = 7.91 ± 0.434 3 NOAEC = 24.2 mg ai/L

Biomass (area under the growth curve)

EC 50 = 56 (54-58) mg ai/L 2
Probit Slope = 7.99 ± 0.388 3 NOAEC = 24.2 mg ai/L

Growth rate

EC 50 = 78 (77-79) mg ai/L 2
Probit Slope = 6.65 ± 0.198 3 NOAEC = 24.2 mg ai/L

Endpoint(s) Effected: cell density, biomass – area under the curve, and growth rate 47825910 Supplemental

Green Algae
Selenastrum capricornutum 99.1 149-F1
Tier 1 study
72 hour static study
6 replicates

Mean measured
concentrations: 0 and 99.7 mg ai/L EC 50 > 99.7 mg ai/L NOAEC = 99.7 mg ai/L

No effects on any endpoints (cell density, biomass – area under the curve, and growth rate) 47825911 Supplemental62 Species %AI Study parameters EC 50 /NOAEC MRID Classification

Green Algae
Selenastrum capricornutum >99.9 149-F6
Tier 1 study
72 hour static study
6 replicates

Mean measured
concentrations: 0 and 101 mg ai/L EC 50 > 101 mg ai/L NOAEC = 101 mg ai/L

No effects on any endpoints (cell density, biomass – area under the curve, and growth rate) 47825912 Supplemental

Green Algae
Selenastrum capricornutum 98.2 149-F11
Tier 1 study
72 hour static study
6 replicates

Mean measured
concentrations: 0 and 97.3 mg ai/L EC 50 > 97.3 mg ai/L NOAEC = 97.3 mg ai/L

No effects on any endpoints (cell density, biomass – area under the curve, and growth rate) 47825913 Supplemental

1 Bold value is the value that will be used to calculate risk quotients

2 Range is 95% confidence interval for endpoint

3 Range is ± the standard error

2. Terrestrial Effects Characterization

a. Terrestrial Animals

Cyflufenamid is classified as practically nontoxic to birds, mammals, and terrestrial insects for acute effects. A reproduction study in rats s howed no frank reproduction effects. Reproductive
effects were observed in the mallard duck a nd bobwhite quail studies. In the bobwhite quail study, body weight effects (14-day surv ivor weight) were seen at th e lowest test dose. Adverse
effects to both monocots and dico ts were observed in non-target te rrestrial plant toxicity studies for vegetative vigor and seedling emergence. Tables 30 through 35 summarize the effects from
the available studies.

(1) Acute Effects

Birds

Acute data was available for technical cyflufen amid but not any of the four environmental degradation products or any form ulations. Based on the acute oral toxicity studies for the bobwhite quail and the zebra finch, cyflufenamid is categorized as practica lly non-toxic to birds on a dose basis (a definitive endpoint was not obtained in the bobwhite study but cyflufenamid would be no more than slightly toxic). There we re no mortalities in either study at the highest
doses tested. The acute oral LD 50 was > 1970 mg ai/kg bw for bobwhite quail and > 2000 mg ai/kg bw for zebra finch. Subl ethal effects in the zebra finch study include transitory clinical effects (ruffled appearance) and reduced male body weight gain at the two highest doses. The NOAEL for the zebra finch is 726 mg ai/kg bw. Ob served sublethal effect s in the acute oral study in bobwhite quail include transient decr eases in body weight and food consumption in63 females at all treatment doses and in ma les at the mid and high treatment doses. The LOAEL for bobwhite quail is 461 mg ai/kg, the lowest dos e tested, based on transitory effects on body weight and food consumption in females. A NOAEL was not identified.

Avian subacute dietary studies are available for the bobwhite quail and mallard duck. Based on these studies, cyflufenamid is categorized as practically non-toxic on a dietary basis. No
mortalities occurred in eith er study. The acute dietary LC 50 was >4900 ppm for bobwhite quail and > 4618 ppm for mallard duck. Reduced food consumption was seen at the highest dose tested in the quail study. Clinical signs (subdue d behavior) and reductions in body weight gain were seen at the two highest doses (2460 and 4900 mg ai/kg diet) in th is study. The NOAEC for the bobwhite quail study is 621 mg ai/kg diet. In the mallard duck study, reduced body weight gain and food consumption was observed at the 4618 mg ai/kg diet level. Sm all to large areas of bare (unfeathered) skin were al so observed post-termination at the highest dose tested. The NOAEC for the mallard duck study is 2224 mg ai/kg diet.

Table 30

. Avian Acute Toxicity to Cyflufenamid

Common Name %AI Study parameters LD 50 /LC 50 NOAEL/

LOAEL MRID Classification /Category

Technical (NF-149)

Bobwhite Quail
Colinus virginianus 95.1 Acute oral study

5 birds/sex/dose level
14 day observation period
<0.15, 461, 951, and 1970 mg ai/kg bw mg/kg bw single dose in corn oil by oral
intubation at a dose volume of 10 ml/kg bw LD 50 > 1970 mg ai/kg bw
NOAEL < 461 mg ai/kg bw
LOAEL = 461 mg ai/kg based on slight/transitory body weight and food consumption decrease in
females. 47620619 Acceptable/
Not applicable

Zebra Finch
Poephila guttata 96.2 Acute oral study

5 birds/sex/dose level
14 day observation period
0 (vehicle), 263, 437, 726, 1205, 2000 mg ai/kg bw single dose in corn oil by oral
intubation at a dose volume of 5 ml/kg LD 50 > 2000 mg ai/kg bw
NOAEL = 726 mg ai/kg
LOAEL = 1205 mg ai/kg based on clinical signs (ruffled feathers) and reduced male body weight gain) 4762020 Acceptable/
Practically
nontoxic 1

Bobwhite Quail

Colinus virginianus 95.1 Subacute dietary study

10 birds/concentration level
5 days on treatment, 3 additional days observation

<3.75, 157, 310, 621, 1230, 2460, and 4900 mg ai/kg diet (ppm), respectively. LC 50 > 4900 ppm
NOAEC = 621ppm
LOAEC = 1230 ppm based on clinical signs of toxicity (subdued behavior), reduced body weight gain, and reduced food consumption 47620621 Acceptable/
Practically
nontoxic 264 Common Name %AI Study parameters LD 50 /LC 50 NOAEL/

LOAEL MRID Classification /Category

Mallard Duck

Anas platyrhynchos 96.2 Subacute dietary study

12 birds/concentration level
5 days on treatment, 3 additional days observation

<12.1, 294, 564, 1236, 2224, and 4618 mg ai/kg diet (ppm), respectively. LC 50 > 4618 ppm
NOAEC = 2224 ppm
LOAEC = 4618 ppm based on reduced body weight gain, decreased food consumption, and post-mortem
abnormalities 47620622 Acceptable/
Practically
nontoxic 2

1 Based on LD 50 (mg/kg) <10 very highly toxic; 10-50 highly toxic; 51-500 moderately toxic; 501-2000 slightly toxic; >2000 practically nontoxic

2 Based on LC 50 (mg/kg) <50 very highly toxic; 50-500 highly toxic; 501-1000 moderately toxic; 1001-5000 slightly toxic; >5000 practically nontoxic

Mammals

Acute mammalian data are available for the t echnical material, a formulation (NF-149 10SC), and five transformation products of cyflufen amid: four plant metabolites/environmental degradation products (149-F, 149-F1, 149-F6, and 149-F11) and the stereoisomer of cyflufenamid (149- E -FB). Based on the acute oral toxicity studies with rats on the technical and formulated product, cyflufenamid is classified as practically nontoxic to mammals. The acute
oral LD 50 was >2000 mg formulation/kg/bw for the formulation and >5000 mg ai/kg/bw for technical cyflufenamid and its stereoisomer (149- E -FB). The acute oral LD 50 was 349 mg ai/kg/bw for the most toxic transformation produc t, 149-F1. All four e nvironmental degradation products were more toxic than t echnical cyflufenamid. One or mo re of the four degradates may be more toxic than the tested formulation (on an ai basis); however it is not certain due to the non-definitive endpoint from the formulation study. The OPP subcommittee on metabolism determined that the plant metabolites/degradates for which acute toxicity data were submitted are
not residues of concern for diet ary exposure due to their low le vels relative to cyflufenamid (DP377139, 5/24/10, G. Kramer)

Table 31. Mammalian Acute Toxicity to Cyflufenamid

Common

Name %AI Study parameters LD 50 /NOAEL MRID Classification /Category

Technical (NF-149)

Laboratory rat 95.2 Acute oral study
0, 3200, 5000 mg ai/kg bw tested

5/sex/dose level
15-day observation period. LD 50 >5000 mg ai/kg bw (M&F)

NOAEL: No NOAEL LOAEL = 3200 mg ai /kg bw based on clinical signs (piloerection, hunched posture, and waddling/unsteady gait) with recovery at all doses by day 4. 47620418 Acceptable/
Practically
nontoxic 165 Common

Name %AI Study parameters LD 50 /NOAEL MRID Classification /Category

Cyflufenamid formulations

Laboratory rat 9.98 NF-149 10SC
Acute oral study
2000 mg formulation/kg bw
tested
Single oral dose given to 2 groups of
3 female rats
15-day observation period. LD 50 >2000 mg formulation/kg bw (F) NOAEL = 2000 mg formulation/kg bw LOAEL >2000 mg formulation/kg bw

LD 50 >199.6 mg ai/kg bw (F) 47620824 Acceptable/
Practically
nontoxic 1

Cyflufenamid transformation products

Laboratory rat 99.8 149-F
Acute oral study

0, 800, 2500, 3200 mg ai/kg bw tested

5/sex/dose level
15-day observation period. LD 50 = 2697 (2384-3051) mg ai/kg bw 2
Probit Slope = 15.7 ± 5.96 3

NOAEL: No NOAEL LOAEL = 800 mg ai/kg based on clinical signs (e.g., piloerection) with recovery at all
doses 47620609 Acceptable/
Practically
nontoxic 1

Laboratory rat 99.8 149-F1
Acute oral study

0, 160, 250, 500, 100 mg ai/kg bw tested

5/sex/dose level
15-day observation period. LD 50 = 349 (248-491) mg ai/kg bw (F); 434 (343-594) mg ai/kg bw (M). 2
Probit Slope = 12.2 ± 4.61 3

NOAEL: No NOAEL LOAEL 160 mg/kg based on clinical signs (piloerection with recovery). 47620610 Acceptable/
Moderately
toxic 1

Laboratory rat >99.9 149-F6
Acute oral study

0, 250, 320, 500, 1000 mg ai/kg bw
tested

5/sex/dose level
15-day observation period. LD 50 = 686 (481-979) mg ai/kg bw (F&M) 2

NOAEL: No NOAEL LOAEL = 160 mg ai/kg based on clinical signs (piloerection with recovery). 47620611 Acceptable/
Slightly toxic 1

Laboratory rat >99.9 149-F11
Acute oral study

0, 500, 1000, 2500 mg ai/kg bw tested

5/sex/dose level
15-day observation period. LD 50 = 1123 (732-1724)mg ai/kg bw (M); 1360 (906-2042) mg ai/kg bw (F) 2

NOAEL: No NOAEL LOAEL = 500 mg ai/kg based on clinical signs (piloerection with recovery). 47620612 Acceptable/
Slightly toxic 166 Common

Name %AI Study parameters LD 50 /NOAEL MRID Classification /Category

Laboratory rat 99.5 149- E -FB (stereoisomer of cyflufenamid)
Acute oral study
5000 mg ai/kg bw
tested LD 50 >5000 mg ai/kg bw (M&F)

NOAEL: No NOAEL LOAEL = 3200 mg ai /kg bw based on clinical signs (piloerection, hunched posture, waddling/unsteady gait, pallid extremities and protru ding eyes seen in
both animals with increased salivation and ungroomed appearance observed in the male only) with recovery by Day 8. 47620613 Acceptable/
Practically
nontoxic 1

1 Based on LD 50 (mg/kg) <10 very highly toxic; 10-50 highly toxic; 51-500 moderately toxic; 501-2000 slightly toxic; >2000 practically nontoxic

2 Range is 95% confidence interval for endpoint

3 Range is ± the standard error

Terrestrial Invertebrates

Acute toxicity testing indi cates that technical cyflufenamid is classified as practically nontoxic to bees. Acute toxicity to bees was assessed based on acute oral and contac t toxicity. The tested formulation (NF-149 10SC) is also classified as practic ally nontoxic to bees. Table 32
summarizes the available studies.

Table 32. Terrestrial Invertebrate Acute Toxicity to Cyflufenamid

Common

Name %AI Study parameters LD 50 /NOAEL MRID Classification/
Category

Technical (NF-149)

Honey bees
Apis mellifera

. 95.2 48 hour acute
contact and oral study

60
bees/concentration

Nominal concentrations: 0, 0 (solvent), and

100 μ g ai/bee 48 hour contact LD 50 > 100

μ g ai/bee

48 hour contact NOAEL =

100 μ g ai/bee

48 hour oral LD 50 > 100 μ g ai/bee

48 hour oral NOAEL = 100

μ g ai/bee 47620707 Acceptable/ Practically nontoxic

Cyflufenamid formulations

Honey bees

Apis mellifera

. 112 g/L NF-149 10SC

48 hour acute
contact and oral study

60
bees/concentration

Nominal
concentrations: 0
and 100 μ g ai/bee 48 hour contact LD 50 > 100

μ g ai/bee

48 hour contact NOAEL =

100 μ g ai/bee

48 hour oral LD 50 > 100 μ g ai/bee

48 hour oral NOAEL = 100

μ g ai/bee 47620708 Acceptable/ Practically nontoxic67 

### (2) Chronic Effects

Birds

One-generation reproductive toxi city studies were conducted w ith technical cyflufenamid on both the mallard duck and bobwhite quail. In the bobwhite quail study, cyflufenamid was
administered in the diet at mean-measured concentrations of <3.75 (LOD), 94.8, 290, and 971 mg ai/kg diet. Multiple repr oductive effects were observed at the high dose in this study including significant reductions in the ratios of number hatched to eggs laid (13%), number hatched to eggs set (11%), 14-da y survivors to eggs set (17%), 14-day survivors (28%), and 14- day survivor weights (6%). Although significant reductions were seen in adult male body weight gain (29-36% vs control) at all dose levels, the effect was determined not to be treatment related. The NOAEC for the bobwhite quail study is 290 mg ai/kg diet.

In mallard duck reproduction study, cyflufenamid wa s administered in the diet at mean-measured concentrations of <3.18 , 99, 296, and 1016 mg ai/kg diet. Decreased body weight in males was observed at the highest dose. Reproductive effects were observe d at the two highest treatment levels. At 1016 mg ai/kg diet, significant reducti ons were observed in hatchling survivors (16% of control). Significant reductions were also observed in ratios of viable embryos to eggs set, live embryos to viable embryos, number hatched to eggs laid, number hatched to eggs set, number hatched to live embryos, and hatchling surv ivors to eggs set at 1016 mg ai/kg diet. The ratio of hatchling survivors to number hatched wa s significantly reduced at 296 mg ai/kg diet but not at 1016 mg ai/kg diet. At th e lowest tested dose (99 mg ai/ kg diet), 14-day survivor weights were mildly (5%), but significantly reduced (p ≤ 0.05). Therefore, a NOAEC for this study could
not be identified.

Table 33. Avian Chronic Toxicity to Cyflufenamid

Common Name %AI Study Parameters NOAEC/LOAEC MRID Classification

Technical (NF-149)

Bobwhite Quail

Colinus virginianus 95.1 Reproduction study
<3.75 (<LOD, control), 94.8, 290, and 971 ppm for 22 weeks. 20 pairs per concentration level. NOAEC: = 290 ppm
LOAEC: 971 ppm based on reproductive effects 47620624 Acceptable

Mallard Duck

Anas platyrhynchos 96.2 Reproduction study
<3.18 (<LOD, control), 99, 296, and 1016 ppm for 21 weeks. 16 pairs per concentration level. NOAEC < 99 ppm

LOAEC = 99 ppm based on reduced 14 day survivor body weight 47620623 Supplemental

Mammals

In a two-generation reproduction to xicity study, cyflufenamid was ad ministered in the diet at levels of 0, 80, 250, and 800 ppm. There were no treatment related effects observed in either generation for estrous cycle, sperm parameters, ma ting, conception, fertility or gestation indices, pre-coital interval, and gestation duration. The LOAEL for parental toxicity is 57.5 mg ai/kg/day based on increased liver and thyr oid weights. The offspring L OAEL of 57.5 mg ai/kg/day is based on reduced body weight gain in both F1 and F2 offspring.68 Table 34. Mammalian Chronic Toxicity to Cyflufenamid

Common Name %AI Study

Parameters NOAEC/LOAEC MRID Classification /Category

Technical (NF-149)

Laboratory rat

Rattus norvegicus 95.2 2-generation reproduction study 32 male
and 32 female rats/group at doses of 0, 5.8, 18.0, or 57.5 mg/kg/day (F) 0. 6.5, 19.9, 66.2 (M) diet Parental systemic NOAEL: 18 mg/kg bw/day LOAEL: 57.5 mg/kg bw/day based on increased liver and thyroid weights -
F0 adults Offspring/Developmental Toxicity

NOAEL: 18 mg/kg bw/day LOAEL: 57.5 mg/kg bw/day based on reduced body weight gain - F1 & F2 offspring Reproductive Toxicity NOAEL: 57.5 mg/kg bw/day. LOAEL > 57.4 mg/kg bw/day. 47620514 Acceptable

1 Bold value is the value that will be used to calculate risk quotients

(3) Field Studies

No field studies have been submitted for cyflufenamid.

b. Terrestrial Plants

Acceptable toxicity studies on the effects of cy flufenamid on seedling emergence and vegetative vigor indicate effects to several plant species resulting from applic ation of cyflufenamid at rates about one and a half to four times greater th an the maximum proposed application rate. The vegetative vigor test was conducted at measured application rates of 0.0339 and 0.0667 lbs ai/A. In this test, the only effect observed in monocot s was survival in onion crops. The NOAEC and

EC 25 values based on this effect ar e 0.0339 and >0.0667 lbs ai/A, respectively. No vegetative vigor effects were obs erved in dicots.

The effect of cyflufenamid on the seedling emerge nce was tested at measured concentrations of 0.0456 and 0.0903 lbs ai/A for oat, ryegrass, co rn, and lettuce; 0.0462 and 0.0877 lbs ai/A for sugarbeet, cabbage, soybean, and radish; 0.0377 and 0.0760 lbs ai/A for tomato; and 0.0428 and
0.0837 lbs ai/A for onion. The most sensitive m onocot species was oat, based on height, with
NOAEC and EC 25 values of <0.0456 and >0.0903 lbs ai/A, respectively. Tomato and cabbage
were the most sensitive dicots. Tomato exhibited dry weight inhibition of 26% at the low application rate. Cabbage exhibited emerge nce inhibitions of 27% at the low rate. Effects at the high application rate for both tomato and cabba ge were lower than the effects at the low application rate. Given normal variability in measured plan t effects, the low application rate of
0.0377 lbs ai/A for tomatoes and 0.0462 lbs ai/A for cabbage were reasonably considered to be

EC 25s for seedling emergence.69 Table 35. Tier I Non-target Terrestri al Plant Toxicity to Cyflufenamid

Species Seedling Emergence

Endpoint

Affected Vegetative Vigor

Endpoint

Affected MRID

No. Study

Classification EC 25

(lb ai/acre) NOAEC/[EC 05 ] 1
(lb ai/acre) EC 25 (lb ai/acre) NOAEC/[EC 05 ] (lb ai/acre)

Cyflufenamid formulations (NF-149 10SC)

Monocots

Onion Allium cepa >0.08 2 0.08 [>0.08] No effects >0.07 2 0.04 [>0.04] Survival 47620709

47620710 Acceptable

Ryegrass
Lolium

perenne >0.09 0.09 [>0.09] No effects >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Oat

Avena sativa >0.09 <0.05 [<0.05] Height >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Corn Zea mays >0.09 0.09 [>0.09] No effects >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Dicots

Sugarbeet Beta vulgaris >0.09 0.09 [>0.09] No effects >0.07 2 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Cabbage

Brassica
oleracea 0.05 <0.05 [<0.05] Emergence >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Soybean Glycine max >0.09 <0.05 [<0.05] Height >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Lettuce

Lactuca

sativa >0.09 0.09 [>0.09] No effects >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Tomato Lycopersicon
esculentum 0.04 2 <0.04 [<0.04] Dry weight >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

Radish Raphanus

sativus >0.09 0.09 [>0.09] No effects >0.07 0.07 [>0.07] No effects 47620709

47620710 Acceptable

1 If the NOAEC value is above the EC 25 , equal to the EC 25 , or below the lowest concentration, an EC 05 value is used
instead.

2 Bold value is the value that will be used to calculate risk quotients70 IV. Risk Characterization

A. Risk Estimation - Integration of Exposure and Effects Data

A quantitative estimation of risk integrates EECs and toxicity estimates and evaluates the likelihood of adverse ecological e ffects to non-target species. In a deterministic approach, an exposure estimate is divided by a single point esti mate of toxicity to cal culate a risk quotient (RQ). The RQ is then compared to Agency Levels of Concern (LOCs, Appendix F ), which serve as criteria for categorizing poten tial risk to non-target organi sms and the need to consider regulatory action.

Risk to aquatic species was assessed based on total toxic cyflufenamid residues because data were not available on the toxicity of the four environmental degradation products to estuarine/marine organisms and vascular aquatic plants. In addition, data were not available on chronic degradate toxicity to a ny aquatic taxa. Studies on fres hwater fish and invertebrates indicate that the four degradates are less toxi c than cyflufenamid to those taxa. Degradate
studies were also submitted for nonvascular plants (green algae); however it is not clear if they are less toxic than cyflufenamid because an acceptable study with the technical grade active ingredient (TGAI) was not submitted on the same species. Nonetheless, the four degradates did not show toxicity at or below the reported aque ous solubility limit of cyflufenamid within the range of 10 to 30°C. Although the environmental de gradates appear less toxic than cyflufenamid
to freshwater fish and inverteb rates, the risk assessment is ba sed on total toxic cyflufenamid residues for all aquatic taxa si nce the refined approach (cyflu fenamid only) would not have altered the risk results for the proposed uses.

1. Risk to Aquatic Animals and Plants

a. Aquatic Animals

(1) Risk Following Acute Exposure

Freshwater Fish and A quatic-Phase Amphibians

The acute aquatic LOC (listed and non-listed species) was not exceeded for any of the 21
scenarios selected to model the aquatic EECs. The scenario re sulting in the highest peak EEC and thus highest RQ is presented in Table 36

.

Table 36. Cyflufenamid: Acut e Risk to Freshwater Fish

Species Toxicity Endpoint (μg/L) Scenario Peak EEC (μg/L) Acute

Risk Quotient 1 Levels of

Concern

Exceeded 2

Rainbow trout
Oncorhynchus mykiss 96-hr LC 50 = 1040
Technical Pome Fruit
NC apples 0.85 0.0008 No

1 Acute Risk Quotients are calculated using the following formula: EEC/LC 50 2 Acute LOC for freshwater fish = 0.05 for endangered specie s, 0.1 for restricted use, and 0.5 for non-listed species71 Freshwater Invertebrates

The acute aquatic RQs for freshwater invertebrate s were not calculated. The test solution was not centrifuged or filtered prior to measurement of cyflufenamid in the acute freshwater invertebrate study with the TGAI and the formulation, even t hough higher concentrations tested exceeded or likely exceeded the solubility limit of the test compound. Wit hout centrifugation, the amount of cyflufenamid that is freely dissolved and bioava ilable cannot be determin ed. Uncertainty in the level of dissolved cyflufenamid in the soluti on for these studies rende rs calculated endpoints suitable for qualitative use only. Furtherm ore, RQs are not reported because the EC 50 is nondefinitive for the study with the lowest EC 50 (i.e., less than 50% immobility occurred at the highest test concentratio n in the TGAI study).

Marine/Estuarine Fish

RQs are not reported because there were no mort alities or sublethal effects observed at the highest test concentration. Further discussion of acute risks to estuarine/marine fish will be provided in the risk description section.

Marine/Estuarine Invertebrates

The acute aquatic LOC (listed and non-listed species) was not exceeded for any of the 21
scenarios selected to model the aquatic EECs. The scenario re sulting in the highest peak EEC and thus highest RQ is presented in Table 37 . There is uncertainty about the toxicity of cyflufenamid to mysid (see risk description for details).

Table 37. Cyflufenamid: Acute Risk to Estuarine/Marine Invertebrates

Species Toxicity Endpoint (μg/L) Scenario Peak EEC (μg/L) Acute

Risk Quotient 1 Levels of

Concern

Exceeded 2

Eastern Oyster

Crassostrea

virginica 96-hr EC 50 = 160
Technical Pome Fruit
NC apples 0.85 0.0053 No

1 Acute Risk Quotients are calculated using the following formula: EEC/LC 50 2 Acute LOC for estuarine/marine invertebrates = 0.05 for e ndangered species, 0.1 for restricted use, and 0.5 for nonlisted species

(2) Risk Following Chronic Exposure

Freshwater Fish and A quatic-Phase Amphibians

The chronic aquatic RQs for freshwater fish were not calculated. The test solution was not centrifuged or filtered prior to m easurement of cyflufenamid in the chronic freshwater fish study, even though some test concentrations exceeded or likely exceeded the solubility limit of cyflufenamid. Without centrifuga tion, the amount of cyflufenamid that is freely dissolved and bioavailable cannot be determined. Uncertainty in the level of dissolved test compound in the solution for this study renders calculated e ndpoints suitable for qualitative use only.72 Freshwater Invertebrates

No acceptable chronic studies on freshwater inverteb rates are available. Therefore, quantitative
risk estimation cannot be conducted. Chronic ri sk to freshwater i nvertebrates cannot be precluded.

Marine/Estuarine Fish

No chronic studies on marine/estuarine fish are av ailable. Therefore, a quantitative estimation of
risk cannot be conducted. Lack of studi es does not precl ude potential risk.

Marine/Estuarine Invertebrates

No chronic studies on marine/estua rine invertebrates are available. Therefore, a quantitative
estimation of risk cannot be conducted. Lack of studies does not pr eclude potential risk.

b. Aquatic Plants

Vascular Plants

The LOC for aquatic plants (listed species) was no t exceeded for any of the 21 scenarios selected to model the aquatic EECs. The scenario resulting in the highest peak EEC and thus highest RQ is presented in Table 38

.

The RQ for non-listed species is not estimated because no effects were observed at the limit concentration (0.247 mg ai/L). Therefore, the EC 50 would be greater than 0.247 mg ai/L. Further discussion of risk will be provided in the risk description section.

Table 38. Cyflufenamid: Risk to Aquatic Vascular Plants

Scenario Peak EEC (ug/L) Non-Listed Vascular Plant RQ 1,2 Listed Vascular Plant RQ 1,3

Pome Fruits

NC apple 0.85 Not estimated; EC 50 >limit test
concentration 0.003

1 Risk Quotients are calculated using the following formula: EEC/EC 50 for non-listed plants and EEC/NOAEC for listed plants. LOC = 1.0 for non-listed and listed plants.

2 RQ is based on non-listed plant toxicity threshold (EC 50 ) of > 247 ug ai/L for freshwater vascular plants.

3 RQ is based on listed plant toxicity threshold (NOAEC) of 247 ug ai/L for freshwater vascular plants.

Nonvascular Plants

RQs were calculated for nonvascular plants; how ever, the dataset for nonvascular plants is incomplete (see risk description for details).

Freshwater diatom data was the only data available suitable for calculation of RQs. The LOC for aquatic plants (listed species) was not exceeded fo r any of the 21 scenarios selected to model the aquatic EECs. The scenario resulting in the high est peak EEC and thus highest RQ is presented
in Table 39

.73 The RQ for non-listed species is not estimated because no effects were observed at the limit concentration (0.269 mg ai/L). Therefore, the EC 50 would be greater than 0.269 mg ai/L.

Further discussion of risk will be provided in the risk description section.

Table 39. Cyflufenamid: Risk to Aquatic Non-Vascular Plants

Scenario Peak EEC (ug/L) Non-Listed Non-Vascular Plant RQ 1,2 Listed Non-Vascular Plant RQ 1,3

Pome Fruits

NC apple 0.85 Not estimated; EC 50 >limit test
concentration 0.003

1 Risk Quotients are calculated using the following formula: EEC/EC 50 for non-listed plants and EEC/NOAEC for listed plants. LOC = 1.0 for non-listed and listed plants.

2 RQ is based on non-listed plant toxicity threshold (EC50) of > 269 ug ai/L for non-vascular plants (freshwater diatom)

3 RQ is based on listed plant toxicity threshold (NOAEC) of 269 ug ai/L for non-vascular plants (freshwater diatom).

2. Risk to Terrestrial Animals and Plants

a. Terrestrial Animals

To assess risks of cyflufenamid to non-target birds and mammals, EECs for cyflufenamid residues on various forage categor ies (short grass, tall grass, broadleaf plants/small insects, fruits/pods/large insects, and seeds) were obtained from the Tier 1 model, T-REX v. 1.4.1, based on foliar spray applications to the proposed crops. The model assumes initial concentrations on plant surfaces based on Kena ga predicted maximum residue s as modified by Fletcher et al. (1994), and assumes first- order dissipation.

For birds, acute RQs are derived using dose-based and dietary-base d acute toxicity values. For mammals, acute RQs are derived using a dose-base d acute toxicity value, and chronic RQs are derived using a dose-based chronic toxicity value (the test materi al was administered by gavage) and a dietary-based chronic toxicity value us ing the standard FDA la boratory rat conversion value provided in the T-REX model. Dietary- based RQs are calculated using EECs expressed in
terms of residue concentration for the various forage categories and toxicity values (LC 50 or NOAEC) expressed in units of dietary concentr ation. Dose-based RQs are calculated using a body weight-adjusted LD 50 and consumption-weighted equiva lent dose sorted by food source and body size. For both birds and mammals, three we ight categories (or sizes ) are considered.

(1) Risk Following Acute Exposure

Birds

Dietary LD 50 s are greater than the highest concentrations tested in avian studies on both the bobwhite quail and zebra finch (1970 and 2000 mg ai/kg bw, respectively). The acute avian
dose-based LC 50 s are greater than the highest concentr ation tested in avian studies on the bobwhite quail and the mallard duck (4900 a nd 4618 ppm, respectively). There were no74 mortalities in either of the acute avian studies . RQs were not estimated using these studies because the acute avian dose and dietary based studi es resulted in non-defi nitive endpoints (i.e.,

LC 50 s > the highest doses tested). Risks to bi rds following acute exposure will be further discussed in the risk description section.

Potential risk to piscivorous birds

The potential acute risk to piscivorous bird s considers exposure via consumption of fish contaminated with cyflufenamid. RQs were not estimated for piscivor ous birds because the acute avian dose and dietary based studies resulted in non-definitive endpoints. Risks to birds following acute exposure will be further disc ussed in the risk description section.

Mammals

The mammalian LD 50 was greater than the highest dose te sted in rat studies on technical cyflufenamid (5000 mg ai/kg bw), its stereoisomer 149- E -FB (5000 mg ai/kg bw), and NF-149 10SC, the tested formulation (2000 mg formulati on/kg bw). There were no mortalities in these
studies. One or more of the four environmental degradation products may be more toxic than the tested formulation (on an ai basis); however it is not certain due to the non-definitive endpoint from the formulation study. RQs were not calcul ated because the formulation study resulted in a non-definitive endpoint which was lower than the LD 50s from studies on the four environmental degradation products. Risks to mammals following acute exposure will be further discussed in the risk description section.

Potential risk to piscivorous mammals

The potential acute risk to piscivorous mammals considers exposure via consumption of fish contaminated with cyflufenamid. RQs were not calculated for piscivorous mammals because the formulation study resulted in a non-definitiv e endpoint which was lower than the LD 50 s from
studies on the four environmen tal degradation products. Risks to piscivorous mammals following acute exposure will be further disc ussed in the risk description section.

Terrestrial invertebrates

Cyflufenamid is classified as practically nontoxic to bees based on acute c ontact and oral toxicity testing with the TGAI and the te sted formulation (NF-149 10SC).

(2) Risk Following Chronic Exposure

Birds

Two chronic avian studies were submitted to the Agency for review. Since a definitive endpoint
could not be established for one of the reproduction studies (i.e ., mallard duck), RQ’s were not
estimated for chronic avian effects. Risks to birds following chronic exposure will be further discussed in the risk description section.75 Potential risk to piscivorous birds

The potential risk to piscivorous birds considers exposure via cons umption of fish contaminated with cyflufenamid. RQ’s were not estimated fo r chronic effects to piscivorous birds because a definitive endpoint could not be established for the chronic study on mallard duck. Risks to piscivorous birds following chronic exposure will be further discussed in the risk description
section.

Mammals

A two-generation rat reproduction to xicity study is available for cy flufenamid. Potential direct chronic effects of cyflufenamid to mammals we re modeled in T-REX using the chronic endpoint from the rat reproduction study. Based on this analysis, the chronic mammalian RQs did not exceed the chronic LOC for any of the modeled exposure scenarios.

Potential risk to piscivorous mammals

The potential risk to piscivorous mammals considers exposure via consumption of fish contaminated with cyflufenamid. The RQs for all species are well below the chronic LOC for birds (i.e., RQs < 0.035).

b. Terrestrial Plants

Acceptable toxicity studies were conducted on the effects of cyflufenamid on seedling emergence and vegetative vigor fo r monocots and dicots. Potential effects of cyflufenamid on plants were modeled in TERRPLA NT using the endpoints from the plant studies. The RQ’s for vegetative vigor and seedling emergence effects are below the LOC for non-listed plants. For
risk estimation the NOAEC is used to determine ri sk to listed plant species. RQs for listed plant species were not calculated since a NOAEC could not be determined for several terrestrial plants. Risks to non-target plants will be furt her discussed in the risk description section.

Table 40. RQ Values for Plants in Dry and Semi-Aquatic Areas Exposed to Cyflufenamid Through Runoff and/or Spray Drift 1

Plant Type Listed Status Dry Semi-Aquatic Spray Drift

Monocot non-listed <0.1 <0.1 <0.1

Dicot non-listed <0 .1 <0.1 <0.1

1 If RQ > 1.0, the LOC is exceeded, resulting in potential for risk to that plant group.

B. Risk Description

The risk hypothesis states that the proposed uses of cyflufen amid have the potential to compromise survival, reproduction, and growth of non-target aquati c and terrestrial animals and plants, including Federally-listed en dangered and threatened species.

Based on the available ecotoxicity data and pred icted environmental exposures, this ecological risk assessment does not support th e presumption of risk to fresh water fish (acute and chronic76 exposure) and invertebrates (acu te exposure), estuarine/marine fish and invertebrates (acute exposure), terrestrial invertebra tes (acute exposure), mammals ( acute and chronic exposure), birds (acute and chronic exposure) , terrestrial plants (non-listed species), and aquatic vascular plants.

However, risk cannot be precluded for several taxonomic groups. The presumption of risk to freshwater invertebrates (chroni c exposure), marine/estuarine fi sh and invertebrates (chronic exposure), aquatic nonvascular plan ts, and terrestrial plants (l isted species) could not be
evaluated in this risk assessment due to the la ck of submitted, acceptable, or sufficient toxicity
data for these taxa. In the cas e of aquatic nonvascular plants, da ta for diatoms (freshwater and marine) suggest no risk; however, risk to this group cannot be precluded because acceptable data
was not available for the other tw o required test organisms (cyanob acteria and green algae). In the case of terrestrial plants, although acceptable Tier 1 studies were submitted, the study results were not sufficient to preclude risk to listed species for four of te n test species (Tier II studies are needed for those species). Mo re details on the risk conclusi ons can be found in the following

pages.

1. Risk to Aquatic Animals and Plants

a. Aquatic Animals

(1) Risk Following Acute Exposure

Freshwater Fish and A quatic-Phase Amphibians

As stated in the risk estimati on section, the acute RQs for freshw ater fish do not exceed the acute LOC (listed and non-listed species) for any of the proposed uses. Therefore, acute risk to freshwater fish is not expected for the proposed uses.

Freshwater Invertebrates

Effects were observed only at concentrations above the reported limit of aqueous solubility of cyflufenamid (0.52 mg ai/L at 20 o C) in studies on the TGAI, the tested formulation, and the four environmental degradates of cyflufenamid. T oxicity of the TGAI and the formulation were based on total cyflufenamid and so it is assumed that the dissolved fraction of cyflufenamid was no lower than the limit of aqueous solubility. Ov erall, the TGAI appeared most sensitive based on 15% mortality (immobility) at the highest test concentration and no effects at or below that concentration in the other studies. RQs were not calculated because the test solution was not filtered or centrifuged prior to measurement of cyflufenamid and the EC 50 was greater than the highest concentration tested in the study, yielding a non-definitive endpoint. Given that the test solution was not centrifuged or filtered when most test concentrations exceeded or likely exceeded the solubility limit of cyflufenamid, exposure, toxicity, and thus risk are likely underestimated by total measured values. Assuming that the disso lved fraction at the highest treatment level was no lower than aqueous solubility at 20 o C (0.52 mg ai/L) and thus toxicity (EC 50 ) was ≥ 0.52 mg ai/L, a comparison can be made to the peak aquatic EECs (0.85 ug ai/L based on total toxic cyflufenamid residues for pome fruits). The acute li sted species LOC would77 not be exceeded as EECs are at least 611 times less than the aqueous solubility limit of cyflufenamid. For the proposed uses, acute toxicity would need to be ≤ 17 ug ai/L to exceed the acute listed species LOC; that level of toxicity is 96.7% lower than the limit of aqueous solubility. Therefore, acute ri sk to freshwater invertebrates is not expected for the proposed

uses.

Marine/Estuarine Fish

No mortalities or sublethal effect s were observed at the highest te st concentration with the TGAI. The highest peak aquatic EEC (0.85 ug ai/L for the proposed uses) is 235 times lower than the

LC 50 (> 200 ug ai/L). Therefore, acu te risk to estuarine/marine fish is not expected for the proposed uses.

Marine/Estuarine Invertebrates

As stated in the risk estimation section, the acu te RQs for estuarine/marine invertebrates based on toxicity to oysters do not exceed the acute LO C (listed and non-listed species) for any of the proposed uses.

Although the mysid appears less sensitive than the oyste r to the TGAI there is the possibility that it is more sensitive. This is because toxicity in the mysid study is based on total cyflufenamid and so toxicity may be underestimated. Thus , there is the possibility that the mysid LC 50 based on dissolved cyflufenamid is lo wer than the oyster EC50 based on dissolved cyflufenamid. For purposes of comparison and risk descripti on it can be assumed that the mysid LC 50 was not lower than the limit of aqueous solubi lity; however there is uncertain ty about solubility under test conditions. Aqueous solubility was not reporte d for saltwater and while it was reported for freshwater, not at 25 o C, the study temperatur e (0.52 mg ai/L at 20 o C and 0.047 mg ai/L at 30 o C). Although solubility in freshwater is expected to differ from saltw ater (likely higher), it can be used as a rough estimate of solubility under test conditions. If the mysid LC 50 based on the dissolved fraction was equal to the lower end of the solubility range (0.047 mg ai/L at 30 o C), the acute LOC (listed and non-listed species) would not be exceeded for the proposed uses based on the highest modeled peak EEC (0.85 ug ai/L, based on total residues for pome fruits). The EECs are at least 55 times less than aqueous solubility at 30 o C. For the proposed uses to exceed the acute listed species LOC (regardless of sol ubility), the mysid LC50 would need to be ≤ 0.017 mg ai/L, which is 97.3% lower than that based on to tal cyflufenamid (0.64 mg ai/L). Therefore, based on the weight of evidence, acute risk to es tuarine/marine invertebra tes is not expected for the proposed uses.

(2) Risk Following Chronic Exposure

Freshwater Fish and A quatic-Phase Amphibians

The NOAEC based on total cyflufenamid was 0.20 mg ai/L. Aqueous solubility at the study temperature, 25 o C, was not reported; however, aqueous so lubility was reported as 0.52 mg ai/L

at 20 o C and 0.047 mg ai/L at 30 o C. Given that the test solution was not centrifuged or filtered
when some of the test concentrations incl uding the NOAEC may have exceeded solubility,78 exposure, toxicity, and risk is likely underestim ated by total measured va lues. Assuming that the NOAEC based on the dissolved fraction was equal to the lower end of the solubility range (0.047 mg ai/L at 30 o C), the chronic LOC would not be exceeded for the proposed uses based on the highest modeled 60-day EEC (0.22 ug ai/L, based on total residues for pome fruits). The EECs are at least 214 times less than aqueous solubility at 30 o C. For the proposed uses to exceed the LOC, the chronic NOAEC would need to be ≤ 0.219 ug ai/L, which is 99.89% lower than the NOAEC based on total cyflufenamid (0.20 mg ai/L). Th erefore, chronic risk to freshwater fish is not expected for the proposed uses.

Freshwater Invertebrates

As stated previously, no acceptable chronic studie s on freshwater invertebrates are available.
Chronic risk to freshwater inve rtebrates cannot be precluded.

Marine/Estuarine Fish

Also stated previously, no chr onic ecotoxicity studies on estuar ine/marine fish have been submitted to the Agency for review. No other info rmation is available for marine/estuarine fish. Therefore, a quantitative estimation of risk can not be conducted. Lack of studies does not preclude potential risk.

Marine/Estuarine Invertebrates

As stated previously, no chroni c ecotoxicity studies on estuarine/ marine invertebrates have been submitted to the Agency for review. No other information is available for marine/estuarine invertebrates. Therefore, a quantitative estimation of risk cannot be conducted. Lack of studies does not preclude potential risk.

b. Aquatic Plants

Vascular

As stated in the risk estimation section, the RQ s for listed aquatic plants do not exceed the LOC for any of the proposed uses. Therefore, risk to lis ted freshwater vascular plants is not expected.

RQs were not calculated for non-listed species b ecause no effects were observed at the limit concentration (the EC 50 is non-definitive). However, a co mparison of EECs to study effects may be used to evaluate potential risk. The EECs for the proposed uses ( ≤ 0.85 ug ai/L) are at least 290 times less than the limit concentration (247 ug ai/L), thus risk to non-listed freshwater vascular plants is not expected due to the proposed uses.

Nonvascular

The nonvascular plant dataset is in complete so RQs were calculated based on available data. As
stated in the risk es timation section, the RQs (based on t oxicity to the freshwater diatom,
Navicula ) for listed aquatic plants do not exceed th e LOC for any of the proposed uses. RQs79 were not calculated for non-listed species be cause no effects were observed at the limit concentration (the EC 50 is non-definitive). However, a co mparison of EECs to study effects may be used to evaluate potential risk. The EECs for the proposed uses ( ≤ 0.85 ug ai/L) are at least
316 times less than the limit c oncentration (269 ug ai/L).

There is uncertainty about toxicity in the Skeletonema study because the measured concentrations are based on total cyflufenamid and so toxicity may be underestimated. For purposes of risk description it could have been assumed that the NOAEC was not lower than the limit of aqueous solubility; however there is uncer tainty about solubility under test conditions. Aqueous solubility was not repor ted for saltwater although it was reported for freshwater as 0.52 mg ai/L at 20 o C. However, solubility in freshwater is expected to differ from saltwater (freshwater likely higher) and in the study it appears th at solubility could not have been higher than about 0.27 mg ai/L. Nonetheless, for the proposed uses to exceed either the listed or nonlisted species LOC, the NOAEC or EC 50 , respectively, would need to be ≤ 0.849 ug ai/L, which is 99.68% lower than the NOAEC (0.273 mg ai/L) and EC 50 (>0.273 mg ai/L) based on total cyflufenamid.

Although there were no effects to Navicula or Skeletonema and no risk to those species expected, there is uncertainty with the estimat ed risk to nonvascular plants because it is based on the results from two algal species rather than the four species which fulfill guideline requirements. In
addition there is no available information on the m ode of action for this pesticide which could be used to make inferences about toxicity to other algal species from the Navicula and Skeletonema results. Given the incomplete dataset and narro w taxonomic representation of the available data (only diatoms), risk to nonvascular plants cannot be precluded.

2. Risk to Terrestrial Animals and Plants

a. Terrestrial Animals

The MILTREX ® 10 SC FUNGICIDE (agricultu ral use only) label states that a maximum of two applications per growing season ma y be applied to the proposed cr ops. Terrestrial exposures are estimated assuming that per season equals per ye ar. This means for all proposed crops only two cyflufenamid application per year are assessed. For some crops, such as strawberries, there may be more than one growing season in a year. In these cases, the predicted terrestrial exposures from the T-REX model may not be sufficiently conservative and the estimated RQs may be higher.

(1) Risk Following Acute Exposure

Birds

As stated in the risk estimati on section, avian dietary-based LD 50 s are greater than the highest
concentrations tested in studi es on bobwhite quail and zebra finch (1970 and 2000 mg ai/kg bw, respectively). The acute avian dose-based LC 50 s are greater than the high est concentration tested
in avian studies on the bobwhite quail and the mallard duck (4900 and 4618 ppm, respectively).
There were no mortalities in the acute avian stud ies. Because the acute avian dose and dietary80 based studies resulted in non-defi nitive endpoints (i.e., no effects we re seen at the highest doses tested), RQs were not estimated using these st udies. However, a comparison of EECs to study effects may be used to evaluate potential ris k. The highest terrestrial dose-based EEC is 11.25 mg ai/kg bw (short grass). This is 175 times lower than highest dose tested at which no mortalities occurred. The highest terrestrial dietary-based EEC is 9.88 ppm (short grass). This EEC is about 460 times lower than the highest dose tested at which there were no mortalities. Based on predicted terrestrial expo sures from the proposed uses, th e available data indicate that
acute risk to birds is not expected.

Potential risk to piscivorous birds

Several characteristics of cyflufenamid indicate th at it has the potential to accumulate in tissues of aquatic organisms. The log of the n -octanol/water partition (K
ow ) coefficient for cyflufenamid is 4.7. Substances with the log K
ow higher than 4 are more likely to associate with fatty tissues and therefore have a high bioaccumula tion potential. In both low-dose (1.0 μ g ai/L) and highdose (1.0 μ g ai/L) BCF studies cyflufenamid was show n to accumulate; however, ninety percent depuration occurs in approximately five days. Five cyflufenamid-based transformation products
are observed in the bioaccumula tion studies including one envir onmental degradate (149-F) and
four metabolites. Stru ctures are shown in Appendix B

.

As stated in the risk estimation section, RQs we re not estimated because the acute avian dose and dietary based studies resulted in non-definitive endpoints. However, a comparison of EECs to study effects may be used to eval uate potential risk. The hi ghest dose tested in each study produced no mortalities and is more than 2000 tim es greater than the highest dose-based EEC of 0.907 mg ai/kg bw (sandpipers) and almost 3000 tim es greater than the highest dietary-based EEC of 1.57 ppm (white pelicans). Based on the available data, acute risk to piscivorous birds is not expected from the proposed uses of cyflufenamid.

Mammals

As stated in the risk esti mation section, the mammalian LD 50s for the both the tested formulation (NF-149 10SC), technical cyflufenam id, and its stereoisomer (149- E -FB) were greater than the highest doses tested in each study (199.6 mg ai/kg bw, 5000 mg ai/kg bw, and 5000 mg ai/kg bw respectively). There were no mort alities in these studies. RQs were not calculated because the
acute studies resulted in non-defi nitive endpoints (i.e., no effects we re seen at the highest doses tested). However, a comparison of EECs to study effects may be used to evaluate potential risk. The highest terrestrial dose-based EEC for mamm als is 9.25 mg ai/kg bw (short grass). This
EEC is about 21.5 times lower than the dose tested (on an ai basis) in th e rat study on the tested formulation and 540 times lower than the highest dose tested in the rat studies on technical cyflufenamid and its stereoisomer.

As stated in the effects char acterization section, one or more of the four environmental degradation products may be more toxic than the tested formulation (on an ai basis); however it
is not certain due to the non-defi nitive endpoint from the formulati on study. Risk is assessed for the four degradates given this uncertainty. Te rrestrial EECs were calcula ted for the degradation products by multiplying the terrestrial cyflufenam id EECs for mammals by the molecular weight81 ratio (molecular weight of the degradate/mol ecular weight of the cyflufenamid) and then normalizing for the maximum percentage of degrad ation product formed. The acute LOC (listed and non-listed species) was not ex ceeded for any of the four environmental degradation products under any of the modeled exposure scenarios (RQs ≤ 0.002).

Based on predicted terrestrial expo sures from the proposed uses, th e available data indicate that
acute risk to mammals is not expected.

Potential risk to piscivorous mammals

Risk to piscivorous mammals via consumption of fish contaminated with cyflufenamid was assessed because cyflufenamid has the potential to accumulate in tissues of aquatic organisms. As previously noted, RQs were not estimated because the acute mammalian studies with cyflufenamid resulted in non-definitive endpoints (i .e., no effects were seen at the highest doses tested). However, a comparison of EECs to study e ffects may be used to evaluate potential risk. The highest dose-based EEC for piscivorous mammals, 0.505 mg/kg- bw/d (fog/water shrew), is about 395 and 10,000 times lower than the highest dose tested in the formulation (on an ai basis) and technical cyflufenamid/stereoi somer studies, respectively.

As previously stated, RQs were calculated for th e four environmental degr adation products given that one or more may be more toxic than the te sted formulation (on an ai basis). A screening level assessment was conducted using the highe st dose-based EEC for piscivorous mammals (0.505 mg/kg-bw/d, based on tota l toxic residues and the K
ow of cyflufenamid). This is a conservative approach because degradate EECs are li kely lower since they are expected to form as only a fraction of total toxic cyflufenamid residue concentrations. Furthermore, the EECs
used for this assessment are based on the bi oaccumulation potential of cyflufenamid and K
ow values indicate that cyflufenamid is more likel y than the four degradates to bioaccumulate in aquatic organisms (K
ow ’s were not reported for the four degradates, however, they were estimated using the KOWIN feature of the EPI Suite program (USEPA 2009)). The acute LOC (listed and non-listed species) was not exceeded for any of the four environmental degradation products under any of the mode led exposure scenarios (RQs ≤ 0.002).

Based on predicted terrestrial expo sures from the proposed uses, th e available data indicate that
acute risk to mammals is not expected.

Terrestrial invertebrates

Cyflufenamid is classified as practically nontoxic to bees based on acute c ontact and oral toxicity testing with the TGAI and the te sted formulation (NF-149 10SC).

(2) Risk Following Chronic Exposure

Birds

In the bobwhite quail, multiple reproductive effect s were observed at the highest administered dose (971 mg ai/kg diet), including reductions in 14-day survivors ( 28%), 14-day survivor82 weights (6%) as well as reductions in ratios of number hatched to eggs laid (13%), number hatched to eggs set (11%), and 14-day survivors to eggs set (17 %). The NOAEC for this study is 290 mg ai/kg. Potential direct chronic effects of cyflufenamid to birds were modeled in T-REX using the chronic endpoint from the bobwhite qu ail study. Based on this analysis, the chronic avian RQs did not exceed the chronic LOC for any of the modeled expos ure scenarios (RQs < 0.03).

As stated in the risk estimati on section, the chronic avian study on the mallard duck resulted in a non-definitive endpoint due to effect s seen at the lowest administ ered dose. A relatively small but significant reduction in surviv or weight was observed at all treatment doses (decreases of 5% at the low dose, 3% at the mid dose, and 7% at the high dose). No othe r adverse effects were
seen at lowest dose tested in this study. However, reproductiv e effects were observed the mid and high treatment levels. The ratio of hatchli ng survivors to number ha tched was significantly reduced at 296 mg ai/kg diet but not at 1016 mg ai/kg diet. Reproductive effects observed at 1016 mg ai/kg diet include reductions in hatchlin g survivors (16% of control), and proportional reductions in viable embryos to eggs set, live embryos to viable embryos, number hatched to eggs laid, number hatched to eggs set, number hatched to live embryos, and hatchling survivors to eggs set. The NOAEC for reproductive effect s for the mallard duck study was 99 mg ai/kg.

Based on effects seen at the lowest administer ed doses in the mallard duck reproduction study, a
chronic NOAEC could not be identified. In th e absence of a NOAEC, RQs cannot be calculated for this study. However, risks can be charac terized based on a comparison of EECs to the dose at which adverse effects occurred. The highest terrestrial dietary-based EEC, 9.88 ppm for short grass, is approximately 10 times lower than the dose at which reductions of 5% in 14-day survivor weights were observed. The differen ce between the EEC and the observed effect dose may be even greater than 10 times given that the T-REX analysis is considered a screening level
risk assessment based on cons ervative assumptions (e.g., use of the maximum single-day EEC, that birds feed exclusively on vegetation, and th at birds feed exclusiv ely on short grass, the vegetation producing the highest EE Cs). Given the conservative nature of the T-REX analysis, the relatively small effect on survivor body weight (5% at the low dose) in the mallard duck, and
the fact that the lowest dose at which effect s were seen is 10 times higher than the highest terrestrial EEC, chronic risk to birds is not expected from the proposed uses.

Potential risk to piscivorous birds

As previously stated, risk to piscivorous bird s via consumption of fish contaminated with cyflufenamid was assessed because cyflufenamid has the potential to accu mulate in tissues of aquatic organisms. RQs were not calculated because the mallard duck study did not produce a definitive endpoint and the NOAEC w ould be lower than that establ ished for the bobwhite quail. However, a comparison of EECs to study effects ma y be used to evaluate potential risk. The highest EEC for piscivorous birds, 1.57 ppm (large river otter), is 63 times lower than the lowest dose at which effects were observed (5% reduction in 14-day survivor weight). Therefore, the proposed use of cyflufenamid is not expected to pose chronic risk to piscivorous birds.83 Mammals

As the risk estimation section states, the chroni c LOC is not exceeded on a dose or dietary basis for any mammalian exposure scenari o. Therefore chronic risk to mammals is not expected from the proposed uses.

Potential risk to piscivorous mammals

As previously stated, risk to piscivorous mamma ls via consumption of fish contaminated with cyflufenamid was assessed because cyflufenamid has the potential to accu mulate in tissues of aquatic organisms. The chronic LOC for ma mmals is not exceeded for any piscivorous mammals. Therefore, chronic ri sk to piscivorous mammals is not expected from the proposed uses due to consumption of fish contaminated with cyflufenamid.

b. Terrestrial Plants

The RQs for vegetative vigor and seedling emergence do not exceed the LOC for non-listed plants. Risk to non-listed terr estrial plants is not expected from the proposed application of cyflufenamid; however, there is some uncertainty because two test species (tomato and cabbage)
showed >25% inhibition in the seedling emergence study.

Assessment of risk to listed terrestrial plants is based on an incomplete dataset. The RQs for vegetative vigor do not exceed the LOC for listed plants. Based on the results of the seedling emergence tests, NOAECs were established for six of the 10 plant species tested. For those six plants, RQ’s do not exceed the LOC for listed plants. However, NOAECs could not be determined for four of the plant species tested (tomato, cabbage, oat, and soybean), thus risk to listed terrestrial plants cannot be precluded.

Seedling emergence tests at the Tier II level are required for four plants (tomato, cabbage, oat, and soybean) to address uncertainties regarding ≥ 25% inhibition to tomato dry weight and cabbage emergence and uncertainti es regarding listed species due to a lack of establishing a

NOAEC or EC 05 for all four plants.

3. Review of Incident Data

With these proposed uses, cyflufenamid will be applied in this country for the first time. Therefore, no incident data are available at this time.

4. Endocrine Effects

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required
determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a84 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.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.
This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.
This list should not be construed as a lis t of known or likely e ndocrine disruptors.

Cyflufenamid is not among the group of 58 pesticid e active ingredients on th e initial list to be
screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/.

5. Federally Threatened and Endang ered (Listed) Species Concerns

Section 7 of the Endangered Species Act, 16 U. S.C. Section 1536(a)(2), requires all federal agencies to consult with the National Marine Fisheries Service (NMFS) for marine and anadromous listed species, or the United States Fish and Wildlife Services (FWS) for listed wildlife and freshwater organisms, if they are proposing an "action" that may affect listed species or their designated habitat. Each federal agency is required under the Act to insure that any action they authorize, fund, or carry out is not likely to jeopardize the c ontinued existence of a listed species or result in the dest ruction or adverse modification of designated critical habitat. To jeopardize the continued existence of a liste d species means "to engage in an action that reasonably would be expected, dire ctly or indirectly, to reduce appreciably the likelihood of both the survival and recovery of a listed species in the wild by re ducing the reproduction, numbers, or distribution of the sp ecies" (50 C.F.R. § 402.02).

To facilitate compliance with the requirements of the Endangered Species Act (subsection (a)(2)), the Office of Pesticide Programs has es tablished procedures to evaluate whether a proposed registration action may directly or indir ectly reduce appreciabl y the likelihood of both the survival and recovery of a listed species in the wild by re ducing the reproduction, numbers, or distribution of any listed spec ies (USEPA, 2004a). After the Agency’s screening level risk assessment is conducted, if any of the Agency’s listed species LOCs are exceeded for either
direct or indirect effect s, an analysis is conducte d to determine if any lis ted or candidate species may co-occur in the area of the proposed pest icide use or areas downstream or downwind that
could be contaminated from drift or runoff/erosi on. If listed or candidate species may be present in the proposed action areas, furt her biological assessment is undert aken. The extent to which85 listed species may be at risk then determin es the need for the development of a more comprehensive consultation package as required by the Endange red Species Act.

Both acute endangered species and chronic risk LOCs are considered in the screening-level risk assessment of pesticide risks to listed species. Endangered species acute LOCs are a fraction of the non-endangered species LOCs or, in the case of endangered plants, RQs are derived using lower toxicity endpoints than non-endangered plan ts. Therefore, concerns regarding listed species within a taxonomic group ar e triggered in exposure situati ons where restricted use or acute risk LOCs are triggered for the same ta xonomic group. The risk assessment also includes an evaluation of the potential probability of indivi dual effects for exposures that may occur at the established endangered species LOC both in the ri sk characterization and the endangered species sections. This probability is calculated usi ng the established dose/re sponse relationship and assumes a probit (probability uni t) dose/response relationship (USE PA, 2004b). This analysis is presented in Section IV.B.5.b(2) below.

The federal action addressed herein is the Se ction 3 new uses for the pesticide product, cyflufenamid. Cyflufenamid is proposed to be used on cucurbit vegetables (crop group 9), low growing berry (crop subgroup 13-07G) except cr anberries, pome fruit (crop subgroup 11), outdoor landscape and outdoor nursery ornamental s, and small fruit vine climbing except fuzzy kiwifruit (crop subgroup 13-07F) for the treatment of powdery mildew.

a. Action Area

For listed species assessments, the action area is c onsidered to be the area affected directly or indirectly by the Federal acti on and not merely the immediat e area where cyflufenamid is applied. At the initial Level 1 screening assessment, broadly described taxonomic groups are considered, and thus, conservati vely assumes that lis ted species within th ose broad groups are co-located with the pesticide trea tment area. This means that te rrestrial plants and wildlife are assumed to be located on or adjacent to the treat ed site and aquatic organisms are assumed to be located in a surface water body adj acent to the treated site. The assessment also assumes that listed species are lo cated within the area of hi ghest exposure to the pesticide, and that exposure will decrease with increasing distance from the treated area.

If the assumptions associated with the screeni ng-level action area result in RQs that are below the listed species LOCs, a "no effect" determina tion conclusion is made with respect to listed species in that taxa, and no furt her refinement of the action area is necessary. Furthermore, RQs below the listed species LOCs for a given ta xonomic group indicate no concern for indirect effects upon listed species that depend upon th e taxonomic group covered by the RQ as a resource. However, in situations where the scre ening assumptions lead to RQs in excess of the listed species LOCs for a given ta xonomic group, a potential for a "may affect" conclusion exists and may be associated with direct effects on listed species belonging to that taxonomic group or may extend to indirect effects upon listed spec ies that depend upon that taxonomic group as a resource. In such cases, additional information on the biology of listed species, the locations of these species, and the locations of use sites and could be considered along with available information on the fate and transport properties of the pesticide to determine the extent to which screening assumptions regarding an action area a pply to a particular listed organism. These86 subsequent refinement steps c ould consider how this information would impact the action area for a particular listed organism and may potentially include area s of exposure that are downwind and downstream of the pesticide use site.

b. Taxonomic Groups Potentially at Risk

The preliminary risk assessment for endangered species indicates that the proposed uses and application rates for cyflufenamid do not or are not likely to exceed the Endangered Species LOCs for any taxonomic groups for which a complete dataset (all required species) of acceptable data are available (see risk description for detail s). However, data was either not submitted or
deemed invalid for freshwater invertebrates (chronic exposure), estuarine/marine fish and invertebrates (chronic exposure) , and two out of four required algal taxa (cyanobacteria and green algae) so risk cannot be precluded. Furthe rmore, risk to listed terrestrial plants cannot be precluded because although acceptable Tier 1 studies were submitted, the study results were not sufficient to preclude risk to four of ten required test species (Tie r II studies are needed for those species).

Concerns For Federally Listed as Endangered and/or Threatened Species

Table 41 summarizes the federally listed species (endangered and/or th reatened) at risk
associated with either direct or indirect effects following app lication of cyflufenamid for the proposed uses.

Table 41. Listed Species Risks Associated With Direct or Indirect Effects from Cyflufenamid Use on Cucurbit Vegetabl es, Low Growing Berries, Pome Fruits, Ornamentals, and Small Climbing Fruit Vines 1

Listed Taxon Direct Effects Indirect Effects
Terrestrial and semi-aquatic plants - monocots Yes 2 No

Terrestrial and semi-aquatic plants – dicots Yes 3 No

Terrestrial invertebrates No 4 No

Birds

No Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates and aquatic non-vascular plants 2,3,6,8
Terrestrial-phase amphibians

No 5 Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 2,3,6,8
Reptiles

No 5 Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates and aquatic non-vascular plants 2,3,6,8

Mammals

No Yes from effects to terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, marine/estuarine fish and invertebrates and aquatic non-vascular plants 2,3,6,887 Listed Taxon Direct Effects Indirect Effects
Aquatic non-vascular plants Yes 6 Yes from effects to freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 6,8
Aquatic vascular plants

No Yes from effects to freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 6,8

Freshwater fish No Yes from effects to freshwater invertebrates and aquatic non-vascular plants 6,8
Aquatic-phase amphibians

No 7 Yes from effects to freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular plants 6,8

Freshwater invertebrates No for acute, Yes for chronic 8 Yes from effects to freshwater invertebrates and aquatic non-vascular plants 6,8

Marine/estuarine fish No for acute, Yes for chronic 8 Yes for marine/estuarine fi sh and invertebrates and aquatic non-vascular plants 6,8

Marine/estuarine invertebrates No for acute, Yes for chronic 8 Yes for marine/estuarine fi sh and invertebrates and aquatic non-vascular plants 6,8

1 Maximum application rate is two applications per year at 0.023 lbs ai/A; yearly application rate of 0.046 lbs ai/A.

2 In tier 1 seedling emergence and vegetative vigor studies, no direct effects are expected for three monocots, however, effects greater than 5% were observed at the lowest test concentration in 1 of the 4 test species considered to fulfill guideline requirements, thus risk cannot be precluded.

3 In tier 1 seedling emergence and vegetative vigor studies, no direct effects are expected for three dicots, however, effects greater than 5% were observed at the lowest test co ncentration in 3 of the 6 test species considered to fulfill guideline requirements, thus risk cannot be precluded.

4 Quantitative risk to terrestrial invertebrates not normally conducted. Direct effects to beneficial terrestrial invertebrates are not expected because cyflufenamid is pr actically non-toxic to bees.

5 Results from avian species used as surrogate for assessing risk to terr estrial-phase amphibians and reptiles.

6 Acceptable/supplemental studi es were available for two of the four al gal species considered to fulfill guideline requirements. No direct effects are expected for the two species with acceptable/supplement al studies; however, risk to nonvascular plants cannot be precluded without acceptable data on the two other species.

7 Results from freshwater fish used as surrogate for assessing risk to aquatic-phase amphibians

8 Studies were not submitted or invalid, thus risk cannot be precluded.

(1) Discussion of Risk Quotients

In cases where RQs could be calculated, the Agency’s LOCs for were not exceeded for the proposed uses of cyflufenamid as outlined in previous sections. In some cases acceptable/supplemental data was available but RQs could not be calculated, however risk is not expected (see risk description section for details). Although qua ntitative risks to terrestrial invertebrates are not estimated, due to the low toxici ty to honey bees, it is assumed that there will
not be risk to beneficial terres trial invertebrates. As previous ly stated, data was either not
submitted or deemed invalid for freshwater inve rtebrates (chronic exposure), estuarine/marine fish and invertebrates (chronic exposure), and tw o out of four required al gal taxa (cyanobacteria and green algae) so risk cannot be precluded for these taxonomic groups. Furthermore, risk to listed terrestrial plants cannot be precluded because although acceptable Tier 1 studies were submitted, the study results were not sufficient to preclude risk to four of ten required test species (Tier II studies are needed for those species).88 (2) Probit Dose Response Relationship

Birds

No RQs were estimated for the acute dose- and dietary-based avian study because the LD 50 ’s

LC 50 ’s were higher than the highest concentration te sted and there were no mortalities in either study. Therefore, RQ’s were not calculated fo r these studies and probabilities of individual
mortalities associated with RQs were not calculated.

Mammals

No RQs were estimated for the acut e studies in rats because the LD 50 s were higher than the highest concentrations tested in studies on the tested formul ation (NF-149 10SC), technical cyflufenamid, and the stereoisomer (149- E -FB). There were no mortal ities in these studies. Therefore, RQ’s were not calcula ted for these studies and probabil ities of individual mortalities associated with RQs were not calculated.

As stated in the effects charac terization section, one or more th e four degradation products may be more toxic than the tested formulation (on an ai basis), however it is not certain due to the non-definitive endpoint from the fo rmulation study. RQs were calc ulated given this uncertainty
and because there were mortalitie s observed in all four studies with the degradation products. The probability is less than 1 in 1E+16 for an i ndividual mortality associated with the maximum calculated RQ value (degradation product 149-F1 yi elded the highest RQ) and a probit slope of 12.2. The corresponding estimate chance of an indi vidual mortality associated with the listed
mammals LOC is 1 in 2.94E+05.

Freshwater fish

The probability is less than 1 in 1E+16 for an individual mortality associated with both the maximum and minimum calculated RQ values, base d the acute freshwater fish study exhibiting the greatest toxicity (rainbow trout, TGAI) and a default slope of 4.5. The corresponding estimate chance of an individual mortality associat ed with the listed freshwater fish species LOC
is 1 in 4.18E+08.

Freshwater invertebrates

Individual effects proba bilities were not calculated for fres hwater invertebrates because acute endpoints were either non-definiti ve, based on total concentrations (dissolved plus undissolved cyflufenamid) instead of only disso lved concentrations, or both.

Marine/Estuarine fish

Individual effects probabilities we re not calculated because the acu te estuarine/marine toxicity endpoint was non-definitive.89 Marine/Estuarine invertebrates

Individual effects probabilities we re not calculated for estuarine/ma rine invertebrates because the mysid EC 50 was based on total concentrations (disso lved plus undissolved cyflufenamid) instead of only dissolved concentrations.

(3) Data Related to Under-represented Taxa

Effects data on under-represented taxonomic groups were not submitted by the Registrant. The In addition, no other studies were ava ilable in the public ECOTOX database.

(4) Implications of Sublethal Effects

Acute Studies

Sublethal effects were observed in acute oral studies in bobwhite quail and zebra finch. In the bobwhite quail study, transient effects were obs erved on body weight and food consumption in
females at all levels and in males at the mid a nd high doses (effects were seen in the first week after treatment not in the second week). Th e LOAEL for bobwhite quail is 461 mg ai/kg, the
lowest dose tested. A NOAEL could not be iden tified for this study. In the zebra finch study, transitory ruffled appearance was observed in two birds at the high dose and in four birds at the next lowest treatment level of 1205 mg ai/kg bw. Reduced male body weight gain was also observed at the two highest treatment levels in this study. The LOAEL for this study is 1205 mg ai/kg bw and the NOAEL for this study is 726 mg ai/kg bw. The highest terrestrial dose-based EEC (11.25 ppm) is 41 times lower than the L OAEL for the bobwhite quail and 107 times lower than the LOAEL for the zebra finch. Therefore, w ith the predicted terrestrial exposures from the proposed uses, it is unlikely that sublethal e ffects will be observed in birds on a dose-basis following acute exposure.

In the acute dietary study with bobwhite quail, sublethal effects including clinical signs (subdued behavior) and reductions in body weight gain and food consumption were s een at the LOAEC of 1230 mg ai/kg bw. In the mallard duck diet ary study decreased body weight gain and food consumption was seen at the highest dose tested (4618 ppm). The highest terrestrial dietarybased EEC (9.88 ppm) is 125 times lower than the LOAEC for the bobwhite quail and about 470
times lower than the LOAEC for the mallard duck. Therefore, with the predicted terrestrial exposures from the proposed uses, it is unlikely that sublethal e ffects will be observed in birds on a dietary-basis following acute exposure.

For mammals, no sublethal effects were observe d in the rat study conducted with the tested formulation (NF-149 10SC). In th e rat study on technical cyflufenam id, some clinical signs were observed at both test concentrations (piloerect ion, hunched posture, and waddling/unsteady gait)
while other effects were observe d only at the highest test co ncentration (lethargy, abnormal respiration, pallid extremities, walking on toes, partially closed eyelid s, increased salivation, increased sensitivity to touch, and ungroomed app earance). Recovery of surviving rats, as judged by external appearance and behavior was complete in all instances by day 4. Similar effects were observed in the study on th e stereoisomer of cyflufenamid (149- E -FB). The highest90 terrestrial dose-based EEC for mammals (9.25 mg ai/kg bw for short grass) is about 340 times
lower than the lowest dose at which transient clinical signs were obs erved in the acute rat toxicity studies on technical cyfluf enamid and its stereoisomer (149- E -FB). In the rat studies on the four degradation products, piloerection was observed with recover y. The highest mammalian dose-based degradate EECs are at least 228 times lo wer than the lowest dose at which transient piloerection was observed in each degradation pr oduct study. Therefore, with the predicted terrestrial exposures from the proposed uses, it is unlikely that sublethal effects will be observed in mammals on a dose-basis following acute exposure.

In freshwater fish, sublethal e ffects were observed at test conc entrations below which mortality was observed. Of the available studies, the great est toxicity was observe d in the rainbow trout exposed to the TGAI. Effects included hype rventilation, coughing, darkened pigmentation, lethargy, nervous/erratic swimming behavior, and loss of coordinati on. The highest peak aquatic EEC (0.85 ug ai/L) is well below the NOAEC (274 ug ai/L). Therefore, it is unlikely that sublethal effects would be observed from the proposed uses.

In the estuarine/marine fish (sheepshead minnow ) study, sublethal effects were not observed at any test concentration. The highest peak a quatic EEC (0.85 ug ai/L) is well below the NOAEC (200 ug ai/L). Therefore, it is unlikely that sublethal effect s would be observed from the proposed uses.

Sublethal effects were observed in the mysi d study. Effects included surfacing, lethargy, and erratic swimming. The highest peak aquatic EEC (0.85 ug ai/L) is well below the NOAEC (240 ug total ai/L); however, there is uncertainty about what th e NOAEC was based on dissolved cyflufenamid. The EEC is still well below the NOAEC assuming that it is no lower than 47 ug ai/L (based on freshwater solubility, see risk desc ription for more details) but it is unknown if the estimate based on freshwater solubility is representa tive of that under test conditions (saltwater). Nonetheless, the NOAEC based on the dissolved fr action would need to be 99.6% lower than the NOAEC based on total cyflufenamid to equal the p eak aquatic EEC. Therefore, it is unlikely that sublethal effects would be observed from the proposed uses.

Chronic Studies

For mammals, there were no effects of treatment in either generation on estrous cycle, sperm parameters, mating, conception, fertility or gestat ion indices, pre-coital in terval or gestation
duration. Increased liver and thyroid weights were observed in parental animals at the highest dose tested in this study (57.5 mg ai/kg bw/day). Reduced body weight gain was observed in F1 and F2 offspring at the highest dose tested. Th e highest terrestrial diet ary-based EEC (9.70 ppm)
is 6 times lower than the dose at which subletha l effects were observed. Therefore, with the predicted terrestrial exposures from the proposed us es, it is unlikely that ch ronic sublethal effects
will be observed in mammals.

Sublethal effects were observed in chronic studies in bobwhite quail and mallard duck. The chronic bobwhite quail study showed significant re ductions in multiple reproductive endpoints at the highest treatment level. Observed reproducti ve effects include the re duced ratios of number91 hatched to eggs laid (13%), num ber hatched to eggs set (11%), 14-day survivors to eggs set (17%) and reductions in 14-day survivors (28% ), and 14-day survivor weights (6%). The NOAEC for this study is 290 mg ai/kg diet. Th e NOAEC is 29 times higher than the highest terrestrial dietary- based EEC (9.88 ppm).

As previously stated, the chronic mallard duck st udy resulted in a non-definitive endpoint due to
effects seen at the lowest administered dose. At all doses the14-day survivor weights were reduced (5% at the low dose, 3% at the mid-dose and 7% at the high dose). At the highest dose tested, significant reduc tions were observed in the followi ng reproduction parameters, hatchling survivors, viable embryos to eggs set, live em bryos to viable embryos, number hatched to eggs laid, number hatched to eggs set, number hatche d to live embryos, and hatchling survivors to eggs set. The magnitude of the reductions genera lly increased with the age of the offspring (i.e., reductions in viable embryo-rela ted endpoints of 2-3% compared to reductions in hatchling survivor-related endpoints of 15-16%). The ratio of hatchling survivors to number hatched was significantly reduced at 296 mg ai/kg diet (p=0.015, 2% of control), but not at the highest level. The highest terrestrial dietary- based EEC (9.88 ppm) is approximately 10 times lower than the dose at which a 5% reduction in 14-day survivor weight was observed. Given the conservative nature of the T-REX analysis (see risk descrip tion for details), the relatively low effect on survivor body weight (5%) observed, and the fact th at the lowest dose at which effects were seen is 10 times higher than the highest terrestrial di etary-based EEC, chronic risk to birds is not expected based on the mallard study. Conse quently, based on both the mallard duck and bobwhite quail, it is unlikely that sublethal eff ects to birds will occur fr om chronic exposure to cyflufenamid based on the proposed uses.

In the early life stage study on freshwater fish, the NOAEC is 97 ug ai/L for sublethal effects other than growth or reproduction. It is based on effects such as paleness, internal bleeding, swollen abdomen, pink feces, and deformed mouths. The NOAEC is much higher than the highest 60-day aquatic EEC (0.22 ug ai/L), alt hough it is based on total cyflufenamid and the NOAEC based on the dissolved fraction may be lowe r. Nonetheless, the NOAEC is still much higher than the EEC under the assump tion that the dissolved fraction is no lower than the limit of aqueous solubility (estimated as 47 ug ai/L, see risk description sec tion for details). Therefore, it is unlikely that sublethal eff ects would be observed from exposure to cyflufenamid for the proposed uses.

c. Indirect Effects Analysis

In conducting a screen for indirect effects, di rect effects LOCs for each taxonomic group are
used to make inferences concer ning the potential for i ndirect effects upon listed species that rely upon non-listed organisms in these taxonomic groups as resources critical to their life cycle. Pesticide-use scenarios, resulting in RQs that are below all direct effect listed species LOCs for all taxonomic groups assessed are considered of no concern for risks to listed species either by
direct or indirect eff ects. However, there may be situa tions where a taxonomic group is not quantitatively assessed (e.g., terres trial insects), but other lines of evidence are sufficiently supportive of concerns for indirect effects on listed organisms that are dependant upon that taxonomic group.92 The Level I screening indirect effects analysis documents t hose types of dependencies upon nonlisted organisms that could be important sources of indirect effects to listed organisms should effective levels of the pesticide coincide with locations of listed species and the biologically based resources upon which they depend. In cases where screening-level acute RQs for a given animal group equal or exceed the endangered sp ecies acute LOC, the Agency uses the dose response relationship from the toxicity study used for calculating the RQ to estimate the probability of acute effects associated with an ex posure equivalent to the EEC. This information serves as a guide to establish the need for and extent of additional analysis that may be performed using Services-provided “species profiles” as well as evaluations of the geographical and temporal nature of the exposure to ascertain if a not likely to adversely affect determination can be made. The degree to which additional analyses are performed is commensurate with the predicted probability of advers e effects from the comparison of dose response information with the EECs. The greater the probabi lity that exposures wi ll produce effects on a taxa, the greater the concern for potential indirect effects for listed species dependant upon that taxa, and therefore, the more intensive the analysis on the potential listed species of concern, their locations relative to the use site, and inform ation regarding the use scenario (e.g., timing, frequency, and geographical extent of pesticide application). Th e greatest concerns would exist when exposure is associated with a risk higher th an the effects probability associated with the non-endangered LOC for a pesticide with an average slope of 4.5.

For cyflufenamid, direct effects are not predicte d for any taxonomic groups for which a complete dataset (all required specie s) of acceptable or supplemental data are available. However, studies were either not submitted, deemed invalid, or were insufficient for assessing risk for freshwater invertebrates (chronic exposure), estuarine/marine fish and invertebrates (chronic exposure), two out of four required algal taxa (cyanobacteria and green algae) , and four out of ten required terrestrial plant species (oat, ca bbage, soybean, and tomato). In the case of aquatic nonvascular plants, data for diatoms (freshwater and marine ) suggest no risk; however, risk to this group cannot be precluded because acceptable/supplement al data was not available for the other two required test organisms (cyanobacteria and green al gae). In the case of terrestrial plants, study
results were sufficient to assess risk to non-listed species but not to listed species. Thus, risk cannot be precluded for listed species within th ose taxonomic groups (direct effects) or listed species that depend on those taxonomi c groups (indirect effects).

d. Critical Habitat

In the evaluation of pesticide eff ects on designated critical habitat, consideration is given to the physical and biological features (constituent elemen ts) of a critical habitat identified by the U.S
Fish and Wildlife and National Mari ne Fisheries Services as esse ntial to the conservation of a listed species and which may require special mana gement considerations or protection. The evaluation of impacts for a screening level pest icide risk assessment focuses on the biological
features that are cons tituent elements and is accomplished using the screening-level taxonomic analysis RQs and LOCs that are used to evaluate direct and indirect effect s to listed organisms.

Based on the available data, this screening-level risk assessment has not identified potential
concerns for indirect effects on li sted species. However, there is uncertainty rega rding taxa for
which data is not available or is available but is insufficient for assessing risk. Thus there is93 uncertainty and risk is presumed for listed orga nism’s dependant upon freshwater invertebrates, estuarine/marine fish and invertebrates, nonvascular plants, and terres trial plants (listed). In light of the potential for indirect effects, the next step for EPA and the Service(s) is to identify which listed species and critical habita t are potentially implicated. Anal ytically, the identification of such species and critical habita t can occur in either of two wa ys. First, the agencies could determine whether the action area overlaps critica l habitat or the occupi ed range of any listed species. If so, EPA would examine whether th e pesticide's potential impacts on non-endangered species would affect the listed spec ies indirectly or dire ctly affect a constituent element of the critical habitat. Alternatively, the agencies could determine which listed species depend on biological resources, or have constituent elements that fall int o, the taxa that may be directly or indirectly impacted by the pesticide. Then EP A would determine whether use of the pesticide overlaps the critical habitat or the occupied range of those lis ted species. At present, the information reviewed by EPA does not permit use of either analytical approach to make a definitive identification of species that are potentially impacted indirectly or critical habitats that is potentially impacted directly by the use of the pesticide. EP A and the Service(s) are working together to conduct the necessary analysis.

This screening-level risk assessment for critical habitat provides a listi ng of potential biological features that, if they are consti tuent elements of one or more critical habitats, would be of potential concern. These corres pond to the taxonomi c groups identified above as being of potential concern for indirect e ffects (terrestrial and semi-aquatic plants (monocots and dicots), freshwater invertebrates, mari ne/estuarine fish and inverteb rates, and aquatic non-vascular plants). This should serve as an initial step in problem formul ation for further assessment of critical habitat impacts outlined above, should additional work be necessary.

e. Co-occurrence Analysis

The goal of the analysis for co-location is to determine whether site s of pesticide use are geographically associated with know n locations of listed species. At the screening level, this analysis is accomplished using the LOCATES 2.10.3 database. The database uses location information for listed species at the county level and compares it to agricultural census data for crop production at the same county le vel of resolution. The product is a listing of federally listed species that are located within counties known to produce the cr op upon which the pesticide will
be used.

Co-occurrence analysis was not performed given the lack of expected risk to cyflufenamid for the proposed uses. As previously stated, studie s were either not submitted, deemed invalid, or were insufficient for assessing risk for fres hwater invertebrates (chronic exposure), estuarine/marine fish and invertebrates (chronic exposure), two out of f our required algal taxa (cyanobacteria and green algae), and four out of ten required terrestrial plant species (oat, cabbage, soybean, and tomato) so risk cannot be precluded for those tax onomic groups. Should that data become available and suggest a potenti al concern for direct effects on listed species within those taxonomic groups then co-occurrence analysis (LOCATES) will be run at that time for those taxonomic groups. Then the registra nt may be asked to provide information on the proximity of Federally listed species within thos e taxonomic groups. This may be satisfied in one of three ways: 1) having membership in the FI FRA Endangered Species Task Force (Pesticide94 Registration [PR] Notice 2000-2); 2) citing FIFRA Endangered Speci es Task Force data; or 3) independently producing these data , provided the information is of sufficient quality to meet FIFRA requirements. The information will be used by the OPP Endangered Species Protection Program to develop recommendations to a void adverse effects to listed species.

C. Description of Assumptions, Limitati ons, Uncertainties, Strengths, and Data Gaps

1. Assumptions, Limitations, and Uncertainties Related to Exposure For

All Taxa

a. Maximum Use Scenario

The screening-level risk assessment focuses on char acterizing potential ec ological risks resulting from a maximum use scenario, which is determ ined from labeled statements of maximum application rate and number of applications with th e shortest time interval between applications. The frequency at which actual uses approach th is maximum use scenario may be dependant on pesticide resistance, timing of applications , cultural practices, and market forces.

2. Assumptions, Limitations, and Uncertainties Related to Exposure For Aquatic Species

a. Aquatic Exposure Model

With the submitted and reviewed data, the following major sources of uncertainty come from the following assumption:

• MILTREX ® 10 SC FUNGICIDE (the agricultural use label) allows two applications of cyflufenamid to be applied per growing s eason. In modeling the aquatic EECs, it is assumed that one growing season equivalent to one year. Therefore, two cyflufenamid applications are modeled per year. For crops like strawberries there is the possibility that there could be more then one growing season per year, therefore the exposure concentrations may be underestimated.

Transformation Products

Toxicity data show cyflufenamid is more acutely toxic to freshwater fish and invertebrates than the four environmental degradation products. Accep table data was also available for toxicity of the environmental degradates to non-vascular plants, however, it is unknown if they are less toxic than cyflufenamid because an acceptable st udy with cyflufenamid on the same species was not submitted. There are no environmental degradate toxicity data for estuarine/marine organisms or aquatic vascular plants. In additi on, no chronic toxicity da ta for the environmental degradates are available for any aquatic taxa. Given the lack of data for some taxa, aquatic exposure modeling was based on total toxic cyfluf enamid residues. Calculating EECs for total toxic cyflufenamid residues provides cons ervative values to calculate RQs.95 Although the environmental degradates appear less toxic than cyflufenamid to freshwater fish and invertebrates, the risk assessment is based on total toxic cyflufenamid residues for all aquatic taxa since the refined approach (cyflufenamid onl y) would not have altere d the risk results for the proposed uses.

3. Assumptions, Limitations, and Uncertainties Related to Exposure for Terrestrial Species

a. Location of Wildlife Species

For this screening-level terrestrial risk assessm ent, a generic bird or mammal was assumed to occupy either the treated field or adjacent areas receivi ng cyflufenamid at the treatment rate on the field. Actual habitat requirements of any part icular terrestrial specie s were not considered, and it was assumed that species occupy, exclus ively and permanently, the modeled treatment

area b. Routes of Exposure

This screening-level assessment for ground and aer ial spray applications of cyflufenamid only considered dietary exposure. Othe r routes of exposure that were not considered in the assessment are incidental soil ingestion exposure, inhalatio n exposure, dermal exposure, and drinking water

exposure.

Incidental soil ingestion exposure

This risk assessment does not consider incidental soil ingestion. Available data suggests that up
to 15% of the diet can consist of incidentally ingested soil de pending on the species and feeding strategy (Beyer et al., 1994). A simple first approximation of soil concentration of pesticide from spray application shows that ingestion of soil at an incidental rate of up to 15% of the diet would not increase dietary exposure.

Inhalation exposure

The screening risk assessment does not consider inhalation exposure. Such exposure may occur through three potential sour ces: (1) spray material in droplet fo rm at the time of application (2) vapor phase pesticide volatilizing from treated surfaces, and (3) airborne particulate (soil, vegetative material, and pesticide dusts).

Dermal Exposure

The screening assessment does not consider de rmal exposure. Dermal exposure may occur through three potential sources: (1) di rect application of spray to te rrestrial wildlife in the treated area or within the drift footprin t, (2) incidental contact with contaminated vegetation, or (3)
contact with contaminated water or soil.96 Drinking Water Exposure

The exposure of a target organism to a pestic ide- active ingredient may be the result of consumption of surface water, ground water or c onsumption of the pesticide in dew or other water on the surfaces of treated vegetation or in puddled water on treated fields. For the active ingredients of a pestic ide end-use product there is a potentia l to dissolve in runoff and puddles on the treated field may contain the chemical.

c. Dietary Intake and Other Limitations of Oral Studies in Terrestrial Species

The avian acute oral study and the avian sub acute dietary study each have limitations for estimating the risk to wild species exposed to pes ticides in the environment. Both studies have a fixed exposure period and do not allow for differences in the responses of i ndividuals to different durations of exposure. With the acute oral study, the chemical is administered in a single dose. This does not mimic wild bird exposure through multiple feedings. Also, it does not account for
the effect of different environmen tal matrices on absorption rate into the gastrointestinal tract of the animal. With the acute dietary study, the end point is reported as the concentration mixed with food that produces a response rather than as the dose ingested. Although food consumption sometimes allows for estimation of a dose, cal culations of the mg/kg/day are confounded by undocumented spillage of feed and how consumpti on is measured over the duration of the test. Usually, if measured at all, food consumption is estimated once at the end of the five-day exposure period. Group housing of birds undergoing testing allows for a measure of only the average consumption per day for a group, and co nsumption estimates can be further confounded
if birds die within a treatment group. In addition, the di etary study utilizes young birds. The exponential growth of young birds co mplicates the estimate of the dose; controls often nearly
double in size over the duration of the test. Sinc e weights are only taken at the initiation and at the end of the exposure period, the dose per body weight (mg/kg) is difficult to estimate with any precision. The interpretation of this test can be further c onfounded by dietary consumption.
Estimation of the acute LC 50 value is not only a function of the in trinsic toxicity of the pesticide, but also the willingness of the bi rds to consume treated food.

In addition to the uncertainties associated with the two toxicity studies utilized for estimating acute risk to birds, other fact ors, not normally taken into acco unt in a screening level risk assessment may narrow the differences between th e dose-based and dietary-based acute RQs for birds. The factors include differences in gross energy and assimilative efficiency of laboratory feed versus food items in the field, basic main tenance metabolic rates between wild birds and captive birds, seasonal free living dietary re quirements for wild birds (including gorging behavior) and specific food avoida nce behavior. These uncertaintie s may either overestimate or
underestimate the risk in a screening level assessment.

Gross Energy and Assimilative Efficiency

This screening level risk assessment does not a llow for gross energy and assimilative efficiency
differences between wildlife food items and laborat ory feed. For example, a typical laboratory avian feed, as used, contains approximatel y 2750 kcal/ kg. The Agency’s Wildlife Exposure97 Factors Handbook (USEPA, 1993) presents the follo wing dry-weight and fresh weight caloric
contents for selected wildlife food items:

Food Item Energy Dry (kcal/kg) Energy Fresh (kcal/kg ) grasses 4200 1300 broadleaf forage 4200 2200
seeds 5100 4700
fruits 2000 1100
insects 5600 1600

On gross energy content alone, direct comparis on of a laboratory dietar y concentration-based
effects threshold to a fresh-wei ght pesticide residue estimate w ould result in an underestimation of field exposure by food consumption by a factor of 1.25 - 2.5 for most food items. Only for seeds would the direct comparison of dietary threshold to residue estimate lead to an overestimate of exposure.

Depending upon species and dietary ma trix, bird assimilation of wild diet energy ranges from 23 - 80%, and mammal’s assimilation ranges from 41 - 85% (USEPA, 1993). If it is assumed that laboratory chow is formulated to maximize assi milative efficiency (e.g., a value of 85%), a potential for underestimation of exposure may ex ist by assuming that consumption of food in the wild is comparable with consumption during laboratory testing.

Metabolic Rates

In the screening process, exposure may be underes timated because metabolic rates are not related to food consumption. For example, the Wildlife Exposure Factors Handbook (USEPA, 1993) includes allometric models for estimating both existing metabolic rate (EMR) and free living metabolic rate (FMR). EMR is the metabolic rate necessary for animal maintenance in captivity without body weight loss, a condition similar to caged test animals. FMR is the energy requirement for an organism in the wild. For pa sserine birds these relationships are as follows:

EMR (kcal/day) = 1.572 (body weight g) 0.6210
FMR (kcal/day) = 2.123 (body weight g) 0.749

Using a weight range for passerines of 10 - 150 g, the EMR predictions range from 6.6 to 35.3, and the FMR ranges from 11.9 to 90.5 kcal/day. Thus, it appears that not accounting for increased energy demands of organisms in the w ild when comparing diet ary residues to dietary toxicity thresholds represen ts about a two-fold underest imation in exposure potential.

Free Living Metabolic Requirements

The screening procedure does not a ccount for situations where the feeding rate may be above or below requirements to meet fr ee living metabolic requirements. Gorging behavior is a possibility under some specific wildlife scenar ios (e.g., bird migration) where the food intake rate may be greatly increased. Kirkwood (1983) has suggested that an upper-bound limit to this behavior might be the typical intake rate multiplied by a factor of 5.98 Avoidance

In contrast is the potential for avoidance, ope rationally defined as animals responding to the presence of noxious chemicals in their food by reduc ing consumption of treated dietary elements. This response is seen in nature where herb ivores avoid plant s econdary compounds. For agrochemicals, Dolbeer et al. (1994) reported that the use of me thiocarb on fruit crops reduced depredation by birds. Of course, chemical treatment of food sources and any subsequent avoidance of those food sources by a species may, in itself, result in detrimental effects on the energetics of the species.

d. Incidental Releases Associated With Use

This risk assessment was based on the assumption that the entire treatment area is subject to pesticide application at the rates specified on the label. Uneven application of the pesticide through changes in calibration of application equi pment, spillage, and localized releases at specific areas of the treated field that are associated with specifics of the type of application equipment were not accounted for in this assessment.

e. Residue Levels Selection

The Agency relies on the work of Fletcher et al . (1994) for setting the assumed pesticide residues in wildlife dietary items. These residue assu mptions are believed to reflect a realistic upperbound residue estimate, although the degree to which this assumption reflects a specific percentile estimate is difficult to quantify. It is important to note that the field measurement efforts used to develop the Fletcher estimates of exposure involve highly varied sampling techniques. It is entirely possi ble that much of these data refl ects residues averaged over the entire above ground plants in th e case of grass and forage samp ling. Depending upon a specific wildlife species’ foraging habits, whole above ground plant samples may either underestimate or overestimate actual exposure.

f. Terrestrial Exposure Model

MILTREX ® 10 SC FUNGICIDE (the agri cultural use only label) allows for two cyflufenamid applications per growing season. Risk was a ssessed assuming that one growing season is equivalent to one year; therefore, two cyflufen amid applications per season is assumed to be equivalent to the maximum number of applications per year.99 4. Assumptions, Limitations and Un certainties Related to Effects

Assessment

a. Data Gaps of Requirements fo r Registration in the United

States under FIFRA

Ecotoxicity Studies for Cyflufenamid

The ecotoxicity database for cyflufenamid is not complete. Ecotoxicity data were not submitted to EPA on chronic toxicity to ma rine/estuarine fish and inverteb rates. Acceptable data are not available for two taxa of aquatic nonvascular pl ants (green algae and cy anobacteria) and chronic toxicity to freshwater invertebrate s. In addition, seedling emergence tests at the Tier II level are needed for four plants (tomato, cabbage, oat, and soybean) to address uncertainties from the available Tier 1 seedling emergence study regardi ng >25% inhibitions to tomato dry weight and cabbage emergence and uncertainti es regarding listed species due to a lack of establishing a

NOAEC or EC 05 for all four plants. Fina lly, physical properties of cyfl ufenamid indicate that it may partition to soil and persist, thus chroni c invertebrate whole sediment studies (two
freshwater and one marine/estuari ne species) are needed to addre ss risk to benthic invertebrates from exposure to cyflufenamid.

End-Use Product Toxicity

No ecotoxicity data have been submitted on th e formulation proposed for registration in the United States except for studies on mammals (acu te), freshwater fish (acute), freshwater invertebrates (acute), terrestrial invertebrates (acu te), and terrestrial plan ts (tier I). Lack of formulation data adds uncertainty to the assessment.

Ecotoxicity Studies for Envi ronmental Degradation Products

Acute ecotoxicity data on the four environm ental degradation products (149-F, 149-F1, 149-F6, and 149-F11) is available for freshwater fish a nd invertebrates, aquatic nonvascular plants, and
mammals but not birds. No studies are available on chronic toxicity.

Studies on freshwater fish and invertebrates indicate that the four degradates are less toxic than the cyflufenamid to those taxa. Studies were al so submitted for nonvascular plants (green algae); however, it is not clear if they are less toxic than cyflufenamid because an acceptable study with the TGAI was not submitted on the same species. In contrast to aquatic organisms, studies on mammals indicate that all four environmental degr adates are more acutely toxic than technical cyflufenamid, although it is uncertain whether or not any of the four degradates are more toxic than cyflufenamid (on an ai) basis in formulatio n NF-149 10SC. No inferences about toxicity to
birds can be made from the mode of action sin ce it is unknown. However, the toxicity to birds
can be calculated at which the LOC would be ex ceeded for the proposed uses after the terrestrial cyflufenamid EECs are corrected for the individu al degradation products concentrations. This was done by multiplying the terrest rial cyflufenamid EECs by the molecular weight ratio (molecular weight of the degradate/molecular we ight of the cyflufenamid) and then normalizing for the maximum percentage of degradation product formed. The de gradation product 149-F100 would need to be at least 107 times more acute ly toxic than technical cyflufenamid on a dose
basis and more than 286 times more toxic on a di etary basis to exceed the LOC. The other three degradation products (149-F1, 149- F6, and 149-F11) would need to be even more toxic than
149-F. The current assessment assumes that it is unlikely that the degradation products would be
100 times or more toxic to birds than technical cyflufenamid.

b. Sublethal Effects

For an acute risk assessment, th e screening risk assessment relie s on the acute mortality endpoint
as well as a suite of sublethal re sponses to the pesticide, as determined by the testing of species response to chronic exposure c onditions and subsequent chronic risk assessment. Consideration
of additional sublethal data in the assessment is exercised on a case-by-ca se basis and only after
careful consideration of th e nature of the sublethal effect meas ured and the extent and quality of available data to support estab lishing a plausible relationship be tween the measure of effect (sublethal endpoint) and th e assessment endpoints.

c. Age Class and Sensitivity of Effects Thresholds

Testing of juvenile organisms may overestimate toxicity at older age classes for pesticidal active ingredients that act directly (without metabolic transformation) because younger age classes may not have the enzymatic systems associated with detoxifying xenobiotics. However, the influence of age may not be uniform for all compounds, and compounds requiring metabolic activation may be more toxic in older age classes. The ri sk assessment uses the most sensitive life-stage information as the conservative screening endpoint.

d. Use of Most Sensitive Species Tested

Screening risk assessment relies on a selected toxicity endpoint from the most sensitive species tested; however, the selected toxicity endpoints do not necessarily reflect sensitivity of the most sensitive species in a given environment. The relative position of the most sensitive species
tested in the distribution of all possible species is a functi on of the overall variability among species to a particular chemical. Toxicity thresh olds may vary up to four orders of magnitude across species for some chemicals (Mayer and E llersieck, 1986). Therefore, risk conclusions may under- or overestimate actual ecol ogical risk for a given species.

5. Assumptions, Limitations, Uncertainties, Strengths and Data Gaps Related to the Acute and Chronic LOC’s

The risk characterization section of the asse ssment document includes an evaluation of the potential for individual effects to listed species at an exposure level equivalent to the LOC. This
evaluation is based on the median lethal dose es timate and dose/response relationship established for the effects study corresponding to each taxonomic group for which the LOCs are exceeded. The slope of the probit-dose response is used to ge nerate a probability of individual effects near
the low end tail of the curve. Predictions base d on low probability events are by nature highly uncertain. Moreover, for this assessment the dose-response curve representing a given taxa is generated from one study using one species. It is likely that the resulting dose-response101 relationship does not represent the response of all species w ithin taxa. Calculating the probability of individual effects at the lower and upper bounds of the slope is designed to address this source of uncertainty but the extent to whic h this captures the variability within taxa is unknown. In some cases, a probit dose-response re lationship cannot be calculated. In these instances, event probabilities are calculated based on a default slope assumption of 4.5 (Urban and Cook, 1986).102 V. Literature Cited

Arnot, J.A. and F.A.P.C. Gobas. 2004. A food web bioaccumulation model for organic chemicals in aquatic ecosystems. Environmental T oxicology and Chemistry, v23 (10), 2343-2355

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Beyer, W.N. 1994. Estimates of soil ingesti on by wildlife. J Wildl Manage 58(2):375-382.

Burns, L. A. 2002. EXAMS (Ex posure A nalysis M odeling S ystem) Version 2.98.4.6. Environmental Research Laboratory. U. S. Environmental Protection Agency. Athens,

GA.

Carsel et al., 1997. PRZM (Pesticide Root Zone Model) Version 3.12.2 Environmental Research Laboratory. U. S. Environm ental Protection Agency. Athens, GA.

Fletcher, J.S., J.E. Nellesson, and T. G. Pfleeger . 1994. Literature review and evaluation of the EPA food-chain (Kenaga) nomogram, an instrume nt for estimating pesticide residues on plants. Environ. Tox. and Chem. 13(9):1383-1391.

Hoerger, F. and E.E. Kenaga. 1972. Pesticide re sidues on plants: correlati on of representative
data as a basis for estimation of th eir magnitude in the environment. IN: F. Coulston and F. Corte, eds., Environmental Quality and Safety: Chemistry, Toxicology and Technology. Vol 1. George Theime Pub lishers, Stuttgart, Germany. pp. 9-28.

Kirkwood JK. 1983. Minireview. A limit to metabolis able energy intake in mammals and birds. Comp Biochem Physiol A 75(1): 1-3.

Mayer, F.L. and M.R. Ellersieck, 1986. Manual of acute toxicity: Interpretation and data base for
410 chemicals of freshwater animals. Resource Publication 160. U. S. Fish and Wildlife Service. Department of the In terior, Washington, D.C., 579 p.

Nisso. 2009. Cyflufenamid IR-4 food use worksh op Rutgers, The State University of New Jersey, http://ir4.rutger s.edu/FoodUse/FUWorkshop/I ndustry%20Talks/Pathology09/ NissoCyflufenamidTalk2009.pdf

Sano, S., Kasahara, I., Yamanaka , H. 2007. Development of a Novel Fungicide, Cyflufenamid J.
Pestic. Sci. 32(2), 137-138.

USEPA. 1993. Wildlife Exposure Factors Hand book. Office of Research and Development, Washington, D.C. EPA/600/R-13/187a.

USEPA. 1998. Guidelines for Ecological Risk A ssessment. Risk Assessment Forum, Office of Research and Development, Washingt on, D.C. EPA/630/R-95/002F. April 1998.

USEPA, 2009. Guidance for Selecting Input Para meters in Modeling th e Environmental Fate and Transport of Pesticides. Version 2.1 October 22, 2009.103 USEPA. 2004a. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs, U.S. Environmental Protection Ag ency. Endangered and Threatened Species Effects Determinations. Office of Prevention, Pesticides and Toxic Substances, Office of Pesticide Programs, Washington, D.C. January 23, 2004.

USEPA. 2004b. Excel spreadsh eet tool IECV1.1 (Individual Eff ect Chance Model Version 1.1). Office of Pesticide Programs, Environmental Fate and Effects Division. (June 22, 2004).

USEPA. 2005. Memorandum: clarification of plant evaluation guidance. United States Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances. October 4, 2005.

USEPA. 2008. T-REX (Terrestrial Residue EXpos ure model) Version 1.4.1 (10/09/08). Environmental Fate And Effects Division, Office Of Pesticide Programs, U.S. Environmental Protection Agency.

USEPA. 2009. EPI Suite TM v4.0. United States Environmental Pr otection Agency. Available for
download at: http://www.epa.gov/oppt/expos ure/pubs/episuitedl.htm

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Urban, D.J. and N.J. Cook. 1986. Hazard Evalua tion Division Standard Evaluation Procedure Ecological Risk Assessment . EPA 540/9-85-001. U.S. Environmental Protection Agency, Office of Pesticid e Programs, Washington, DC.

Willis, G.H. and L.L. McDowell. 1987. Pesticid e persistance on foliage. Environ. Contam.
Toxicol. 100:23-73.

VI. Appendices
A. Environmental Fate a nd Effects Study Bibliography B. Chemical Structures of Cyflufen amid and Its Transformation Products C. Ecological Effects Data
D. PRZM/EXAMS Results
E. KABAM Results F. Risk Quotient Method and Levels of Concern