Cymoxanil Notice of Filing:  IR-4 Pesticide Petitions 7E7282 and 7E7283

EPA Registration Division contact: Susan Stanton (703)305-5218

EPA has received pesticide petitions (PP Nos. 7E7282 and 7E7283) from
the Interregional Research Project No. 4 (IR-4), 500 College Road East,
Suite 201 W., Princeton, New Jersey  98540, 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 tolerances
for residues of the fungicide cymoxanil;
2-cyano-N-[(ethylamino)carbonyl]-2-(methoxyimino)acetamide, in or on the
raw agricultural commodities as follows:

  

PP 7E7282:  Leaf petioles, subgroup 4B at 6 parts per million (ppm)

PP 7E7283:  Leafy greens, subgroup 4A and Cilantro at 19 ppm; Bulb
vegetables group 3-07 at 1.1 ppm; and Caneberry subgroup 13-07A at 4.0
ppm.  The petition also proposes to remove existing tolerances of  4.0
ppm on Lettuce, head and Caneberry, which would be replaced by the
proposed subgroup tolerances on Leafy greens subgroup 4A and Caneberry
subgroup 13-07A.

EPA has determined that the petitions contain 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
petitions. Additional data may be needed before EPA rules on the
petitions.

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. 

Leaf Lettuce

Magnitude of residue data were collected from field trials conducted in
California (region 10), Maryland (region 2) and Florida (region 3). 
Residues of cymoxanil ranged from <0.05 to 14 ppm (no washing).  

Celery

Magnitude of residue data were collected from field trials conducted in
California (region 10), Florida (region 3) and Michigan (region 5). 
Data was also collected from field trials conducted in Canada (Ontario
and Quebec, region 5).  Residues of cymoxanil ranged from <0.05 to 2.5
ppm (no washing or trimming).  

Spinach

Magnitude of residue data were collected from field trials conducted in
California (region 10), Colorado (region 9), New York (region 1), New
Jersey (region 2) and Texas (region 6).  Residues of cymoxanil ranged
from 1.3 to 13.5 ppm (unwashed).  

Dry bulb onion

Magnitude of residue data were collected from field trials conducted in
New York (region 1), Texas (region 6), Colorado (region 9) and
Washington (region 11).  Residues of cymoxanil were <0.05 ppm.

Green onion

Magnitude of residue data were collected from field trials conducted in
California (region 10), New Jersey (region 2), Wisconsin (region 5),
Texas (region 6), Idaho (region 11) and Oregon (region 12).  Residues of
cymoxanil ranged from <0.05 to 0.43 ppm.

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 was not required with cymoxanil.  No acute
neurotoxicity has been observed in short-term or subchronic studies
(including repeated dose neurotoxicity studies).

	2. Genotoxicty. 

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

Bacterial gene mutation           			Salmonella typhimurium    	Negative

Mammalian gene mutation in vitro  		CHO/HGPRT           		Negative

Mammalian chromosome aberrations in vitro		CHO                 	
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 a 2-generation cymoxanil rat reproduction study, the NOAEL for both
parents and offspring was approximately 7 mg/kg/day, based on decreased
body weight, weight gain and food consumption in adults and decreased
offspring neonatal viability or weight at 32 mg/kg/day or greater. 
There were no reproductive or fertility effects at any dietary level.   


In developmental studies, EPA has selected a maternal NOAEL of 25
mg/kg/day in rats and a developmental NOAEL of 10 mg/kg/day.  In
rabbits, EPA has selected a maternal NOAEL of 32 mg/kg/day and a
developmental NOAEL of 4 mg/kg/day.  In both species the developmental
effects included delayed ossifications or skeletal variations.

In a developmental neurotoxicity study, the maternal and offspring
NOAELs were both 50 mg/kg/day based on body weight effects at 100
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 8.25
mg/kg/day based on body weight and weight gain effects at 82.4 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.

  

In a subchronic study in dogs, the LOEL was 3 mg/kg/day based on
decreased body weight and food consumption in females.  Although, a NOEL
was not established in the dog subchronic study, 3 mg/kg/day was found
to be a NOAEL in a subsequent chronic study in dogs.

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.  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,
tested, 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 chronic NOAEL for dogs was 3.0 mg/kg/day in males based on  body
weight gain and hematology changes at 5.7 mg/kg/day, and 3.1 mg/kg/day
in females, the highest dose tested.  

	6. Animal metabolism. 

When administered by gavage to rats, cymoxanil was readily absorbed and
eliminated. Absorption reached maximum concentrations in whole blood
within 4 hours post-dosing.  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 metabolite profile
in urine and feces was similar between sexes, among dose groups, and
between dosing regimens (single vs. multiple).

	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 has tolerances established in the United States on cucurbits,
head lettuce, hops, peppers, potatoes, tomatoes, grapes, and
caneberries.  This tolerance petition proposes the following new uses in
the United States: bulb vegetables, leafy greens and cilantro leaves,
leaf petiole crop groups. There are no residential uses.

	1. Dietary exposure. 

The chronic dietary RfD of 0.04 mg/kg/day is based on a NOAEL of 4.1
mg/kg/day from the two-year rat feeding study and an uncertainty factor
of 100.  EPA selected an acute dietary RfD of 0.04 mg/kg for females
13-50 based on a NOAEL of 4.0 mg/kg/day in a rabbit developmental study.

	i. Food. 

Chronic Dietary Exposure Assessment

Chronic dietary cymoxanil exposure risk resulting from the proposed use
of cymoxanil on bulb vegetables, leafy greens including cilantro leaves,
and leaf petiole vegetables, as well as on cucurbits, fruiting
vegetables, potatoes, grapes, hops, and caneberries was estimated using
the Dietary Exposure Evaluation Model with the Food Commodity Intake
Database (DEEM-FCIDTM, Exponent, Inc., Version 2.16). The analysis
employed overall-mean field-trial values and employed crop treated
percentages based on 5-year annual averages for currently labeled crops
and projections of the 5-year annual averages for proposed crops.  For
the general U.S. population and all subpopulations <1% of the chronic
RfD was used.  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 Tier 3 acute dietary exposure analysis resulting from the proposed
use of cymoxanil on bulb vegetables, leafy greens including cilantro
leaves, and leaf petiole vegetables as well as on cucurbits, fruiting
vegetables, head lettuce, potatoes, grapes, hops, and caneberries was
conducted with the acute module of the DEEM-FCIDTM software.  The acute
dietary analysis used field trial residue data in a probabilistic
assessment, which also employed processing factors and 5-year maximum
annual percent crop treated values.

     

The acute exposure analysis demonstrates that an adequate margin of
safety exists for the only population group of interest, adult females. 
(An aRfD was not established for other populations since an effect
attributable to a single exposure was not observed in the oral toxicity
studies.) The results of the acute dietary exposure analysis for
cymoxanil indicate that the predicted exposure to the only relevant
population group, females 13-49 years, is 0.001776 mg/kg/day, 4% of the
aRfD at the 99.9th percentile.  Cymoxanil clearly meets the Food Quality
Protection Act (FQPA) standard of reasonable certainty of no harm. 

	ii. Drinking Food. 

Surface water exposure was estimated using the EXPRESS v.1.00.00.12
(PRZM-EXAMS) model.  Ground water exposure was estimated using SCI-GROW
v 2.3.  These are screening level models used for determining upper
bound concentrations of pesticides in surface water and ground water. 
Results indicate that a reasonable certainty exists that cymoxanil
residues in drinking water will not contribute significantly to the
acute and chronic human risk. 

     

The predicted chronic concentration for cymoxanil under worst-case
conditions was 0.00102 parts per billion (ppb) in ground water and 0.04
ppb in surface water.  When the higher surface water concentration was
included in the dietary risk assessment, there was little change from
the food-only chronic risk assessment; for the general U.S. population
and all population subgroups <1% of the cRfD was used, indicating a
significant margin of safety.  

The predicted acute concentration for cymoxanil under worst-case
conditions was 0.00102 parts per billion (ppb) in ground water and 3.5
ppb in surface water.  When the higher surface water concentration was
included in the dietary risk assessment, there was little change from
the food-only acute risk assessment; the predicted exposure at the
99.9th percentile for the only relevant population, females (13-49
years), was 0.001933 mg/kg/day, 5% of the aRfD.  Since the % aRfD for
the only relevant population group is well below 100%, the acute dietary
safety of cymoxanil, including the contribution of drinking water,
clearly meets the 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

 To date, no international tolerances exist for cymoxanil.

