NEW CHEMICAL REGISTRATION 

(Section 3) 

ECOLOGICAL RISK ASSESSMENT 

Cyflufenamid; fungicide

US EPA PC # 555550 

N

H

N O O F

F

CF3

Chemical Name(s): (Z)-N-[α-(Cyclopropylmethoxyimino)-2,3-difluoro-6-(trifluoromethyl) 

benzyl]-2-phenylacetamide (IUPAC), (Z)-N-[[(Cyclopropylmethoxy) amino][2,3-difluoro-6-

(trifluoromethyl)phenyl]methylene] 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 Concentration (0.85 lb ai/gallon) 

CYFLUFENAMID 10 SC FUNGICIDE (EPA Reg. No.8033-xxx); 

10% Suspension Concentration (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 Division 
2

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 the 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 ................................................................................................ 33 

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 ............................................................... 44 
3

(4) Pome Fruit ......................................................................................................... 44 

(5) Small Fruit Vine Climbing Except Fuzzy Kiwi Fruit ....................................... 45 

b. Aquatic Exposure Monitoring and Field Data .......................................................... 45 

c. Aquatic Bioaccumulation 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 ........................................................................................................... 59 

2. Terrestrial Effects Characterization .............................................................................. 62 

a. Terrestrial Animals ................................................................................................... 62 

(1) Acute Effects ..................................................................................................... 62 

(2) Chronic Effects ................................................................................................. 67 

(3) Field Studies...................................................................................................... 68 

b. Terrestrial Plants ....................................................................................................... 68 

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 ........................................................................................................... 72 

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 ....................................................................................................... 75 

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 ........................................................................................................... 78 

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 ....................................................................................................... 83 

3. Review of Incident Data ............................................................................................... 83 
4

4. Endocrine Effects .......................................................................................................... 83 

5. Federally Threatened and Endangered (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, Uncertainties, Strengths, and Data Gaps ....... 94 

1. Assumptions, Limitations, and Uncertainties Related to Exposure 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 Uncertainties 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 Uncertainties Related to Effects Assessment ............... 99 

a. Data Gaps of Requirements for Registration 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, Strengths and Data Gaps Related to the 

Acute and Chronic LOC’s .................................................................................................. 100 

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

VI. APPENDICES ...................................................................................................................103
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I. Executive Summary 

A. Nature of the Chemical Stressor 

Cyflufenamid [(Z)-N-[α-(Cyclopropylmethoxyimino)-2,3-difluoro-6-(trifluoromethyl) benzyl]-2-

phenylacetamide; CAS Reg. No 180409-60-3] is a new 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-cycle stages (Nisso, 2009 and Sano et al., 2007). 

The proposed registration of cyflufenamid includes 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 subgroup 13-07F) for the treatment of powdery mildew. There are 

two end-use products, MILTREX® 10 SC FUNGICIDE and CYFLUFENAMID 10 SC 

FUNGICIDE. MILTREX® 10 SC FUNGICIDE is labeled for agricultural use only (crop groups 

listed above) while CYFLUFENAMID 10 SC FUNGICIDE is only labeled for outdoor 

landscape and outdoor nursery ornamentals. For agricultural uses, cyflufenamid can be applied 

at a rate of 0.022 lb ai/A twice per growing season while the cyflufenamid 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 indicate no direct adverse effects 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 invertebrates (chronic), estuarine/marine fish and 

invertebrates (chronic), and aquatic nonvascular plants (cyanobacteria and green algae), so risk 

cannot be precluded for these taxonomic groups (listed or non-listed species). Furthermore, risk 

to listed terrestrial plants cannot be precluded due to observed effects (> 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 effects cannot be precluded for species dependent on 

freshwater invertebrates, estuarine/marine fish and invertebrates, 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 organisms and vascular aquatic plants. In 

addition, data were not available on chronic degradate toxicity to any taxa. Studies on 

freshwater fish and invertebrates indicate that the four degradates are less toxic than 

cyflufenamid to those taxa. Studies were also submitted for nonvascular plants (green algae); 

however, it is not clear if the degradates are less toxic than cyflufenamid 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 cyflufenamid within the range of 10 to 30°C. 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 assessing risk 

for “cyflufenamid only” would not alter the risk results for the proposed uses. 

Risk was assessed assuming that one growing season 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 Conclusions for Terrestrial Animals and Plants 

from the Proposed New Uses of Cyflufenamid1

Taxonomic 

Group Risk Endpoint Summarized Risk Characterization and Important Uncertainties

Birds, Reptiles 

and Terrestrial 

Phase 

Amphibians 

Acute Risk 

Dose-based LD50s and dietary-based LC50s are greater than the highest 

concentrations tested in four avian studies. There were no mortalities 

in any of the acute avian studies and 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 calculated. 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 LC50s 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 lowest 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 Conclusions for Aquatic Animals and Plants 

from the Proposed New Uses of Cyflufenamid1 

Taxonomic 

Group 

Risk 

Endpoint Summarized Risk Characterization and Important Uncertainties

Freshwater Fish 

and Aquatic 

Phase 

Amphibians 

Acute Risk None of the acute LOCs are exceeded, 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 are 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 study; 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 mixture of configurational isomers—NF-149 (Zisomer) 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 higher 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 cyflufenamid is through aerobic soil 

metabolism or runoff of soil to which cyflufenamid is adsorbed. Cyflufenamid is moderately 

persistent to persistent in terrestrial and aquatic environments. It is not susceptible to abiotic 

degradation under typical environmental conditions. Aerobic soil and aquatic metabolism halflives range from one week to more than a year. It has a high soil partition coefficient (Koc) 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 cyflufenamid from soil and water is not 

likely. Cyflufenamid has the potential to bioaccumulate in aquatic organisms. A fish 
8

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 processes, such as hydrolysis and photolysis. 

Aerobic soil metabolism studies indicate 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 water 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-m3

/mol at 20°C) 

suggest that volatilization of cyflufenamid from soil and water are not likely dissipation routes. 

Cyflufenamid adsorbs to soils with a soil partition coefficient (Koc) ranging from 1934 to 3087 

mL/g. It may reach surface water by penetrating 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 Kow of cyflufenamid is 4.7, therefore, it has the potential to bioaccumulate in aquatic 

organisms. BCF factors are between 250 and 1000 in both low-dose (1.0 μg ai/L) and high-dose 

(10.0 μg ai/L) BCF studies. Ninety percent depuration occurs in approximately five days. Five 

cyflufenamid-based transformation products are reported in the BCF study—one environmental 

degradation product, N-Cyclopropylmethoxy-2,3-difluoro-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 the 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 transformation products of cyflufenamid: its E-isomer, 

carbon dioxide, 149-F, 149-F1 (2,3-Difluoro-6-trifluoromethylbenzamidine), 149-F11 [(Z)-N-(αCyclopropylmethoxyimino-2,3-difluoro-6-trifluoromethylbenzyl)carbamoyl acetic acid], 149-F6 

(2,3-Difluoro-6-trifluoromethyl-benzamide), and a major unidentified volatile compound. 149-F, 

149-F1, 149-F11, and 149-F6 are referenced to as the four environmental degradation products 

through out this assessment. The identified degradation 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 spray drift. Furthermore, cyflufenamid may 

penetrate the foliar canopy during application or may wash off 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 bodies. The environmental degradation 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 leach 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 four degradation products to nonvascular plants, 

however, it is unknown if they are less toxic than cyflufenamid because an acceptable study for 

cyflufenamid on the same species was not submitted. There are no degradate toxicity data for 

estuarine/marine organisms or aquatic vascular plants. In addition, no chronic toxicity data for 

the four degradates are available for any aquatic taxa. Given the lack of data for some taxa, as a 

conservative approach, aquatic exposure modeling was based on total toxic cyflufenamid 

residues. This includes cyflufenamid, its isomer, and the four environmental degradation 

products. Total toxic residues are considered to be highly mobile, highly soluble, and persistent 

under all environmental conditions. Using the Tier II PRZM-EXAMS modeling scenario for 

North Carolina apples, the maximum estimated environmental concentrations (EECs) for total 

toxic cyflufenamid residues in surface water is 0.85 μg/L for the peak 1 in 10 year peak 

concentration. The calculated EECs are driven by the relatively long half-life values used for the 

total toxic cyflufenamid residues. Assessing risk for “cyflufenamid 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 its degradation products. The environmental fate 

properties of these compounds indicate that some are more persistent and mobile than 

cyflufenamid. The degradation products may be transported to other terrestrial environments 

through runoff. These compounds are also expected leach into the sub-soil reducing the 

exposure potential. 

Using the T-REX model 1.4.1 with the default foliar dissipation half-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 half-life was used for risk assessment since the 
10

refined 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 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 application 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 degradation products (149-F, 149-

F1, 149-F6, and 149-F11) may be more acutely toxic to mammals than the tested formulation (on 

an ai basis); however it is not certain due to the non-definitive 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 maximum 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 indicates 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 and undissolved) concentrations, or both. Those 

taxa are freshwater invertebrates (immobility observed) and estuarine/marine fish (no effects 

observed) and invertebrates (saltwater mysid; mortality and sublethal effects observed). 

No effects on fathead minnow growth were observed following chronic exposure; however other 

sublethal effects were observed and no fish survived at the highest test concentration. Toxicity 

was based on total cyflufenamid so actual toxicity may have been lower than reported. 

No effects on growth were observed in a vascular aquatic plant study and two nonvascular plant 

studies (freshwater and marine diatoms). Toxicity was based on total cyflufenamid in the marine 

diatom study. 

Ecological effects are unknown for some taxa because studies were either not submitted or were 

deemed invalid for freshwater invertebrates (chronic), estuarine/marine fish and invertebrates 

(chronic), and aquatic nonvascular plants (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 for the bobwhite quail; however it 
11

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 frank reproduction effects from exposure to 

cyflufenamid; however, increased liver and thyroid 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 the mallard duck and bobwhite quail following 

chronic exposure to cyflufenamid. Growth effects 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 agricultural use only label, states that a maximum 

of two applications per growing season may 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 intended 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 using a total toxic residue approach which 

requires input parameter assumptions. This approach should provide conservative 

exposure concentrations for the 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 enough 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 identified degradates, input values are assumed 

to be equivalent to the value for cyflufenamid. 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 study 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 registrant indicates that 

vapor phase activity observed is from cyflufenamid and not one of the environmental 

degradation products1

 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 uncertainties 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 VOC-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) and chronic exposure to freshwater invertebrates were found to 

be scientifically invalid (see Appendix C for details). In addition, the results from the available 

Tier I seedling emergence study indicate the need for Tier II testing on four species (tomato, 

cabbage, oat, and soybean). Finally, physical properties of cyflufenamid indicate that it may 

partition to soil and persist, thus chronic invertebrate whole sediment studies are needed to 

address risk to benthic invertebrates. The following studies are considered data needs:

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

A new aquatic invertebrate 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 invertebrates is not available. Cyflufenamid is 

highly acutely toxic to estuarine/marine invertebrates. 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 chronic 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 toxicity 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 toxicity. If an acceptable rainbow trout chronic 

study is submitted, there will be sufficient data to estimate the chronic toxicity to 

estuarine/marine fish. Alternatively, the estimate can be made if an acceptable acute 

fathead minnow study is submitted in addition to redoing the chronic fathead minnow 

study (see below). The estimate would be based on an acute to chronic ratio comparison 

using the acute and chronic freshwater fish studies (same species) and the acceptable 

acute study with sheepshead minnow. A valid comparison is contingent upon having 

definitive endpoints for the acute and chronic freshwater fish studies. 

• Aquatic plant growth (cyanobacteria and green algae) (850.5400) 

New toxicity studies with cyanobacteria and green algae are needed to address 

uncertainties regarding risk to nonvascular plants. Existing data (freshwater and marine 

diatoms) suggest that risk to aquatic nonvascular 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 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 studies. Given the 

incomplete dataset and narrow taxonomic representation 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 maximum 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 application rate 1.6 to 2 times higher than the 

maximum proposed application rate. However, a Tier II seedling emergence study is 

needed for four plants (tomato, cabbage, oat, and soybean) to address uncertainties 

regarding listed species due to a lack of establishing a NOAEC or EC05 for all four plants. 

• Chronic invertebrate whole sediment study using 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 Kow value (≥

3), a high Koc (≥ 1000), one Kd value ≥ 50 mL/g, and is persistent in sediment (aerobic 

soil and aquatic sediment metabolism half-life > 10 days). See environmental fate and 
14

transport summary for details. These data indicate that the compound may partition to 

sediment and persist. Use sites may include freshwater and marine/estuarine areas, thus 

tests on freshwater and estuarine species are requested to address this uncertainty. 

A protocol should be submitted for approval 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 Associated Contaminants on Survival, Growth, and 

Reproduction), and EPA 600/R-01/020 (Leptocheirus plumulosus in USEPA 2001 

Method for Assessing the Chronic Toxicity of Marine and Estuarine SedimentAssociated Contaminants 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 studies because toxicity endpoints were based on total 

cyflufenamid (both dissolved and undissolved) concentrations due to a failure to centrifuge or 

filter samples prior to analysis when concentrations were near or above the limit of solubility. 

As such, toxicity may be underestimated. Nonetheless, risk is not expected for the proposed uses 

(see risk description section for details). 

Although risk is not expected for the proposed uses and additional studies are not needed at this 

time, the following studies may be needed if higher EECs are anticipated (e.g., from a proposed 

new use). If additional studies are requested then special emphasis should be given to 

centrifugation or filtration to reduce uncertainty in the study results. 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 EECs 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 effects observed in the chronic 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 LD50 for the fathead minnow would indicate 

whether or not the fathead minnow was the most sensitive species tested. Having an 

acute and chronic study on the same species reduces uncertainty about chronic toxicity. 

This is because data from the two studies allows for calculation of an acute to chronic 

ratio which can be used to estimate chronic toxicity in cases where the chronic study was 

not conducted on the most acutely sensitive species. It cannot be determined from the 
15

available data if fathead minnow is more sensitive than the test species used in the 

available acute studies (rainbow trout and bluegill sunfish) and therefore chronic risk may 

be underestimated. However, the 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 sensitive 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 sensitivity 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 chronic fathead minnow study and run a matching 

acute fathead minnow study. No matter which study is conducted; there should be 

special emphasis on centrifugation or filtration 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 invertebrates (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 underestimated. Thus, there is the 

possibility that the mysid LC50 based on dissolved cyflufenamid is lower than the oyster 

EC50 based on dissolved cyflufenamid. 

b. Assessment of Uncertainties in the Terrestrial Risk Assessment 

Uncertainty exists in the assessment of chronic risk to birds because a treatment related effect 

was observed at the lowest test concentration 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 uncertainty 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 acutely toxic than technical cyflufenamid. 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 least 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 degradation products (149-F1, 149-F6, and 149-F11) would need to be 
16

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 than technical cyflufenamid. 

F. Endangered Species Considerations 

Table 3 summarizes the federally listed species (endangered and/or threatened) at risk associated 

with either direct or indirect effects following application of cyflufenamid for the proposed uses. 

Table 3. Listed Species Risks Associated With Direct or Indirect Effects from 

Cyflufenamid Use on Cucurbit Vegetables, Low Growing Berries, Pome Fruits, 

Ornamentals, and Small Climbing Fruit Vines1

Listed Taxon Direct Effects Indirect Effects

Terrestrial and semi-aquatic 

plants - monocots Yes2 No 

Terrestrial and semi-aquatic 

plants – dicots Yes3 No 

Terrestrial invertebrates No4 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 plants2,3,6,8

Terrestrial-phase amphibians 

No5 

Yes from effects to terrestrial and semi-aquatic 

plants (monocots and dicots), freshwater 

invertebrates, marine/estuarine fish and 

invertebrates, and aquatic non-vascular plants2,3,6,8

Reptiles 

No5 

Yes from effects to terrestrial and semi-aquatic 

plants (monocots and dicots), freshwater 

invertebrates, marine/estuarine fish and 

invertebrates and aquatic non-vascular plants2,3,6,8

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 plants2,3,6,8

 Aquatic non-vascular plants Yes6 Yes from effects to freshwater invertebrates, 

marine/estuarine fish and invertebrates, and aquatic 

non-vascular plants6,8

Aquatic vascular plants 

No

Yes from effects to freshwater invertebrates, 

marine/estuarine fish and invertebrates, and aquatic 

non-vascular plants6,8

Freshwater fish No Yes from effects to freshwater invertebrates and 

aquatic non-vascular plants6,8

Aquatic-phase amphibians 

No7 

Yes from effects to freshwater invertebrates, 

marine/estuarine fish and invertebrates, and aquatic 

non-vascular plants6,8

Freshwater invertebrates No for acute, Yes for chronic8 Yes from effects to freshwater invertebrates and 

aquatic non-vascular plants6,8

Marine/estuarine fish No for acute, Yes for chronic8 Yes for marine/estuarine fish and invertebrates and 

aquatic non-vascular plants6,8

Marine/estuarine invertebrates No for acute, Yes for chronic8 Yes for marine/estuarine fish and invertebrates and 

aquatic non-vascular plants6,8

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 concentration 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 practically non-toxic to bees. 5

 Results from avian species used as surrogate for assessing risk to terrestrial-phase amphibians and reptiles. 6

 Acceptable/supplemental studies were available for two of the four algal species considered to fulfill guideline 

requirements. No direct effects are expected for the two species with acceptable/supplemental 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-(trifluoromethyl)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

CF3

Figure 1. Chemical Structure of Cyflufenamid 

Table 4. Chemical Identification of Cyflufenamid 

Chemical Name(s) (Z)-N-[α-(Cyclopropylmethoxyimino)-2,3-difluoro-6-(trifluoromethyl)benzyl]-2-

phenylacetamide (IUPAC) 

(Z)-N-(α -Cyclopropylmethoxyimino-2,3-difluoro-6-trifluoromethylbenzyl)-2-

phenylacetamide (IUPAC) 

(Z)-N-(α -Cyclopropyl-methoxyimino-2,3-difluoro-6-trifluoromethylbenzyl)-2-

phenylacetamide (IUPAC) 

(Z)-N-[[(Cyclopropylmethoxy)amino][2,3-difluoro-6-

(trifluoromethyl)phenyl]methylene]benzeneacetamide (CAS) 

N-[(Z)-[(Cyclopropylmethoxy)amino][2,3-difluoro-6-

(trifluoromethyl)phenyl]methylene]benzeneacetamide (CAS) 

Chemical Abstracts 

Service (CAS) 

Registry Number 

180409-60-3 

Company Code(s) NF-149, NS-0036, 149-(Z)-FB 
18

Empirical Formula C20H17F5N2O2

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 ingredient 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 are no previously prepared ecological risk 

assessments by the Agency for cyflufenamid uses. 

B. Stressor Source and Distribution 

The stressor is the chemical cyflufenamid when applied to terrestrial non-food and food use 

crops to control powdery mildew. The proposed uses include cucurbit vegetables (crop 

subgroups 9a and 9b), low growing berry (crop subgroup 13-07G) except cranberries, pome fruit 

(crop group 11), outdoor landscape and outdoor nursery 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 apples can also be found in a number of other 

states including Michigan, New York, Ohio, and Wisconsin, in addition 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 application sites as shown in 

Table 5 including nurseries, residential proprieties, commercial, institutional, and recreational 

areas such as outdoor malls, educational campuses, campgrounds, golf courses, and parks. These 

three crops underscore the potential widespread use of cyflufenamid in the United States. The 

proposed cyflufenamid applications by crop group or subgroup are provided in Table 5. 
19

0

12500

25000

37500

50000

California

Florida

Georgia

Michigan

New Jersey

New York

North Carolina

Ohio

South Carolina

Texas

Wisconsin

All Other Reported States

State

Total 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

California

Florida

Michigan

New York

North Carolina

Ohio

Oregon

Pennsylvania

Washington

Wisconsin

State

Total 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

Maine

Massachusetts

Michigan

Minnesota

New York

North Carolina

Ohio

Oregon

Pennsylvania

Vermont

Virginia

Washington

West Virginia

Wisconsin

All Other Reported States

State

Total 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 Grown1

Cucurbit Vegetables 

(9a and 9b) 

Field 

Nursery 

Low Growing Berries

(13-07G) 

Field 

Nursery 

Outdoor Landscape and Outdoor Nursery Ornamentals2

Abelia, acalypha (copper-leaf), achillea (yarrow), ageratum, amelanchier (juneberry 

shadbush), amorpha (false indigo), aster, azalea, barberry, 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, sunflower (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 purposes), 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 homeowner application; however, it does not restrict 

application sites. 
21

1. Nature of the Chemical Stressor 

Cyflufenamid [(Z)-N-[α-(Cyclopropylmethoxyimino)-2,3-difluoro-6-(trifluoromethyl) benzyl]-2-

phenylacetamide; CAS Reg. No 180409-60-3] is a new pesticide active ingredient submitted for 

registration in the United States. Technical grade cyflufenamid 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 the technical product is 149-(E)-FB. 

a. Mode of Action (MoA) of Cyflufenamid 

The biochemical mode of action 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 there 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 ingredient the actual usage is not known. There are 

two end-use products, MILTREX® 10 SC FUNGICIDE and CYFLUFENAMID 10 SC 

FUNGICIDE. Both of these formulations contains <0.3% 149-(E)-FB. MILTREX® 10 SC 

FUNGICIDE is proposed for use on a variety of terrestrial food uses (agriculture only) while 

CYFLUFENAMID 10 SC FUNGICIDE 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 listed on the label. Both labels state, “do not apply directly to 

water, or to areas where surface water 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 FUNGICIDE 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 twice 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 that 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 and invertebrates, marine/estuarine fish and invertebrates, aquatic plants, 

terrestrial plants, birds, mammals, and terrestrial invertebrates. 
22

Consistent with the process described in the Overview Document (EPA, 2004a), this risk 

assessment uses a surrogate species approach in its evaluation of cyflufenamid. Toxicological 

data generated from surrogate test species, which are intended to be representative of broad 

taxonomic groups, are used to extrapolate to potential effects on a variety of species (receptors) 

included under these taxonomic groupings. 

Acute and chronic toxicity data from studies submitted by pesticide registrants are used to 

evaluate the potential direct effects of cyflufenamid to the aquatic and terrestrial receptors 

identified in this section. This includes toxicity data on the technical 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 ecological effects of cyflufenamid to these non-target taxonomic 

groups. In addition, the table provides a preliminary overview of the potential acute toxicity of 

cyflufenamid by providing the acute toxicity classification 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 reproduction 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 concentrations while treatment related growth effects were observed 

only in mallard duck (14-day survivor weight at all test concentrations). In the fish study there 

was no effect on growth; however other sublethal effects were observed (internal bleeding, 

swollen abdomen, pink feces, and deformed mouth) and no fish survived at the highest test 

concentration. 

Table 6. Summary of the Taxonomic Groups and the Surrogate Species Tested to 

Understand Potential Acute Ecological Effects of Cyflufenamid to These Non-Target 

Taxonomic Groups 

Taxonomic Group Surrogate Species Acute Toxicity Classification1

Birds2

Mallard Duck (Anas platyrhynchos) 

Bobwhite Quail (Colinus virginianus) 

Zebra finch (Poephila guttata) 

Practically non-toxic 

Practically non-toxic5

Practically non-toxic 

Mammals Laboratory rat (Rattus norvegicus) Practically non-toxic 

Insects Honey bee (Apis mellifera) Practically non-toxic 

Freshwater fish3 Bluegill sunfish (Lepomis macrochirus) 

Rainbow trout (Oncorhynchus mykiss) 

Not classified6

Moderately toxic 

Freshwater invertebrates Water flea (Daphnia magna) Not classified6, 7

Estuarine/marine fish Sheepshead minnow (Cyprinodon 

variegatus) Not classified6

Estuarine/marine 

invertebrates 

Mysid shrimp (Americamysis bahia)

Eastern oyster (Crassostrea virginica)

Not classified7

Highly toxic 

Terrestrial plants Monocots4

Dicots4 Not applicable 

Aquatic plants and algae 

Duckweed (Lemna gibba) 

Cyanobacteria (Anabaena flos-aquae) 

Marine diatom (Skeletonema costatum) 

Not applicable 
23

Taxonomic Group Surrogate Species Acute Toxicity Classification1

Freshwater diatom (Navicula 

pelliculosa) 

Green Algae (Selenastrum 

capricornutum) 1

 Based on toxicity to cyflufenamid. 

2

 Birds represent surrogates for terrestrial-phase amphibians and reptiles. 3

 Freshwater fish may be surrogates for aquatic-phase amphibians. 4

 Four species of monocots (onion, ryegrass, oat, and corn) and six species of dicots (sugarbeet, cabbage, soybean, lettuce, 

tomato, and radish). 

5

 Classified as practically nontoxic on a dietary basis but not classified on a dose 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 development 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 hedgerows, meadows, fallow fields or grasslands, 

woodlands, riparian habitats, and other uncultivated areas) that may receive drift, eroded soil, or 

runoff. Aquatic ecosystems at risk are water bodies 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 coastal areas, aquatic habitat also includes marine 

ecosystems including estuaries, embayment’s, and near shore environments. 

 

D. Assessment Endpoints 

Assessment endpoints represent the actual environmental value that is to be protected, defined by 

an ecological entity (species, community, or other entity) and its attribute or characteristics 

(EPA, 1998). For cyflufenamid, the ecological entities may include the following: birds, 

mammals, freshwater fish and invertebrates, estuarine/marine fish and invertebrates, terrestrial 

insects, terrestrial plants, and aquatic plants and algae. The attributes for each of these entities 

may include growth, reproduction, and survival. 

E. Conceptual Model 

A conceptual model provides a written description and visual representation of the predicted 

relationships between cyflufenamid and its environmental 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 concentrations. An exposure pathway is the means by which a pesticide 

moves in the environment from the application site to non-target organisms. The evaluation of 
24

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 terrestrial and aquatic organisms. When used in 

accordance with the proposed label, cyflufenamid can result in potential adverse effects upon the 

survival, growth, and reproduction of non-target terrestrial and aquatic organisms.

2. Conceptual Diagram 

The conceptual model diagram is a generic graphic depiction of the risk hypotheses identified in 

the previous section. It is assumed that cyflufenamid and its environmental degradation products 

are capable of affecting exposed terrestrial and aquatic organisms if environmental 

concentrations are sufficiently elevated as a result 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 exposure 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 may 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 concentrations. An exposure pathway is the means by which a 

contaminant moves in the environment from a source to an ecological receptor. For this pathway 

to be complete, it must have a source, a release 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 assessment of these pathways thus includes an 

examination of the sources and potential migration pathways for constituents, and the 

determination of potential exposure 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 cyflufenamid-bearing soil particulates to adjacent fields 

(soil erosion) or deposition of cyflufenamid-bearing soil particulates from wind erosion. The 

high Kocs(>1900) of cyflufenamid suggest that leaching to ground water and recharge to surface 

water would not be a route of exposure. However, cyflufenamid degradation products are 
25

Figure 5. Conceptual Diagram for Aquatic and Terrestrial Risk. Cyflufenamid (black lines); cyflufenamid tproducts (gray lines); major concern (solid lines); 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 recharge to surface water, as well as reach 

surface water through runoff. Typically, 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 expected to increase surface water EECs because it 

may take several years for the chemicals in ground water supplies to reach surface water and 

such chemicals will likely be diluted when they reach surface water. Although there is potential 

for ground water contamination by cyflufenamid degradation products, it is expected that the 

total toxic residue approach used in this assessment will provide surface water EECs that are 

protective for all aquatic environments. In the future, if monitoring data does not support this 

assumption then this approach should be reexamined. Long-range transport of cyflufenamid and 

its degradation products was not assessed. Additional data are required in order to conduct such 

an assessment. 

This screening-level assessment for spray applications of cyflufenamid 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. Further discussion of these routes can be found in the 

Assumptions, Limitations and Uncertainties Related 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 consistent 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 use 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 maximum labeled application rates and methods of 

application. Measures of effects data are obtained from registrant submitted studies or from 

literature studies identified by ECOTOX in order to determine the direct and indirect effects to 

all taxa. The public ECOTOXicology database (ECOTOX) 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 plants, and wildlife. ECOTOX was created and is 

maintained by the USEPA, Office of Research and Development, and the National Health and 

Environmental Effects Research Laboratory's Mid-Continent Ecology Division. 
27

Table 7 summarizes the measures of ecological effects and exposure used to assess ecological 

risk following exposure to cyflufenamid with the proposed uses. 

Table 7. Measures of Ecological Effects and Exposure for Cyflufenamid 

Assessment Endpoint Surrogate Species and 

Measures of Ecological 

Effect1,2 

Measures of Exposure 

Birds3 Survival Bobwhite quail and Zebra finch acute 

oral LD50 

Bobwhite quail and Mallard duck 

subacute dietary LC50 Maximum residues on food 

items (foliar) Reproduction and growth Mallard duck LOAEC and Bobwhite 

Quail reproduction NOAEC6

Mammals Survival Laboratory rat acute oral LD50

Reproduction and growth Laboratory rat reproduction 

NOAEL/LOAEL 

Freshwater fish4 Survival Rainbow trout 96-hr LC50 Peak EEC8

Reproduction and growth Fathead minnow NOAEC/LOAEC 60-day average EEC8

Freshwater 

invertebrates 

Survival Water flea 48-hr EC50 Peak EEC8

Reproduction and growth No acceptable study available 21-day average EEC8

Estuarine/marine fish Survival Sheepshead minnow 96-hr LC50 Peak EEC8

Reproduction and growth No study available 60-day average EEC8

Estuarine/marine 

invertebrates 

Survival Eastern oyster 96-hr EC50 

Saltwater mysid 96-hr EC50

Peak EEC8 

Reproduction and growth No study available 21-day average EEC8

Terrestrial plants5 Survival and growth Monocot seedling emergence EC25

and NOAEC7

Monocot vegetative vigor EC25 and 

NOAEC 

Dicot seedling emergence EC25 and 

NOAEC7

Dicot vegetative vigor EC25 and 

NOAEC 

Estimates of runoff and spray 

drift to non-target areas 

Insects Survival (not quantitatively 

assessed) 

Honey bee acute contact LD50 Maximum application rate 

Aquatic plants and 

algae 

Survival and growth Duckweed 7-day EC50 and NOAEC 

Freshwater diatom 96-hr EC50 and 

NOAEC 

Marine diatom 96-hr EC50 and 

NOAEC 

Peak EEC8 

1

LD50 = Lethal dose to 50% of the test population; NOAEC = No observed adverse effect concentration; LOAEC = 

Lowest observed adverse effect concentration; LC50 = Lethal concentration to 50% of the test population; EC50/EC25 = 

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 growing berries, pome fruit, outdoor landscape and 

outdoor nursery ornamentals, and small fruit vines are calculated using PRZM (Pesticide Root 

Zone Model, version 3.12.3, June 2006; Carsel et al., 1997) and EXAMS (EXposure Analysis 

Modeling System, 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 application sites receiving total toxic cyflufenamid 

residues through runoff, erosion, and spray drift for specific scenarios. PRZM simulates 

pesticide application, movement, and transformation on an agricultural field and the resultant 

pesticide loadings to a receiving water body via runoff, erosion, and spray drift. EXAMS 

simulates the fate of the pesticide and resulting concentrations in the water body. The standard 

scenario used for ecological pesticide assessments assumes application to a 10-hectare 

agricultural field that drains into an adjacent 1-hectare water body, 2-meters deep (20,000 m3

volume) with no outlet (farm pond). PRZM-EXAMS was used to estimate screening-level 

exposure of aquatic organisms to total toxic cyflufenamid 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 concentration is used for assessing chronic exposures 

to aquatic invertebrates. 

(2) KABAM 

KABAM (KOW (based) Aquatic BioAccumulation Model) v.1.0 is used to estimate potential 

bioaccumulation of hydrophobic organic pesticides such 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 pesticide concentrations in fish tissues consumed by 

humans (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 octanolwater partition coefficient (KOW) to estimate uptake and elimination 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 dose- and dietary-based exposures and associated 

risks to mammals and birds consuming aquatic organisms, using an approach that is similar to 

the T-REX model (USEPA 2008). 

 

KABAM incorporates 7 trophic levels to describe 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 the 
29

year), medium sized fish (e.g., adult bluegill), and larger upper-trophic level fish (e.g., 

largemouth bass). 

 

Cyflufenamid concentrations in organisms of the aquatic trophic levels listed above were used to 

estimate acute and chronic exposures of piscivorous mammals and birds consuming fish. For 

mammals, available chronic toxicity data on cyflufenamid was used to calculate risk quotients 

(RQs) for estimated exposures due to bioaccumulation 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 submitted 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 estimates is for birds (also acting as surrogate for 

reptiles and terrestrial-phase amphibians) and mammals with an exposure route emphasis on 

uptake through the diet. The cyflufenamid residues 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 ingredient in a given exposure scenario. 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 terrestrial animals to cyflufenamid was based on 

potential foliar applications of cyflufenamid. 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 application rates (Hoerger and 

Kenaga, 1972; Fletcher et al., 1994). Essentially, for a single application, there is a linear 

relationship between the amount of pesticide applied and the amount of pesticide residue present 

on a given food item. Food item residue levels are then linearly adjusted based on application 

rate. The upper-bound estimates are used to estimate risks since these values represent the highend exposure that may be encountered for terrestrial species that consume food items that have 

received label-specified pesticide application. Although these represent higher-end estimates, 

they do not represent the highest possible exposure estimates. 

T-REX is a simulation model that, in addition to incorporating the relationship between 

application rate and food item residue concentrations, accounts for pesticide degradation in the 

estimation of terrestrial EECs. T-REX calculates pesticide residues on each type of food item on 

a daily interval for one year. A first-order decay 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 dependent on the foliar dissipation 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 degradation. The initial application occurs on day 0 (t=0) and the model 

runs for 365 days. Over the 365-day run, the highest 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 long the pesticide remains in or on food items after application. 

In many cases, neither empirically determined foliar 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 refined 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 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 application 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 used to predict EECs from terrestrial 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-lying area of terrestrial habitat that is wet but may dry up at times 

throughout the year. TerrPlant incorporates two similar conceptual models for depicting dry and 

semi-aquatic areas of terrestrial habitats. For both models, a non-target area is adjacent to the 

target area. Pesticide exposures to plants in the non-target area are estimated to receive runoff 

and spray drift from the target area. 

For a dry area adjacent to the treatment area, runoff 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 drain into an area with equal size containing 

seedlings, resulting in 1, 2, or 5% of the application rate being deposited. For semi-aquatic 

areas, runoff exposure is estimated as channel runoff. 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 receiving area results in 10, 20, 

or 50% of the application rate being deposited on soil with emerging or emerged seedlings. With 

pesticides which are ground incorporated, the runoff EEC is decreased because the application 

rate is divided by the incorporation depth before 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 selected by the model user. 

Exposures through runoff and spray drift are then compared to measures of survival and growth 

(e.g. effects to seedling emergence and vegetative vigor) to develop RQ values. 

The model compares the combined deposition estimates from runoff and spray drift to adverse 

effect levels measured in seedling emergence studies. In addition, RQs are derived for plants 
31

with consideration for spray drift 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 emergence 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 concentrate 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 food and non-food crops. Proposed crops and possible sites treated 

with cyflufenamid are listed in Table 5. Proposed application rates are shown in Table 8. There 

are no rotational crop plant back restrictions 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 and CYFLUFENAMID 10 SC FUNGICIDE for 

agricultural use only (cucurbit vegetables, low growing berries, pome 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 cycle 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. Therefore, 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 other mode of action fungicides.” Since the mode of cyflufenamid 

action is unknown it is unclear what alternatives exist. 

The CYFLUFENAMID 10 SC FUNGICIDE label excludes homeowner applications; however, 

it does not restrict application sites. Therefore, applications to residential property are implied. 
32

Table 8. Proposed Application Rates for Cyflufenamid Use on Cucurbit Vegetables, Low Growing BerLandscape and Nursery Ornamentals, Pome Fruit, and Small Fruit Vines 

Crop 

Application 

Rate Range 

(lbs ai/A) 

Maximum Single 

Application Rate

(lbs ai/A) 

Maximum 

Application 

Rate Per 

Growing 

Season 

(lbs ai/A) 

Maximum 

Number of 

Applications

Minimum 

Interval Applic

Cucurbit 

Vegetables 

 (9a and 9b) 

not applicable 0.011 0.022 2 7 days A

Low Growing 

Berries (13-

07G) Except 

Cranberries 

0.011-0.022 0.022 0.044 2 14 days A

Outdoor 

Landscape 

and Outdoor 

Nursery 

Ornamentals 

up to 0.023 0.023 0.046 2 14 day A

Pome Fruit 

(11) not applicable 0.022 0.044 2 14 day A

Small fruit 

Vine 

Climbing 

Subgroup 

(13-07D) 

Except Fuzzy 

Kiwifruit 

0.011-0.022 0.022 0.044 2 7 days1 A

1 Minimum 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 mixture of configurational isomers—NF-149 (Zisomer) and 149-(E)-FB. The Z-isomer is always present in higher concentrations than the Eisomer; 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 environments. It is not susceptible to abiotic 

degradation under typical environmental conditions. Aerobic soil and aquatic metabolism halflives range from one week to more than a year. It has a high soil partition coefficient (Koc) and 

will adsorb strongly to soils and sediments. However, particulates adsorbed to soil could move 

off-site by soil erosion to adjacent water bodies. Its low vapor pressure and Henry’s Law 

Constant suggests that volatilization from soil and water is not likely. Based on the Log Kow, 

cyflufenamid has the potential to bioaccumulate in aquatic organisms. A fish bioaccumulation 

study shows that cyflufenamid accumulates and depurates readily within five days. 

Table 9 presents physical, chemical, and environmental fate characteristics of cyflufenamid and 

its known environmental degradation products. The proposed environmental degradation 

pathway is provided in Figure 6, along with key environmental 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 processes in the environment. 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 aqueous solutions at pH 7 was stable to direct photolysis (MRID 

47620713). The estimated photolysis half-life of cyflufenamid is 220 days, which is 

significantly longer than the duration of the study. 
34

Table 9. Environmental Fate and Transport Characteristics for Cyflufenamid and its Environmental Deg

Parameter Cyflufenamid 149-F11 149-F 149-F1 149-F6 

Molecular Weight 

g/mol 

412.36 

MRID 47620712a 

380.27 

MRID 47620721s 

294.22 

MRID 47620722s 

224.13 

MRID 47620723s 

225.12 

MRID 47620724s 

Water Solubility 

20 °C 

0.52 mg/L 

MRID 47620416s

0.842 g/L 

MRID 47620721s 

0.925 g/L 

MRID 47620722s 

60.89 g/L 

MRID 47620723s 

9.013 g/L 

MRID 47620724s 

Vapor Pressure 

20 °C 

3.54 x 10-5 Pa 

MRID 47620417s not reported not reported not reported Not Reported 

Henry’s Law 

Constant 

20 °C 

2.8 x 10-7 atm-m3 / mol 

calculated not reported not reported not reported not reported 

Log Kow (Log 

noctanol/water 

partition coefficient) 

20 °C, pH 6.75 

4.70 

MRID 47620415s not reported not reported not reported not reported 

Hydrolysis Half-life 

(t1/2) pH 7 

Stable 

MRID 47620712s not reported not reported not reported not reported 

Aquatic Photolysis 

Half-life (t1/2) pH 7 

Stable 

MRID 47620713s not reported not reported not reported not reported 

Adsorption 

Coefficient (Kd) 

38, 17, 74, 

and 32 mL/g 

MRID 47620728s 

0.25, 0.25, 0.36, 

and 0.13 mL/g 

MRID 47620729s 

0.64, 0.13, 1.17, 

and 0.85 mL/g 

MRID 47620730s 

1.32, 0.58, 1.50, 

and 2.85 mL/g 

MRID 47620802s 

0.21, 0.09, 0.29, 

and 0.30 mL/g 

MRID 47638208s 

Soil Partition 

Coefficient (Koc) 

2202, 2199, 3087, 

and 1934 mL/g 

MRID 47620728 

not applicable 

51, 33, 70, 

and 66 mL/g 

MRID 47620730s 

91, 88, 77, and 

213 mL/g 

MRID 47620802s 

9, 9, 12, and 

16 mL/g 

MRID 47638208s 

Binding Correlation organic content not to organic content organic content organic content organic content 

Aerobic Soil 

Metabolism Halflife (t1/2) 

21 and 19 days 

MRID 47620715s 

7 days, MRID 47620716s 

9, 122, and 19 

MRID 47620717s 

19 and 408 days 

MRID 47620718s 

41 days, MRID 47620719s 

3, 3, and 4 days 

MRID 47620721s 

11, 6, and 14 days 

MRID 47620722s 

161, 330, 

and 118 days 

MRID 47620723s 

2310, 866, and 

1386 days 

MRID 47620724s 

Aerobic Aquatic 

Metabolism 

Half-life (t1/2) 

128 and 50 days 

(total system) 

MRID 47620726s 

not calculated not calculated not calculated not calculated 

Anaerobic Aquatic 

Metabolism 

Half-life 

Stable 

MRID 47620725s

and 47620727a 

not reported not reported not reported not reported 

1Registrant submitted studies listed above are classified as either a. acceptable or s. supplemental. Half-life values are based on best fit 
35

N

H

N O O F

F

CF3

N

H

N O O F

F

CF3

O

OH

NH2

N O F

F

CF3

NH2

F NH

F

CF3

NH2

F O

F

CF3

Cyflufenamid, NF-149

t1/2 = 7->365 days

Koc= 1934-3087 mL/g soil

Water Solubility = 0.5 mg/L

Field Dissipation = 365 days

149-F11

t1/2 = 3-4 days

Kd= 0.13-0.36 mL/g soil

Water Solubility = 0.8 g/L

Field Dissipation = 3 days Reduction

Mineralization Deamination

CO2

149-F

t1/2 = 6-14 days

Koc= 33-70 mL/g soil

Water Solubility = 0.9 g/L

Field Dissipation = 120 days

149-F1

t1/2 > 120 days

Koc= 77-213 mL/g soil

Water Solubility = 60.9 g/L

Field Dissipation = 457 days*

149-F6

t1/2 >> 120 days

Koc= 9-16 mL/g soil

Water Solubility = 9.0 g/L

Field Dissipation = 60 days

O

HO

Phenyl-acetic acid

N

H

F N O

F

CF3

O

149-(E)-FB

Oxidation

Hydrolysis

* study termination

CO2

Hydrolysis

Figure 6. Degradation Pathway for Cyflufenamid; A summary of the important 

environmental fate characteristics of cyflufenamid and its degradation 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 sampling 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 conditions. The calculated non-linear half-lives for 

cyflufenamid correlate well with the observed DT50 while the calculated linear half-lives do not. 

This supports a biphasic transformation. Several of the aerobic soil metabolism studies where 

conducted using foreign soils. These soils may represent potential use sites 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 studies, the nonlinear half-lives for cyflufenamid range from 7 

to 408 days (74 ± 130 days) depending on the soil (MRIDs 47620715, 47620716, 47620717, 

47620718, and 47620719). In seven of the eight soils tested (one soil was studied twice), data 

collection extends long enough to establish an accurate half-life and to observe the DT50. In six 

of those seven soils, the observed DT50 was between 8 and 30 days while the calculated nonlinear 

half-lives range from 7 to 40 days. In the other aerobic soil metabolism study, the calculated 

linear half-life is higher (408 days) than the other experiments (MRID 47620718). The registrant 

does not provide an explanation for this discrepancy. In one of the aforementioned aerobic soil 

metabolism studies, CO2 was approximately 52% of the AR at the end of the study (373 days). 

In another aerobic soil metabolism study, the accumulation of an unidentified volatile compound 

was observed to steadily increase to approximately 10% at study termination (MRID 47620715). 

Cyflufenamid was shown to be stable under anaerobic conditions. Cyflufenamid did not degrade 

in the anaerobic soil metabolism study (MRID 47620725 and 47620727). 

In aquatic environments, cyflufenamid degrades under aerobic conditions. In two different 

water:soil test systems cyflufenamid has linear half-lives of approximately 128 and 43 days and 

DT50 of 100 and between 30 and 59 days, respectively (MRID 47620726). In one of the aerobic 

aquatic metabolism study, the observed DT50 for cyflufenamid is approximately 100 days for the 

entire system (water and sediment). In several aerobic aquatic metabolism studies including this 

aerobic aquatic metabolism study, the applied radioactivity remains >15% in the water layer at 

study termination (100 days). 

Field Dissipation 

Field dissipation studies were conducted in three different U.S. locations—California, Georgia, 

and New York. These studies showed that cyflufenamid dissipates with half-lives between 

approximately 2 and 11 days (5.3 ± 4.8 days). In the terrestrial field studies, 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 degradation product observed in soil samples taken at 

depths >15 cm. At the Georgia site, 149-F was observed 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 identification 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; Arrow 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 (Kow) 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 μg ai/L) and a high exposure level (10.0 μg 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-cyclopropylmethoxyimino-2,3-difluoro-6-

trifluoromethylbenzyl)-2-(4-hydroxyphenyl)acetamide (149-F-4-OH-B), N-phenylacetyl-2,3-

difluoro-6-trifluoromethylbenamidoxime (149-F4B), N-(α-cyclopropylmethoxyimino-2,3-

difluoro-6-trifluoromethylbenzyl)-2-(3-hydroxyphenyl)acetamide (149-F-3-OH-B), and N-(αCyclopropylmethoxyimino-2,3-difluoro-6-trifluoromethylbenzyl)-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 residues was observed in the BCF studies. 

Transformation

Although cyflufenamid (Z-isomer) is present in higher quantities it can be converted to 149-(E)-

FB. Under all study conditions the Z-isomer was present in higher concentrations that the Eisomer. In all submitted studies 149-(E)-FB was not observed to be ≤12.6% applied radio 

activity, which means that it is a major transformation 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 products, 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-difluoro-6-trifluoromethyl 

benzyl)carbamoylacetic acid] accumulate to >10% in a number of the submitted laboratory 

studies. One other degradation product, 149-F6 [2,3-Difluoro-6-trifluoromethyl 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 experiment 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 has the potential to persist in the environment due to its long half-life. 

The observed DT50 for 149-F is 6 to 16 days (MRID 47620722). The calculated non-linear halflives range from 6 to 14 days (10 ± 4 days) and the calculated linear half-lives range from 14 

days to 22 days (17 ± 4 days). For 149-F1, a DT50 of >120 days was observed (MRID 

47620723). The calculated linear half-lives range from 136 to 347 days (222 ±111 days). The 

observed DT50 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 DT50 was not observed during the course 

of the experiments, therefore, it is assumed to be >120 days (MRID 47620724). The calculated 

linear and nonlinear half-life values for 149-F6 range from 866 to 2311 days (1521 ± 731 days) 

for three different soils. 
38

Transport

Batch equilibrium data for cyflufenamid suggest that the compound adsorbs to soil and is 

“slightly mobile” according to the FAO classification [organic carbon partition coefficients (Koc) 

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 partitioning does not correlate with the organic 

content of the soil (MRID 47620729). Adsorption coefficients (Kd) 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 organic carbon content of the test soil. Kocs range from 33 to 70 

mL/g soil. 149-F is also soluble in water (0.925 g/L). 

149-F6 does adsorb to organic surfaces and is considered “highly mobile or mobile” according to 

the FAO classification (MRID 47638208). Kocs 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 mobile” according to the FAO classification. The 

soil partition coefficient correlates with the organic carbon content of the test soil. Kocs 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 steady-state within 24 hours. In several 

water:soil/sediment test systems, more than half of the applied radioactivity is found in 

sediment/soil within one week of cyflufenamid application. 

Laboratory studies indicate that cyflufenamid is not volatile (<2% volatilization). 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 growing berries, pome fruit, outdoor landscape and 

outdoor nursery ornamentals, and small fruit vines 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 assessment 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 reason, this assessment incorporates 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, aqueous photolysis, aerobic soil metabolism, etc.) 

are used to calculate the amount of cyflufenamid, 149-F11, 149-F, 149-F1, and 149-F6 present in 

each study at each sampling interval. The total concentrations 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 according to the input parameter guidance. 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 cyflufenamid as well as its degradation products and the 

data cannot be combined, the most conservative plausible values are used. This is based on the 

assessor’s best judgment. Rational for choosing 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 the five compounds considered 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 determine if soil binding is correlated with organic 

carbon content (i.e. the coefficient of variation for Koc values is less than that for Kd values) for 

cyflufenamid and its four degradates. Binding correlation for each compound is provided in 

Table 9. When binding is correlated with organic carbon content the partition coefficient (Koc) 

is also listed in Table 9. 

Studies indicate that degradate 149-F6 is not only highly mobile in soil, 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 toxic cyflufenamid residues was calculated and the 

corresponding half-life value for each study is reported. These values are reported in Table 9. 

The 90th percentile confidence bound on the mean total 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 toxic cyflufenamid residues was calculated and the 

corresponding half-life value determined for each study. These values are reported in Table 9. 

The 90th percentile confidence bound on the mean total toxic cyflufenamid half-life value is 235 

+ [(3.078 x 159)/√2)] = 581 days. 

Model Scenario

When more than one standard scenario exists for a given crop group or subgroup all are 

modeled. Standard scenarios, the 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 initial application date. Meteorological data 

corresponding to the location of the standard scenario was used to indentify dates when 

conditions are conducive for powdery mildew and 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 disease development.” This implies that cyflufenamid may be applied 

at anytime during the growing season. Again, meteorological data was referenced to identify 

dates when pest pressure may be high and runoff potential is high for each standard scenario 

location. This information was used in conjunction with crop profiles to choose the dates that 

are used in the mode runs. EECs for aerial applications are reported. 
41

Table 10. Chemical Specific Input Parameters Used in PRZM-EXAM Modeling to Estimate Total Toxic CResidue Concentrations Resulting From the Proposed Uses on Cucurbit Vegetables, Low Growing BerriesOutdoor Landscape and Nursery Ornamentals, and Small Fruit Vines 

Input Parameter (Symbol; Unit) Value for Cyflufenamid Value for Total Toxic Cyflufenamid Residues Basis for Total Toxic Cyflufenamid Residue Input Selection 

Molecular Weight (g/mole) 412.36 412.36 value for cyflufenamid MHenry’s constant (atm-m3/mol at 20 oC) 2.8 x 10-4 2.8 x 10-4 value for cyflufenamid 

calc

pressu

Vapor Pressure (torr at 20 oC) 2.7 x 10-7 2.7 x 10-7 value for cyflufenamid 

San

Yaman

20

Solubility in Water (at 20 oC) 0.52 mg/L 60890 mg/L most conservative value; value for 149-F1 MHydrolysis Half-life (t1/2 at pH 7) 0 0 value for cyflufenamid MAquatic Photolysis Half-life (t1/2 at pH 7) 0 0 value for cyflufenamid MAerobic Soil Metabolism [upper 90th

percentile confidence bound on the mean half-life value (t1/2; days)] 

134 314 recalculated for total toxic residues using original data1 MRID 

47620

Aerobic Aquatic Metabolism Half-life [water column; upper 90th percentile 

confidence bound on the mean half-life value (t1/2; days)] 

209 581 recalculated for total toxic residues using original data1 M

Anaerobic Aquatic Metabolism Half-life [benthic; upper 90th percentile confidence 

bound on the mean half-life value (t1/2; 

days)] 

0 0 value for cyflufenamid MR

Average Soil Partition Coefficient (Koc; 

mL/g) 2355.5 11.5 most conservative value; value for 149-F6 M

1 Half-lives are recalculated according to half-life guidance for a new set of data that combine all stressors (total toxic residues) so that 

represent 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 Parameters Used in PRZM-EXAM Modeling to 

Estimate Total Toxic Cyflufenamid Residue Concentrations 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 

Rate2

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 

01/05 
43

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 uses on cucurbit vegetables, low growing berries, 

pome fruits, outdoor landscape and nursery, and small climbing fruit vines are listed in Tables 

12 thru 16, respectively. The model output files are provided in Appendix D. Cyflufenamid 

applications to North Carolina apples provide the most conservative Tier II EECs for total toxic 

residues. Tier II EECs for total toxic cyflufenamid residues are not expected to exceed 0.85 μg/L 

for the 1-in-10 year return peak (used in acute assessments), 0.75 μg/L for the 1-in-10 year 96-

hour, 0.46 for the 21-day mean concentration (used in chronic assessments), and 0.22 μg/L for 

the 1-in-10 year 60-day mean concentration (used in chronic assessments). 

(1) Cucurbit Vegetables 

Four cucurbit vegetable scenarios were selected to represent the crop group including cucumber 

and melons. Three different melon scenarios exist. 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 

μg/L (ppb)

96-hour 

μg/L (ppb)

21-day 

μg/L (ppb)

60-day 

μg/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 0.041 
44

 (2) Low Growing Berries Except Cranberries 

Four Tier II model scenarios exist for low growing berries. The New York grape scenario 

provides the most conservative Tier II EECs. Tier II surface water EECs as a result of these uses 

are shown in Table 13. 

Table 13. Estimated Environmental Exposure Concentrations of Total Toxic 

Cyflufenamid Residues in Surface Water from Cyflufenamid Use on Low 

Growing Berries 

Scenario

1-in-10 year annual exceedance probability for EECs 

Peak 

μg/L (ppb)

96-hour 

μg/L (ppb)

21-day 

μg/L (ppb)

60-day 

μg/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 surrogates for outdoor landscape and ornamental 

landscape. Uses on ornamental trees and shrubs beyond nurseries may include residential 

property, public areas, commercial areas, institutional areas, industrial areas, industrial areas, 

rights-of-way and other easements, and recreational 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 Exposure 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 

μg/L (ppb)

96-hour 

μg/L (ppb)

21-day 

μg/L (ppb)

60-day 

μg/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 exist 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 concentrations in surface water as a result 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 

μg/L (ppb)

96-hour 

μg/L (ppb)

21-day 

μg/L (ppb)

60-day 

μg/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 scenarios for small vine climbing fruit. These are the 

same scenarios used to model low growing berries 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 Concentrations 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 

μg/L (ppb)

96-hour 

μg/L (ppb)

21-day 

μg/L (ppb)

60-day 

μg/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 States. Therefore, aquatic exposure monitoring and 

field data are not available. 

c. Aquatic Bioaccumulation Assessment 

Available data on the octanol-water partition coefficient (Kow) for cyflufenamid indicates that 

this pesticide may accumulate in aquatic food webs. Because the Log Kow is > 4.0, KABAM 

v.1.0 was used to estimate concentrations of cyflufenamid residues in tissues of aquatic 

organisms resulting from bioaccumulation. Input parameters are provided in Table 17 and 

estimated concentrations of total toxic cyflufenamid residues in fish are provided in Table 18. 

Output files from KABAM are provided in Appendix E. 
46

Table 17. Input parameters for Cyflufenamid Residues Used in KABAM 

Characteristic 

Total Toxic 

Residue 

Value 

Comments 

Log KOW 4.7 Value for cyflufenamid was used (MRID 47620415). Data is not 

available for the environmental degradates. 

KOW 50118.7 Calculated 

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

47620728

Time to steady 

state (TS; days) 16 days This value is calculated automatically from the Log KOW value entered above. 

Pore water EEC 

(μg/L) 0.1294a

Value generated by PRZM/EXAMS benthic 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 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) 0.4635a

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 total toxic cyflufenamid fate characteristics. 

Table 18. Estimated Concentrations 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 and extent of pesticide 

application with respect to the location and behavior of those species. OPP’s terrestrial exposure 

model generates exposure estimates assuming that the animal is present on the use site at the 

time that pesticide levels are highest. The upper-bound pesticide residue concentration on food 

items is calculated from both initial applications and any additional applications, taking into 

account pesticide degradation between applications. Although this approach is conservative, it is 

reasonable, particularly when considering acute risks. For acute risks, the assumption is that the 
47

duration of exposure is a single day and, again, occurs when residue 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 residue levels are highest and furthermore that it 

repeatedly forages on the use site although the frequency and duration of foraging events on the 

use site are not explicitly considered or specified. 

The current screening-level approach does not directly relate timing 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 address the temporal and spatial co-occurrence of 

cyflufenamid use and sensitive ecological processes. However, pesticides are frequently used 

from spring through fall; crop cultivation frequently 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 wildlife species. The 

increased energy demands associated with these activities (as opposed to hibernation, for 

example) can increase the potential for exposure to pesticide-contaminated food items since 

agricultural areas can represent a concentrated source of relatively 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 area immediately surrounding the use area. 

Currently, the Agency does not require toxicity studies on reptiles and amphibians 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, exposure to birds would be greater due to higher 

relative food consumption. While this assumption is likely true, there are no supported 

relationships regarding the relative toxicity of a compound to birds and herpetofauna. The lack of 

toxicity data on reptiles and amphibians 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-REX simulations for the proposed uses of 

cyflufenamid at the maximum label rates provided in Table 8. 
48

Table 19. Terrestrial Food-Item Residue Estimates for Birds with Cyflufenamid Proposed 

Uses 

Crop Food Item Maximum Dose-Based 

EECs (mg/kg)1,2

Dietary-Based 

EECs1,3

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 EECs 
49

Table 20. Terrestrial Food-Item Residue Estimates for Mammals with Cyflufenamid 

Proposed Uses 

Size Class 

(grams) 

Dietary and Dose-Based EECs1 

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 EECs2

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 EECs2

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 EECs2

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 EECs2

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 EECs2

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 EECs 
50

 (2) TERRPLANT 

 

Effects on non-target terrestrial plants are most likely to occur as a result of spray drift and/or 

runoff from ground applications. TerrPlant is typically used by EFED as a Tier 1 model for 

screening level assessments of pesticides. TerrPlant derives pesticide EECs in runoff and in 

drift. Table 21 lists predicted EECs for non-target terrestrial plants based on the maximum 

proposed application rate for cyflufenamid. 

Table 21. Estimated Environmental Concentrations for Terrestrial Plants Based on the 

Proposed Uses of Cyflufenamid1

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 bioaccumulation of hydrophobic organic pesticides in 

freshwater aquatic ecosystems and risks to mammals 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 humans (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 (KOW) to estimate 

uptake and elimination 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 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 use scenario resulting in the highest peak aquatic 

EEC (NC pome fruits). 
51

Table 22. EECs for Mammals and Birds Consuming 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, strawberry and apple crops (MRID 47620811, 42620809, 

42620810, 47638213). Half-life values for representative 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 overall risk results for the 

proposed uses. 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 application rates (2% higher maximum 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 Aquatic-Phase Amphibians

Acute toxicity testing indicates that technical cyflufenamid is moderately toxic to freshwater 

fish. Available data on the four environmental 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 analytical 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 20o

C). Therefore, the concentrations are reported as mg ‘total’ ai/L. 

Table 23. Freshwater Fish Acute Toxicity to Cyflufenamid 

Common Name %AI Study parameters LC50/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 LC50 = 1.04 (0.651-1.43) 

mg ai/L2,3

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 toxic1 
53

Common Name %AI Study parameters LC50/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 LC50 >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 LC50 = 41.3 (24.3 to 

+infinity) mg ai/L3

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 toxic1 

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 LC50 >103 mg ai/L 

NOAEC = 103 mg ai/L 

No effects observed 

47825902 Supplemental/ 

Practically nontoxic1

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 LC50 >98.5 mg ai/L 

NOAEC = 98.5 mg ai/L 

No effects observed 

47825903 Supplemental/ 

Not applicable 
54

Common Name %AI Study parameters LC50/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 LC50 >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 LC50 >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 LC50 (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 cyflufenamid 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 concentration 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 data 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) indicates 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 uncertainty above the limit 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% immobility at 1.73 mg total ai/L; Formulation: 0% 

immobility at 5.19 mg total ai/L) and 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 classified as supplemental because the water samples were 

not centrifuged or filtered prior to analytical determination. Without 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 aqueous 
55

solubility limit of the technical grade active ingredient (0.52 mg ai/L at 20oC). Therefore, the 

concentrations are reported as mg ‘total’ ai/L and are not useful for risk quotient (RQ) 

calculations, but can contribute to risk description. 

Table 24. Freshwater Invertebrate Acute Toxicity to Cyflufenamid

Common Name %AI Study parameters EC50/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 EC50 >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 EC50 = 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 toxic1

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 EC50 = 14.4 (11.2-18.9) 

mg ai/L2 

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 toxic1

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 EC50 >103 mg ai/L 

Probit Slope = N/A 

NOAEC = 103 mg ai/L 

No effects observed 

47825907 Acceptable/ 

Practically nontoxic1
56

Common Name %AI Study parameters EC50/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 EC50 >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 EC50 = 46.9 (27.5-134) 

mg total ai/L2 

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 toxic1

1

Based on EC50 (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 indicates that technical cyflufenamid is at most highly toxic to estuarinemarine fish. 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 25 summarizes the effects 

from the available study. 
57

Table 25. Estuarine/Marine Fish Acute Toxicity to Cyflufenamid 

Common Name %AI Study parameters LC50/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 LC50 >0.20 mg ai/L 

NOAEC = 0.20 mg ai/L 

No effects observed

47620702 Acceptable/ 

Not applicable 

Marine/Estuarine Invertebrates

Acute toxicity testing indicates 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 analytical determination. Without centrifugation or filtration, the amount of 

chemical that is freely dissolved and bioavailable cannot be determined. This is a problem 

because at minimum, the two highest test concentrations were likely above the aqueous solubility 

limit of cyflufenamid and some of the lower treatment 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 25o

C and aqueous solubility 

(freshwater) was reported as 0.52 mg ai/L at 20o

C and 0.047 mg ai/L at 30oC. Furthermore, 

solubility in saltwater was not reported and is expected to differ from that in freshwater (likely 

lower). Without centrifugation or filtration, the amount 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 contribute to risk description. 
58

Table 26. Estuarine/Marine Invertebrate Acute Toxicity to Cyflufenamid 

Common Name %AI Study parameters EC50 /LC50/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 EC50 = 0.16 (0.12-0.21) 

mg ai/L 2,3

Slope = 4.77± 1.374 

NOAEC = 0.09 mg ai/L 

LOAEC = 0.24 mg ai/L based 

on reduction in shell growth. No 

mortalities.

47620630 Acceptable/ 

Highly toxic1

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 LC50 = 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 LC50/EC50 (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 filtered prior to analytical determination. This is 

a problem because at minimum, the highest nominal 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. The number of test concentrations and how much 

they exceeded solubility is uncertain because the study was conducted at 25o

C and aqueous 

solubility was reported as 0.52 mg ai/L at 20o

C and 0.047 mg ai/L at 30oC. Without 

centrifugation or filtration, the amount 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 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 effect 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-F1, 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 approximately 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 concentration was made directly from the secondary stock solution 

after serial dilution of the primary stock solution). In addition, the limit concentration (0.017 and 

0.035 mg ai/L) calculated from a single application rate (0.023 lbs ai/A) and maximum annual 

application rate (0.046 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 
60

bioavailability of the compound in the highest two concentrations and that no dose-response 

effects were observed, the NOAEC and EC50 values are determined to be 0.247 and >0.247 mg 

ai/L, respectively. 

Table 28. Vascular Aquatic Plant Toxicity to Cyflufenamid 

Species %AI Study parameters EC50/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 

EC50 > 0.247 mg ai/L 

NOAEC = 0.247 mg ai/L1

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 Navicula 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-F1, 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 degradates 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 study, it is acceptable only as a Tier I 

study. The highest nominal concentrations tested (500 and 1000 μg ai/L) are approximately at or 

distinctly above the solubility limit (520 μg ai/L) reported in the study. However, the two 

concentrations were not centrifuged prior to analytical determination. 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 concentration was made directly 

from the secondary stock solution after serial dilution of the primary stock solution). In addition, 

the limit concentration (17 and 35 μg ai/L) calculated from a single application rate (0.023 lbs 

ai/A) and maximum annual application rate (0.046 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 compound in the highest two concentrations and that no 

dose-response effects were observed, the NOAEC and EC50 values are determined to be 0.269 

and >0.269 mg ai/L. 
61

Table 29. Non-Vascular Aquatic Plant Toxicity to Cyflufenamid 

Species %AI Study parameters EC50/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 

EC50 > 0.269 mg ai/L 

NOAEC = 0.269 mg ai/L1

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 

EC50 > 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 

EC50 = 55 (52-57) mg ai/L2

Probit Slope = 7.91 ± 0.4343

NOAEC = 24.2 mg ai/L 

Biomass (area under the growth 

curve) 

EC50 = 56 (54-58) mg ai/L2

Probit Slope = 7.99 ± 0.3883

NOAEC = 24.2 mg ai/L 

Growth rate 

EC50 = 78 (77-79) mg ai/L2

Probit Slope = 6.65 ± 0.1983

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 

EC50 > 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 Supplemental 
62

Species %AI Study parameters EC50/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 

EC50 > 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 

EC50 > 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 showed no frank reproduction effects. Reproductive 

effects were observed in the mallard duck and bobwhite quail studies. In the bobwhite quail 

study, body weight effects (14-day survivor weight) were seen at the lowest test dose. Adverse 

effects to both monocots and dicots were observed in non-target terrestrial 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 cyflufenamid but not any of the four environmental 

degradation products or any formulations. Based on the acute oral toxicity studies for the 

bobwhite quail and the zebra finch, cyflufenamid is categorized as practically 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 were no mortalities in either study at the highest 

doses tested. The acute oral LD50 was > 1970 mg ai/kg bw for bobwhite quail and > 2000 mg 

ai/kg bw for zebra finch. Sublethal 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. Observed sublethal effects in the acute oral 

study in bobwhite quail include transient decreases in body weight and food consumption in 
63

females at all treatment doses and in males at the mid and high treatment doses. The LOAEL for 

bobwhite quail is 461 mg ai/kg, the lowest dose 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 either study. The acute dietary LC50 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 (subdued behavior) and reductions in body weight gain 

were seen at the two highest doses (2460 and 4900 mg ai/kg diet) in this 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. Small to large areas of 

bare (unfeathered) skin were also 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 LD50/LC50 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 

LD50 > 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 

LD50 > 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 

nontoxic1

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. 

LC50 > 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 

nontoxic2
64

Common Name %AI Study parameters LD50/LC50 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. 

LC50 > 4618 ppm 

NOAEC = 2224 ppm 

LOAEC = 4618 ppm based 

on reduced body weight gain, 

decreased food consumption, 

and post-mortem 

abnormalities 

47620622 Acceptable/ 

Practically 

nontoxic2 

1

 Based on LD50 (mg/kg) <10 very highly toxic; 10-50 highly toxic; 51-500 moderately toxic; 501-2000 slightly toxic; >2000 

practically nontoxic 

2 Based on LC50 (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 technical material, a formulation (NF-149 10SC), 

and five transformation products of cyflufenamid: 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 LD50 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 LD50 was 349 mg 

ai/kg/bw for the most toxic transformation product, 149-F1. All four environmental degradation 

products were more toxic than technical cyflufenamid. One or more 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 dietary exposure due to their low levels relative to cyflufenamid 

(DP377139, 5/24/10, G. Kramer) 

Table 31. Mammalian Acute Toxicity to Cyflufenamid 

Common 

Name

%AI Study parameters LD50 /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. 

LD50 >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 

nontoxic1
65

Common 

Name

%AI Study parameters LD50 /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. 

LD50 >2000 mg formulation/kg bw (F) 

NOAEL = 2000 mg formulation/kg bw 

LOAEL >2000 mg formulation/kg bw 

LD50 >199.6 mg ai/kg bw (F) 

47620824 Acceptable/ 

Practically 

nontoxic1

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. 

LD50= 2697 (2384-3051) mg ai/kg bw2

Probit Slope = 15.7 ± 5.963

NOAEL: No NOAEL 

LOAEL = 800 mg ai/kg based on clinical 

signs (e.g., piloerection) with recovery at all 

doses 

47620609 Acceptable/ 

Practically 

nontoxic1

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. 

LD50= 349 (248-491) mg ai/kg bw (F);

434 (343-594) mg ai/kg bw (M). 2 

Probit Slope = 12.2 ± 4.613

NOAEL: No NOAEL 

LOAEL 160 mg/kg based on clinical signs 

(piloerection with recovery). 

47620610 Acceptable/ 

Moderately 

toxic1

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. 

LD50 = 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 toxic1

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. 

LD50 = 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 toxic1
66

Common 

Name

%AI Study parameters LD50 /NOAEL MRID Classification

/Category

Laboratory rat 99.5 149-E-FB 

(stereoisomer of 

cyflufenamid) 

Acute oral study 

5000 mg ai/kg bw 

tested 

LD50 >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 protruding eyes seen in 

both animals with increased salivation and 

ungroomed appearance observed in the 

male only) with recovery by Day 8. 

47620613 Acceptable/ 

Practically 

nontoxic1

1

 Based on LD50 (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 indicates that technical cyflufenamid is classified as practically nontoxic to 

bees. Acute toxicity to bees was assessed based on acute oral and contact toxicity. The tested 

formulation (NF-149 10SC) is also classified as practically nontoxic to bees. Table 32

summarizes the available studies. 

Table 32. Terrestrial Invertebrate Acute Toxicity to Cyflufenamid 

Common 

Name

%AI Study parameters LD50 /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 μg ai/bee 

48 hour contact LD50 > 100 

μg ai/bee 

48 hour contact NOAEL = 

100 μg ai/bee 

48 hour oral LD50 > 100 μg 

ai/bee 

48 hour oral NOAEL = 100 

μg 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 μg ai/bee 

48 hour contact LD50 > 100 

μg ai/bee 

48 hour contact NOAEL = 

100 μg ai/bee 

48 hour oral LD50 > 100 μg 

ai/bee 

48 hour oral NOAEL = 100 

μg ai/bee 

47620708 Acceptable/ 

Practically nontoxic 
67

 (2) Chronic Effects 

Birds

One-generation reproductive toxicity studies were conducted with 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 reproductive 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-day 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 was 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 observed at the two highest treatment 

levels. At 1016 mg ai/kg diet, significant reductions 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 survivors to eggs set at 1016 mg ai/kg diet. The 

ratio of hatchling survivors to number hatched was significantly reduced at 296 mg ai/kg diet but 

not at 1016 mg ai/kg diet. At the 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 toxicity study, cyflufenamid was administered 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, mating, 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 thyroid weights. The offspring LOAEL 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 cyflufenamid on seedling emergence and vegetative 

vigor indicate effects to several plant species resulting from application of cyflufenamid at rates 

about one and a half to four times greater than 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 monocots was survival in onion crops. The NOAEC and 

EC25 values based on this effect are 0.0339 and >0.0667 lbs ai/A, respectively. No vegetative 

vigor effects were observed in dicots. 

The effect of cyflufenamid on the seedling emergence was tested at measured concentrations of 

0.0456 and 0.0903 lbs ai/A for oat, ryegrass, corn, 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 monocot species was oat, based on height, with 

NOAEC and EC25 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 emergence inhibitions of 27% at the low rate. Effects at the 

high application rate for both tomato and cabbage were lower than the effects at the low 

application rate. Given normal variability in measured plant 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 

EC25s for seedling emergence. 
69

Table 35. Tier I Non-target Terrestrial Plant Toxicity to Cyflufenamid

Species

Seedling Emergence

Endpoint 

Affected

Vegetative Vigor

Endpoint 

Affected

MRID 

No. Study 

Classification EC25 

(lb 

ai/acre)

NOAEC/[EC05]

1 

(lb ai/acre)

EC25

 (lb 

ai/acre)

NOAEC/[EC05] 

(lb ai/acre)

Cyflufenamid formulations (NF-149 10SC)

Monocots

Onion 

Allium cepa >0.082 0.08 [>0.08] No effects >0.072 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 >0.072 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 

0.042 <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 EC25, equal to the EC25, or below the lowest concentration, an EC05 value is used 

instead. 

2 Bold value is the value that will be used to calculate risk quotients 
70

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 effects to non-target species. In a deterministic approach, an 

exposure estimate is divided by a single point estimate of toxicity to calculate a risk quotient 

(RQ). The RQ is then compared to Agency Levels of Concern (LOCs, Appendix F), which serve 

as criteria for categorizing potential risk to non-target organisms 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 any aquatic taxa. Studies on freshwater fish and invertebrates 

indicate that the four degradates are less toxic 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 aqueous solubility limit of cyflufenamid within the 

range of 10 to 30°C. 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 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 Aquatic-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 resulting in the highest peak EEC 

and thus highest RQ is presented in Table 36. 

Table 36. Cyflufenamid: Acute Risk to Freshwater Fish 

Species Toxicity Endpoint 

(μg/L)

Scenario Peak EEC 

(μg/L)

Acute 

Risk 

Quotient1

Levels of 

Concern 

Exceeded2

Rainbow trout 

Oncorhynchus 

mykiss 

96-hr LC50= 1040 

Technical 

Pome Fruit 

NC apples 

0.85 0.0008 No

1

 Acute Risk Quotients are calculated using the following formula: EEC/LC50 2 Acute LOC for freshwater fish = 0.05 for endangered species, 0.1 for restricted use, and 0.5 for non-listed species 
71

Freshwater Invertebrates

The acute aquatic RQs for freshwater invertebrates 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 though higher concentrations tested exceeded or 

likely exceeded the solubility limit of the test compound. Without centrifugation, the amount of 

cyflufenamid that is freely dissolved and bioavailable cannot be determined. Uncertainty in the 

level of dissolved cyflufenamid in the solution for these studies renders calculated endpoints 

suitable for qualitative use only. Furthermore, RQs are not reported because the EC50 is nondefinitive for the study with the lowest EC50 (i.e., less than 50% immobility occurred at the 

highest test concentration in the TGAI study). 

Marine/Estuarine Fish

RQs are not reported because there were no mortalities 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 resulting 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 

Quotient1

Levels of 

Concern 

Exceeded2

Eastern Oyster 

Crassostrea 

virginica 

96-hr EC50= 160 

Technical 

Pome Fruit 

NC apples 

0.85 0.0053 No

1

 Acute Risk Quotients are calculated using the following formula: EEC/LC50 2 Acute LOC for estuarine/marine invertebrates = 0.05 for endangered species, 0.1 for restricted use, and 0.5 for nonlisted species 

 (2) Risk Following Chronic Exposure 

Freshwater Fish and Aquatic-Phase Amphibians

The chronic aquatic RQs for freshwater fish were not calculated. The test solution was not 

centrifuged or filtered prior to measurement of cyflufenamid in the chronic freshwater fish study, 

even though some test concentrations exceeded or likely exceeded the solubility limit of 

cyflufenamid. Without centrifugation, 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 endpoints suitable for qualitative use only. 
72

Freshwater Invertebrates

No acceptable chronic studies on freshwater invertebrates are available. Therefore, quantitative 

risk estimation cannot be conducted. Chronic risk to freshwater invertebrates cannot be 

precluded. 

 

Marine/Estuarine Fish

No chronic studies on marine/estuarine fish are available. Therefore, a quantitative estimation of 

risk cannot be conducted. Lack of studies does not preclude potential risk. 

Marine/Estuarine Invertebrates

No chronic studies on marine/estuarine invertebrates are available. Therefore, a quantitative 

estimation of risk cannot be conducted. Lack of studies does not preclude potential risk. 

 b. Aquatic Plants 

Vascular Plants

The LOC for aquatic plants (listed species) was not 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 EC50 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 RQ1,2 Listed Vascular Plant RQ1,3

Pome Fruits 

NC apple

0.85 Not estimated; EC50>limit test 

concentration 0.003 

1

 Risk Quotients are calculated using the following formula: EEC/EC50 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 > 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; however, 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 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 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 EC50 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 

RQ1,2

Listed Non-Vascular Plant RQ1,3

Pome Fruits 

NC apple

0.85 Not estimated; EC50>limit test 

concentration 0.003 

1

 Risk Quotients are calculated using the following formula: EEC/EC50 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 categories (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 Kenaga predicted maximum residues as modified by Fletcher et al.

(1994), and assumes first-order dissipation. 

For birds, acute RQs are derived using dose-based and dietary-based acute toxicity values. For 

mammals, acute RQs are derived using a dose-based acute toxicity value, and chronic RQs are 

derived using a dose-based chronic toxicity value (the test material was administered by gavage) 

and a dietary-based chronic toxicity value using the standard FDA laboratory 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 (LC50 or 

NOAEC) expressed in units of dietary concentration. Dose-based RQs are calculated using a 

body weight-adjusted LD50 and consumption-weighted equivalent dose sorted by food source 

and body size. For both birds and mammals, three weight categories (or sizes) are considered. 

 (1) Risk Following Acute Exposure 

Birds

Dietary LD50s 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 LC50s are greater than the highest concentration tested in avian studies on the 

bobwhite quail and the mallard duck (4900 and 4618 ppm, respectively). There were no 
74

mortalities in either of the acute avian studies. RQs were not estimated using these studies 

because the acute avian dose and dietary based studies resulted in non-definitive endpoints (i.e., 

LC50s > the highest doses tested). Risks to birds following acute exposure will be further 

discussed in the risk description section. 

Potential risk to piscivorous birds 

The potential acute risk to piscivorous birds considers exposure via consumption of fish 

contaminated with cyflufenamid. RQs were not estimated for piscivorous birds because the 

acute avian dose and dietary based studies resulted in non-definitive endpoints. Risks to birds 

following acute exposure will be further discussed in the risk description section. 

Mammals

The mammalian LD50 was greater than the highest dose tested 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 formulation/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 calculated because the formulation study resulted in a 

non-definitive endpoint which was lower than the LD50s 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-definitive endpoint which was lower than the LD50sfrom 

studies on the four environmental degradation products. Risks to piscivorous mammals 

following acute exposure will be further discussed in the risk description section. 

Terrestrial invertebrates

Cyflufenamid is classified as practically nontoxic to bees based on acute contact and oral toxicity 

testing with the TGAI and the tested 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 consumption of fish contaminated 

with cyflufenamid. RQ’s were not estimated for 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 toxicity study is available for cyflufenamid. Potential direct 

chronic effects of cyflufenamid to mammals were 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 for monocots and dicots. Potential effects of cyflufenamid on 

plants were modeled in TERRPLANT 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 risk 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 further 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 Drift1

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 cyflufenamid have the potential to 

compromise survival, reproduction, and growth of non-target aquatic and terrestrial animals and 

plants, including Federally-listed endangered and threatened species. 

Based on the available ecotoxicity data and predicted environmental exposures, this ecological 

risk assessment does not support the presumption of risk to freshwater fish (acute and chronic 
76

exposure) and invertebrates (acute exposure), estuarine/marine fish and invertebrates (acute 

exposure), terrestrial invertebrates (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 (chronic exposure), marine/estuarine fish and invertebrates (chronic 

exposure), aquatic nonvascular plants, and terrestrial plants (listed species) could not be 

evaluated in this risk assessment due to the lack of submitted, acceptable, or sufficient toxicity 

data for these taxa. 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 data 

was not available for the other two required test organisms (cyanobacteria 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 ten test species (Tier II studies are 

needed for those species). More details on the risk conclusions 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 Aquatic-Phase Amphibians

As stated in the risk estimation section, the acute RQs for freshwater 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 20oC) in studies on the TGAI, the tested formulation, and the four 

environmental degradates of cyflufenamid. Toxicity 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. Overall, 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 EC50 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 dissolved fraction at the highest 

treatment level was no lower than aqueous solubility at 20o

C (0.52 mg ai/L) and thus toxicity 

(EC50) 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 listed species LOC would 
77

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 risk to freshwater invertebrates is not expected for the proposed 

uses. 

Marine/Estuarine Fish

No mortalities or sublethal effects were observed at the highest test concentration with the TGAI. 

The highest peak aquatic EEC (0.85 ug ai/L for the proposed uses) is 235 times lower than the 

LC50 (> 200 ug ai/L). Therefore, acute risk to estuarine/marine fish is not expected for the 

proposed uses. 

Marine/Estuarine Invertebrates

As stated in the risk estimation section, the acute RQs for estuarine/marine invertebrates based 

on toxicity to oysters do not exceed the acute LOC (listed and non-listed species) for any of the 

proposed uses. 

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 underestimated. Thus, there is the possibility that the mysid LC50 based 

on dissolved cyflufenamid is lower than the oyster EC50 based on dissolved cyflufenamid. For 

purposes of comparison and risk description it can be assumed that the mysid LC50 was not lower 

than the limit of aqueous solubility; however there is uncertainty about solubility under test 

conditions. Aqueous solubility was not reported for saltwater and while it was reported for 

freshwater, not at 25oC, the study temperature (0.52 mg ai/L at 20oC and 0.047 mg ai/L at 30oC). 

Although solubility in freshwater is expected to differ from saltwater (likely higher), it can be 

used as a rough estimate of solubility under test conditions. If the mysid LC50 based on the 

dissolved fraction was equal to the lower end of the solubility range (0.047 mg ai/L at 30oC), 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 30oC. For the proposed uses to exceed the 

acute listed species LOC (regardless of solubility), the mysid LC50 would need to be ≤ 0.017 mg 

ai/L, which is 97.3% lower than that based on total cyflufenamid (0.64 mg ai/L). Therefore, 

based on the weight of evidence, acute risk to estuarine/marine invertebrates is not expected for 

the proposed uses. 

 (2) Risk Following Chronic Exposure 

Freshwater Fish and Aquatic-Phase Amphibians

The NOAEC based on total cyflufenamid was 0.20 mg ai/L. Aqueous solubility at the study 

temperature, 25o

C, was not reported; however, aqueous solubility was reported as 0.52 mg ai/L 

at 20o

C and 0.047 mg ai/L at 30oC. Given that the test solution was not centrifuged or filtered 

when some of the test concentrations including the NOAEC may have exceeded solubility, 
78

exposure, toxicity, and risk is likely underestimated by total measured values. 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 30o

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 30oC. 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). Therefore, chronic risk to freshwater fish is 

not expected for the proposed uses. 

Freshwater Invertebrates

As stated previously, no acceptable chronic studies on freshwater invertebrates are available. 

Chronic risk to freshwater invertebrates cannot be precluded. 

 

Marine/Estuarine Fish

Also stated previously, no chronic ecotoxicity studies on estuarine/marine fish have been 

submitted to the Agency for review. No other information is available for marine/estuarine fish. 

Therefore, a quantitative estimation of risk cannot be conducted. Lack of studies does not 

preclude potential risk. 

Marine/Estuarine Invertebrates

As stated previously, no chronic 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 RQs for listed aquatic plants do not exceed the LOC 

for any of the proposed uses. Therefore, risk to listed freshwater vascular plants is not expected. 

RQs were not calculated for non-listed species because no effects were observed at the limit 

concentration (the EC50 is non-definitive). However, a comparison 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 incomplete so RQs were calculated based on available data. As 

stated in the risk estimation section, the RQs (based on toxicity to the freshwater diatom, 

Navicula) for listed aquatic plants do not exceed the LOC for any of the proposed uses. RQs 
79

were not calculated for non-listed species because no effects were observed at the limit 

concentration (the EC50 is non-definitive). However, a comparison 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 concentration (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 uncertainty about solubility under test conditions. 

Aqueous solubility was not reported for saltwater although it was reported for freshwater as 0.52 

mg ai/L at 20o

C. However, solubility in freshwater is expected to differ from saltwater 

(freshwater likely higher) and in the study it appears that 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 EC50, respectively, would need to be ≤ 0.849 ug ai/L, which 

is 99.68% lower than the NOAEC (0.273 mg ai/L) and EC50 (>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 estimated 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 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 and narrow 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 (agricultural use only) label states that a maximum of two 

applications per growing season may be applied to the proposed crops. Terrestrial exposures are 

estimated assuming that per season equals per year. 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 estimation section, avian dietary-based LD50s are greater than the highest 

concentrations tested in studies on bobwhite quail and zebra finch (1970 and 2000 mg ai/kg bw, 

respectively). The acute avian dose-based LC50s are greater than the highest 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 studies. Because the acute avian dose and dietary 
80

based studies resulted in non-definitive endpoints (i.e., no effects were seen at the highest doses 

tested), RQs were not estimated using these studies. However, a comparison of EECs to study 

effects may be used to evaluate potential risk. 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 exposures from the proposed uses, the available data indicate that 

acute risk to birds is not expected. 

Potential risk to piscivorous birds

Several characteristics of cyflufenamid indicate that it has the potential to accumulate in tissues 

of aquatic organisms. The log of the n-octanol/water partition (Kow) coefficient for cyflufenamid 

is 4.7. Substances with the log Kow higher than 4 are more likely to associate with fatty tissues 

and therefore have a high bioaccumulation potential. In both low-dose (1.0 μg ai/L) and highdose (1.0 μg ai/L) BCF studies cyflufenamid was shown to accumulate; however, ninety percent 

depuration occurs in approximately five days. Five cyflufenamid-based transformation products 

are observed in the bioaccumulation studies including one environmental degradate (149-F) and 

four metabolites. Structures are shown in Appendix B. 

As stated in the risk estimation section, RQs were 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 evaluate potential risk. The highest dose tested in each study 

produced no mortalities and is more than 2000 times greater than the highest dose-based EEC of 

0.907 mg ai/kg bw (sandpipers) and almost 3000 times 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 estimation section, the mammalian LD50s for the both the tested formulation 

(NF-149 10SC), technical cyflufenamid, 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 mortalities in these studies. RQs were not calculated because the 

acute studies resulted in non-definitive endpoints (i.e., no effects were 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 mammals 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 the 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 characterization 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-definitive endpoint from the formulation study. Risk is assessed for 

the four degradates given this uncertainty. Terrestrial EECs were calculated for the degradation 

products by multiplying the terrestrial cyflufenamid EECs for mammals by the molecular weight 
81

ratio (molecular weight of the degradate/molecular weight of the cyflufenamid) and then 

normalizing for the maximum percentage of degradation product formed. The acute LOC (listed 

and non-listed species) was not exceeded for any of the four environmental degradation products 

under any of the modeled exposure scenarios (RQs ≤ 0.002). 

Based on predicted terrestrial exposures from the proposed uses, the 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 effects 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/stereoisomer studies, respectively. 

As previously stated, RQs were calculated for the four environmental degradation products given 

that one or more may be more toxic than the tested formulation (on an ai basis). A screening 

level assessment was conducted using the highest dose-based EEC for piscivorous mammals 

(0.505 mg/kg-bw/d, based on total toxic residues and the Kow of cyflufenamid). This is a 

conservative approach because degradate EECs are likely 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 bioaccumulation potential of cyflufenamid and Kow

values indicate that cyflufenamid is more likely than the four degradates to bioaccumulate in 

aquatic organisms (Kow’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 modeled exposure scenarios (RQs ≤ 0.002). 

Based on predicted terrestrial exposures from the proposed uses, the available data indicate that 

acute risk to mammals is not expected. 

Terrestrial invertebrates

Cyflufenamid is classified as practically nontoxic to bees based on acute contact and oral toxicity 

testing with the TGAI and the tested formulation (NF-149 10SC). 

 (2) Risk Following Chronic Exposure 

Birds

In the bobwhite quail, multiple reproductive effects were observed at the highest administered 

dose (971 mg ai/kg diet), including reductions in 14-day survivors (28%), 14-day survivor 
82

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 quail study. Based on this analysis, the chronic 

avian RQs did not exceed the chronic LOC for any of the modeled exposure scenarios (RQs <

0.03). 

As stated in the risk estimation section, the chronic avian study on the mallard duck resulted in a 

non-definitive endpoint due to effects seen at the lowest administered dose. A relatively small 

but significant reduction in survivor 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 other adverse effects were 

seen at lowest dose tested in this study. However, reproductive effects were observed the mid 

and high treatment levels. The ratio of hatchling survivors to number hatched 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 hatchling 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 effects for the mallard duck study was 99 mg ai/kg. 

Based on effects seen at the lowest administered doses in the mallard duck reproduction study, a 

chronic NOAEC could not be identified. In the absence of a NOAEC, RQs cannot be calculated 

for this study. However, risks can be characterized 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 difference 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 conservative assumptions (e.g., use of the maximum single-day EEC, 

that birds feed exclusively on vegetation, and that birds feed exclusively on short grass, the 

vegetation producing the highest EECs). 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 effects 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 birds via consumption of fish contaminated with 

cyflufenamid was assessed because cyflufenamid has the potential to accumulate in tissues of 

aquatic organisms. RQs were not calculated because the mallard duck study did not produce a 

definitive endpoint and the NOAEC would be lower than that established for the bobwhite quail. 

However, a comparison of EECs to study effects may 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 chronic LOC is not exceeded on a dose or dietary basis 

for any mammalian exposure scenario. Therefore chronic risk to mammals is not expected from 

the proposed uses. 

Potential risk to piscivorous mammals

As previously stated, 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. The chronic LOC for mammals is not exceeded for any piscivorous 

mammals. Therefore, chronic risk 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 terrestrial 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 uncertainties regarding listed species due to a lack of establishing a 

NOAEC or EC05 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), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 
84

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors. 

Cyflufenamid is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/. 

 5. Federally Threatened and Endangered (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 continued existence of a 

listed species or result in the destruction or adverse modification of designated critical habitat. 

To jeopardize the continued existence of a listed species means "to engage in an action that 

reasonably would be expected, directly or indirectly, to reduce appreciably the likelihood of both 

the survival and recovery of a listed species in the wild by reducing the reproduction, numbers, 

or distribution of the species" (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 established procedures to evaluate whether a 

proposed registration action may directly or indirectly reduce appreciably the likelihood of both 

the survival and recovery of a listed species in the wild by reducing the reproduction, numbers, 

or distribution of any listed species (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 effects, an analysis is conducted to determine if any listed or candidate species 

may co-occur in the area of the proposed pesticide use or areas downstream or downwind that 

could be contaminated from drift or runoff/erosion. If listed or candidate species may be present 

in the proposed action areas, further biological assessment is undertaken. The extent to which 
85

listed species may be at risk then determines the need for the development of a more 

comprehensive consultation package as required by the Endangered 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 plants. Therefore, concerns regarding listed 

species within a taxonomic group are triggered in exposure situations where restricted use or 

acute risk LOCs are triggered for the same taxonomic group. The risk assessment also includes 

an evaluation of the potential probability of individual effects for exposures that may occur at the 

established endangered species LOC both in the risk characterization and the endangered species 

sections. This probability is calculated using the established dose/response relationship and 

assumes a probit (probability unit) dose/response relationship (USEPA, 2004b). This analysis is 

presented in Section IV.B.5.b(2) below. 

The federal action addressed herein is the Section 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 cranberries, pome fruit (crop subgroup 11), 

outdoor landscape and outdoor nursery ornamentals, 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 considered to be the area affected directly or 

indirectly by the Federal action and not merely the immediate area where cyflufenamid is 

applied. At the initial Level 1 screening assessment, broadly described taxonomic groups are 

considered, and thus, conservatively assumes that listed species within those broad groups are 

co-located with the pesticide treatment area. This means that terrestrial plants and wildlife are 

assumed to be located on or adjacent to the treated site and aquatic organisms are assumed to be 

located in a surface water body adjacent to the treated site. The assessment also assumes that 

listed species are located within the area of highest exposure to the pesticide, and that exposure 

will decrease with increasing distance from the treated area. 

If the assumptions associated with the screening-level action area result in RQs that are below 

the listed species LOCs, a "no effect" determination conclusion is made with respect to listed 

species in that taxa, and no further refinement of the action area is necessary. Furthermore, RQs 

below the listed species LOCs for a given taxonomic group indicate no concern for indirect 

effects upon listed species that depend upon the taxonomic group covered by the RQ as a 

resource. However, in situations where the screening assumptions lead to RQs in excess of the 

listed species LOCs for a given taxonomic 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 species 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 apply to a particular listed organism. These 
86

subsequent refinement steps could consider how this information would impact the action area 

for a particular listed organism and may potentially include areas 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 details). 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. 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). 

Concerns For Federally Listed as Endangered and/or Threatened Species

Table 41 summarizes the federally listed species (endangered and/or threatened) at risk 

associated with either direct or indirect effects following application of cyflufenamid for the 

proposed uses. 

Table 41. Listed Species Risks Associated With Direct or Indirect Effects from 

Cyflufenamid Use on Cucurbit Vegetables, Low Growing Berries, Pome Fruits, 

Ornamentals, and Small Climbing Fruit Vines1

Listed Taxon Direct Effects Indirect Effects

Terrestrial and semi-aquatic 

plants - monocots Yes2 No 

Terrestrial and semi-aquatic 

plants – dicots Yes3 No 

Terrestrial invertebrates No4 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 plants2,3,6,8

Terrestrial-phase amphibians 

No5 

Yes from effects to terrestrial and semi-aquatic 

plants (monocots and dicots), freshwater 

invertebrates, marine/estuarine fish and 

invertebrates, and aquatic non-vascular plants2,3,6,8

Reptiles 

No5 

Yes from effects to terrestrial and semi-aquatic 

plants (monocots and dicots), freshwater 

invertebrates, marine/estuarine fish and 

invertebrates and aquatic non-vascular plants2,3,6,8

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 plants2,3,6,8
87

Listed Taxon Direct Effects Indirect Effects

 Aquatic non-vascular plants Yes6 Yes from effects to freshwater invertebrates, 

marine/estuarine fish and invertebrates, and aquatic 

non-vascular plants6,8

Aquatic vascular plants 

No

Yes from effects to freshwater invertebrates, 

marine/estuarine fish and invertebrates, and aquatic 

non-vascular plants6,8

Freshwater fish No Yes from effects to freshwater invertebrates and 

aquatic non-vascular plants6,8

Aquatic-phase amphibians 

No7 

Yes from effects to freshwater invertebrates, 

marine/estuarine fish and invertebrates, and aquatic 

non-vascular plants6,8

Freshwater invertebrates No for acute, Yes for chronic8 Yes from effects to freshwater invertebrates and 

aquatic non-vascular plants6,8

Marine/estuarine fish No for acute, Yes for chronic8 Yes for marine/estuarine fish and invertebrates and 

aquatic non-vascular plants6,8

Marine/estuarine invertebrates No for acute, Yes for chronic8 Yes for marine/estuarine fish and invertebrates and 

aquatic non-vascular plants6,8

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 concentration 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 practically non-toxic to bees. 5

 Results from avian species used as surrogate for assessing risk to terrestrial-phase amphibians and reptiles. 6

 Acceptable/supplemental studies were available for two of the four algal species considered to fulfill guideline 

requirements. No direct effects are expected for the two species with acceptable/supplemental 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 quantitative risks to terrestrial 

invertebrates are not estimated, due to the low toxicity to honey bees, it is assumed that there will 

not be risk to beneficial terrestrial invertebrates. As previously stated, 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 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 LD50’s 

LC50’s were higher than the highest concentration tested and there were no mortalities in either 

study. Therefore, RQ’s were not calculated for these studies and probabilities of individual 

mortalities associated with RQs were not calculated. 

Mammals

No RQs were estimated for the acute studies in rats because the LD50s were higher than the 

highest concentrations tested in studies on the tested formulation (NF-149 10SC), technical 

cyflufenamid, and the stereoisomer (149-E-FB). There were no mortalities in these studies. 

Therefore, RQ’s were not calculated for these studies and probabilities of individual mortalities 

associated with RQs were not calculated. 

As stated in the effects characterization section, one or more the 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 formulation study. RQs were calculated given this uncertainty 

and because there were mortalities observed in all four studies with the degradation products. 

The probability is less than 1 in 1E+16 for an individual mortality associated with the maximum 

calculated RQ value (degradation product 149-F1 yielded the highest RQ) and a probit slope of 

12.2. The corresponding estimate chance of an individual 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, based 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 associated with the listed freshwater fish species LOC 

is 1 in 4.18E+08. 

Freshwater invertebrates

Individual effects probabilities were not calculated for freshwater invertebrates because acute 

endpoints were either non-definitive, based on total concentrations (dissolved plus undissolved 

cyflufenamid) instead of only dissolved concentrations, or both. 

Marine/Estuarine fish

Individual effects probabilities were not calculated because the acute estuarine/marine toxicity 

endpoint was non-definitive. 
89

Marine/Estuarine invertebrates

Individual effects probabilities were not calculated for estuarine/marine invertebrates because the 

mysid EC50 was based on total concentrations (dissolved 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 available 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 observed on body weight and food consumption in 

females at all levels and in males at the mid and high doses (effects were seen in the first week 

after treatment not in the second week). The LOAEL for bobwhite quail is 461 mg ai/kg, the 

lowest dose tested. A NOAEL could not be identified 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 LOAEL for the bobwhite quail and 107 times lower 

than the LOAEL for the zebra finch. Therefore, with the predicted terrestrial exposures from the 

proposed uses, it is unlikely that sublethal effects 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 seen at the LOAEC of 

1230 mg ai/kg bw. In the mallard duck dietary 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 effects will be observed in birds on 

a dietary-basis following acute exposure. 

For mammals, no sublethal effects were observed in the rat study conducted with the tested 

formulation (NF-149 10SC). In the rat study on technical cyflufenamid, some clinical signs were 

observed at both test concentrations (piloerection, hunched posture, and waddling/unsteady gait) 

while other effects were observed only at the highest test concentration (lethargy, abnormal 

respiration, pallid extremities, walking on toes, partially closed eyelids, increased salivation, 

increased sensitivity to touch, and ungroomed appearance). 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 the stereoisomer of cyflufenamid (149-E-FB). The highest 
90

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 observed in the acute rat 

toxicity studies on technical cyflufenamid and its stereoisomer (149-E-FB). In the rat studies on 

the four degradation products, piloerection was observed with recovery. The highest mammalian 

dose-based degradate EECs are at least 228 times lower than the lowest dose at which transient 

piloerection was observed in each degradation product 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 effects were observed at test concentrations below which mortality 

was observed. Of the available studies, the greatest toxicity was observed in the rainbow trout 

exposed to the TGAI. Effects included hyperventilation, coughing, darkened pigmentation, 

lethargy, nervous/erratic swimming behavior, and loss of coordination. 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 aquatic EEC (0.85 ug ai/L) is well below the NOAEC 

(200 ug ai/L). Therefore, it is unlikely that sublethal effects would be observed from the 

proposed uses. 

Sublethal effects were observed in the mysid 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 the 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 description for more details) but it is unknown if the 

estimate based on freshwater solubility is representative of that under test conditions (saltwater). 

Nonetheless, the NOAEC based on the dissolved fraction would need to be 99.6% lower than the 

NOAEC based on total cyflufenamid to equal the peak 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 gestation indices, pre-coital interval 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. The highest terrestrial dietary-based EEC (9.70 ppm) 

is 6 times lower than the dose at which sublethal effects were observed. Therefore, with the 

predicted terrestrial exposures from the proposed uses, it is unlikely that chronic 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 reductions in multiple reproductive endpoints at 

the highest treatment level. Observed reproductive effects include the reduced ratios of number 
91

hatched to eggs laid (13%), number 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. The NOAEC is 29 times higher than the highest 

terrestrial dietary-based EEC (9.88 ppm). 

As previously stated, the chronic mallard duck study 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 reductions were observed in the following reproduction parameters, hatchling 

survivors, 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 magnitude of the reductions generally increased with the age of the offspring (i.e., 

reductions in viable embryo-related 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 description for details), the relatively low effect on 

survivor body weight (5%) observed, and the fact that the lowest dose at which effects were seen 

is 10 times higher than the highest terrestrial dietary-based EEC, chronic risk to birds is not 

expected based on the mallard study. Consequently, based on both the mallard duck and 

bobwhite quail, it is unlikely that sublethal effects to birds will occur from 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), although it is based on total cyflufenamid and the 

NOAEC based on the dissolved fraction may be lower. Nonetheless, the NOAEC is still much 

higher than the EEC under the assumption that the dissolved fraction is no lower than the limit of 

aqueous solubility (estimated as 47 ug ai/L, see risk description section for details). Therefore, it 

is unlikely that sublethal effects would be observed from exposure to cyflufenamid for the 

proposed uses. 

 c. Indirect Effects Analysis 

In conducting a screen for indirect effects, direct effects LOCs for each taxonomic group are 

used to make inferences concerning the potential for indirect 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 effects. However, there may be situations where a taxonomic group is not 

quantitatively assessed (e.g., terrestrial 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 those 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 species 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 exposure 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 adverse effects from the comparison of dose response information with 

the EECs. The greater the probability that exposures will 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 information regarding the use scenario (e.g., timing, 

frequency, and geographical extent of pesticide application). The greatest concerns would exist 

when exposure is associated with a risk higher than 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 predicted for any taxonomic groups for which a complete 

dataset (all required species) 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, cabbage, 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/supplemental data was not available for the other two 

required test organisms (cyanobacteria and green algae). 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 those taxonomic groups (direct effects) or listed 

species that depend on those taxonomic groups (indirect effects). 

 d. Critical Habitat 

In the evaluation of pesticide effects on designated critical habitat, consideration is given to the 

physical and biological features (constituent elements) of a critical habitat identified by the U.S 

Fish and Wildlife and National Marine Fisheries Services as essential to the conservation of a 

listed species and which may require special management considerations or protection. The 

evaluation of impacts for a screening level pesticide risk assessment focuses on the biological 

features that are constituent elements and is accomplished using the screening-level taxonomic 

analysis RQs and LOCs that are used to evaluate direct and indirect effects to listed organisms. 

Based on the available data, this screening-level risk assessment has not identified potential 

concerns for indirect effects on listed species. However, there is uncertainty regarding taxa for 

which data is not available or is available but is insufficient for assessing risk. Thus there is 
93

uncertainty and risk is presumed for listed organism’s dependant upon freshwater invertebrates, 

estuarine/marine fish and invertebrates, nonvascular plants, and terrestrial 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 habitat are potentially implicated. Analytically, the identification of 

such species and critical habitat can occur in either of two ways. First, the agencies could 

determine whether the action area overlaps critical habitat or the occupied range of any listed 

species. If so, EPA would examine whether the pesticide's potential impacts on non-endangered 

species would affect the listed species indirectly or directly 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 into, the taxa that may be directly or 

indirectly impacted by the pesticide. Then EPA would determine whether use of the pesticide 

overlaps the critical habitat or the occupied range of those listed 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. EPA and the Service(s) are working 

together to conduct the necessary analysis. 

This screening-level risk assessment for critical habitat provides a listing of potential biological 

features that, if they are constituent elements of one or more critical habitats, would be of 

potential concern. These correspond to the taxonomic groups identified above as being of 

potential concern for indirect effects (terrestrial and semi-aquatic plants (monocots and dicots), 

freshwater invertebrates, marine/estuarine fish and invertebrates, and aquatic non-vascular 

plants). This should serve as an initial step in problem formulation 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 sites of pesticide use are 

geographically associated with known 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 level of resolution. The product is a listing of federally listed 

species that are located within counties known to produce the crop 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, 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, 

cabbage, soybean, and tomato) so risk cannot be precluded for those taxonomic groups. Should 

that data become available and suggest a potential 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 registrant may be asked to provide information on the 

proximity of Federally listed species within those taxonomic groups. This may be satisfied in one 

of three ways: 1) having membership in the FIFRA Endangered Species Task Force (Pesticide 
94

Registration [PR] Notice 2000-2); 2) citing FIFRA Endangered Species 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 avoid adverse effects to listed species. 

C. Description of Assumptions, Limitations, 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 characterizing potential ecological risks resulting 

from a maximum use scenario, which is determined from labeled statements of maximum 

application rate and number of applications with the shortest time interval between applications. 

The frequency at which actual uses approach this 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 season. 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. Acceptable 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 study 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 addition, no chronic toxicity data 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 cyflufenamid residues. Calculating EECs for total 

toxic cyflufenamid residues provides conservative 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 only) would not have altered 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 assessment, a generic bird or mammal was assumed to 

occupy either the treated field or adjacent areas receiving cyflufenamid at the treatment rate on 

the field. Actual habitat requirements of any particular terrestrial species were not considered, 

and it was assumed that species occupy, exclusively and permanently, the modeled treatment 

area

 b. Routes of Exposure 

This screening-level assessment for ground and aerial spray applications of cyflufenamid only 

considered 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. 

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 depending 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 sources: (1) spray material in droplet form 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 dermal exposure. Dermal exposure may occur 

through three potential sources: (1) direct application of spray to terrestrial wildlife in the treated 

area or within the drift footprint, (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 pesticide- active ingredient may be the result of 

consumption of surface water, ground water or consumption 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 pesticide end-use product there is a potential 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 subacute dietary study each have limitations for 

estimating the risk to wild species exposed to pesticides in the environment. Both studies have a 

fixed exposure period and do not allow for differences in the responses of individuals 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 environmental matrices on absorption rate into the gastrointestinal tract of 

the animal. With the acute dietary study, the endpoint 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, calculations of the mg/kg/day are confounded by 

undocumented spillage of feed and how consumption 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 consumption estimates can be further confounded 

if birds die within a treatment group. In addition, the dietary study utilizes young birds. The 

exponential growth of young birds complicates the estimate of the dose; controls often nearly 

double in size over the duration of the test. Since 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 confounded by dietary consumption. 

Estimation of the acute LC50 value is not only a function of the intrinsic toxicity of the pesticide, 

but also the willingness of the birds to consume treated food. 

In addition to the uncertainties associated with the two toxicity studies utilized for estimating 

acute risk to birds, other factors, not normally taken into account in a screening level risk 

assessment may narrow the differences between the 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 maintenance metabolic rates between wild birds and 

captive birds, seasonal free living dietary requirements for wild birds (including gorging 

behavior) and specific food avoidance behavior. These uncertainties may either overestimate or 

underestimate the risk in a screening level assessment. 

Gross Energy and Assimilative Efficiency

This screening level risk assessment does not allow for gross energy and assimilative efficiency 

differences between wildlife food items and laboratory feed. For example, a typical laboratory 

avian feed, as used, contains approximately 2750 kcal/ kg. The Agency’s Wildlife Exposure 
97

Factors Handbook (USEPA, 1993) presents the following 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 comparison of a laboratory dietary concentration-based 

effects threshold to a fresh-weight pesticide residue estimate would 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 matrix, 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 assimilative efficiency (e.g., a value of 85%), a 

potential for underestimation of exposure may exist 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 underestimated 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 passerine 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 wild when comparing dietary residues to dietary 

toxicity thresholds represents about a two-fold underestimation in exposure potential.

Free Living Metabolic Requirements 

The screening procedure does not account for situations where the feeding rate may be above or 

below requirements to meet free living metabolic requirements. Gorging behavior is a 

possibility under some specific wildlife scenarios (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, operationally defined as animals responding to the 

presence of noxious chemicals in their food by reducing consumption of treated dietary elements. 

This response is seen in nature where herbivores avoid plant secondary compounds. For 

agrochemicals, Dolbeer et al. (1994) reported that the use of methiocarb 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 equipment, 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 assumptions 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 possible that much of these data reflects residues averaged over the 

entire above ground plants in the case of grass and forage sampling. Depending upon a specific 

wildlife species’ foraging habits, whole aboveground plant samples may either underestimate or 

overestimate actual exposure. 

 f. Terrestrial Exposure Model 

MILTREX® 10 SC FUNGICIDE (the agricultural use only label) allows for two cyflufenamid 

applications per growing season. Risk was assessed assuming that one growing season is 

equivalent to one year; therefore, two cyflufenamid applications per season is assumed to be 

equivalent to the maximum number of applications per year. 
99

4. Assumptions, Limitations and Uncertainties Related to Effects 

Assessment 

a. Data Gaps of Requirements for 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 marine/estuarine fish and invertebrates. Acceptable data are not 

available for two taxa of aquatic nonvascular plants (green algae and cyanobacteria) and chronic 

toxicity to freshwater invertebrates. 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 regarding >25% inhibitions to tomato dry weight and 

cabbage emergence and uncertainties regarding listed species due to a lack of establishing a 

NOAEC or EC05 for all four plants. Finally, physical properties of cyflufenamid indicate that it 

may partition to soil and persist, thus chronic invertebrate whole sediment studies (two 

freshwater and one marine/estuarine species) are needed to address risk to benthic invertebrates 

from exposure to cyflufenamid. 

End-Use Product Toxicity

No ecotoxicity data have been submitted on the formulation proposed for registration in the 

United States except for studies on mammals (acute), freshwater fish (acute), freshwater 

invertebrates (acute), terrestrial invertebrates (acute), and terrestrial plants (tier I). Lack of 

formulation data adds uncertainty to the assessment. 

Ecotoxicity Studies for Environmental Degradation Products

Acute ecotoxicity data on the four environmental degradation products (149-F, 149-F1, 149-F6, 

and 149-F11) is available for freshwater fish and 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 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 TGAI was not submitted on the same species. In contrast to aquatic organisms, studies on 

mammals indicate that all four environmental degradates 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 formulation NF-149 10SC. No inferences about toxicity to 

birds can be made from the mode of action since it is unknown. However, the toxicity to birds 

can be calculated at which the LOC would be exceeded for the proposed uses after the terrestrial 

cyflufenamid EECs are corrected for the individual degradation products concentrations. This 

was done by multiplying the terrestrial cyflufenamid EECs by the molecular weight ratio 

(molecular weight of the degradate/molecular weight of the cyflufenamid) and then normalizing 

for the maximum percentage of degradation product formed. The degradation product 149-F 
100

would need to be at least 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 

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, the screening risk assessment relies on the acute mortality endpoint 

as well as a suite of sublethal responses to the pesticide, as determined by the testing of species 

response to chronic exposure conditions and subsequent chronic risk assessment. Consideration 

of additional sublethal data in the assessment is exercised on a case-by-case basis and only after 

careful consideration of the nature of the sublethal effect measured and the extent and quality of 

available data to support establishing a plausible relationship between the measure of effect 

(sublethal endpoint) and the 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 risk 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 function of the overall variability among 

species to a particular chemical. Toxicity thresholds may vary up to four orders of magnitude 

across species for some chemicals (Mayer and Ellersieck, 1986). Therefore, risk conclusions 

may under- or overestimate actual ecological 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 assessment 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 estimate 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 generate a probability of individual effects near 

the low end tail of the curve. Predictions based 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-response 
101

relationship does not represent the response of all species within 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 which this captures the variability within taxa is 

unknown. In some cases, a probit dose-response relationship 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 Toxicology and Chemistry, v23 (10), 2343-2355. 

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

Burns, L. A. 2002. EXAMS (Exposure Analysis Modeling System) 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. Environmental 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 instrument for estimating pesticide residues on 

plants. Environ. Tox. and Chem. 13(9):1383-1391. 

Hoerger, F. and E.E. Kenaga. 1972. Pesticide residues on plants: correlation of representative 

data as a basis for estimation of their magnitude in the environment. IN: F. Coulston and 

F. Corte, eds., Environmental Quality and Safety: Chemistry, Toxicology and 

Technology. Vol 1. George Theime Publishers, Stuttgart, Germany. pp. 9-28. 

Kirkwood JK. 1983. Minireview. A limit to metabolisable 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 Interior, Washington, D.C., 579 p. 

Nisso. 2009. Cyflufenamid IR-4 food use workshop Rutgers, The State University of New 

Jersey, http://ir4.rutgers.edu/FoodUse/FUWorkshop/Industry%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 Handbook. Office of Research and Development, 

Washington, D.C. EPA/600/R-13/187a. 

USEPA. 1998. Guidelines for Ecological Risk Assessment. Risk Assessment Forum, Office of 

Research and Development, Washington, D.C. EPA/630/R-95/002F. April 1998. 

USEPA, 2009. Guidance for Selecting Input Parameters in Modeling the 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 Agency. 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 spreadsheet tool IECV1.1 (Individual Effect 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 EXposure 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 SuiteTM v4.0. United States Environmental Protection Agency. Available for 

download at: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm. 

Urban, D.J. and N.J. Cook. 1986. Hazard Evaluation Division Standard Evaluation Procedure 

Ecological Risk Assessment. EPA 540/9-85-001. U.S. Environmental Protection 

Agency, Office of Pesticide Programs, Washington, DC. 

Willis, G.H. and L.L. McDowell. 1987. Pesticide persistance on foliage. Environ. Contam. 

Toxicol. 100:23-73. 

VI. Appendices 

 A. Environmental Fate and Effects Study Bibliography 

B. Chemical Structures of Cyflufenamid and Its Transformation Products 

 C. Ecological Effects Data 

 D. PRZM/EXAMS Results 

 E. KABAM Results 

 F. Risk Quotient Method and Levels of Concern