Document ID: EPA-HQ-OPP-2006-0743-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-11-15T05:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)

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

 

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TEMPLATE:

E.I. du Pont de Nemours and Company

PP No. (to be assigned)

EPA has received a pesticide petition (PP No. to be assigned) from the
Interregional Research Project No. 4 (IR-4), 681 U.S. Highway #1 South,
North Brunswick, New Jersey 08902-3390, 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 commodity Caneberries at 4.0 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 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.

	3. Magnitude of residues. 

Caneberries

Magnitude of residue data were collected from field trials conducted in
Washington (region 12), Oregon (region 12), California (region 10), and
Canada (regions 5 and 12).  Residues of cymoxanil ranged from 0.24 to
2.2 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			960 mg/kg		Category III

Dermal LD50		Rabbit			>2000 mg/kg		Category III

Inhalation LC50	Rat			>5.06 mg/L		Category IV

Eye irritation		Rabbit			Very slight irritant	Category 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 is a fungicide currently registered in the United States for
use on cucurbits, head lettuce, hops, peppers, potatoes and tomatoes
with a proposed use on grapes submitted previously. In addition,
tolerances have been approved for cymoxanil on imported grapes. This
tolerance petition proposes the following new uses in the United States:
caneberries. 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 cucurbits, fruiting vegetables, head lettuce, potatoes,
grapes, hops, and caneberries was estimated using the Dietary Exposure
Evaluation Model with the Food Commodity Intake Database (DEEM-FCIDTM,
Exponent, Inc., Version 2.14). 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 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 0.000605 mg/kg/day, 2% 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 0.000877 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 0.000877 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 0.000721 mg/kg/day, 2% 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.

Pesticide Petition for Tolerance                                        
                   	AGRICULTURAL COMMODITIES

for Cymoxanil	                                                          
        Caneberries

Copyright by E.I. du Pont de Nemours and Company

Wilmington, DE 19880-0038 (July 2006)