Document ID: EPA-HQ-OPP-2018-0636-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2018-10-24T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Richard Gebken, 703-305-6701

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

OAT AGRIO., LTD

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from OAT AGRIO CO., LTD. 1-3-1 Kanda Ogawa-machi, Chiyoda-ku Tokyo 101-0052, Japan c/o Landis International, Inc, PO Box 5126, Valdosta, GA 31603-5126 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180

(Options (pick one)
   
   	1. by establishing a tolerance for residues of 

	Cyflumetofen (2-methoxyethyl α-cyano-α-[4-(1,1-dimethylethyl)phenyl]-β-oxo-2-(trifluoromethyl)benzenepropanoate) for the import commodity coffee at 0.08 parts per million (ppm).  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. Metabolism studies on fruit crops (mandarin, apple, and eggplant) 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 0.54 lbs ai/acre). In all three plant metabolism 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 fruit 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 fruit at a PHI of 14 days.  In all three plant metabolism studies, the metabolic profile and pathways were comparable. Consequently, sufficient data are available to extrapolate the nature of the residue in other crops.

	2. Analytical method. In Study No. EAS S17-04257, cyflumetofen in the samples of green coffee bean and roasted coffee bean were extracted with acetonitrile on a shaker. After centrifugation, the extract was diluted with water, filtered and analyzed by Liquid Chromatography coupled with Tandem Mass Spectrometry (LC-MS/MS) in a positive ionization mode.  Metabolite B-1 in the samples of green coffee bean and roasted coffee bean were extracted with H2O: acetonitrile (7:3, v:v), followed by acetonitrile on a shaker. After centrifugation, the extract was diluted with water, filtered and analyzed by LC-MS/MS in a negative ionization mode.  Cyflumetofen and B-1 in the samples of instant coffee were extracted with 0.02% formic acid in acetonitrile on a shaker. After centrifugation, the extract was diluted with water, filtered and analyzed by LC-MS/MS. The method performance was verified before and during sample analysis by determining the recoveries from control samples fortified with cyflumetofen/B-1 at 0.01/0.01 ppm (Limit of Quantitation, LOQ) and 0.1/0.1ppm (10x LOQ) for green coffee bean, roasted coffee bean and instant coffee. The LOD (Limit of Detection) for cyflumetofen and B-1 was calculated as 0.0029 ppm and 0.0017 ppm for green coffee bean, 0.0025 ppm and 0.0017 ppm for roasted coffee bean, and 0.0019 ppm and 0.0011 ppm for instant coffee.

	3. Magnitude of residues. Cyflumetofen 20% suspension concentrate (Okay(TM) 200 g/L) was applied to coffee to determine residue levels in five field trials conducted in several distinct geographic areas of Brazil (Nepomuceno, MG; Laranjal Paulista, SP; Sooretama, ES; Espirito Santo Pinhal, SP; Abatiá, PR) in which coffee is grown commercially (Study No. EAS S17-04257). An application rate equivalent to 0.18 lbs ai/A was applied to the test crops twice with a 14-day retreatment interval. Samples of coffee berries were collected from trial plots at maturity, 14 days after the last test substance application (DALA). At one decline trial, samples were also collected at 0, 7, and 21 DALA. Coffee berry samples were harvested by hand from the plot, field dried for 19-46 days, and then peels were mechanically removed to obtain the green coffee beans. After removing the peel to obtain the green coffee beans, samples were collected, bagged and frozen on the same day. All samples were placed directly into separate, pre-labeled, sample containers.  One trial for generation of processed commodity matrices included an additional plot treated with Okay 200 g/L at a 5X exaggerated rate. At that trial, a bulk sample of green coffee berries was collected, peeled to obtain the green coffee beans, frozen and transferred to a processor. The green bean samples were stored frozen for 16-29 days and used to produce roasted coffee beans and instant coffee.

Cyflumetofen average residues in green coffee bean samples collected at 14 DALA were 0.026 (decline trial), 0.031, <LOQ (<0.01), 0.045 and 0.019 ppm.   Average residues of metabolite B-1 in samples collected at 14 DALA were 0.017 (decline trial), 0.022, 0.035, <LOQ (0.01) and 0.014 ppm.  Average residues of cyflumetofen in samples collected at 0, 7 and 21 DALA were 0.065, 0.048 and 0.016 ppm (with outlier of 0.0635 ppm excluded), respectively.  Average residues of metabolite B-1 in samples collected at 0, 7 and 21 DALA were 0.08, 0.023 and 0.011, respectively.  Average residues of cyflumetofen and metabolite B-1 were found at 0.247 and 0.102 ppm, respectively, in the RAC green coffee beans from the 5X treated plot from which the processed fractions were generated. No residues of cyflumetofen were detected in either the roasted beans or instant coffee processed fractions. However, average residues of metabolite B-1 were detected in roasted beans at 0.127 ppm and in instant coffee at 0.0457 ppm. Therefore, there is no concentration (concentration factor <0.04) of cyflumetofen residues observed in roasted coffee beans or instant coffee. No concentration of metabolite B-1 residues was observed for instant coffee (concentration factor <0.5), but a slight concentration of residues was observed in the roasted coffee beans (concentration factor of 1.2).  The Brazilian label provides directions to apply approximately 0.18 lb ai/A twice with a 14-day retreatment interval and a 14-day pre-harvest interval.

B. Toxicological Profile

	1. Acute toxicity.  Cyflumetofen has favorable acute toxicity. Study results place technical cyflumetofen in toxicity category III for acute oral and in toxicity category IV for both acute dermal and acute inhalation toxicity. Cyflumetofen was determined to be a dermal sensitizer. Cyflumetofen was not acutely neurotoxic.

	2. Genotoxicity. 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.  Cyflumetofen was negative for inducing mutations in an in vitro mutation (Ames) test and did not induce chromosome aberrations in Chinese hamster lung cells in studies that were conducted with and without metabolic activation. Cyflumetofen was shown to be genotoxic at precipitating and/or cytotoxic concentrations in an in vitro mouse lymphoma test (using L5178Y cells) both with and without metabolic activation. However, cyflumetofen was not genotoxic in an in vivo DNA-repair assay and no evidence of clastogenicity was observed in an in vivo micronucleus test. Overall, the weight of the evidence demonstrates that cyflumetofen is not genotoxic.

	3. Reproductive and developmental toxicity. 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. There were no treatment related adverse effects observed in maternal animals at the highest dose tested.
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. 
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 life stages.

	4. Subchronic toxicity. In a rat 28-day feeding study, the NOAEL was determined to be 500 ppm (37.6/40.8 mg/kg/day in males/females). The LOAEL was 1000 ppm (75.1/79.8 mg/kg/day in males/females) based on increased adrenal weight and histopathology. Adverse findings in the adrenal gland were observed across species in rats, mice and dogs in subchronic and chronic oral toxicity studies. This consisted of increased organ weight and vacuolation and hypertrophy of adrenal cortical cells. At high doses a vacuolation of the interstitial cells of the ovary was also observed in rats. 
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. However, the Agency has determined that the requirement for this study is not needed at this time.  For short-and intermediate-term inhalation risk assessments, an oral NOAEL was selected from three studies as described in the chronic dietary section below.  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. Cyflumetofen was determined to be not neurotoxic in a subchronic neurotoxicity study.

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. Cyflumetofen was determined to be non-immunotoxic. 

	5. Chronic toxicity. In a rat chronic toxicity study, the NOAEL was determined to be 500 ppm (16.5/20.3 mg/kg/day in males/females). With a LOAEL of 1500 ppm (49.5/61.9 mg/kg/day in males/females) which was 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.

In a supplemental rat chronic toxicity 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.

In a dog chronic toxicity study, the NOAEL was determined to be 30 mg/kg/day. The LOAEL was 300 mg/kg/day, based on vacuolation and histopathology findings in the adrenals.

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.

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.

	6. Animal metabolism. There were a series of metabolism studies conducted for cyflumetofen. [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.

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 treated samples.  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.

	7. Metabolite toxicology. Toxicity studies were conducted with metabolites B-1 and B-3. The acute oral LD50 for B-1 was >2000 mg/kg. B-1 was negative for inducing mutations in an in vitro mutation (Ames) test and did not induce chromosome aberrations in human lymphocytes in studies that were conducted with and without metabolic activation. B-1 is not genotoxic. 

B-3 was negative for mutagenicity in most strains tested in an in vitro (Ames) assay but was positive with Salmonella typhimurium strain T A 100 both with and without metabolic activation.

No effects were observed when B-3 was tested in an in vitro chromosome aberration assay with human lymphocytes. B-3 was positive in an in vitro mouse lymphoma test (L5178Y cells) without activation but was negative with metabolic activation. There were no effects observed in an in vivo rat liver UDS test with B-3.

	8. Endocrine disruption. Cyflumetofen does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system. There is no evidence that cyflumetofen has any effect on endocrine function in developmental, reproduction or developmental neurotoxicity studies.  Furthermore, histological investigation of endocrine organs in chronic dog, rat and mouse studies did not indicate that the endocrine system is targeted by cyflumetofen.

C. Aggregate Exposure

	1. Dietary exposure. An assessment was conducted to evaluate the potential risk due to acute and chronic dietary exposure of the U.S. population and sub-populations to residues of cyflumetofen in food and drinking water. The dietary exposure assessment for cyflumetofen was conducted using tolerance level residues, 100% crop treated factors, and processing factors from EPA guideline studies. The crops and residue values used in the assessment were: tomato= 0.4 ppm, pome fruit crop group 11-10 = 0.3 ppm, grapes = 0.6 ppm, strawberry = 0.6 ppm, citrus fruit crop group 10-10 = 0.3 ppm, citrus oil= 16 ppm, tree nuts crop group 14 = 0.01 ppm, tea = 40 ppm, and coffee = 0.08 ppm. The chronic dietary endpoint is based on a NOAEL of 16.5 mg/kg bw/day with a safety factor of 100 which resulted in a cPAD = 0.17 mg/kg bw/day.

	i. Food. 
Acute Dietary Exposure Assessment
No acute dietary exposure and risk analysis was performed since there were no appropriate studies identified in the toxicology database that demonstrated evidence of toxicity attributable to a single dose.

Chronic Dietary Exposure Assessment
The chronic dietary exposure is shown in the table below. The exposure includes all food commodities. The dietary food only exposure used less than 5.0 % of the cPAD for the most highly exposed population (Children 1-2).

Table 1. Summary of Chronic Dietary Exposure Considering All Current and Proposed Tolerances for Cyflumetofen. The assessment includes food only.
Population Subgroups
Exposure Estimate
%cPAD
U.S. Population
0.001682
1.0
All Infants
0.002831
1.7
Children 1-2 years
0.007234
4.3
Children 3-5 years
0.004962
2.9
Children 6-12 years
0.002228
1.3
Youth 13-19 years
0.001232
0.7
Adults 20-49 years
0.001200
0.7
Adults 50+ years
0.001317
0.8
Females 13-49 years
0.001237
0.7
%cPAD =percent of chronic population adjusted dose.

Exposure estimates based on tolerance values, 100% CT for all crops/commodities and experimentally determined default processing factors. The results indicate that the exposures for cyflumetofen are well below the EPA level of concern.

Chronic Aggregate Exposure and Risk (food and water)
The aggregate chronic risk includes residues of cyflumetofen from food and water. The results demonstrate there are no safety concerns for any subpopulation based on the proposed new uses, and that the results clearly meet the FQPA standard of reasonable certainty of no harm.

Table 2. Summary of the Chronic Aggregate Exposure for Cyflumetofen. The assessment includes food and water.
Population Subgroups
Exposure Estimate
%cPAD
U.S. Population
0.001689
1.0
All Infants
0.002856
1.7
Children 1-2 years
0.007243
4.3
Children 3-5 years
0.004969
2.9
Children 6-12 years
0.002234
1.3
Youth 13-19 years
0.001237
0.7
Adults 20-49 years
0.001206
0.7
Adults 50+ years
0.001323
0.8
Females 13-49 years
0.001243
0.7

	ii. Drinking water. Since this is an import tolerance petition, no impact to the drinking water is expected from the use of cyflumetofen on coffee.  The existing water residue profile will not change; therefore, the previous dietary contribution for water from all direct and indirect sources was 0.00033 ppm.

	2. Non-dietary exposure. Since this is an import tolerance petition, non-dietary exposure is not expected from the use of cyflumetofen on coffee.

D. Cumulative Effects

	Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to cyflumetofen and any other substances and cyflumetofen does not appear to produce a toxic metabolite produced by other substances.

E. Safety Determination

	1. U.S. population. The aggregate chronic risk includes residues of cyflumetofen from food and water. The results demonstrate there are no safety concerns for any subpopulation based on the proposed new uses, and that the results clearly meet the FQPA standard of reasonable certainty of no harm.

	2. Infants and children. Based on this risk assessment, it is concluded that there is a reasonable certainty that no harm will result to infants or children from the aggregate exposure to cyflumetofen.

F. International Tolerances

	Cyflumetofen is currently registered in the US for use on citrus, pome fruit, grapes, strawberries, tomatoes, tree nuts and ornamentals.  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. Per 40 CFR §180.677 cyflumetofen has the following tolerances for residues:

Commodity					Parts per million
Almond, hulls					4.0
Citrus, oil					16
Fruit, citrus, group 10-10			0.30
Fruit, pome, group 11-10			0.30
Grape						0.60
Nut, tree, group 14-12				0.01
Strawberry					0.60
Tomato					0.40

In addition, cyflumetofen has the following CODEX MRLs:

Commodity					MRL (mg/Kg)
Almond hulls					4.0
Citrus fruits					0.3
Citrus oil, edible				36
Dried grapes (currants, raisins, sultanas)	1.5
Edible offal (mammalian)			0.02
Grapes						0.6	
Mammalian fats (except milk fats)		0.01
Meat (non-marine)				0.01
Milks						0.01
Pome fruit					0.4
Strawberry					0.6
Tomato					0.3
Tree nuts					0.01