Document ID: EPA-HQ-OPP-2017-0400-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-10-23T04:00Z

COMPANY NOTICE OF FILING -  FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE (7/1/2006)

Docket ID Number: EPA-HQ-OPP-2017-0400

EPA Registration Division contact: Tony Kish, PM 22 (703) 308-9443

Interregional Research Project Number 4

Pesticide Petition (PP) Number 7E8575

EPA has received a pesticide petition (PP No. 7E8575) 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 180.503 by establishing a tolerance for residues of the fungicide cymoxanil, 2-cyano -N- [(ethylamino)carbonyl]-2-(methoxyimino) acetamide, in or on the raw agricultural commodities Carrot, roots at 0.03 parts per million (ppm); Ginseng at 0.02 ppm; Mango at 0.02 ppm; Brassica, leafy greens, subgroup 4-16B at 15.0 ppm; Leafy greens subgroup 4-16A at 19.0 ppm; Leaf petiole vegetable subgroup 22B at 6.0 ppm; Vegetable, tuberous and corm, subgroup 1C at 0.05 ppm; Vegetable, fruiting, group 8-10 at 0.2 ppm; Arugula at 19.0 ppm; Upland cress at 19.0 ppm; Garden cress at 19.0 ppm; Celtuce at 6.0 ppm; and Fennel, Florence at 6.0 ppm.

Additionally, a regional tolerance for residues of the fungicide cymoxanil, 2-cyano -N- [(ethylamino)carbonyl]-2-(methoxyimino) acetamide, is proposed for Bean, succulent at 0.05 ppm.

Remove established tolerances for residues of the fungicide cymoxanil, 2-cyano -N- [(ethylamino)carbonyl]-2-(methoxyimino) acetamide, in or on the raw agricultural commodities Cilantro, leaves at 19.0 ppm; Leafy greens, subgroup 4A at 19.0 ppm; Leaf petioles, subgroup 4B at 6.0 ppm; Potato at 0.05 ppm; Vegetable, fruiting, group 8 at 0.2 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 cymoxanil is adequately understood in three diverse crops: potatoes, tomatoes, and lettuce. The results of these plant metabolism studies indicate that cymoxanil degrades extensively to primarily the amino acid glycine, with subsequent re-incorporation into other naturally-occurring products, such as glucose.

	2. Analytical method. 

An analytical enforcement method is available for determining these plant residues by high performance level chromatography (HPLC) with ultraviolet (UV) detection. The limit of quantitation allows monitoring of crops with cymoxanil residues at or above the levels proposed in these tolerances.  The LOQ is 0.05 ppm for cymoxanil.

	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 cymoxanil ranged from <0.02 to 0.024 ppm.

Ginseng - Magnitude of residue data were collected from field trials conducted in Wisconsin (region 5).  Residues of cymoxanil were all <0.02 ppm.

Mango - Magnitude of residue data were collected from field trials conducted in Florida (region 13).  Residues of cymoxanil were all <0.02 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 cymoxanil ranged from <0.05 to 8.4 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 cymoxanil in seeds without pods were <0.05 ppm and ranged from <0.05 to 0.40 ppm in plants with pods.

B. Toxicological Profile

	1. Acute toxicity.  

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

Oral LD50		Rat			285-960 mg/kg	Category II-III
Dermal LD50		Rabbit			>2000 mg/kg		Category III
Inhalation LC50	Rat			>5.06 mg/L		Category IV
Eye irritation		Rabbit			Mild-slight irritant	Category III-IV
Dermal irritation	Rabbit			Slight irritant		Category IV
Dermal sensitization	Guinea Pig		Not a sensitizer

An acute neurotoxicity study with cymoxanil was not required based on adequate information in the database to identify a dose and endpoint for single-exposure dietary effects.

	2. Genotoxicty. 

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

Bacterial gene mutation           			Salmonella typhimurium    	Negative
Mammalian gene mutation in vitro  		CHO/HGPRT           		Negative
Mammalian chromosome aberrations in vitro		Hyman lymphocytes               	Positive
Mammalian chromosome aberrations in vivo 		Mouse micronucleus  		Negative
Unscheduled DNA synthesis in vitro     		Primary rat hepatocytes	Positive
Unscheduled DNA synthesis in vivo     		Primary rat hepatocytes 	Negative
                             				and spermatocytes

	3. Reproductive and developmental toxicity. 

In rat two-generation reproduction studies, EPA concluded the parental NOAELs to range from 31.6-42.8 mg/kg/day based on reduced body weight, body weight gain, and food consumption. The offspring NOAELs ranged from 6.5-14.9 mg/kg/day based on decrease early postnatal pup survival/viability and decreased pup weights.     

EPA has selected a developmental NOAEL in rabbits of 8 mg/kg/day as the point of departure for the ARfD for females 13-49 years of age based cleft palate and hydrocephalus.  

In a developmental neurotoxicity study, EPA has selected a maternal NOAEL of 100 mg/kg/day, the highest dose tested, based on the lack of adverse effects and an offspring NOAEL of 5 mg/kg/day based on decreased pup survival during post-natal days 2-5 at 50 mg/kg/day.  

	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 also conducted in rats.
     
In a subchronic toxicity/neurotoxicity study in rats with cymoxanil, the NOAEL was 47.6 mg/kg/day in males and 59.9 mg/kg/day in females based on the following changes at higher concentrations: decreased body weights in both sexes, decreased food efficiency in females, and minimal to mild testicular and epididymal changes in males.  In a concurrent 90-day rat neurotoxicity study, there was no evidence of neurotoxicity at any level.  The neurotoxicity NOAEL was 3000 ppm (224 mg/kg/day), the highest dose tested.
     
The subchronic NOAEL for male mice administered cymoxanil was 82.4 mg/kg/day based on body weight and weight gain effects at 294 mg/kg/day and above.  The NOAEL for females was 121 mg/kg/day based on increases in spleen and liver weights at 433 mg/kg/day and above.
  
Based on subchronic studies in dogs, EPA selected a NOAEL of 5 mg/kg/day due to decreased body weight and reduced RBC values at a LOAEL of 10 mg/kg/day.  

Subchronic 28-day studies were conducted in rats and mice to evaluate the immunotoxicity potential of cymoxanil.   Cymoxanil was not immunotoxic up to and including the highest dose tested which was 1,600 ppm in rats (108 and 117 mg/kg/day in males and females, respectively), 1,200 ppm (218 mg/kg/day) in male mice, and 2,400 ppm (552 mg/kg/day) in female mice.

In a 28-day dermal study in rats there were no effects at any dose tested. The 28-day dermal NOAEL was 1,000 mg/kg/day, the highest dose tested.

	5. Chronic toxicity. 

Chronic studies with cymoxanil were conducted on rats, mice, and dogs 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.  

Cymoxanil was not oncogenic in lifetime feeding studies in rats and mice.  EPA has classified cymoxanil as Not Likely to be Carcinogenic to Humans.  The chronic NOAEL for cymoxanil in rats was 4.1 mg/kg/day in males and 5.4 mg/kg/day in females based on body weight and nutritional changes and non-neoplastic lesions in several organs (lungs, liver, testes, eye, sciatic nerve) at higher dietary concentrations.  In mice, the chronic NOAELs for cymoxanil were 4.2 and 5.8 mg/kg/day for males and females, respectively, based on changes in organ weights, gastrointestinal effects in females and liver, testes, and epididymal effects in males at the LOAEL.  There was no evidence of carcinogenicity.
     
The lowest NOAEL for chronic toxicity in dogs selected by EPA was 3.0 mg/kg/day based on body weight changes at 5.6 mg/kg/day.  

	6. Animal metabolism. 

When administered by gavage to rats, cymoxanil was readily absorbed and eliminated.  A rapid and almost complete elimination was observed in the urine and feces. The majority of radioactivity was recovered within 96 hours, mainly in urine but also in feces. Radioactivity in the tissues and carcass was less than 1%.  In the urine and feces, the majority of the radioactivity was free and/or conjugated glycine. 2-Cyano-2-methoxyimino-acetic acid was also found in low levels in the urine and trace levels in the feces. Intact cymoxanil was less than 1% in feces and not detected in the urine. The metabolic pathway involves hydrolysis of cymoxanil and the degradation to glycine, which in turn is incorporated into natural constituents or further metabolized.  

	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 cymoxanil is negligible.

C. Aggregate Exposure

Cymoxanil 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. In addition, tolerances have been approved for cymoxanil on imported grapes. 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. 

The chronic dietary RfD of 0.03 mg/kg/day is based on the one-year dog study and a total uncertainty factor of 100.  EPA selected an acute dietary population adjusted dose (PAD) of 0.08 mg/kg/day for females 13-49 based on a rabbit developmental tox study and an acute PAD of 0.50 for the general population (including infants and children) from a rat developmental neurotox study.  

	i. Food and Drinking Water. 

Chronic Dietary Exposure Assessment

Chronic dietary cymoxanil exposure risk resulting from the proposed and registered uses of cymoxanil was estimated using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCID[TM], Version 4.02). The analysis employed overall-mean field-trial values and a very conservative assumption of 100% crop treated for all crops.  A worst case estimated chronic drinking water concentration was included in the assessment of chronic aggregate exposure (food and water) for cymoxanil.

For the general U.S. population and all sub-populations, the estimated chronic dietary exposure to cymoxanil from food and drinking water is well below 100% of the chronic RfD.  This chronic dietary risk estimate for cymoxanil shows that an adequate margin of safety exists for all population subgroups and that no effects would result from dietary exposure to cymoxanil. 
                                                          
Acute Dietary Exposure

The acute dietary exposure analysis resulting from the proposed and registered uses of cymoxanil was conducted with the acute module of the DEEM-FCID[TM] software.  The acute dietary (food and drinking water) analysis used field trial residue data, processing factors and a very conservative assumption of 100% crop treated for all crops.  A worst case estimated acute drinking water concentration was included in the assessment of acute aggregate exposure (food and water) for cymoxanil.

 The results of the acute dietary exposure analysis (food and drinking water) for cymoxanil indicate that the predicted exposure, is well below the relevant PADs for the US population, adult females and all sub-populations, demonstrating that an adequate margin of safety exists for all populations.  Cymoxanil clearly meets the Food Quality Protection Act (FQPA) standard of reasonable certainty of no harm.  
	
	2. Non-dietary exposure. 

Cymoxanil products are not labeled for residential non-food uses, thereby eliminating the potential for residential exposure. Non-occupational, non-dietary exposure for cymoxanil 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 cymoxanil should be cumulative with those of any other chemical compounds or with each other. Cymoxanil is a unique cyanoacetamide and is chemically unrelated to any other commercial plant disease control agent. Its biochemical mode of action on fungi appears to be unique; it is theorized to act through inhibition of multiple cellular processes, but a definitive mechanism has not been completely elucidated. Similarly, the mechanism of action underlying observed toxicological effects in mammals is not fully characterized and there is no reliable information to suggest that cymoxanil has a mechanism of toxicity in common with any other compound.     

Given the distinct chemical and toxicological profile of cymoxanil, its 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 reasonable certainty that no harm will result from the aggregate exposure of residues of cymoxanil.  No additional safety factors are warranted.

	2. Infants and children. 

Based on the completeness and reliability of the toxicity data base, the lack of toxicological endpoints of special concern, the lack of any indication that children are more sensitive than adults to cymoxanil, and the conservative exposure assessment, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure of residues of cymoxanil, including all anticipated dietary exposure and all other non-occupational exposures. Accordingly, there is no need to apply an additional safety factor for infants and children.

F. International Tolerances

1. EU

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

2. Canada

Cymoxanil 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

3.  Japan

MRL's established for cymoxanil are available at the following link:
http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=33300