Document ID: EPA-HQ-OPP-2017-0397-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-10-23T04:00Z

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[Interregional Research Project #4 (IR-4)]

PP No. (to be assigned) <>

EPA has received a pesticide petition (PP Nos. to be assigned) from Interregional Research Project No. 4 (IR-4), Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W., Princeton, New Jersey  08540, proposing, 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 180.587 by establishing a general tolerance for residues of the fungicide famoxadone (3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione), in or on the raw agricultural commodities Carrot, roots at 0.6 parts per million (ppm); Ginseng at 0.3 ppm; Mango at 0.9 ppm; Brassica, leafy greens, subgroup 4-16B at 40.0 ppm; Vegetable, tuberous and corm, subgroup 1C at 0.02 ppm; Vegetable, fruiting, group 8-10, except tomato at 4.0 ppm; Leafy greens subgroup 4-16A, except spinach at 25.0 ppm; Leaf petiole vegetable subgroup 22B at 25.0 ppm; Arugula at 25.0 ppm; Upland cress at 25.0 ppm; Garden cress at 25.0 ppm; Celtuce at 25.0 ppm; and Fennel, Florence at 25.0 ppm.

Additionally, a regional tolerance for residues of the fungicide famoxadone (3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione), is proposed for Bean, succulent at 0.15 ppm.

Remove established tolerances for residues of the fungicide famoxadone (3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione), in or on the raw agricultural commodities Cilantro, leaves at 25.0 ppm; Potato at 0.02 ppm; Vegetable, fruiting, group 8, except tomato at 4.0 ppm; Vegetable, leafy, except Brassica, group 4, except spinach at 25.0 ppm. 

EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of the 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.

The plant metabolism of famoxadone is adequately understood in 3 distinct crops (tomatoes, potatoes, grapes) to support the proposed tolerances. These studies showed no significant metabolites (all < 10% total radioactive residue (TRR)) in the RACs (tubers, tomato fruit, and grape berries). The only significant residue in any of the studies was the parent compound, famoxadone, occurring primarily as surface residues (grape berries, and tomato fruit). No residues were detected in potato tubers. Thus, the proposed tolerance expression is for the parent compound, famoxadone (DPX-JE874) only.

 

	2. Analytical method. 

An analytical enforcement method is available for determining famoxadone plant residues in or on potatoes, cucurbit vegetables (cucumbers, melons, and squash), fruiting vegetables (tomatoes, peppers), and head lettuce using gas-liquid chromatography (GC) with nitrogen phosphorus detection (NPD). The method is applicable to high and medium moisture, oily and non-oily crops and related matrices. The limit of quantitation (LOQ) is 0.02 ppm.  The LOQ is 0.02 ppm for leafy vegetables and green onion.  The LOQ is 0.05 ppm for dry bulb onion.
        
The analytical enforcement for use on tomato processed fractions and also the RAC, tomato, utilizes column switching liquid chromatography with ultraviolet (UV) detection. The LOQ is 0.02 ppm.
     
The LOQ in each method allows monitoring of crops with famoxadone residues at or above the levels proposed in these tolerances.

	3. Magnitude of residues. 

Carrot

Magnitude of residue data were collected from field trials conducted in California (region 10), Georgia, South Carolina (region 2), Texas (region 6), Ohio (region 5) and Washington (region 12).  Residues of famoxadone ranged from 0.021 to 0.37 ppm.

Ginseng

Magnitude of residue data were collected from field trials conducted in Wisconsin (region 5).  Residues of famoxadone ranged from 0.055 to 0.11 ppm.

Mango

Magnitude of residue data were collected from field trials conducted in Florida (region 13).  Residues of famoxadone ranged from 0.21 to 0.41 ppm.

Mustard Greens

Magnitude of residue data were collected from field trials conducted in California (region 10), Georgia, North Carolina, South Carolina (region 2), Florida (region 3), Tennessee (region 4), Texas (region 6) and Michigan (region 5).  Residues of famoxadone ranged from 1.8 to 19 ppm (no washing or trimming).  

Lima beans

Magnitude of residue data were collected from field trials conducted in Ohio (region 1), Georgia, South Carolina, Maryland and New Jersey (region 2), Tennessee (region 4), and Wisconsin (region 5).  Residues of famoxadone in seeds without pods ranged from <0.02 to 0.069 ppm and ranged from 6.4 to 23 ppm in plants with pods.

B. Toxicological Profile

	1. Acute toxicity.  

A battery of acute toxicity tests on technical famoxadone places it in the following Toxicity Categories:

Oral LD50		Rat		> 5000 mg/kg				Category IV
Dermal LD50		Rabbit		>2000 mg/kg				Category III
Inhalation LC50	Rat		>5.3 mg/L				Category IV
Eye irritation		Rabbit		Moderately irritating			Category  III
Dermal irritation	Rabbit		Moderately irritating			Category  III
Dermal sensitization	Guinea Pig	Not a Sensitizer			

In an acute neurotoxicity test, famoxadone was not neurotoxic to rats.  The no observed adverse effect level (NOAEL) was 1,000 mg/kg in males, based on systemic toxicity at 2,000 mg/kg.  The NOAEL in females was 2,000 mg/kg, the highest dose tested (HDT).

	2. Genotoxicty. 

Famoxadone was tested in a battery of assays to evaluate genotoxicity with the following results. Based on the weight-of-evidence, famoxadone is not considered to be genotoxic.

Bacterial gene mutation           		Salmonella and E. Coli    	Negative
Mammalian gene mutation in vitro  	CHO/HGPRT           		Negative
Mammalian chromosome aberrations	 Human Lymphocytes		Positive without activation
in vitro							Negative with activation
Mammalian chromosome aberrations 	Mouse micronucleus  		Negative
in vivo
Unscheduled DNA synthesis in vitro 	Primary rat hepatocytes	Negative
Unscheduled DNA synthesis in vivo 	Primary rat hepatocytes 	Negative

	3. Reproductive and developmental toxicity. 

The results of a series of studies indicated that there were no reproductive or developmental hazards associated with famoxadone.
    
In a 2-generation rat reproduction study, the NOAEL for both adults and offspring was 200 ppm (11.3-14.2 mg/kg/day) based on clinical signs, decreased body weights, effects on nutritional parameters, and liver toxicity in adults and decreased weight of pups.  Effects on pups occurred only at a maternal effect level and may have been secondary to altered growth and nutrition in the dams.  There were no effects on reproduction (mating, fertility, reproductive organs) up to and including the highest concentration tested, 800 ppm (44.7-53.3 mg/kg/ day). 

In studies conducted to evaluate developmental toxicity potential, famoxadone was neither teratogenic nor uniquely toxic to the conceptus.  In a rat developmental toxicity study, the maternal NOAEL was 250 mg/kg/day based on decreased weight gain and food consumption at 500 mg/kg/day.  The fetal NOAEL was 1,000 mg/kg/day, the HDT.  In rabbits, the maternal and developmental NOAEL was 350 mg/kg/day based on weight loss, decreased food consumption, clinical signs, fecal impactions, and subsequent abortion, resorptions, and post implantation loss at 1,000 mg/kg/day.  These effects were considered related to the physical properties of the dosing solution at the highest concentration.

	4. Subchronic toxicity. 

Subchronic (90-day) feeding studies were conducted with rats, mice, and dogs. In addition, the following subchronic feeding studies were conducted: A 90-day in rats to evaluate neurotoxicity and 28-day feeding studies in rats and mice to evaluate immunotoxicity.  A 28-day dermal study was conducted in rats.
    
In a 90-day feeding study in rats, EPA considered the NOAEL to be 50 ppm (3.3 and 4.2 mg/kg/day in male and females, respectively) based on changes in weight gain, food consumption and mild hemolytic anemia at 200 ppm (13 and 17 mg/kg/day, respectively).  In a subchronic neurotoxicity study in rats, there was no evidence of neurotoxicity up to and including the highest concentration tested, 800 ppm (46.9 and 59.3 mg/kg/day for males and females, respectively).  The NOAEL for systemic toxicity was 200 ppm (11.7 and 14.4 mg/kg/day in males and females, respectively) based on body weight and nutritional effects at 800 ppm.
    
In mice, the subchronic NOAEL was 350 ppm (62.4 and 79.7 mg/kg/day in males and females, respectively), based on hepatotoxicity and mild anemic effects at higher concentrations.
    
In a 90-day feeding study in dogs, the NOAEL was 40 ppm (1.3 mg/kg/day) in males.  In females, 40 ppm (1.4 mg/kg/day) was a marginal effect level for lens lesions.  Effects observed at 300 ppm (10 mg/kg/day) or higher included lens lesions, body weight and nutritional effects, hemolytic anemia, and hyperkalemia with associated clinical signs. 
    
Famoxadone was tested in 28-day feeding studies in rats and mice, designed to evaluate immunotoxicity.  There was no evidence of immunotoxicity in either species.  The NOAEL for systemic toxicity was 200 ppm (14 and 16 mg/kg/day in males and females, respectively) in rats and 2,000 ppm (417 mg/kg/day) in female mice.  There were no effects in males at 7000 ppm (1186 mg/kg/day), the HDT.  
    
In a 28-day repeated dose dermal study, the NOAEL for male rats was 250 mg/kg/day based on changes in liver enzymes at 500 mg/kg/day.  The NOAEL for female rats was 1,000 mg/kg/day, the HDT.

	5. Chronic toxicity. 

Chronic studies with famoxadone were conducted on rats, mice, dogs, and monkeys to determine oncogenic potential and/or chronic toxicity of the compound.  Effects generally similar to those observed in the 90-day studies were seen in the chronic studies.  

There was no evidence of carcinogenicity in the lifetime feeding studies in rats and mice.  In rats, the chronic NOAEL was 200 ppm (8.4 mg/kg/day) in male rats and 40 ppm (2.2 mg/kg/day) in female rats based on body weight changes, nutritional effects, slight hemolytic anemia, and mild hepatotoxicity at higher dietary concentrations.  In mice, the chronic NOAEL was 700 ppm (96 and 130 mg/kg/day for males and females, respectively) based on slight hepatotoxicity in males and females and amyloidosis in females at 2,000 ppm (274 and 392 mg/kg/day in males and females, respectively).
    
In a 1-year feeding study in dogs, the only effect observed was lens lesions at 300 ppm (8.8 and 9.3 mg/kg/day for males and females, respectively). The NOAEL for these lesions was 40 ppm (1.2 mg/kg/day in both sexes).  In a 1-year gavage study, the NOAEL in cynomolgus monkeys was 100 mg/kg/day in both males and females based on slight hemolytic anemia in both sexes at the 1,000 mg/kg/day dose level. There were no other effects observed at any level.  No eye lesions were found at any dose level.

	6. Animal metabolism. 

Famoxadone was rapidly eliminated in the rat, primarily by fecal excretion and to a lesser extent in the urine.  Absorption and metabolism of famoxadone was limited.  There was no accumulation in organs or tissues.  Parent famoxadone and two hydroxylated metabolites were the major components recovered in feces. Glucuronide and sulfate conjugates of metabolites were identified in bile.  No significant qualitative or quantitative in absorption, distribution, metabolism and excretions were observed by sex, dose level, repeated dosing, or between rats and dogs. 

	7. Metabolite toxicology. 

There are no metabolites of toxicological significance to mammals.

	8. Endocrine disruption. 

Chronic, lifespan, and multi-generational bioassays in mammals and acute and subchronic studies on aquatic organisms and wildlife did not reveal endocrine effects. Any endocrine-related effects would have been detected in this definitive array of required tests. The probability of any such effect due to agricultural uses of famoxadone is negligible.

C. Aggregate Exposure

Famoxadone is a fungicide currently registered in the United States for use on cucurbits, head lettuce, peppers, potatoes, tomatoes, grapes, hops, caneberries, bulb vegetables, leafy vegetables, and cilantro. This tolerance petition proposes the following new uses in the United States:  carrot, roots; ginseng; mango; brassica, leafy greens, subgroup 4-16B; and bean, succulent (East of the Rocky Mountains) There are no residential uses.

	1. Dietary exposure.

For the chronic dietary endpoint, EPA selected the marginal effect level of 1.4 mg/kg/day from the subchronic dog study and added an additional uncertainty factor of 10x for no NOEL and use of a subchronic study.  With inter- and intraspecies factors the total uncertainty factor is 1000x for a chronic RfD of 0.0014 mg/kg/day.   This is considered extremely conservative since a NOEL of 1.2 mg/kg/day was established in the chronic dog study, and there were no lens lesions at any dose on a chronic primate study. No acute dietary endpoint was selected since no effects attributable to a single oral exposure were identified in toxicology studies with famoxadone.

	i. Food and drinking water. 

Chronic Dietary Exposure Assessment

Chronic dietary exposure, resulting from the proposed and registered uses of famoxadone, is well within acceptable limits for all sectors of the population. The chronic module of the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCID[TM]), Version 4.02 was used to conduct the assessment with a chronic RfD of 0.0014 mg/kg/day. The analysis employed overall-mean field-trial values and employed crop treated percentages for currently labeled crops and 100% crop treated for proposed crops.  A worst case estimated chronic drinking water concentration was included in the assessment of chronic aggregate exposure (food and water) from famoxadone.
    
For the general U.S. population and all sub-populations, the estimated chronic dietary exposure to famoxadone from food and drinking water is below 100% of the chronic RfD.  Since the %cRfD for all populations are well below 100%, the chronic dietary safety of famoxadone clearly meets the standard of reasonable certainty of no harm.
                                                                          			
               
Acute Dietary Exposure

Based on the results of toxicity studies, including an acute neurotoxicity study, no endpoint attributable to a single oral dose of famoxadone was identified.

	2. Non-dietary exposure.

Famoxadone products are not labeled for residential non-food uses, thereby eliminating the potential for residential exposure. Non-occupational, non-dietary exposure for famoxadone has not been estimated because the proposed products are limited to commercial crop production. Therefore, the potential for non-occupational exposure is insignificant.

D. Cumulative Effects

 EPA's consideration of a common mechanism of toxicity is not necessary at this time because there is no indication that toxic effects of famoxadone should be cumulative with those of any other chemical. Famoxadone is a member of a new class of fungicides that acts by inhibition of mitochondrial respiration. Famoxadone's biochemical mode of action on fungi and toxicological profile in animals appear to be unique.
    
Given the distinct chemical, biological and toxicological profile, famoxadone's low acute toxicity, absence of genotoxic, oncogenic, developmental or reproductive effects and low exposure potential, the expression of cumulative human health effects with any other natural or synthetic pesticide is not anticipated.

E. Safety Determination

	1. U.S. population. 

Based on the completeness and reliability of the toxicity data and the conservative exposure assessments, there is a reasonable certainty that no harm will result from the aggregate exposure of residues of famoxadone including all anticipated dietary exposure and all other non-occupational exposures.  No additional safety factors are warranted.

	2. Infants and children.

Based on the completeness and reliability of the toxicity data, the lack of toxicological endpoints of special concern, the lack of any indication of greater sensitivity of children, and the conservative exposure assessment, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure to residues of famoxadone from all anticipated sources of dietary and non-occupational exposure. Accordingly, there is no need to apply an additional safety factor for infants and children.

F. International Tolerances

1. EU

MRL's established for famoxadone are available at the following link:
http://ec.europa.eu/food/plant/pesticides/eu-pesticides-database/public/?event=pesticide.residue.CurrentMRL&language=EN

2. CODEX

MRL's established for famoxadone are available at the following link:
http://www.fao.org/fao-who-codexalimentarius/standards/pestres/pesticide-detail/en/?p_id=208

3. Canada

Famoxadone MRL's are established by Canada and are available in the link below:
http://www.pmra-arla.gc.ca/english/legis/maxres-e.html - proposedmrls

4.  Japan

MRL's established for famoxadone are available at the following link:
http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=56900