UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND

                                                           POLLUTION PREVENTION

MEMORANDUM

Date:		14 January 2014

Subject:	Cyflumetofen.  Revised 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.

PC Code:  138831
DP Barcode:  D398246
Decision No.:  459424
Registration No.:  7969-GGA, 7959-GGT, 7969-GGL
Petition No.:  2F7973
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical / Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.:  400882-07-7
MRID No.:  NA
40 CFR:  TBD

From:		Donald Wilbur, Chemist/Risk Assessor
		Shalu Shelat, Industrial Hygienist
		Yung Yang, Ph.D., Toxicologist
		Risk Assessment Branch VI
		Health Effects Division (7509P)

Through:	Anna Lowit, Senior Toxicologist
		Dana Vogel, Deputy Division Director
		Risk Assessment Review Committee (RARC)
		Health Effects Division (7509P)

		Donna Davis, Acting Chief
		Risk Assessment Branch VI
		Health Effects Division (7509P)

To:		Driss Benmhend/Richard Gebken, PM10
		Insecticide Branch
		Registration Division (7505P)

The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  BASF has requested registration of the new miticide cyflumetofen for foliar use on citrus fruit, grapes, pome fruit, strawberry, tomato, tree nuts, and ornamentals.  The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, residential, occupational, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from these proposed uses of cyflumetofen.

HED has evaluated the toxicity and exposure databases for cyflumetofen and has conducted a human health risk assessment which is provided in this document.  Based on this assessment, HED has determined that there are no potential risk estimates of concern for the proposed uses of cyflumetofen.

The HED team members contributing to this risk assessment include Donald Wilbur (residue chemistry, dietary exposure assessment, and risk assessment), Shalu Shelat (occupational and residential exposure assessments), and Yung Yang (hazard assessment).  Stephen Wente of the Environmental Fate and Effects Division (EFED) performed the drinking water assessment.

                               Table of Contents
1.0	Executive Summary	5
2.0	HED Recommendations	7
2.1	Data Deficiencies	8
2.2	Tolerance Considerations	8
2.2.1	Enforcement Analytical Method	8
2.2.2	Recommended Tolerances	8
2.2.3	Revisions to Petitioned-For Tolerances	9
2.2.4	International Harmonization	9
2.3	Label Recommendations	10
3.0	Introduction	10
3.1	Chemical Identity	10
3.2	Physical/Chemical Characteristics	10
3.3	Pesticide Use Pattern	10
3.4	Anticipated Exposure Pathways	11
3.5	Consideration of Environmental Justice	11
4.0	Hazard Characterization and Dose-Response Assessment	12
4.1	Toxicology Studies Available for Analysis	12
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	12
4.2.1	Dermal Absorption	13
4.3	Toxicological Effects	13
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	14
4.4.1	Completeness of the Toxicology Database	14
4.4.2	Evidence of Neurotoxicity	14
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	14
4.4.4	Residual Uncertainty in the Exposure Database	15
4.5	Toxicity Endpoint and Point of Departure Selections	15
4.5.1	Dose-Response Assessment	15
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	16
4.5.3	Cancer Classification and Risk Assessment Recommendation	17
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	18
5.0	Dietary Exposure and Risk Assessment	20
5.1	Metabolite/Degradate Residue Profile	20
5.1.1	Summary of Plant and Animal Metabolism Studies	20
5.1.2	Summary of Environmental Degradation	21
5.1.3	Comparison of Metabolic Pathways	22
5.1.4	Residues of Concern Summary and Rationale	22
5.2	Food Residue Profile	24
5.3	Water Residue Profile	25
5.4	Dietary Risk Assessment	25
5.4.1	Description of Residue Data Used in Dietary Assessment	26
5.4.2	Percent Crop Treated Used in Dietary Assessment	26
5.4.3	Acute Dietary Risk Assessment	26
5.4.4	Chronic Dietary Risk Assessment	26
5.4.5	Cancer Dietary Risk Assessment	26
5.4.6	Summary Table	27
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	27
6.1	Residential Handler Exposure	27
6.2	Post-Application Exposure	28
6.3	Residential Risk Estimates for Use in Aggregate Assessment	28
6.4	Residential Bystander Post-application Inhalation Exposure	29
6.5	Spray Drift	29
7.0	Aggregate Exposure/Risk Characterization	30
7.1	Acute Aggregate Risk	30
7.2	Short-Term Aggregate Risk	30
7.3	Chronic Aggregate Risk	31
7.4	Cancer Aggregate Risk	31
8.0	Cumulative Exposure/Risk Characterization	31
9.0	Occupational Exposure/Risk Characterization	32
9.1	Short-/Intermediate- Term Handler Risk	32
9.2	Short-/Intermediate- Term Post-Application Risk	35
9.2.1	Dermal Post-application Risk	35
9.2.2	Inhalation Post-application Risk	35
10.0	References	37
Appendix A.  Toxicology Profile and Executive Summaries	38
A.1	Toxicology Data Requirements	38
A.2	Toxicity Profiles	39
A.3	Hazard Identification and Endpoint Selection	42
A.4	Executive Summaries	45
A.5	Summary of Toxicological Doses and Endpoints for Cyflumetofen	64
Appendix B. Metabolism Summary Table	65
B.1	Structures of Cyflumetofen Metabolites	65
B.2	Tabular Summary of Metabolites and Degradates	68
Appendix C.  Physical/Chemical Properties	71
Appendix D.  Review of Human Research	72
Appendix E.  Residue Summary Table	73

1.0	Executive Summary

Cyflumetofen (2-methoxyethyl α-cyano-α-[4-(1,1-dimethylethyl)phenyl]-β-oxo-2-(trifluoromethyl)benzenepropanoate) is a new active ingredient from BASF that belongs to the acrylonitrile class of chemicals with a novel insecticidal mode of action  -  mitochondria complex II electron transport inhibition. It is a selective contact miticide that is effective on all mite life stages.  It is currently proposed only for foliar applications via ground or aerial equipment.  Cyflumetofen is formulated as a 20% suspension concentrate (SC).  BASF is proposing uses/tolerances on tree nuts (crop group 14-12), pome fruits (crop group 11-10), citrus (crop group 10-10), grapes, strawberries, tomatoes, and 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).

The toxicology database is considered complete for cyflumetofen.  A subchronic inhalation study was not available; however, the HASPOC 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.  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 co-critical 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 no evidence of increased qualitative or quantitative susceptibility in the rat 2-generation reproduction study; however, the rat and rabbit developmental studies indicate susceptibility in the pups.  There is evidence of increased quantitative susceptibility in the rabbit developmental toxicity study, since developmental effects at the limit dose were observed where no maternal toxicity was present.  There is evidence of increased qualitative susceptibility in the rat developmental toxicity study as developmental effects were seen at the same dose that caused an increase in adrenal weights and organ-to-body weight ratio in the maternal animals.  Notwithstanding, the degree of concern for these effects in infants and children is low because the rat and rabbit developmental effects have clearly defined NOAEL/LOAELs and the dose selected for chronic risk assessment is protective of these effects.  There is no evidence of neurotoxicity in any of the submitted studies for cyflumetofen. Further, highly conservative exposure estimates were incorporated into the risk assessment; therefore, reduction of the 10X FQPA safety factor to 1X is considered appropriate.

Cyflumetofen has been classified as having "Suggestive Evidence of Carcinogenic Potential" in accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005). 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.

The residue chemistry database is considered complete for cyflumetofen for the purposes of this petition.  The nature and magnitude of the residue in plants has been adequately delineated.  The residue of concern in plants is the parent compound only.  No cyflumetofen residues are expected in livestock commodities based on the submitted ruminant metabolism study and the calculated dietary burden.  Adequate storage stability, method validation data and processing studies have been submitted.  An adequate LC/MS/MS (liquid chromatography/tandem mass spectrometry) analytical method is available to enforce the proposed tolerances.  As part of the joint review process, harmonization of recommended tolerance levels was achieved.

Environmentally, the cyflumetofen molecule has very low water solubility and is expected to degrade quickly through multiple fate processes (with half-lives of hours to several days) under environmental conditions.  As this is a new active ingredient, there are no monitoring data available, thus drinking water concentrations were estimated using models.

An acute reference dose was not selected for cyflumetofen; therefore, the Agency conducted only a chronic dietary (food and drinking water) exposure and risk assessment.  This assessment was conducted using tolerance level residues, empirical processing factors where available, 100% crop treated and modeled surface water exposure estimates.  Using assumptions considered to be highly conservative, the chronic dietary risk estimates are below HED's level of concern (<100% of the chronic population adjusted dose (cPAD)), and range from <1% of the 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.

The proposed uses of cyflumetofen on ornamentals may result in adult residential handler and post-application exposure.  This exposure is expected to be only short-term 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.  These assessments were conducted according to HED's 2012 Residential Standard Operating Procedures (SOPs) and 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).

Since there are no acute points of departure identified, an acute aggregate risk assessment was not conducted.  HED 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.  Chronic dietary risk is not of concern.

No dermal hazard has been identified for cyflumetofen; therefore occupational handler and post-application risks were assessed for the inhalation route of exposure only.  All estimated short- and 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.

This risk assessment relies, in part, on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re-entry Task Force (ARTF) database; and the Residential SOPs (Residential Handler) are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.

2.0	HED Recommendations

Provided a revised Section F to amend the proposed tolerances is submitted as noted in Section 2.2 below, there are no hazard, exposure, or risk considerations that would preclude granting the requested uses of cyflumetofen or establishing the tolerances required to support those uses.

2.1	Data Deficiencies

There are no data deficiencies relating to toxicology, residue chemistry, or occupational/residential exposure assessment associated with this action.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An adequate analytical method is available to enforce the HED recommended tolerances for cyflumetofen in plant commodities.  The high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method, BASF D1003, has been adequately validated, has undergone a successful ILV (independent laboratory validation), is considered adequately radio-validated and has been reviewed by the Agency for appropriateness as an enforcement method.   BASF method D1003 has a limit of quantitation (LOQ) of 0.01 ppm for residues of cyflumetofen in all matrix types.  The method limit of detection (LOD) for residues of cyflumetofen in all matrices, except orange oil, has been set at 0.002 ppm, or approximately 20% of the LOQ.  Orange oil has an LOD of 0.0035 ppm.

BASF method D1003 is described briefly as follows.  Residues of cyflumetofen are extracted from crop matrices by shaking with acetonitrile followed by acetonitrile-water (hexane is also added for extractions from oil).  An aliquot of the extract is concentrated to remove the acetonitrile (the hexane phase is also removed from oil extractions) and acidified with formic acid.  The residues are then partitioned with a mixture of ethyl acetate-cyclohexane.  An aliquot of the organic phase is concentrated in the presence of 0.1% formic acid in water, and re-dissolved in 0.1% formic acid in acetonitrile for HPLC-MS/MS determination.

Cyflumetofen has also been subjected to analysis by the Food and Drug Administration (FDA) multi-residue method (MRM) protocols.  Cyflumetofen is not adequately recovered through any of the FDA multi-residue protocols.

2.2.2	Recommended Tolerances

HED recommends that 40 CFR be amended by establishing tolerances for residues of cyflumetofen in plant commodities as listed in Table 2.2.2.  For the purposes of this petition, tolerances for residues of cyflumetofen were derived using the Organization for Economic Cooperation and Development Maximum Residue Level (OECD MRL) Calculation Procedures.  Based on the HED Interim Guidance on Tolerance Expressions (S. Knizner, 05/27/2009), the following tolerance expression is recommended.

      Tolerances are established for residues of the insecticide cyflumetofen, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels for cyflumetofen is to be determined by measuring only cyflumetofen, 2-methoxyethyl α-cyano-α-[4-(1,1-dimethylethyl)phenyl]-β-oxo-2-(trifluoromethyl)benzenepropanoate, in or on the commodity.
Table 2.2.2.  Tolerance Summary for Cyflumetofen
Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments

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
Not required, raisin is covered by RAC grape tolerance
Nut, tree, group 14-12
                                     0.01
                                     0.01

Strawberry
                                      0.6
                                     0.60

Tomato
                                      0.2
                                     0.40

2.2.3	Revisions to Petitioned-For Tolerances

HED is recommending that tolerances be set for the commodities requested by the registrant at the levels requested, with the changes noted below.  Additionally, minor modifications to some commodity definitions are recommended.  The petitioner had requested tolerances on Fruit, citrus, group 10; Fruit, pome, group 11; and Nut, tree, group 14.  To be consistent with updated Agency naming-conventions for crop groups, these have been changed to Fruit, citrus, group 10-10; Fruit, pome, group 11-10; and Nut, tree, group 14-12.  The requested changes to tolerance levels are shown above in Table 2.2.2.

The proposed tolerance level of 0.2 ppm for tomato should be increased to 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.  The proposed tolerance for grape, raisin of 0.9 ppm is not required since the tolerance for the raw agricultural commodity grape at 0.60 ppm is adequate to account for any residue concentration shown in the processed commodity.

2.2.4	International Harmonization

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).  Harmonization of tolerance expression and levels for plant commodities was achieved during the review process.  Based on the submitted ruminant metabolism data and the limited livestock feedstuffs associated with this petition, HED concludes the proposed uses can be classified as 40 CFR 180.6 (a)(3), no reasonable expectation of finite residues in ruminant livestock commodities; therefore, the U.S. will not need to set tolerances for ruminant livestock commodities.  However, since PMRA is not legally able to waive the requirement for a tolerance based on no reasonable expectation of finite residues, tolerances at the LOQ of the enforcement analytical method will be established in Canada for ruminant livestock commodities.  No Codex MRLs have been established for cyflumetofen.

2.3	Label Recommendations

There are no label recommendations relating to toxicology, residue chemistry, or occupational/residential exposure assessment associated with this action.

3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Cyflumetofen Nomenclature
Compound
Chemical Structure

Common name
Cyflumetofen
Company experimental name
BAS 9210 I, OK 5101
IUPAC name
2-methoxyethyl (RS)-2-(4-tert-butylphenyl)-2-cyano-3-oxo-3-(α , α ,α -trifluoro-o-tolyl) propionate
CAS name
2-methoxyethyl α-cyano-α-[4-(1,1-dimethylethyl)phenyl]-β-oxo-2-(trifluoromethyl)benzenepropanoate
CAS #
400882-07-7
End-use product/EP
Nealta TM , Sultan [TM]

3.2	Physical/Chemical Characteristics

Cyflumetofen has low water solubility.  Its octanol/water partition coefficient suggests that it is a hydrophobic compound that is more fat soluble than water soluble, exhibiting a tendency to dissolve in fats, oils, lipids, and non-polar solvents more readily than in water.  Further, cyflumetofen has a low vapor pressure.  The physiochemical properties for this active ingredient are shown in Appendix C, Table C.1.

3.3	Pesticide Use Pattern

Cyflumetofen end-use products Nealta[TM]  and Sultan[TM] are both formulated as a 20% suspension concentrate (SC).  Two applications may be made per season at a maximum single application rate of 0.2 lbs ai/acre with retreatment intervals of 14 to 21 days as stated on the proposed product labels.  The maximum seasonal application rate is 0.4 lbs ai/A/season for all use sites.  Applications may be made using open-cab ground-boom sprayers, airblast sprayers, and aerial equipment for the proposed occupational uses, while handheld equipment is allowed for both occupational and as well as residential uses.   Aerial application is allowed only on tomatoes.  Chemigation is prohibited on all proposed use sites. The proposed preharvest interval (PHI) ranges from 1 to 14 days depending on the use.

Table 3.3.  Summary of Directions for Use of Cyflumetofen
                                 Proposed Use
                             Application Equipment
                          Formulation [EPA Reg. No.]
                            Applic. Rate (lb ai/A)
                          Max. No. Applic. per Season
                     Max. Seasonal Applic. Rate (lb ai/A)
                                  PHI (days)
                        Use Directions and Limitations
                                 Citrus Fruit
                             Airblast, Groundboom
                        Nealta
[EPA Reg. No. 7969-GGA]
                                      0.2
                                       2
                                      0.4
                                       7
Do not apply by air to citrus fruit, pome fruit, strawberries, or tree nuts. Aerial only allowed on tomatoes. Do not apply through an irrigation system.

                         Retreatment interval: 14 days
                                    Grapes

                                      14

                                  Pome Fruit

                                       7

                                Tree Nut Group

                                       7

                                  Strawberry
                                  Groundboom

                                       1

                                    Tomato
                              Groundboom, Aerial

                                       3

                                  Ornamentals
                       Groundboom and handheld equipment
                        Sultan
[EPA Reg. No. 7969-GGT]
                                  0.2

(0.002
                                lbs ai/gallon)
                                       2
                                      0.4
                                      n/s
DO NOT apply by chemigation or air. DO NOT use on vegetables grown in greenhouses for crop production or in vegetable production of transplant for outdoor use.

                       Retreatment interval: 14- 21 days

3.4	Anticipated Exposure Pathways
THE REGISTRATION DIVISION HAS REQUESTED AN ASSESSMENT OF HUMAN HEALTH RISK TO SUPPORT THE PROPOSED NEW USEs of cyflumetofen on citrus fruit, grapes, pome fruit, strawberry, tomato, tree nuts, and ornamentals.  Humans may be exposed to cyflumetofen in food and drinking water, since cyflumetofen may be applied directly to growing crops and application may result in cyflumetofen reaching surface and ground water sources of drinking water.  Cyflumetofen is being proposed for use on ornamentals (i.e., residential landscape areas) and may be applied in residential settings; therefore there is a potential for exposure in residential or non-occupational settings.  In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is also a potential for post-application exposure for workers re-entering treated fields.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

4.1	Toxicology Studies Available for Analysis

The toxicology database is complete and the toxicity profile can be characterized for a wide range of effects, including potential developmental, reproductive, neurotoxic, mutagenic, carcinogenic, and immunotoxic effects. The HASPOC determined that a subchronic inhalation study is not needed for cyflumetofen (TXR# 0056691, July 3, 2013) based on a weight of evidence (WOE) approach that considered all of the available hazard and exposure information for cyflumetofen, including:  1) the physical/chemical properties of cyflumetofen including its low volatility (4.43 x 10[-8] mm Hg at 25 ºC); (2) its low acute inhalation toxicity (Toxicity Category IV); and (3) the use of an oral POD results in MOEs that are >=5,500, and above the Agency's level of concern.  The available toxicity studies for cyflumetofen are listed in Table A.1 in Appendix A.

4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)

There were a series of metabolism studies conducted for cyflumetofen.  Detailed information is provided in the Appendix A.4.8.  [14]C-cyflumetofen was rapidly absorbed following administration of the low dose, with plasma levels of radioactivity peaking at 1 hour post-dosing.  Absorption was slightly slower following administration of the high dose, with peak plasma levels attained at 2-4 hours post-dosing indicating saturation of absorption.  At the high dose, females demonstrated higher Cmax and area under the curve (AUC) values than males.

At 72 hours post-dosing, the gastrointestinal tract, carcass, liver and kidney contained the highest proportions of radioactivity.  Most of the radioactivity excreted in urine from low dose rats (90-96%) was eliminated within 24 hours after dosing, whereas at the high dose, excretion was slower with only 74-88% eliminated within 24 hours of dosing.  At both low and high doses, 60-89% of the radioactivity excreted in feces was eliminated within 24 hours of dosing.

The unchanged parent was not detected in the urine of any test group. Metabolite AB-3 was identified as a major metabolite in the urine of female rats but was a minor urinary metabolite in males. Metabolite AB-2 was a minor metabolite in urine of all test groups except females from the low dose group, in which residues for this metabolite reached 4% of the administered dose.
The major metabolites detected in the bile from all test groups were the glucuronic acid conjugates of metabolites AB-1 and AB-3.  Metabolite AB-2 was also detected at lower levels in the bile from all test groups.  Unique metabolites identified in the bile of rats administered the A-ring or B-ring label included the glucuronic acid conjugate of A-6 and the glutathione conjugate of B-1, respectively.

[14]C-cyflumetofen was metabolized in the rat primarily by hydrolytic cleavage of the trifluoromethylbenzoyl moiety resulting in metabolite B-1 (trifluoromethylbenzoic acid) and A-18.   Another minor pathway included successive hydroxylation of the tert-butyl side chain.

4.2.1	Dermal Absorption

A dermal absorption study was submitted which supports an estimated dermal absorption of 11%.  However, since no dermal hazard has been identified for cyflumetofen, no dermal endpoint was selected for use in risk assessment.

4.3	Toxicological Effects

The major target organ in rats, mice, and dogs following short-term and long-term oral exposure is the adrenal glands characterized with increased organ weight and histopathology (vacuolation and hypertrophy of the adrenal cortical cells). The adrenal effects are the most sensitive and protective endpoint for all lifestages and populations of concern since there is no progression of toxicity over time.

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. There is no evidence of neurotoxicity or immunotoxicity in any of the submitted studies for cyflumetofen.  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. In the developmental toxicity study in rabbits, delays in skeletal ossification were observed at the mid- and high-doses where the maternal toxicity was observed. The only adverse external alteration observed was a downward flexion of the forepaws (2 fetuses from one litter) or hind paws (1 fetus from one litter) in the high-dose (1000 mg/kg/day) group with observed maternal toxicity. The incidences were slightly above historical controls and were considered a treatment-related adverse effect.

In the rat reproduction study, adrenal effects (increased weight and histopathology) were observed in the parental and offspring animals at the mid- and high-doses. Serum hormone concentrations were measured in the F1 parental rats. The FSH, progesterone, and 17 β-estradiol levels in the mid- and high-dose female groups were significantly lower than the corresponding values in the control groups. No hormonal effect was observed in the F1 male rats at any dose level. Overall reproductive performance showed that there were no corresponding changes in reproductive performance at any dose level.

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.

4.4	Safety Factor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA Safety Factor (for the protection of infants and children) be reduced to 1X.  An FQPA Safety Factor of 1X is appropriate for the following reasons:

The toxicity database is complete and adequate to assess safety for infants and children.  There is no evidence of increased qualitative or quantitative susceptibility in the rat 2-generation reproduction study.  While there is evidence of increased susceptibility in the rabbit and rat developmental studies, 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.  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.  Further details may be found in the following sections.

4.4.1	Completeness of the Toxicology Database

The database is complete and adequate to characterize potential pre- and/or post-natal risk for infants and children.

4.4.2	Evidence of Neurotoxicity

There are acute and subchronic neurotoxicity studies available.  No evidence of neurotoxicity was observed in any of the submitted studies for cyflumetofen.  A developmental neurotoxicity study is not required.

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased qualitative or quantitative susceptibility in the rat 2-generation reproduction study; however, the rat and rabbit developmental studies indicate susceptibility in the pups.  There is evidence of increased quantitative susceptibility in the rabbit developmental toxicity study, since developmental effects (changes in ossicification, paw flexion, and decreased fetal body weights) at the limit dose were observed where no maternal toxicity was present.  There is evidence of increased qualitative susceptibility in the rat developmental toxicity study as developmental effects (increased incidence of incompletely ossified sternal centra) were seen at the same dose that caused an increase in adrenal weights and organ-to-body weight ratio in the maternal animals.  Notwithstanding, the degree of concern for these effects in infants and children is low because the rat and rabbit developmental effects have clearly defined NOAEL/LOAELs and the dose selected for chronic risk assessment is protective of these effects. Therefore, the PODs based on adrenal effects in rat are health protective of all lifestages.

4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  Since the dietary and residential exposure estimates were based on conservative assumptions, HED is confident that this assessment does not underestimate dietary (food and water) or residential exposure.

The chronic dietary exposure assessment used tolerance level residues for all commodities, 100% crop treated (% CT), and empirical processing estimates when available or DEEM(TM) 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, HED 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.

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

The detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A.3.

No appropriate endpoint attributable to a single exposure (dose) was identified from studies including an acute neurotoxicity study and developmental toxicity studies in rats and rabbits. An acute RfD was not established for the general population including infants, children, and females age 13-49.  In the developmental toxicity study in rabbits, increased incidence of paw flexion was observed at 1000 mg/kg/day and was slightly above historical controls. Maternal toxicity, decreased fetal body weight, and incomplete ossification were also observed at this dose. Paw flexion was considered to be associated with ossification effects (i.e., all three pups that exhibited paw flexions also had incomplete ossification).  Delays in ossification and developmental delays are not typically considered to occur as a result of exposure to a single dose and therefore are not appropriate as endpoints for acute risk assessment.

For the chronic dietary, three studies were selected as co-critical studies for endpoint selection. These studies are appropriate for the duration and populations of concern since there is no progression of toxicity over time. The NOAEL and LOAEL selected were based on the weight of evidence from the three studies which had similar target organ toxicities. The point of departure of 16.5 mg/kg/day (NOAEL) was selected from the 90-day and the chronic toxicity/ carcinogenicity rat studies, which have similar NOAELs and LOAELs based on effects on the adrenals.  In the 2-generation reproduction study, a lower NOAEL of 9.2 mg/kg/day was identified with a LOAEL of 30.6 mg/kg/day based on effects on the adrenals; however, this NOAEL of 9.2 mg/kg/day was not selected as the POD for risk assessment since it is considered to be a function of calculated compound intake (based on food consumption) rather than a lower NOAEL/LOAEL per se.  The POD of 16.5 mg/kg/day selected is still protective of similar effects seen at 30.6 mg/kg/day in the 2-generation reproduction toxicity study, the 28 day rat study at LOAEL of 75 mg/kg/day, the chronic mouse study at LOAEL of 537/483 mg/kg/day (M/F), and the chronic dog study at LOAEL of 300 mg/kg/day.

There is no incidental oral exposure expected based on the current use pattern; however, an endpoint was selected during the full review of the database.  Similar to the chronic endpoint selection, three studies were selected as co-critical studies for short- and intermediate-term incidental oral exposure. These studies are appropriate for the duration since there is no progression of toxicity over time. The point of departure of 16.5 mg/kg/day (NOAEL) was selected from the 90-day and the chronic toxicity/carcinogenicity rat studies.  The LOAEL of 30.6 mg/kg/day was selected based on effects on the adrenals from the 2-generation reproduction study.

For short- and intermediate-term dermal exposure, no appropriate endpoint was identified for risk assessment.  A 28-day dermal toxicity study in rats is available; however, no adverse effects were seen at the highest dose tested of 1000 mg/kg/day, including the endpoints of concern (adrenal effects).  Although developmental/reproductive effects (not assessed in the dermal study) were observed in the developmental and reproductive toxicity studies, the effects occurred at dermal equivalent doses above the limit dose or in the presence of parental toxicity.  Therefore, since no effects were observed in adults at the limit dose, no developmental or reproductive effects would be expected to occur due to parental dermal exposure.

A route-specific subchronic inhalation toxicity study is not available for cyflumetofen.  For short-and intermediate-term inhalation risk assessments, an oral NOAEL was selected from three studies as described in the chronic dietary.  These studies are appropriate for the duration since there is no progression of toxicity over time. The point of departure of 16.5 mg/kg/day (NOAEL) was selected from the 90-day and the chronic toxicity/carcinogenicity rat studies, which have similar NOAELs and LOAELs. The LOAEL of 30.6 mg/kg/day was selected from the 2-generation reproduction study.  Since an oral study was selected, absorption via inhalation is presumed to be equivalent to oral absorption.   There is no proposed long-term use; therefore, risk assessment for long-term inhalation exposure is not required.

A 100X uncertainty factor is applied (interspecies factor of 10X and intraspecies factor of 10X) for chronic dietary risk assessments.  For inhalation risk assessment, the level of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined interspecies (10X) and intraspecies (10X) uncertainty factors.

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources (oral, dermal, and inhalation) and then determine whether the individual exposures can be combined if they have the same toxicological effects.  Since no dermal hazard has been identified for cyflumetofen, a dermal assessment was not conducted.  However, inhalation and oral routes can be combined since the points of departure are based on the same studies and the toxicological effects are the same.

4.5.3	Cancer Classification and Risk Assessment Recommendation

The carcinogenic potential of cyflumetofen was evaluated following dietary administration to male and female Fischer 344 rats and male and female CD-1 mice. Two separate studies were conducted in both species. In 2004, the Registrant conducted a carcinogenicity study in Fischer 344 rats and a carcinogenicity study in CD-1 mice. Since there was no evidence of carcinogenicity in either species, and to address concern regarding the adequacy of the doses tested in the above studies, the Registrant elected to conduct supplemental studies to evaluate higher doses in mice and rats.

Cyflumetofen was administered in the diet to groups of 50 rats/sex/dose for 104 weeks. One study was conducted at doses of 0, 150, 500 and 1500 ppm (0, 4.9, 16.5, and 49.5 mg/kg/day in males and 6.14, 20.3, and 61.9 mg/kg/day in females) while a second high dose study was conducted at 0 and 6000 ppm (0 and 220 mg/kg/day in males and 0 and 287 mg/kg/day in females). There was limited evidence of carcinogenicity characterized by the presence of thyroid c-cell tumors and interstitial cell tumors of the testes in male rats only at the highest dose tested (HDT).  There was no evidence of carcinogenicity in female rats at any dose level.  The doses tested in the rat study were considered to be adequate to assess the carcinogenic potential of cyflumetofen.

The thyroid c-cell tumors were determined to be treatment-related based on the following considerations: a statistically significant trend and a pair-wise significance (both at p < 0.05) for thyroid c-cell adenocarcinomas when compared to controls; a statistically significant trend (p < 0.05) and a pair-wise significance (p<0.01) for thyroid c-cell adenomas and/or adenocarcinomas combined; and the incidences of the adenocarcinomas (31%) and the combined tumors (57%) exceeded the historical control range from the testing laboratory (c-cell adenocarcinoma, 6-18%, and combined c-cell adenoma/carcinomas, 26-50%).

The testicular interstitial cell tumors, although exacerbated by treatment were not considered to be biologically relevant since this tumor (Leydig cell, LCT) is extremely common in the F344 rat, with a reported background incidence of 56-100% in 2-year cancer studies. The reasons for the different background incidence rate for LCT among species stem from both quantitative and qualitative differences in the Leydig cell response to hormonal stimuli. The rat Leydig cell is extremely sensitive to slight changes in circulating luteinizing hormone (LH) levels. Among rat strains, the F344 rat is particularly susceptible to this process and is not considered a relevant model for studying LCT. By contrast, the incidence rate in humans of LCT is very low (i.e., 0.00004%). Similarly, rats are known to have approximately 13-times more LH receptors per cell than humans (Hutaniemi, 1983). Because of the differences present between the human and the rat Leydig cells, non-genotoxic compounds that cause LCTs in rats have little relevance to humans. The data with cyflumetofen supports this species and strain-specific effect on the Leydig cells.

Additionally, the carcinogenic potential of cyflumetofen was evaluated following dietary administration to male and female CD-1 mice. Two studies were conducted in the mice. Cyflumetofen was administered to groups of 52 mice/sex/dose for 78 weeks. One study was conducted at doses of 0, 150, 500, 1500 and 5000 ppm (0, 15.5, 54.3, 156 and 537mg/kg/day in males and 14.3, 48.1, 144 and 483 mg/kg/day in females) while a second high dose study was conducted at 0 and 10,000 ppm (0 and 1143 mg/kg/day in males and 1132 mg/kg/day in females. There was no evidence of carcinogenicity in male or female mice at any dose level. The doses tested in the mouse were considered adequate to assess the carcinogenic potential of 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 (TXR# 0056862).

4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4.  Summary of Toxicological Doses and Endpoints for Cyflumetofen for Use in Dietary, Non-Occupational and Occupational Human Health Risk Assessments*
                              Exposure/ Scenario
                              Point of Departure
                                 Uncertainty/
                              FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (All populations)
An acute reference dose has not been established for either the general population or for Females 13-49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a single dose for these populations.
Chronic Dietary (All Populations)

NOAEL =
16.5 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x

Chronic RfD = 0.17 mg/kg/day

cPAD = 0.17
mg/kg/day

Three co-critical studies:
90-day feeding study in rats
LOAEL = 1000 ppm (54.5/62.8 mg/kg/day in M/F) based on hematology and organ weight changes in the liver, adrenal, kidney and ovaries; and histopathology effects in the adrenals and the ovaries. NOAEL=300 ppm (16.5/19 mg/kg/day in males/females)

Chronic toxicity/carcinogenicity study in rats
LOAEL = 1500 ppm (49.5/61.9 mg/kg/day in M/F) based on increased adrenal weights and histopathology. NOAEL=500 ppm (16.5/20.3 mg/kg/day in males/females)

Two generation reproduction study in rats
Parental: LOAEL = 500 ppm (30.6/46.6  mg/kg/day in M/F) based on increased organ weight and histopathology in adrenals. NOAEL=150 ppm (9.2/13.8 mg/kg/day in males/females)
Dermal
(Short-, Intermediate- and Long-Term)
No dermal hazard was identified. No appropriate endpoint was selected for risk assessment.
Inhalation (Short-, Intermediate- and Long-Term)
NOAEL =
16.5 mg/kg/day
UFA= 10x
UFH= 10x
FQPA SF= 1x

Occupational and Residential LOC for MOE = 100
Same as chronic dietary endpoint
Cancer (oral, dermal, inhalation)
CARC Classification: Suggestive Evidence of Carcinogenic Potential.

* The complete summary of toxicological doses and endpoints for cyflumetofen can be found in Appendix A.5.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

5.0	Dietary Exposure and Risk Assessment

5.1	Metabolite/Degradate Residue Profile

A tabular summary of the major metabolites and degradates for cyflumetofen are shown in Appendix B, Tables B.1 and B.2.

5.1.1	Summary of Plant and Animal Metabolism Studies

Plants
Metabolism studies on fruit crops (mandarin, apple, and eggplant) were submitted/reviewed and found to be scientifically acceptable.  The studies were conducted with a single foliar application of [14]C-cyflumetofen, either labeled on the butylphenyl ring (label A) or the benzoyl ring (label B) at a rate of 600 g ai/ha (~1.5x the maximum seasonal label application rate of 0.4 lbs ai/acre).

The metabolism was seen to be limited in the three studies.  The major part of the total radioactive residue (TRR) remained on the surface of fruits and leaves (56% to 97% TRR) and was easily removed by solvent rinses.  The parent cyflumetofen was identified as the major component, accounting for 67% to 87% TRR on fruits and leaves 7 days after application, and 44% to 81% TRR after 30 days.  Degradation compounds were recovered at a level lower than 10% TRR, except for the metabolite B-1 (2-trifluoromethylbenzoic acid) resulting from the cleavage of the parent molecule and representing up to 11% TRR in mandarin (0.06 ppm) and 15% TRR in eggplant (0.06 ppm).  In addition B-1 conjugates (metabolites U1 and U2) were detected up to 16% TRR in eggplant fruits at a PHI of 14 days.

The nature of the residue for cyflumetofen in the proposed crops is considered to be adequately understood.  Metabolism in these three crops shared a common metabolic pathway with cyflumetofen as the primary component.  However, in the absence of data on small grains, leafy vegetables, and root/tuber crops, this data set is not considered adequate to define the nature of the residue in all plants.  Therefore, if new uses on small grains, leafy vegetables, bulb vegetables, head/stem brassica, oilseeds, and/or root/tuber crops are proposed in the future, then additional metabolism studies may be required to reconsider the residues of concern in plants.  The available metabolism data are only considered adequate to support uses on fruits, cucurbit vegetables, and fruiting vegetables.

Rotational Crops
Confined rotational crop data were submitted, reviewed and found to be scientifically acceptable.  Cyflumetofen was applied to bare sandy loam soil in plastic containers at an application rate of 1 x 400 g ai/ha (approximately 0.357 lb/A, ~0.9x the proposed maximum single application rate).  The nature and the quantities of the radioactive residues were investigated in lettuce (immature and mature), white radish (top and root) and spring wheat (forage, hay, straw, chaff and grain) after plantback intervals (PBIs) of 30, 120 and 365 days.  Although the metabolic profile was similar across the rotational crop matrices, significant differences were shown between the two different radiolabels (benzoyl or butylphenyl), and the metabolic pathway in rotational crops is significantly different than that in primary crops.

Following application to bare soil, the degradation of cyflumetofen in rotational crops appears to follow four major pathways: hydrolytic cleavage of the parent molecule results in the formation of the metabolite B-1 (trifluoromethyl benzoic acid) - which is only detectable with the benzoyl label - and one or several butylphenyl label-specific intermediates which were not identified.  The predominant metabolite in the case of the benzoyl label, trifluoroacetic acid (TFA), can be derived from cyflumetofen or the metabolite B-1.  The butylphenyl label-specific cleavage products (such as the goat metabolite A-2) which is formed by hydrolysis of the formic acid ester, decarboxylation and hydrolytic detachment of the trifluoromethyl benzoyl moiety) are further transformed to a series of minor (<0.01 ppm), mainly unidentified medium-polar metabolites.

Livestock
The metabolism of cyflumetofen was investigated in lactating goats following repeated oral administration of [14]C- cyflumetofen, labeled either in the benzoyl ring (benzoyl label) or in the tert-butylphenyl ring (butylphenyl label).  Cyflumetofen was administered by gavage (two animals per label) for twelve (benzoyl label) or ten (butylphenyl Label) consecutive days at a nominal dose of 12 ppm feed (~171x the maximum reasonably balanced diet (MRBD)). There are no poultry feedstuffs associated with the proposed uses; therefore a poultry metabolism study is not required and was not submitted.

Cyflumetofen and its metabolites were rapidly excreted by lactating goats, mainly via feces and urine.  For both labels, only low portions of the administered dose were retained in edible tissues and organs.  In edible tissues, parent cyflumetofen was only identified in fat of the benzoyl label.  Metabolite B-1 was identified in all matrices of the benzoyl label as the sole benzoyl label-specific metabolite.  The major metabolic pathway of cyflumetofen in lactating goats comprises hydrolytic cleavage of the trifluoromethylbenzoyl moiety resulting in metabolite B-1.

The submitted goat metabolism studies adequately address the requirement to elucidate the nature of the residue for cyflumetofen in ruminants.  Based on the ruminant metabolism data and the limited livestock feedstuffs associated with this petition, the proposed uses can be classified as 40 CFR 180.6 (a)(3), no reasonable expectation of finite residues in ruminant livestock commodities.  However, this decision may be reconsidered if the use pattern changes and/or additional livestock feedstuffs are proposed in the future.  Additionally, if additional uses are proposed that contain poultry feedstuffs, a poultry metabolism study will be required.

5.1.2	Summary of Environmental Degradation

Cyflumetofen has limited solubility in water (28 ug/L) and is quite lipophilic; therefore, it is expected to absorb to foliage surfaces and soil (Koc of 131,826) at the site of application.  Once deposited, either at the site of application or farther afield through spray drift (or through erosion of cyflumetofen bearing soil particles), the parent molecule is expected to degrade quickly through multiple fate processes (half-lives of hours to several days) under environmental conditions.  Cyflumetofen forms many degradates with a wide range of fate properties (e.g., from highly soluble to less soluble than the parent).  The two bonds on either side of the cyano group readily break in all of the fate studies involving water other than photolysis (hydrolysis, aerobic and anaerobic soil and aquatic metabolism, and terrestrial field dissipation studies), which means that cyflumetofen is not persistent in the environment (Hydrolysis DT50 = 9.75 hours at pH 7) and rapidly converts to degradates via biotic and abiotic hydrolysis reactions.  Many degradates are much more persistent than the parent.

5.1.3	Comparison of Metabolic Pathways

Metabolism in plants was similar, with parent cyflumetofen being the primary component in most matrices.  Other identified metabolites were B-1, A-12, AB-6 and AB-7.  The major metabolic pathway in plants consisted of the hydrolytic cleavage of the benzoyl moiety leading to metabolite B-1 followed by conjugation.  Metabolites AB-6 and AB-7 were primarily photochemical metabolites found as surface residue in crop matrices. Residues in plants tend to be surface residues.

Metabolism in rotational crops was seen to be very different from that in primary crops.  Depending on the position of the radiolabel, either trifluoroacetic acid (TFA) or a series of medium-polar metabolites in minor concentrations were detected.

Metabolism studies performed in rat and goat showed a common metabolic pathway in animals. In both goat and rat, cyflumetofen is rapidly absorbed and excreted.  Cyflumetofen is metabolized in goat and rat primarily by hydrolytic cleavage of the trifluoromethylbenzoyl moiety resulting in metabolite B1 (trifluoromethylbenzoic acid) (goat and rat) and A-18 (rat) as primary metabolites. Another minor pathway includes hydroxylation and oxidation of the tert-butyl side chain.  The metabolic pathways in both rat and goat were qualitatively similar.

5.1.4	Residues of Concern Summary and Rationale

The HED Residues of Concern Knowledgebase Sub-committee (ROCKS) considered the available data on the nature and magnitude of residues of cyflumetofen and concluded that for the subject crops, the parent compound only be included for tolerance enforcement and dietary risk assessment.  At this time, there is no reasonable expectation of finite residues in livestock so the committee had no recommendation on residues of concern in livestock.  For drinking water, the ROCKS recommended including the parent cyflumetofen and all of the AB degradates.  The reasoning behind these recommendations is as follows:

Primary Crops:   Parent cyflumetofen was detected as a main residue in the primary crop metabolism studies and crop field trials. It is considered an appropriate marker of misuse on primary crops and is recommended as the residue of concern for tolerance enforcement.  The metabolite B-1 was also a major residue in some commodities.  The ROCKS recommended inclusion of parent only for risk assessment purposes based on the following weight of evidence analysis:
   * The structure of metabolite B-1 is unlike the parent (i.e., it is a carboxylate and its molecular weight is 2 times lower);
   * The octanol:water partition coefficient of parent cyflumetofen is much higher than that of B-1 (Log P = 4.3 versus 2.5, respectively), indicating  that B1 is much more water soluble.  As a carboxylate, B-1is also likely to be charged (predicted pKa = 3.12) in the body (pH 7.4) and readily excretable by renal anion transporters, decreasing the likelihood of re-absorption;
   * Rat metabolism studies show that B-1 is likely a detoxification product of parent cyflumetofen.  Once formed, B-1 undergoes conjugation with glutathione (phase II metabolism) resulting in a higher excretion potential;
   * The structure of metabolite B-1 resembles benzoic acid (the trifluoromethyl group in B-1 is unlikely to change reactivity), which exhibits very low single- and repeated-dose toxicity (NOAEL  800 mg/kg/day; http://toxnet.nlm.nih.gov, accessed 02/25/2013).
If new uses are requested in the future, additional metabolism studies may be required to reconsider the residues of concern in plants.

Rotational Crops:  The major residue found in rotational crops was trifluoroacetic acid (TFA).   The ROCKS recommended excluding it from risk assessment consideration for the following reasons:  1) TFA is a polar, low molecular weight organic acid with no structural resemblance to the parent molecule, 2) the toxicity of TFA is due to its strong acidity (pKa<1) and at physiological pH, TFA would exist as an anion and not the acid and would therefore not exhibit acid toxicity (http://www.afeas.org/environ.html), and 3) it is not likely to contribute to toxic effects found for cyflumetofen.  Since there were no major residues of toxicological concern in the rotational crop studies, no residues of concern for tolerance enforcement or risk assessment were identified.

Livestock:  Based on the submitted ruminant metabolism data and the limited feedstuffs associated with this petition, the ROCKS concurred with the team that the proposed uses can be classified as 40 CFR 180.6 (a)(3), no reasonable expectation of finite residues in livestock commodities. The residues of concern may be reconsidered if the use pattern changes and/or additional livestock feedstuffs are proposed in the future.

Drinking Water:  The ROCKS recommended inclusion of parent cyflumetofen, the degradates AB-1, AB-7, AB-11, AB-15, and three dimers of AB-1 (AB-1 dimer, AU16 and AU17) as residues of concern in the drinking water risk assessment. Estimated drinking water concentrations would be based on total residues of parent and the degradates listed above, expressed as parent cyflumetofen. Since the degradates are structurally similar to the parent cyflumetofen, similar toxicity is assumed. The degradate B-1 is not recommended based on the rationale explained above and B-3 is excluded as well based on its structure being significantly distinct from the parent. The octanol:water partition coefficient of parent cyflumetofen is much higher than B-3, and no alerts were reported in DEREK while the parent show alerts that may be correlated to effects observed in the toxicity studies. The other degradates containing the t-butylphenyl moiety, A-1, A-2, A-12, and A-18, are excluded based on structural differences to parent, significantly lower octanol:water partition coefficients than parent cyflumetofen, or presence in the rat metabolism study (i.e. A-12 and A-18).

The residues of concern for cyflumetofen are summarized below in Table 5.1.4.

Table 5.1.4.  Summary of Metabolites and Degradates Recommended for inclusion in the Risk
Assessment and Tolerance Expression
Matrix
                     Residues Included In Risk Assessment
                   Residues Included In Tolerance Expression
Plants[1]
                                 Cyflumetofen
                                 Cyflumetofen
Rotational crops
                                      NA
                                      NA
Livestock (ruminants and poultry)
                                      NA
                                      NA
Drinking Water
                       Cyflumetofen + AB Degradates[2]
                                      NA
NA  -  Not applicable.
[1] If new uses on small grains, leafy vegetables and root/tuber crops are proposed in the future, then additional metabolism studies may be required to reconsider the residues of concern.
[2] AB degradates include AB-1, AB-7, AB-11, AB-15, and three dimers of AB-1 (AB-1 dimer, AU16 and AU17).  Refer to Appendix B for the names and/or chemical structures of the AB degradates.

5.2	Food Residue Profile

The results from plant metabolism studies in mandarin, eggplants, and apples conducted following a foliar treatment of formulated cyflumetofen indicate that the major component of the extractable residue was unchanged parent cyflumetofen in both fruit and leaves, and that residues are generally low. The only major metabolite found in/on fruits was metabolite B-1 (free and conjugate), with residues exceeding 10% of the TRR in mandarin and eggplants only.  The highest residues are generally found in the foliage (leaves) of plants, and not in the fruit itself.  The residue is expected to be a surface residue consisting of primarily parent compound and minor photolytic degradates, as the majority of the radioactivity was removed by acetonitrile surface rinses.  The available metabolism data in plants shows that cyflumetofen undergoes limited translocation or degradation.

Adequate residue chemistry data have been provided for cyflumetofen.  Field trials are of adequate number and geographic representation and showed levels of cyflumetofen residues found in the edible portions of target crops ranging from <0.01 ppm (almonds and pecan nutmeat) to 0.5 ppm (citrus, pome fruit, tomato, strawberry and grapes). Residues decline with increasing pre-harvest intervals (PHIs).  Levels of cyflumetofen residues in livestock feedstuffs were higher and ranged from 0.3-2.0 ppm (see Appendix E Table E.1 for a summary of the residue data for cyflumetofen).  The data were generated using a validated data collection method and are adequately supported by frozen storage stability data, with the exception of tomato which was corrected for residue loss during freezer storage. Sufficient processing studies were submitted for apple, citrus, tomato, and grape to elucidate the fate of cyflumetofen in processed commodities derived from these crops, with concentration only seen in citrus oil and raisins.  HED determined that the proposed uses of cyflumetofen are classified as 180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock commodities.  Metabolism in rotational crops was seen to be very different from that in primary crops.  Depending on the position of the radiolabel, either trifluoroacetic acid (TFA) or a series of medium-polar metabolites in minor concentrations were detected.

5.3	Water Residue Profile

Cyflumetofen is a new active ingredient; therefore, there are no monitoring data currently available for the parent molecule or its residues of concern in drinking water.  Estimated drinking water concentrations (EDWCs) were generated using OPP's standard suite of models.  The EDWCs from surface water sources were calculated using Tier II models Pesticide Root Zone Model (PRZM) and Exposure Analysis Modeling System (EXAMS).  Estimated groundwater EDWCs were calculated using the model Screening Concentrations in Ground Water (SCI-GROW, version 2.3, 07/29/03) as well as Pesticide Root Zone Model-Groundwater (PRZM-GW, version 1.0, December 11, 2012).

Maximum application rates for cyflumetofen as a high-end estimate of exposure in drinking water were modeled based on the proposed labels.  In accord with recommendations of the ROCKS, a total toxic residues approach was used for the modeling that included cyflumetofen, the degradates AB-1, AB-7, AB-11, AB-15, and three dimers of AB-1 (AB-1 dimer, AU16 and AU17).  Surface water EDWCs were corrected for a percent cropped area (PCA) of 0.91.  The PRZM/EXAMS surface water simulations of a NY grapes scenario produced the highest surface water EDWCs of 4.7 ug/L for acute exposure, 0.33 ug/L for chronic exposure, and 0.28 ug/L for long-term cancer exposure.  The SCI-GROW groundwater simulation produced the highest groundwater EDWC of 2.4 x 10[-3] ug/L for both acute and chronic exposures.  The maximum surface and ground water EDWCs for use in the human health risk assessment for cyflumetofen are shown in Table 5.3.

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for Cyflumetofen
Scenario
                          Surface Water Conc., ppb a
                           Groundwater Conc., ppb b
Acute
                                      4.7
                                    0.0024
Chronic (non-cancer)
                                     0.33
                                    0.0024
Chronic (cancer)
                                     0.28
                                Not Determined
[a] From the Tier II PRZM-EXAMS (NY grape scenario)
[b] From the SCI-GROW model
Highest value for use in risk assessment is in bolded

5.4	Dietary Risk Assessment

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-FCID) 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).

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.
5.4.1	Description of Residue Data Used in Dietary Assessment

 The chronic dietary exposure and risk analysis was based on tolerance-level residues, 100% crop treated assumptions, and both empirical and default processing factors.  Empirical processing factors derived from apple, orange, grape, and tomato processing studies were incorporated into the assessment for all processed commodities with the exception of dried tomato, where the DEEM default processing factor was used.    Estimates of residues in drinking water were directly incorporated in the assessments (see Section 5.3).

5.4.2	Percent Crop Treated Used in Dietary Assessment

The chronic dietary exposure and risk assessment assumed 100% crop treated for all commodities included in the assessment.

5.4.3	Acute Dietary Risk Assessment

As previously stated, 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.

5.4.4	Chronic Dietary Risk Assessment

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 protective of human health, the chronic dietary risk estimates are below HED's level of concern (<100% of the chronic population adjusted dose (cPAD)) and range from <1% of the 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.

5.4.5	Cancer Dietary Risk Assessment

Cyflumetofen has been classified as having "Suggestive Evidence of Carcinogenic Potential" 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. The Agency has determined that quantification of risk using a non-linear approach (i.e., reference dose (RfD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to cyflumetofen (see Section 4.5.3).  The results of the chronic dietary risk assessment are discussed in Section 5.4.4.

5.4.6	Summary Table

Table 5.4.6.  Summary of Chronic Dietary (Food + Drinking Water) Exposures and Risk for Cyflumetofen
Population Subgroup
                                cPAD, mg/kg/day
                              Exposure, mg/kg/day
                                    Risk,
                                    % cPAD
U.S. Population
                                     0.17
                                   0.000829
                                     <1
All infants (< 1 year)

                                   0.002493
                                      1.5
Children 1-2 yrs

                                   0.003842
                                      2.3
Children 3-5 yrs

                                   0.002562
                                      1.5
Children 6-12 yrs

                                   0.001275
                                     <1
Youth 13-19 yrs

                                   0.000573
                                     <1
Adults 20-49 yrs

                                   0.000527
                                     <1
Adults 50-99 yrs

                                   0.000596
                                     <1
Females 13-49 yrs

                                   0.000548
                                     <1
*The subpopulation with the highest risk estimates is bolded

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

Cyflumetofen is being proposed for use on ornamentals (i.e., residential landscape areas) and may be applied in residential settings (Sultan[TM] EPA Reg. No. 7969-GGT).   Therefore, residential handler and residential post-application exposure assessments have been conducted according to HED's 2012 Residential Standard Operating Procedures (SOPs).

6.1	Residential Handler Exposure

The proposed uses of cyflumetofen on ornamentals may result in residential handler exposure.  Residential handler exposure is expected to be short-term in duration as intermediate- or long-term exposures are not likely because of the intermittent nature of applications by homeowners.  Residential handlers are assumed to be wearing short-sleeved shirts, short pants, shoes and socks during application of cyflumetofen (i.e., no protective equipment).  The assessments were conducted assuming the maximum application rate (0.2 lbs ai/acre, 0.002 lbs ai/gallon) and used unit exposure values and estimates for area treated or amount handled along with algorithms taken from HED's 2012 Residential SOPs.

The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:
   * Mixing/Loading/Applying Liquid to ornamentals with Hose-End Sprayer
   * Mixing/Loading/Applying Liquid to ornamentals with Manually-pressurized handwand
   * Mixing/Loading/Applying Liquid to ornamentals with Backpack
   * Mixing/Loading/Applying Liquid to ornamentals with a Sprinkler Can

Since no dermal hazard was identified for cyflumetofen in the toxicological database, only inhalation exposure assessments were conducted for residential handlers.  Inhalation margins of exposure (MOEs) are above the LOC of 100 for all scenarios assessed and are not of concern (MOEs >= 100).  Short-term inhalation residential handler estimated exposure and risk estimates are shown in Table 6.1 below.

Table 6.1.  Short-Term Residential Handler Non-cancer Exposure and Risk Estimates for Cyflumetofen
                               Exposure Scenario
                               Level of Concern
                      Inhalation Unit Exposure (mg/lb ai)
                          Maximum Application Rate[1]
                                (lbs ai/gallon)
                    Area Treated or Amount Handled Daily[2]
                                   (gallons)
                                  Inhalation

                              Dose (mg/kg/day)[3]
                                    MOE[4]
                            Mixer/Loader/Applicator
                         Manually-pressurized handwand
                                      100
                                     0.018
                                     0.002
                                       5
                                   0.0000023
                                   7,300,000
                               Hose-end Sprayer

                                    0.0014
                                     0.002
                                      11
                                  0.00000039
                                  43,000,000
                                   Backpack

                                     0.14
                                     0.002
                                       5
                                   0.000018
                                    940,000
                                 Sprinkler can

                                    0.0014
                                     0.002
                                       5
                                  0.00000018
                                  94,000,000
1	Based on registered or proposed label (EPA Reg. No. 7969-GGT)
2	Based on HED's 2012 Residential SOPs
3	Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day or gallons/day) / BW (80 kg)
4	Inhalation MOE = Inhalation NOAEL (16.5 mg/kg/day) / Inhalation Dose (mg/kg/day)

6.2	Post-Application Exposure

There is the potential for post-application exposure to individuals (adults and children 6 < 11 years old) as a result of being in an environment that has been previously treated with cyflumetofen.  However, since no dermal hazard was identified in the toxicity database for cyflumetofen, a quantitative residential post-application dermal risk assessment is not required and was not completed.  Post-application inhalation exposure while performing activities in previously treated gardens was not assessed due to the low vapor pressure (4.43 x 10[-8] mm Hg @ 25 ºC) and the expected dilution in outdoor air after an application has occurred.

For the residential ornamental/landscape use scenario, post-application non-dietary ingestion exposure is not assessed for children (1 < 2 years old).  The potential for exposure via non-dietary ingestion for young children is greatly diminished since young children are not expected to engage in the types of activities associated with these areas (e.g., gardening) or utilize these areas for prolonged periods of play.

6.3	Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 reflects the residential risk estimates that are recommended for use in the aggregate assessment for cyflumetofen.
   * The recommended residential exposure for use in the adult (male and female) aggregate assessment reflects inhalation exposure from mixing/loading/applying the liquid cyflumetofen formulation with a backpack sprayer (0.002 lbs ai/gallon).
   * There is no recommended residential contribution to the children aggregate assessment.
Table 6.3.  Recommendation for the Short-Term Residential Exposures for the Cyflumetofen Aggregate Assessment[1]
                                   Lifestage
                              Residential Handler

                              Dose (mg/kg/day)[2]
                                    MOE[3]

                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Total
                                  Short-Term
Adult Handler
                                      N/A
                                   0.000018
                                   0.000018
                                      N/A
                                    940,000
                                    940,000
1	Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.
2	Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 6.1.  Total = dermal + inhalation.
3	Residential Handler MOE = the MOEs associated with the highest doses identified in Table 6.1.  Total = 1 / (1/Dermal MOE) + (1/Inhalation MOE).

6.4	Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for cyflumetofen at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (4.43 x 10[-8] mm Hg @ 25 ºC), and the low proposed use rate (0.2 lb ai/A).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for cyflumetofen.

6.5	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for cyflumetofen.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.

7.0	Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For cyflumetofen, potential exposures from food, drinking water, and residential scenarios were aggregated.  This assessment is based on the changes in the new Residential SOPs implemented in January of 2012.

7.1	Acute Aggregate Risk

Acute aggregate risk estimates include exposure to residues in food and water alone; therefore, the acute aggregate risk estimates are equivalent to the acute dietary risk assessment.  However, for cyflumetofen, no toxic effects attributable to a single dose were observed in the toxicology database.  As a result, an acute aggregate risk assessment is not required for this chemical.

7.2	Short-Term Aggregate Risk

There is a potential for short-term exposure to cyflumetofen via dietary and residential exposure pathways.  To estimate short-term aggregate risk, HED therefore combined chronic dietary (food and water) exposures (as a measure of average background dietary exposure) with short-term residential exposures.  These pathways lead to exposure via oral (background) and inhalation (primary) routes only, since no dermal hazard has been identified for cyflumetofen.

The most conservative residential exposure scenario was chosen for the adult population which reflects inhalation exposure from mixing/loading/applying the liquid cyflumetofen formulation with a backpack sprayer (refer to Section 6.3).  For background dietary exposure, the adult sub-population with the highest exposure (adults 50-99) was chosen since this is protective for all other adult sub-populations.  There are no residential exposures expected for children (refer to Section 6.2); therefore a short-term aggregate risk assessment for children is not required and was not performed.

Short-term aggregate margins of exposure for adults (all adult sub-populations) are above the LOC of 100 and are not of concern (MOEs >= 100).  Short-term estimated exposures and risks are shown below in Table 7.2.
Table 7.2.  Short-Term Aggregate Risk Calculations
                                  Population
                     Short- or Intermediate-Term Scenario

                                NOAEL mg/kg/day
                                    LOC[1]
                      Max Allowable Exposure[2] mg/kg/day
                 Average Food and Water Exposure[3] mg/kg/day
                       Residential Exposure[4] mg/kg/day
                          Total Exposure[5] mg/kg/day
                Aggregate MOE (food, water, and residential) 6
Adults 50-99
                                     16.5
                                      100
                                     0.165
                                   0.000596
                                   0.000018
                                   0.000614
                                    27,000
[1] Intraspecies factor= 10x; Interspecies factor = 10x
[2] Maximum Allowable Exposure (mg/kg/day) = NOAEL (16.5 mg/kg/day)/LOC (100)
3 Average food and water exposure for adults = chronic dietary exposure for adults 50-99 (the highest exposed adult sub-population)
[4] Residential Exposure = [Inhalation Exposure]
[5] Total Exposure = Avg Food & Water Exposure + Residential Exposure) - Refer to Table 6.3
[6] Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]

7.3	Chronic Aggregate Risk

As there are no uses that are expected to result in long-term residential exposure, long-term (chronic) aggregate risk includes only chronic dietary (food and water) exposure.  As noted in Section 5.4.4, there are no chronic dietary risks of concern for cyflumetofen.

7.4	Cancer Aggregate Risk

Cancer aggregate risk estimates for the general U.S. population include chronic exposure to residues in food and water as well as residential sources.  Cyflumetofen has been classified as having "Suggestive Evidence of Carcinogenic Potential" 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. The Agency has determined that quantification of risk using a non-linear approach (i.e., reference dose (RfD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to cyflumetofen (see Section 4.5.3).  Based on this, since the chronic dietary risk assessment (refer to Section 5.4.4) is considered to be protective of any cancer effects, a separate quantitative cancer aggregate risk assessment is not required.

8.0	Cumulative Exposure/Risk Characterization

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/.

9.0	Occupational Exposure/Risk Characterization

An occupational exposure and risk assessment was conducted to support the proposed uses of cyflumetofen.  Full details of that assessment are included in the occupational and residential memorandum listed in the reference section and the results are briefly summarized here.

9.1	Short-/Intermediate- Term Handler Risk

Cyflumetofen is a selective contact miticide that is effective on all mite life stages.  Application methods, maximum application rates and use sites were summarized previously in Table 3.3.  The occupational exposure and risk assessment generally addresses risks to workers exposed in an occupational setting via the dermal and inhalation routes of exposure.  However, since no dermal hazard was identified in the toxicity database for cyflumetofen, a quantitative dermal assessment is not required and risks were quantitatively assessed for inhalation exposure only.  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.

Estimates of inhalation exposure were calculated for various levels of personal protective equipment (PPE).  Results are presented for "baseline" level of attire defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline attire with various levels of PPE as necessary (e.g., gloves, respirator, etc.).  The cyflumetofen product labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirts, long pants, protective eyewear, chemical-resistant gloves, and shoes plus socks.

All occupational handler scenarios assessed for the proposed uses of cyflumetofen resulted in estimated inhalation margins of exposure (MOEs) above the LOC of 100 for all scenarios assessed and, therefore, are not of concern (MOEs >=100).  Occupational handler risk estimates are shown in Table 9.1.

Table 9.1.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Cyflumetofen
                               Exposure Scenario
                                Crop or Target
                           Inhalation Unit Exposure
                                (μg/lb ai)[1]
                                    Maximum
                              Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                  Inhalation

                                   Baseline

                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                 Mixer/Loader
                                    Aerial
                                    Tomato
                                     0.219
                                0.2 lb ai/acre
                                      350
                                   0.000191
                                    86,000
                                   Airblast
                    Nursery (ornamentals, container stock)
                                     0.219

                                      20
                                   0.000011
                                   1,500,000

                Citrus Fruit, Grapes, Pome Fruit, Tree Nut Group
                                     0.219

                                      40
                                   0.0000219
                                    750,000
                                  Groundboom
                         Field-grown ornamental crops
                                     0.219

                                      40
                                   0.000022
                                    750,000

                    Nursery (ornamentals, container stock)
                                     0.219

                                      60
                                   0.000033
                                    500,000

         Greenhouse (ornamentals, roses, cut flowers, container stock)
                                     0.219

                                      60
                                   0.000033
                                    500,000

     Citrus Fruit, Grapes, Pome Fruit, Strawberry, Tomato, Tree Nut Group
                                     0.219

                                      80
                                   0.000044
                                    380,000
                                  Applicator
                                    Aerial
                                    Tomato
                                     0.068
                                0.2 lb ai/acre

                                      350
                                   0.0000595
                                    280,000
                                   Airblast
                    Nursery (ornamentals, container stock)
                                     4.71

                                      20
                                   0.000235
                                    70,000

               Citrus Fruit, Grapes, Pome Fruit, Tree Nut Group
                                     4.71

                                      40
                                   0.000471
                                    35,000
                                  Groundboom
                         Field-grown ornamental crops
                                     0.34

                                      40
                                   0.000034
                                    490,000

                    Nursery (ornamentals, container stock)
                                     0.34

                                      60
                                   0.000051
                                    320,000

         Greenhouse (ornamentals, roses, cut flowers, container stock)
                                     0.34

                                      60
                                   0.000051
                                    320,000

     Citrus Fruit, Grapes, Pome Fruit, Strawberry, Tomato, Tree Nut Group
                                     0.34

                                      80
                                   0.000068
                                    240,000
                                    Flagger
                                    Flagger
                                    Tomato
                                     0.35
                                0.2 lb ai/acre
                                      350
                                   0.000306
                                    54,000
                            Mixer/Loader/Applicator
                         Backpack
(broadcast foliar)
         Greenhouse (ornamentals, roses, cut flowers, container stock)
                                      140
                                0.002 lb ai/gal

                                      40
                                    0.00014
                                    120,000

                                   Forestry
                                     2.58

                                      40
                                  0.00000258
                                   6,400,000

                    Nursery (ornamentals, container stock)
                                      140

                                      40
                                    0.00014
                                    120,000

                       Landscaping, trees/shrubs/bushes
                                      140

                                      40
                                    0.00014
                                    120,000

                          Landscaping, plants/flowers
                                      140

                                      40
                                    0.00014
                                    120,000
               Manually-pressurized Handwand
(broadcast foliar)
         Greenhouse (ornamentals, roses, cut flowers, container stock)
                                      30

                                      40
                                    0.00003
                                    550,000

                    Nursery (ornamentals, container stock)

                       Landscaping, trees/shrubs/bushes

                          Landscaping, plants/flowers

                             Interior landscaping

              Mechanically-pressurized Handgun
(broadcast foliar)
                         Citrus Fruit, Tree Nut Group
                                      3.9
                                0.002 lb ai/gal
                                     1000
                                   0.0000975
                                    170,000

         Greenhouse (ornamentals, roses, cut flowers, container stock)
                                      120

                                     1000
                                     0.003
                                     5,500

                    Nursery (ornamentals, container stock)
                                      3.9
                                0.002 lb ai/gal

                                     1000
                                   0.0000975
                                    170,000

                       Landscaping, trees/shrubs/bushes
                                      3.9

                                     1000
                                   0.0000975
                                    170,000
1	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (September 2012); Level of mitigation: Baseline.
2	Based on registered or proposed label (Reg. No. 7969-GGT; 7969-GGA).
3	Exposure Science Advisory Council Policy #9.1.
4	Inhalation Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (kg).
5	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).
9.2	Short-/Intermediate- Term Post-Application Risk

9.2.1	Dermal Post-application Risk

There is the potential for post-application exposure to workers as a result of proposed uses of cyflumetofen.  However, since no dermal hazard was identified in the toxicity database for cyflumetofen, a quantitative occupational post-application dermal risk assessment is not required and was not completed.

9.2.2	Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for cyflumetofen at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (4.43 x 10[-8] mm Hg @ 25 ºC), and the low proposed use rate (0.2 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for cyflumetofen.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting tree nuts is another potential source of post-application inhalation exposure.  However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post-application inhalation exposure during these dusty mechanical harvesting activities.  The non-cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100).

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

Additionally, the Worker Protection Standard  (WPS) for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].  It is assumed that the user will have met the ventilation requirement within the 12 hour REI (unless there is no ventilation capability, then the user must wait 24 hours).  It is reasonable to assume that based on the WPS ventilation requirements, postapplication inhalation exposure will be negligible.

10.0	References

I. Negrón-Encarnación, 26-March-2013, D408530, Cyflumetofen.  Report of the Residues of 	Concern Knowledgebase Subcommittee (ROCKS).

S. Shelat, 07-January-2014, D408532, Cyflumetofen.  Occupational and Residential Exposure
	Assessment for a Proposed Use on Citrus Fruit, Grapes, Pome Fruit, Strawberry, Tomato, 	Tree Nut Group, and Ornamentals.

J. Van Alstine, 03-July-2013, TXR No. 0056691, Cyflumetofen:  Summary of the Hazard and 	Science Policy Council (HASPOC) Meeting of June 6, 2013:  Recommendations on the 	Need for an Inhalation Study.

S. Wente, 12-June-2013, D410981, Drinking Water Exposure for Cyflumetofen Section 3 New 	Use on Citrus, Pome Fruits, Grapes, Strawberries, Tomatoes, Tree Nuts, and 	Ornamentals.

D. Wilbur, 26-June-2013, D408533, Cyflumetofen.  Chronic Aggregate Dietary (Food and 	Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on 	Grape, Strawberry, and Tomato.

D. Wilbur, 09-July-2013, D408531, Cyflumetofen.  Petition for the Establishment of Permanent 	Tolerances and Registration for Use on Citrus (Crop Group 10-10), Pome Fruits (Crop 	Group 11-10), Tree Nuts (Crop Group 14-12), Grape, Strawberry, and Tomato.  	Summary of Analytical Chemistry and Residue Data.

Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

The requirements (40CFR §158.340) for the food use of cyflumetofen are in Table A.1.

Table A.1.  Toxicology Data Requirements for Cyflumetofen
                                     Test

                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)
870.3150    Oral Subchronic (non-rodent)
870.3200    21/28-Day Dermal
870.3250    90-Day Dermal
870.3465    90-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                     yes
                                      no
                                    yes[a]
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (non-rodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)
870.4100b  Chronic Toxicity (non-rodent)
870.4200a  Oncogenicity (rat)
870.4200b  Oncogenicity (mouse)
870.4300    Chronic/Oncogenicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation (bacterial)
870.5300    Mutagenicity -- Gene Mutation (mammalian)
870.5375    Mutagenicity -- Structural Chromosomal Aberrations
870.5395    Mutagenicity -- Other Genotoxic Effects	        870.5500    Mutagenicity -- Other Genotoxic Effects
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotoxicity Screening Battery (rat)
870.6200b  90-Day Neurotoxicity Screening Battery (rat)
870.6300    Developmental Neurotoxicity
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                      no
                                      no
                                      yes
                                      yes
                                      no
870.7485    General Metabolism
870.7600    Dermal Penetration			        870.7800    Immunotoxicity
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
[a]Inhalation study was waived by the HASPOC.

A.2	Toxicity Profiles

Table A.2-1.  Acute Toxicity Profile - Test Substance
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
                                   870.1100
Acute oral [Rat]
                                   48542669
                                >2000 mg/kg
                                      III
                                   870.1200
Acute dermal [Rat]
                                   48542671
                                >5000 mg/kg
                                      IV
                                   870.1300
Acute inhalation [Rat]
                                  48542672-3
                                 >2.65 mg/L
                                      IV
                                   870.2400
Acute eye irritation [Rabbit]
                                   48542675
                               Minimal irritant
                                      II
                                   870.2500
Acute dermal irritation [Rabbit]
                                   48542674
                                Not an irritant
                                      IV
                                   870.2600
Skin sensitization [Guinea pig]
                                   48542676
                                Skin sensitizer
                                      NA

Table A.2-2.  Subchronic, Chronic and Other Toxicity Profile
                         Guideline Number/ Study Type
                     MRID(s) (year)/ Classification/Doses
                                    Results
870.3200
28-day dermal toxicity
[rat]
48542686 (2010)
0, 100, 300, 1000 mg/kg/day (mkd),
6 hours/day for 5 days/week
Acceptable/Guideline
The NOAEL is 1000 mg/kg/day. The LOAEL was not determined.

28-day feeding study (rat)
48542678 (2004)
0, 100, 500, 1000, 5000 ppm
M: 0, 7.5, 37.6, 75.1, 384 m/k/d
F: 0, 8.05, 40.8, 79.8, 409 m/k/d
Acceptable/nonguideline
The NOAEL is 500 ppm (37.6/40.8 mg/kg/day in males/females). The LOAEL is 1000 ppm (75.1/79.8 mg/kg/day in males/females) based on increased adrenal weight and histopathology.
870.3100
90-Day feeding study [rat]
48542682 (2004)
0, 100, 300, 1000, 3000 ppm
M:0, 5.4, 16.5, 54.5 167 m/k/d,
F: 0, 6.28, 19.0, 62.8,193 m/k/d
Acceptable/guideline
The NOAEL is 300 ppm (16.5/19.0 mg/kg/day in males/females).  The LOAEL is 1000 ppm (54.5/62.8 mg/kg/day in males/females) based on the hematology and organ weight changes in the liver, adrenal, kidney and ovaries; and histopathology effects in the adrenals and the ovaries.
28-day feeding study (mouse)
48542679 (2004)
0, 100, 500, 1000, 5000 ppm
M: 0, 13.1, 67.2,135,663 m/k/d;
F: 0, 14.5, 74.9, 150, 763 m/k/d
Acceptable/nonguideline
The NOAEL is 1000 ppm (135/150 mg/kg/day in males/females). The LOAEL is 5000 ppm (663/763 mg/kg/day in males/females) based on increased adrenal weights and adrenal vacuolation.

870.3100
90-Day feeding study [mouse]
48542683 (2004)
0, 300, 1000, 3000, 10000 ppm M: 0, 35.4, 117, 348, 1200 m/k/d
F: 0, 45.0, 150, 447, 1509 m/k/d
Acceptable/guideline
The NOAEL is 1000 ppm (117/150 mg/kg/day in males/females). The LOAEL is 3000 ppm (348/447 mg/kg/day in males/females), based on decreased body weights in females, and diffuse hypertrophy and vacuolation of cortical cells in the adrenals in both sexes.
870.3150
90-Day oral (capsule) study [dog]
48542684 (2003)
0, 30, 300, 1000 mkd (M/F) (capsule)
Acceptable/guideline
The NOAEL is 300 mg/kg/day. The LOAEL is 1000 mg/kg/day, based on decreased body weight and body weight gain, increased adrenal weights (males only) and vacuolation of the adrenals.
870.3700
Prenatal developmental [rabbit]
48542706 (2003)
0, 50, 250, 1000 mkd
Gavage GD 6-28
Acceptable/guideline
The maternal NOAEL is 1000 mg/kg/day (the highest dose tested).
The developmental NOAEL is 250 mg/kg/day. The developmental LOAEL is 1000 mg/kg/day based on changes in ossification, paw flexion and decreased fetal body weights.
870.3700
Prenatal developmental
[rats]
48542704 (2001)
0, 50, 250, 1000 mkd
Gavage, GD 6-19
Acceptable/guideline
The maternal NOAEL is 50 mg/kg/day. The maternal LOAEL is 250 mg/kg/day, based on an increase in adrenal weights and organ to body weight ratio.
The developmental NOAEL is 50 mg/kg/day.The developmental LOAEL is 250 mg/kg/day, based on an increased incidence of incompletely ossified sternal centra.
870.3800
Reproduction and fertility effects
[rat]
48542702 (2004)
0, 150, 500, 1500 ppm
(0,9.2, 30.6, 89.4/0, 13.8, 46.6, 141.1 mkd, M/F)
Acceptable/guideline
The parental NOAEL is 150 ppm (9.2/13.8 mg/kg/day in males/females). Parental LOAEL is 500 ppm (30.6/46.6 mg/kg/day in males/females) based on effects on the adrenals (increased organ weights and histopathology).
The reproductive NOAEL in females is 150 ppm (13.8 mg/kg/day). Reproductive LOAEL in females is 500 ppm (46.6 mg/kg/day) based on hormone changes (significantly decreased FSH, progesterone, and 17 β-estradiol). The reproductive the NOAEL in males is 1500 ppm (89.4 mg/kg/day); the LOAEL in males is not determined,
The offspring NOAEL is 150 ppm (9.2/13.8 mg/kg/day in males/females).Offspring LOAEL is 500 ppm (30.6/46.6 mg/kg/day in males/females) based on effects on the adrenals (increased organ weights and histopathology) in both sexes.
870.4100a
Chronic toxicity
[rat]
48542696 (2004)
0, 50, 150, 500,1500 ppm
(0, 4.9, 16.5, 49.5/0, 6.1, 20.3, 61.9 mkd, M/F)
Acceptable/guideline
The NOAEL is 500 ppm (16.5/20.3 mg/kg/day in males/females). The LOAEL is 1500 ppm (49.5/61.9 mg/kg/day in males/females) based on increased adrenal weights, hyperplasia and hypertrophy of the adrenal cortex in both sexes, and luminal dilatation of the gland in the uterine horn in females.
870.4100a
Chronic toxicity
[rat]
49029701 (2013)
0, 6000 ppm
(0, 250/319 mkd, M/F)
Acceptable/guideline
In this supplemental study, the LOAEL was 6000 ppm (250/319 mg/kg bw/day in males/females) based on increased adrenal weights accompanied by gross pathology and histopathology lesions noted in both sexes, vacuolation of the interstitial gland cell of the ovary and hyperplasia of the interstitial cell of the testes.  Only one dose was tested.
870.4100b
Chronic toxicity
[dog]

48542685 (2008)
0,30, 300, 1000 mkd (capsule)
Acceptable/guideline
The NOAEL is 30 mg/kg/day. The LOAEL is 300 mg/kg/day, based on vacuolation and histopathology findings in the adrenals.

870.4200a
Carcinogenicity
[rat]
46542697 (2004)
0, 50, 150, 500,1500 ppm
(0, 4.9, 16.5, 49.5/0, 6.1, 20.3, 61.9 mkd, M/F)
Acceptable/guideline
The NOAEL is 500 ppm (16.5/20.3 mg/kgkday for males and females). The LOAEL is 1500 ppm (49.5/61.9 mg/kg/day in males/females) based on increased adrenal weights, hyperplasia and hypertrophy of the adrenal cortex in both sexes, and luminal dilatation of the gland in the uterine horn in females.
There was no treatment related increase in tumor incidence when compared to controls.
870.4200a
Carcinogenicity
[rat]
49226601 (2013)
0 or 6000 ppm
(0, 220/287 mkd, M/F)
Acceptable/guideline
The LOAEL for this supplementary study is 6000 ppm, based on effects on clinical signs of toxicity (females), decreased body weight (both sexes) and body weight gain (males), changes in hematological parameters (males), organ weights (both sexes), and histopathology findings (both sexes).  Only one dose was tested. Increased incidence was observed in thyroid C-cell tumours (carcinomas, as well as adenomas and carcinomas combined) in males only as well as an increase in the incidence of testicular interstitial cell tumours. There was no treatment related increase in tumor incidence in females when compared to controls.
870.4200b
Carcinogenicity
[mouse]
48542698 (2004)
0,150,500,1500,5000 ppm
(0,15.5/14.3, 54.3/48.1,156/144, 537/483 mkd, M/F)
Acceptable/guideline
The NOAEL is 1500 ppm (156/144 mg/kg/day in males/females); the LOAEL is 5000 ppm (537/483 mg/kg/day in males/females) based on increased incidence of diffuse adrenal cortical cell vacuolation and increased adrenal wt in males.
There was no treatment related increase in tumor incidence when compared to controls.
870.4200b
Carcinogenicity
[mouse]
49209101 (2013)
0, 6000 ppm
(0,1143/1132 mkd, M/F)
Acceptable/guideline
The LOAEL for this confirmatory study is 10,000 ppm (1143/1132 mg/kg/day, in males/females), based on clinical signs of toxicity, increased adrenal weights, enlarged spleen and an increased incidence of extramedullary hematopoiesis in the spleen of treated females and an increased incidence of diffuse adrenal cortical cell vacuolation and deposition of brown pigment in the cortico-medullary junction of the adrenals in both sexes.. At the dose tested, there was no treatment-related increase in tumor incidence when compared to controls.
870.5100
Gene Mutation
(TA98, TA100, TA1535, TA1537 of S. typhimurium and WP2 uvrA E.coli)
48542687 (2001)
Acceptable/guideline
Negative
870.5300
In vitro mammalian cell gene mutation test (Mouse lymphoma cell)
48542692 (2007)
Acceptable/guideline
Positive (+/- S9)
870.5375
In vitro mammalian chromosome aberration test (CHL)
48542691 (2011)
48542689 (2003)
Acceptable/guideline
Negative
870.5395
Mammalian bone morrow micronucleus test
48542694 (2003)
Acceptable/guideline
Negative
870.5550
In vivo, Unscheduled DNA synthesis (UDS)
48542695 (2007)
Acceptable/guideline
Negative
870.7485
Metabolism and pharmacokinetics
[rat]
48542662,48542661,48542667, 48542663, 48542665, 48542664, 48542666, 48542668, 48542825
(2004-2011)
Acceptable/guideline
[14]C-cyflumetofen is fairly rapidly absorbed and eliminated. The test material was fairly well absorbed at the low dose (approximately 68-78% of the administered dose), but less so at the high dose (approximately 35-46% of the administered dose). Saturation of absorption was evident at the high dose, and was more pronounced in males than in females.  Only low levels of radioactivity were retained in tissues up to 72 hours post-dosing, with the highest levels observed in the gastrointestinal tract, liver and kidneys. The parent compound was extensively metabolized following administration of a low dose of [14]C-cyflumetofen, but poorly metabolized following administration of a high dose. It appears as though the parent molecule is metabolized via cleavage of the tolyl and phenyl ring structures.
870.7600
Dermal penetration
[rat]
48542724 (2011)
Single dose: 2, 20, 2000 ug/cm[2]
Acceptable/guideline
Dermal absorption factor (11%)
870.6200
Acute Neurotoxicity - Rats
48542702 (2010)
0, 125, 500, 2000 mg/kg (gavage)
Acceptable/guideline
The NOAEL is 2000 mg/kg, the highest dose tested. No LOAEL was established.
No evidence of neurotoxicity.
870.6200
Subchronic neurotoxicity
[rat]
48542708 (2012)
0, 500, 1500, 5000 ppm
(0, 30/41, 89/99, 293/353 mkd, M/F)
Acceptable/guideline
The systemic NOAEL is 500 ppm (30/41 mg/kg/day in males/females). The systemic LOAEL is 1500 ppm (89/99 mg/kg/day in males/females) based on the increased adrenal weights in females and the altered adrenal histopathology of both sexes.
No evidence of neurotoxicity at 5000 ppm (HDT).
870.7800
Immunotoxicity
[rat]
48542726 (2011)
0, 500, 1500, or 5000 ppm
(0, 33, 107, 349 mkd, females only)
Acceptable/Guideline
The NOAEL for systemic toxicity is 500 ppm (33 mg/kg/day) in female rats. The systemic toxicity LOAEL was 1500 ppm (107 mg/kg/day) based upon increased adrenal weights and correlating histopathology.
The NOAEL for immunotoxicity is 5000 ppm (349 mg/kg/day).The immunotoxicity LOAEL was not observed.

A.3	Hazard Identification and Endpoint Selection

A.3.1	Acute Reference Dose (aRfD) - General Population and Females Age 13-49
Study Selected: None