Proposed Unconditional Registration of the New active 

ingredient Cyflumetofen for foliar application 

on Citrus (Crop Group 10-10), Pome Fruits

(Crop Group 11-10), Grapes, Strawberries, 

Tomatoes, Tree Nuts (Crop Group 14-12) and 

Ornamentals

U.S. Environmental Protection Agency

Office of Pesticide Programs

Registration Division
2

Proposed Unconditional Registration

of the New Active Ingredient Cyflumetofen

for foliar application on Citrus

(Crop Group 10-10), Pome Fruits

(Crop Group 11-10), Grapes,

Strawberries, Tomatoes,

Tree Nuts (Crop Group 14-12)

and Ornamentals

Approved by: _____________________

Lois Rossi, Director

Registration Division

Office of Pesticide Programs

Date: ______________________
3

Proposed Unconditional Registration of the New Active Ingredient Cyflumetofen for foliar 

application on tree nuts (crop group 14-12), pome fruits (crop group 11-10), citrus (crop 

group 10-10), grapes, strawberries, tomatoes and ornamentals

REGULATORY PROPOSAL

The U.S. Environmental Protection Agency referred to thereafter as EPA or the Agency, is 

proposing to grant the registrations for pesticide products containing the new active ingredient, 

cyflumetofen, a miticide formulated as a technical and two end use products. Cyflumetofen 

belongs to the acrylonitrile class of chemicals and is a selective contact miticide that is effective 

on all mite life stages. The proposed use sites for cyflumetofen are tree nuts (crop group 14-12), 

pome fruits (crop group 11-10), citrus (crop group 10-10), grapes, strawberries, tomatoes and 

ornamentals. 

Cyflumetofen is currently registered in Japan, Korea, Brazil, and in the European Union 

(ornamentals). The present action was conducted as a joint review with Health Canada’s 

Pesticide Management Regulatory Authority (PMRA) and Mexico’s Federal Commission for the 

Protection against Sanitary Risk (COFEPRIS).

Three miticide products are under consideration, one technical and two end-use products 

(SultanTM and NealtaTM). Sultan is intended for use on ornamentals and NealtaTM for use on tree 

nuts, pome fruits, citrus, grapes, strawberries, and tomatoes. 

I. CHEMICAL INFORMATION

Chemical Name: Cyflumetofen (2-methoxyethyl α-cyano-α-[4-(1,1-dimethylethyl)phenyl]-βoxo-2-(trifluoromethyl)benzenepropanoate).

EPA PC Code: 138831

Chemical Abstracts Service (CAS) Number: 400882-07-7

Mode of Action: Cyflumetofen is a non-systemic, contact miticide that provides knockdown and 

residual control of tetranychid mites. It has a novel insecticidal mode of action and acts as a 

mitochondria complex II electron transport inhibitor resulting in knockdown and residual control 

of the egg, nymph, and adult stages of tetranychid mites.

Registrant: BASF Corporation

Proposed Products: Cyflumetofen is proposed for registration as a technical product, and two 

end use products (Sultan and Nealta). 

The end-use products, formulated as suspension concentrates are to be applied as a foliar spray

up via ground equipment. Aerial applications are proposed for tomatoes only. The proposed 

maximum single application rate and maximum application rate per crop cycle or year are 0.2 lb 

a.i. /A and 0.4 lb a.i. /A, respectively, corresponding to a maximum of 2 applications per crop 

cycle or year. The proposed minimum application interval is 14 days.
4

II. HUMAN HEALTH RISK

A summary of the human health effects and risk of cyflumetofen as assessed in the Agency

document entitled “Cyflumetofen. New Active Ingredient Human Health Risk Assessment to 

Support Uses on Citrus (Crop Group 10-10), Pome Fruits Crop Group 11-10), Tree Nuts (Crop 

Group 14-12), Grape, Strawberry, and Tomato” is provided below.

A. Summary of Toxicological Effects

The toxicological database for cyflumetofen is considered complete. A subchronic inhalation 

study was not available; however, the Agency determined that the requirement for this study is 

not needed at this time. The major target organ in rats, mice, and dogs following short-term and 

long-term oral administration of cyflumetofen is the adrenal glands characterized by increased 

organ weight and histopathology (vacuolation and hypertrophy of the adrenal cortical cells). 

Cyflumetofen has low acute toxicity by oral, dermal, and inhalation routes of exposure. It is 

minimally irritating to the eyes but not to the skin. It is a skin sensitizer. Decreased serum 

hormone concentrations (FSH, progesterone, and 17 β-estradiol) were observed in the mid- and 

high-dose F1 females in a rat reproduction study while no hormonal effect was observed in the F1

male rats at any dose level. However, there were no corresponding changes in reproductive 

performance at any dose level. In the developmental toxicity study in rats, an increased 

incidence of wavy ribs was noted at the high- dose (1000 mg/kg/day), while an increased 

incidence of incompletely ossified sternal centra was observed at the mid- and high-dose levels. 

These incidences occurred in the presence of maternal toxicity; no skeletal malformations were 

noted. In the developmental toxicity study in rabbits, a downward flexion of the forepaws and/or 

hind paws was observed in the high-dose (1000 mg/kg/day) group pups and delays in skeletal 

ossification were observed in pups at the mid- and high-doses. Maternal toxicity (adrenal 

effects) was also observed at the mid- and high- doses. No evidence of neurotoxicity or 

immunotoxicity was observed in any of the submitted studies for cyflumetofen.

No acute reference dose (aRfD) was established to assess acute dietary risks since there was no 

evidence of toxicity attributable to a single dose for the general U.S. population, infants and 

children, or females 13-49 years of age in any studies. For the chronic dietary risk assessment, a 

chronic reference dose (cRfD) of 0.17 mg/kg/day was established for assessments of all 

populations, with a no observed adverse effect level (NOAEL) of 16.5 mg/kg/day and a lowest 

observed adverse effect level (LOAEL) of 30.6 mg/kg/day based on effects on the adrenals 

(increased organ weight and histopathology), which is the target organ. Three rat studies (90-day

subchronic, chronic toxicity/carcinogenicity, and reproduction studies) were selected as cocritical studies for the chronic dietary endpoint. These studies are appropriate for the duration 

and populations of concern since there is no progression of toxicity over time. No dermal hazard 

was identified for cyflumetofen. For short- and intermediate-term inhalation exposure, the 

NOAEL of 16.5 mg/kg/day with a LOAEL of 30.6 mg/kg/day based on effects on the adrenals

was selected from the same co-critical studies chosen for the chronic reference dose. 

The risk assessments conducted for cyflumetofen were based on the most sensitive endpoints in 

the toxicity database, and the NOAELs selected for risk assessment are considered protective of 

potential developmental, neurotoxic, and immunotoxic effects for infants and children. There is 
5

no evidence of increased qualitative or quantitative susceptibility in the developmental rat study

or in the rat 2-generation reproduction study. In the rabbit developmental toxicity study, a lower 

NOAEL was observed for the developmental effects compared to maternal effects. However, 

the developmental effects have clearly defined NOAEL/LOAELs and NOAEL for such effects is 

more than 10-fold higher than the PODs. Therefore, the PODs based on adrenal effects in rat are 

health protective of all lifestages. There is no evidence of neurotoxicity in any of the submitted 

studies for cyflumetofen.

The mutagenic potential of cyflumetofen, its metabolites, and an impurity was tested in in vitro

and in vivo studies. There was no concern for mutagenicity for the parent, the metabolites or the 

impurity. Consequently, mutagenicity can be ruled out as a possible mode of action for tumor 

formation. 

In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

the Cancer Assessment Review Committee (CARC) classified cyflumetofen as “Suggestive 

Evidence of Carcinogenic Potential”. This classification is based on the presence of a single 

tumor type (thyroid c-cell) in one sex (male) and one species (rat), and the lack of concern for 

mutagenicity. When there is suggestive evidence of carcinogenicity, the Agency does not attempt 

a dose-response assessment as the nature of the data generally would not support one. Therefore, 

the Agency has determined that quantification of risk using a non-linear approach (i.e. the 

chronic reference dose) will adequately protect for all chronic toxicity, including carcinogenicity, 

likely to result from exposure to cyflumetofen.

B. Food Quality Protection Act (FQPA) Safety Factor

EPA has determined that reliable data show that the safety of infants and children would be 

adequately protected if the FQPA safety factor (SF) were reduced to 1x for all exposure 

scenarios. That decision is based on the following findings:

 The toxicity database for cyflumetofen is complete. 

 There is no evidence of increased pre- and/or postnatal susceptibility for cyflumetofen. 

 No evidence of Immunotoxicity.

 There is no evidence of increased qualitative or quantitative susceptibility in the 

developmental rat and rabbit studies or in the rat 2-generation reproduction study. These 

studies have clearly defined NOAEL/LOAELs. There is no evidence of neurotoxicity in 

the acute and subchronic neurotoxicity studies for cyflumetofen, and a developmental 

neurotoxicity study is not required. 

 There are no residual uncertainties in the exposure database. Since the dietary and 

residential exposure estimates were based on conservative assumptions, EPA is confident 

that this assessment does not underestimate dietary (food and water) or residential 

exposure. 
6

 The chronic dietary exposure assessment used tolerance level residues for all 

commodities, 100% crop treated (% CT), and empirical processing estimates when 

available or DEEMTM default processing factors. The drinking water assessment utilized 

water concentration values generated by models and associated modeling parameters 

which are designed to produce conservative, health protective, high-end estimates of 

water concentrations which are not likely to be exceeded. For these reasons it can be 

concluded that the chronic dietary exposure analysis does not underestimate risk from 

chronic exposure to cyflumetofen. Similarly, EPA does not believe that the residential 

exposure estimates are underestimated because they are also based on conservative 

assumptions including maximum application rates and standard values for unit exposures, 

acreage treated/amount handled. Based on the use of conservative assumptions with 

respect to potential exposure from food, water and residential uses, the assessment will 

not underestimate children’s exposure to cyflumetofen. 

C. Cumulative Effects

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to cyflumetofen and any other substances and cyflumetofen does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that cyflumetofen has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 

D. Aggregate Risk Assessment

1. Dietary (Food + Drinking Water) Risk:

A chronic aggregate dietary food and drinking water exposure and risk assessment was

conducted using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database DEEM-FCIDTM (Version 3.16). This software uses 2003-2008 food 

consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and 

Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). 

Acute Dietary Risk: No acute dietary exposure and risk analysis was performed since there were 

no appropriate studies identified in the toxicology database that demonstrated evidence of

toxicity attributable to a single dose.

Chronic Dietary Risk: A partially refined chronic analysis was conducted that was based on 

tolerance-level residues, 100% crop treated (%CT) assumptions, and both empirically derived 

and default processing factors. Using assumptions considered to be highly conservative, EPA 

has concluded that chronic risk estimates from exposure to cyflumetofen are below EPA’s level 

of concern (<100% of the chronic population adjusted dose (cPAD)), and range from <1% of the 
7

cPAD for the general U.S. population to 2.3% of the cPAD for the highest exposed population 

subgroup of children 1-2 years old.

2. Residential Risk:

The proposed uses of cyflumetofen on ornamentals (i.e., residential settings), may result in adult 

residential handler and post-application exposure. This exposure is expected to be only shortterm in duration (i.e., 1 to 30 days) as intermediate- or long-term exposures are not likely based 

on the intermittent nature of applications by homeowners. Since no dermal hazard was identified 

for cyflumetofen in the toxicological database, only inhalation exposure assessments were 

conducted. The resulting inhalation margins of exposure (MOEs) for all scenarios are not of 

concern since they are above the level of concern (LOC) of 100 (MOEs ≥ 100). 

E. Occupational Risk Assessment

1. Handler Exposure and Risk: 

The occupational exposure and risk assessment addresses risks to workers exposed in an 

occupational setting via the dermal and inhalation routes of exposure. Since no acute points of 

departure are identified, an acute aggregate risk assessment was not conducted. EPA has 

conducted short-term and long-term (chronic) aggregate risk assessments for cyflumetofen. 

Short-term aggregate MOEs are above the LOC of 100 and are not of concern (MOEs ≥ 100). 

The long-term (chronic) aggregate assessment includes only dietary (food and water) exposure as 

long-term residential exposure is not expected. 

2. Occupational Post-Application Exposure and Risk: 

“Post-application” means exposures that occur when individuals are present in an environment 

that has been previously treated with a pesticide (also referred to as re-entry exposure). Such 

exposures may occur when workers enter previously treated areas to perform job functions, 

including activities related to crop production, such as scouting for pests or harvesting. Based on 

the proposed use pattern of cyflumetofen, short- and intermediate-term exposures are anticipated 

for handlers for the following reasons: (1) the product can be applied twice per season (2) the 

product can be applied to multiple application sites, (3) there may be a large agribusiness and/or 

commercial applicators who may apply a product over a period of weeks, and (4) repeated use of 

miticides with similar modes of action can lead to build up therefore rotating miticides with 

different modes of action reduces the potential for developing mite resistance. Long-term

exposure is not expected for the proposed use patterns.

No dermal hazard has been identified for cyflumetofen; therefore occupational handler and postapplication risks were assessed for the inhalation route of exposure only. All estimated shortand intermediate-term handler inhalation risk estimates are above the Agency’s level of concern

(MOEs ≥ 100). Based on the Agency's current practices, a quantitative post-application 

inhalation exposure assessment was not performed for cyflumetofen.
8

III. ENVIRONMENTAL RISK

A summary of the environmental fate and ecological effects and risks of cyflumetofen as 

assessed in the Agency document entitled “Cyflumetofen: New Chemical Ecological Risk 

Assessment for Section 3 New Use on Citrus, Pome Fruits, Grapes, Strawberries, Tomatoes, 

Tree Nuts, and Ornamentals” is provided below.

A. Environmental Fate

1. Persistence:

Cyflumetofen is not persistent in the environment and rapidly converts to degradates via abiotic 

hydrolysis reactions (DT50 = 9.75 hours at pH 7) and biotic reactions with (DT50 of less than 21 

days). Many of the degradates (e.g., A-2, A-18, AB-1, and B-1) are much more persistent than 

the parent.

For comparison, cyflumetofen has a comparatively low water solubility of 0.0277 mg/L at 20oC 

and Koc of 131,826 L/kg-organic carbon. Only degradates AB-11, AB-12, AB-1 dimer, AU16 

(dimer), and AU17 (dimer) are predicted to have lower water solubility than the parent. 

Similarly, only degradates AB-12, AB-1 dimer, and AU17 (dimer) are predicted to have higher 

Kocs than the parent. Therefore, the vast majority of the degradates are expected to be more 

mobile than the parent. 

2. Mobility: 

Since cyflumetofen is used by foliar application, residues may be deposited into soil via wash off

from rainfall or irrigation activities as well as directly deposited onto soil during the application. 

Cyflumetofen appears to be non-volatile. This is supported by its water solubility (0.0277 mg/L 

at 20oC) and low vapor pressure (< 4.43 × 10-8torr at 25oC) and Henry’s Law constant (< 9.3 × 

10-7Pa*m3/mol at 20oC).

3. Bioaccumulation: 

The measured BCF (bio-accumulation in fish) is approximately 200× in whole fish (other tissues 

were not measured separately) based on TRR (total radioactive residues). The BCF study is 

somewhat problematic in that the TRR were still increasing at the end of the accumulation phase. 

The identity of radioactivity measured in the BCF study was not determined in the fish BCF 

study. Therefore, it is unknown whether it is parent, degradate(s), or some combination of parent 

and degradate(s) that is accumulating in the fish. However, the rate of accumulation appears to 

slow over the 21 day accumulation phase with concentrations only doubling from day 1 

(approximately 100×) to day 21 (approximately 200×). Therefore, given the high metabolism of 

Cyflumetofen evident in fish and high depuration rates of degradates, bioaccumulation in fish 

resulting from Cyflumetofen pesticide applications is not a concern. 
9

B. Ecological Risk

Ecological risk characterization integrates the results of the exposure and ecotoxicity data to 

evaluate the likelihood of adverse ecological effects. The means of integrating the results of 

exposure and ecotoxicity data is called the risk quotient method. For this method, risk quotients 

(RQs) are calculated by dividing exposure estimates by ecotoxicity values, both acute and 

chronic (RQ = Exposure/Toxicity). RQs are then compared to EPA's levels of concern (LOCs). 

The LOCs are criteria used by the Agency to indicate potential risk to non-target organisms. The 

criteria indicate whether a pesticide, when used as directed, has the potential to cause adverse 

effects to non-target organisms. The ecological risk profile is described in detail below.

1. Aquatic Organisms

Risk to Fish (Freshwater): The acute RQs calculated for freshwater fish represent risk based on 

the conservative assumption that the collective toxicity of parent cyflumetofen and all degradates 

are equivalent to the toxicity of the most toxic chemical among the parent and degradates for 

which data is available (i.e., degradate A-2). Even under this conservative assumption, acute 

aquatic animal LOCs (>0.05) were not exceeded for freshwater fish regardless of use suggesting 

that the likelihood of adverse effects to freshwater fish from acute exposure as a result of the 

proposed uses of cyflumetofen is low. 

 

It should be noted that the freshwater fish acute toxicity study with A-2 yielded a NOAEC of 

<5.04 mg a.i./L. This NOAEC is based on sublethal effects including unbalanced swimming, 

faulty respiratory function, loss of equilibrium, and non-typical pigmentation observed at the 

lowest concentration tested. Overall, the likelihood of adverse effects to freshwater fish from 

acute exposure to A-2 is considered low because: 1) acute RQs calculated using the LC50

endpoint did not exceed LOCs; 2) no sublethal effects were observed in fish acute toxicity

studies with parent cyflumetofen where the organisms were presumably exposed to A-2 as a 

result of rapid hydrolysis, and 3) TTR surface water EECs, which represent parent cyflumetofen 

and multiple degradates including A-2, are at least 3 orders of magnitude less than the observed 

NOAEC for A-2. 

The aquatic chronic LOC (=1) conducted using both parent and degradates, is not exceeded for 

freshwater fish regardless of use, suggesting that the likelihood of adverse effects to freshwater 

fish from chronic exposure as a result the proposed uses of cyflumetofen is low.

Risk to Aquatic Invertebrates (Freshwater): Similar to fish, aquatic invertebrate acute and 

chronic toxicity studies with technical grade cyflumetofen were conducted as limit tests because 

of the low solubility of cyflumetofen (i.e., 28.1 μg/L at 20°C). Mean-measured concentrations of 

17.2 and 16.2 μg a.i./L for Daphnia magna (acute and chronic tests, respectively), 6.30 μg a.i./L 

for Eastern oyster and 22.7 μg a.i./L for mysid shrimp were achieved using a saturator column 

and flow-through exposure. An acute toxicity study with Daphnia magna was also conducted 

with a 20.4% formulation of cyflumetofen which results in a mean-measured concentration of 

744 μg a.i. /L. 
10

Based on studies with daphnids, Eastern oyster, and mysid shrimp, technical grade cyflumetofen 

is practically non-toxic to aquatic freshwater invertebrates up to the tested solubility limit on an 

acute basis.

Daphnia toxicity tests were conducted with cyflumetofen degradates A-2, B-1, and B-2; tests 

with the latter two degradates were limit tests. A-2 is slightly toxic to freshwater invertebrates 

with an EC50 of 10.52 mg a.i. /L; B-1 is practically non-toxic to freshwater invertebrates with an 

EC50 of >177 mg a.i./L; and B-2 is practically non-toxic up to the limit concentration (i.e., 0.020 

mg a.i./L. The NOAEC for the study with A-2 was set at 3.83 mg a.i. /L based on immobility

observed at higher concentrations. In the studies with B-1 and B-2, since there was no 

statistically-significant immobility, the NOAEC was set at the highest treatment concentration 

(i.e., 177.5 mg a.i. /L and 0.020 mg a.i. /L, respectively).

The aquatic chronic LOC (=1) conducted using both parent and degradates, is not exceeded for 

aquatic freshwater invertebrates regardless of use, suggesting that the likelihood of adverse 

effects to freshwater fish from chronic exposure as a result the proposed uses of cyflumetofen is 

low.

Risk to Aquatic Invertebrates (Estuarine/marine): Estuarine/marine fish and invertebrate RQs 

were not calculated because of the lack of appropriate toxicity endpoints. Based on a 

comparison of acute toxicity endpoints between freshwater and estuarine/marine organisms, 

there is no indication that estuarine/marine fish/invertebrates are more sensitive to parent 

cyflumetofen than freshwater fish/invertebrates. In addition, estuarine/marine fish/invertebrates 

would have to be several orders of magnitude more sensitive than freshwater fish/invertebrates to 

the most toxic degradate tested, A-2, to exceed Agency LOCs suggesting that the likelihood of 

adverse effects to estuarine/marine fish and invertebrates as a result of the proposed uses of 

cyflumetofen is low.

Risks to Aquatic Plants: Aquatic plant Tier II studies were conducted with technical grade 

cyflumetofen. In addition, a Tier I green algal study was conducted with a 20.4% formulation of 

cyflumetofen. Toxicity endpoints for studies testing technical grade cyflumetofen are based on 

initial-measured concentrations because the rapid hydrolysis of cyflumetofen typically resulted 

in concentrations that were below the level of detection or quantification at study termination. 

No effects were noted in any of the aquatic plant studies.

Toxicity tests with the green alga Pseudokirchneriella subcapitata were conducted with the 

cyflumetofen degradates AB-11 and B-1. There were no effects in the limit test with AB-11. In 

the test with B-1, the EC50 was non-definitive (i.e., >102.7 mg a.i. /L), and there was no NOAEC 

(i.e., <0.10 mg a.i. /L) due to statistically-significant effects at the lowest treatment 

concentration. However, there is uncertainty associated with the latter study because of the lack 

of a clear concentration-response relationship.

Risks to Benthic Invertebrates: The aquatic acute and chronic LOCs were calculated using 

parent and degradates. LOCs (>0.05 and 1, respectively) are not exceeded for sedimentdwelling (benthic) invertebrates regardless of use suggesting that the likelihood of adverse 
11

effects to benthic invertebrates from acute or chronic exposure to cyflumetofen for all proposed 

uses is low. 

Chronic spiked sediment tests with Chironomus riparius were conducted with degradates AB-1 

and AB-1 dimer. Endpoints in the test with AB-1 were based on reduced emergence rates with 

NOAECs of 36.1 mg a.i./kg-dw, 34.2 mg a.i. /L, and 9.06 mg a.i. /L for sediment, pore water, 

and overlying water. There were no statistically-significant effects on rates of emergence or 

development in the test with AB-1 resulting in the NOAEC being set at the highest treatment 

concentration: 75.3 mg a.i./kg-dw, 5.61 μg a.i. /L, and 27.4 μg a.i. /L for sediment, pore water, 

and overlying water. 

2. Terrestrial Organisms

Risk Concerns for Birds, Reptiles, and Terrestrial-Phase Amphibians: Avian acute RQs were 

not calculated because avian acute oral and subacute-dietary toxicity studies for cyflumetofen 

have non-definitive endpoints. Instead, the most sensitive, non-definitive acute dose- and 

dietary-based toxicity values for birds were compared directly to the highest avian acute doseand dietary-based EECs for the proposed uses of cyflumetofen. An acute oral study with 

bobwhite quail yielded the most sensitive, non-definitive avian dose-based toxicity endpoints, 

LD50 > 2000 mg a.i./kg-bw and NOAEL = 74 mg a.i./kg-bw based on the sublethal effect of 

hunched posture. A sub-acute dietary study with bobwhite quail yielded the most sensitive, nondefinitive avian dietary-based endpoints, LC50 > 5033 mg a.i./kg-diet and NOAEC = 1133 mg 

a.i./kg-diet based on the sublethal effect of reduced weight gain. 

The highest avian dose-based EECs correspond to those for small birds (20 g) and range from 

1.33 (seeds) to 96.10 (short grass) mg/kg-bw. Dietary-based EECs range from 5.27 

fruits/pods/seeds) to 84.38 (short grass) mg/kg-diet. These EECs are unlikely to cause avian 

mortality since they are roughly 2-3 orders of magnitude lower than test concentrations that 

caused no mortality in toxicity study. Similarly, these EECs are unlikely to cause reduced 

weight gain since they are at least an order of magnitude greater than test concentrations that 

caused this sublethal effect in the bobwhite quail sub-acute dietary study. However, the range of 

dose-based EECs does include test concentrations that were associated with sublethal effects 

(i.e., hunched posture) in the acute oral study with bobwhite quail. Given that hunched posture 

was not observed in the sub-acute dietary or chronic, reproductive studies with bobwhite quail, 

the potential for cyflumetofen to cause this effect as a result of the proposed uses is low. 

Therefore, this comparative analysis suggests that the likelihood of adverse effects to birds, 

reptiles and terrestrial-phase amphibians from acute exposure to cyflumetofen for all proposed 

uses is low. 

Avian chronic, dietary-based RQs were calculated for the maximum application rate for each 

proposed use of cyflumetofen using the NOAEC from the bobwhite quail reproduction study

(154 mg a.i./kg-diet). Avian chronic, dietary-based RQs range from 0.03 to 0.55 across all uses 

and feeding categories. Therefore, the avian chronic LOC of 1 is not exceeded for birds of any

feeding categories regardless of the proposed use. This suggests the likelihood of adverse effects 

to birds; reptiles and terrestrial-phase amphibians from chronic exposure to cyflumetofen for all 

proposed uses are low.
12

Risk Concerns for Mammals: No mammalian acute dose-based RQs were calculated because 

the mammalian acute oral toxicity study for cyflumetofen has a non-definitive endpoint. No 

mammalian acute dietary-based RQs were calculated because a mammalian acute dietary-based 

endpoint (i.e., LC50, mg/kg-diet) is not available. 

An acute oral study with female Wistar rats yielded the non-definitive dose-based toxicity

endpoint of LD50 > 2000 mg a.i./kg-bw. The highest mammalian dose-based EECs correspond 

to those for small mammals (15 g) and range from 1.12 (seeds) to 80.45 (short grass) mg/kg-bw. 

These EECs are unlikely to result in mammalian mortality or sublethal effects since they are 

roughly 2-3 orders of magnitude lower than test concentrations that caused no mortality or 

transitory sublethal effects in the acute oral toxicity study. Therefore, this comparative analysis 

suggests that the likelihood of adverse effects to mammals from acute exposure to cyflumetofen 

for all proposed uses is low.

Mammalian chronic dose- and dietary-based RQs were calculated for the maximum application 

rate for each proposed use of cyflumetofen using the NOAEC from a rat 2-generation 

reproduction study (150 mg/kg-diet, 9.21 mg/kg-bw/day). Mammalian chronic dose- and 

dietary-based RQs range from 0.03 to 3.97 and 0.22 to 0.56, respectively, across all uses and 

feeding categories. The mammalian chronic LOC of 1 is exceeded in small and medium 

mammals consuming short grass, tall grass, broadleaf plants, or arthropods and large mammals 

consuming short grass or tall grass. In spite of these exceedances, EPA believes the actual risk 

of chronic effects is low for several reasons. The chronic RQs reflect exposure at the site of 

application, following 2 applications at the maximum use rate. RQs would be expected to get 

closer to the no effect levels as the distance from the treated area increases, and when lower 

application rates or fewer applications are used. Further, the RQs assume that mammals forage 

for food exclusively in the treated area. Additionally, the models used to estimate concentrations 

of cyflumetofen in the environment are conservative screening models, designed to provide highend exposure estimates, a more refined assessment would likely show further reduction in the 

likelihood of actual risk to mammals. Typical use rates are expected to further reduce the levels 

of concern. Although the risk of chronic effects on mammals is low, it cannot be entirely 

discounted. To mitigate potential chronic risk to mammals, EPA proposes requiring labeling 

language intended to reduce the area of potential exposure to cyflumetofen residues by reducing 

inadvertent off-target exposure via drift and runoff. (See Proposed Regulatory Decision section).

Risk Concerns for Terrestrial (Upland and Semi-Aquatic) Plants: RQs for dicots were 

calculated for the maximum application rate and application method (ground) for each proposed 

use. For non listed dicots, RQs were below 1. However, for listed dicots, RQs are greater than 

1. These RQs were generated using the EC25 and NOAEC for the most sensitive dicot from the 

seedling emergence study (tomato, EC25/NOAEC = 0.0393/0.000706 lb a.i. /A) and dicot 

NOAEC from the vegetative vigor study (NOAEC = 0.273 lb a.i. /A). RQs for monocots were 

not calculated due to a lack of appropriate seedling emergence endpoints in the most sensitive 

species, oats. Doses in this study did produce effects that were observed at levels to approximate 

a 25% inhibition of shoot weight and length. The EC25 (i.e., seedling emergence) was calculated 

for the other 3 monocots studies (onion, corn, and ryegrass). 
13

Overall, adverse effects to terrestrial plants (listed dicots and all monocots) from exposure to 

cyflumetofen as a result of the proposed uses are possible. The Agency reviewed 10 terrestrial 

plants studies (4 monocots and 6 dicots) to assess the effects of cyflumetofen. The results of the 

tests on all the dicots and most monocots were deemed acceptable. Of the 4 monocots tested 

(i.e., oat, onion, corn, ryegrass), only the study with oat was deemed supplemental. No effects 

were noted in the adult plants. Therefore, a NOAEC for monocots was not established. RQs 

were all less than 1, and the LOC was not exceeded for the other tested monocots (i.e., onion, 

corn, and ryegrass). Because of the uncertainties in the oat study, the Agency is proposing to add 

an additional buffer zone of 15 feet to further protect against any potential effects of emerging 

non listed plants. This additional measure is also similar to how the chemical has been proposed 

to be labeled in Canada. If the registrant wishes to have the 15 foot buffer reexamined, they

could repeat the oat study and see if a clearer dose response relationship is achieved. 

Additionally, label language is being added with the intent to alert the users to spray drift 

exposure concerns when emerging seedlings are present. Therefore, the Agency believes the 

potential risks are acceptable in light of the benefits. (See Proposed Regulatory Decision 

section). 

Risk Concerns for Beneficial Invertebrates: While exposure potential exists via pathways such 

as spray drift, available toxicity data for cyflumetofen indicate that it is practically non-toxic to 

honeybees and other beneficial invertebrates on an acute contact and an acute oral basis. Acute 

limit tests with two beneficial terrestrial arthropods – the parasitic wasp (A. rhopalosiphi) and the 

predatory mite (T. pyri) – using a 20.3% formulation of cyflumetofen both yielded a LR50 of 

>1.2 lb a.i./A and a NOAEC of 1.2 lb a.i./A which are greater than the single maximum 

application rate of 0.2 lb a.i./A for cyflumetofen.

IV. PROPOSED REGULATORY DECISION

Under Section 3(c)(5) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the 

Agency is proposing unconditional registration for pesticide products containing the new active 

ingredient cyflumetofen for use on tree nuts (crop group 14-12), pome fruits (crop group 11-10), 

citrus (crop group 10-10), grapes, strawberries, tomatoes and ornamentals. The products under 

consideration for the new uses are:

 Cyflumetofen Technical

 SultanTM miticide

 NealtaTM miticide

Section 3(c)(5) of FIFRA authorizes the Agency to approve the registration of a pesticide 

without condition, if the Administrator determines that (i) its composition is such as to warrant 

the proposed claims for it, (ii) its labeling and other material required to be submitted comply

with the requirements of this Act, (iii) it will perform its intended function without unreasonable

adverse effects on the environment, and (iv) when used in accordance with widespread and 

commonly recognized practice it will not generally cause unreasonable adverse effects on the

environment.
14

In reference to the first and second determinations above, the compositions of the pesticides are 

such that the proposed claims are warranted and the Agency received satisfactory data to conduct 

risk assessments for the uses proposed.

In reference to the third determination above, the Agency believes that the use of cyflumetofen

will not cause any unreasonable adverse human health or ecological effects. This determination 

is based on the findings in the Agency’s conservative human health and environmental risk 

assessments. 

As explained earlier (see section III. B.2), the proposed uses of cyflumetofen may pose adverse 

effects to terrestrial plants (listed dicots and all monocots). Additionally, potential chronic risks 

to small and medium mammals consuming short grass, tall grass, broadleaf plants, or arthropods 

and large mammals consuming short grass or tall grass may be expected as a result of the 

proposed cyflumetofen uses. EPA believes the actual risk of chronic effects is low for several

reasons. The chronic RQs reflect exposure at the site of application, following 2 applications at 

the maximum use rate. RQs would be expected to get closer to the no effect level as the distance 

from the treated area increases, and when lower application rates or fewer applications are used. 

Further, the RQs assume that all mammals forage for food exclusively in the treated area. 

Additionally, the models used to estimate concentrations of cyflumetofen in the environment are 

conservative screening models, designed to provide high-end exposure estimates, a more refined 

assessment would likely show further reduction in the likelihood of actual risk to mammals. 

Although the risk of chronic effects on mammals is low, it cannot be entirely discounted. 

Moreover, a buffer zone of 15 feet from the edge of the treated fields will significantly reduce 

RQs and LOCs for terrestrial plants from exposure via spray drift. Therefore to mitigate 

potential chronic risk to mammals and terrestrial plants (listed dicots and all monocots), the 

applicant has agreed to add the following labeling language intended to reduce the area of 

potential exposure to cyflumetofen residues by reducing inadvertent off-target exposure via drift 

and runoff:

 Removal of aerial application from the label 

 Inserting the following section: To ensure the protection of threatened or endangered 

species, it is important to maintain spray drift loadings below levels of concern for any 

area adjacent to the application site that is not excluded as possible habitat for these 

organisms, the following restrictions apply:

o Buffer distance: 15 feet 

o Release Height: 20 inches 

o Droplet Size: A combination of spray nozzles and appropriate pressure must be 

selected to provide ASABE standard S571.1 droplet size category of fine (DV0.5 of ≥ 

180 microns) or coarser than fine. 

o Maximum ground wind speed: 15 mph 

The Agency believes that with the revised labeling as described above, 1) their composition are

such as to warrant the proposed claims for them, (ii) the labeling and other material required to 

be submitted comply with the requirements of this Act, (iii) these pesticides will perform their

intended function without unreasonable adverse effects on the environment, and (iv) when used 
15

in accordance with widespread and commonly recognized practice these pesticides will not 

generally cause unreasonable adverse effects on the environment. Therefore, the Agency

proposes to grant these unconditional registrations and establish permanent tolerances as 

summarized below.

Commodity Proposed 

Tolerance 

(ppm)

EPA-Recommended 

Tolerance (ppm)

Almond, hulls 4.0 4.0

Citrus, oil 16.0 16

Fruit, citrus, group 10-10 0.3 0.30

Fruit, pome, group 11-10 0.3 0.30

Grape 0.6 0.60

Grape, raisin 0.9 N/A*

Nut, tree, group 14-12 0.01 0.01

Strawberry 0.6 0.60

Tomato 0.2 0.40**

*Not required, raisin is covered by RAC grape tolerance

** EPA is establishing a tolerance for tomato at 0.40 ppm to fully account for residue loss from 

the field trial samples during freezer storage from the time of harvest to the time of analysis.

As stated earlier, this present action was conducted as a joint review with Health Canada’s 

Pesticide Management Regulatory Authority (PMRA) and Mexico’s Federal Commission for the 

Protection against Sanitary Risk (COFEPRIS). Harmonization of tolerance expression and levels 

for plant commodities was achieved during the review process.

As required by FIFRA, the Agency published a notice of receipt (NOR) of this application in the 

Federal Register (77 FR 65878, 10/31/2012) to register pesticide products containing the new 

active ingredient cyflumetofen. A notice of filling (NOF) was also published to announce the 

filling of a petition requesting the establishment of regulation for residues of cyflumetofen in or 

on various commodities (77 FR 30481, 05/23/2012). No comments were received on either

notice.

A. Data Requirements

There are no outstanding data requirements for cyflumetofen.

B. Labeling Requirements

In order to mitigate potential chronic risk to mammals and terrestrial plants (listed dicots and all 

monocots), the applicant has agreed to add the following labeling language intended to reduce 

the area of potential exposure to cyflumetofen residues by reducing inadvertent off-target 

exposure via drift and runoff:
16

 Do not apply via aerial application

 Inserting the following section: To ensure the protection of threatened or endangered 

species, it is important to maintain spray drift loadings below levels of concern for any

area adjacent to the application site that is not excluded as possible habitat for these 

organisms, following restrictions apply:

o Buffer distance: 15 feet 

o Release Height: 20 inches 

o Droplet Size: A combination of spray nozzles and appropriate pressure must be 

selected to provide ASABE standard S571.1 droplet size category of fine (DV0.5 of ≥ 

180 microns) or coarser than fine. 

o Maximum ground wind speed: 15 mph