Document ID: EPA-HQ-OPP-2009-0057-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-08T04:00Z

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ENVIRONMENTAL PROTECTION AGENCY

Notice of Filing of a Pesticide Petition for the Establishment of
Tolerances for Residues of Nicosulfuron in or on Food Commodities

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of tolerances for residues of
nicosulfuron in or on food commodities under the Federal Food, Drug, and
Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of
1996 (FQPA).

FOR FURTHER INFORMATION CONTACT: By mail: Mindy Ondish,  Risk Manager
(RM 25), Registration Division, (7505P), Office of Pesticide Programs,
Environmental Protection Agency, Ariel Rios Building 1200 Pennsylvania
Avenue, N. W., Washington, DC 20460.  Office location and telephone
number: (703) 605-0723, Arlington, VA., Email: ondish.mindy@epa.gov.

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various raw
agricultural commodities under section 408(d) of the Federal Food, Drug,
and Comestic Act (FFDCA), 21 U.S.C. 346a (d). EPA has determined that
this petition contains data or information regarding the elements set
forth in section 408(d)(2); 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.

    

List of Subjects

Environmental Protection, Agricultural Commodities, Food Additives, Feed
Additives, Pesticides and Pests, Reporting and Recordkeeping
Requirements.

Summary of Petition

A summary of the pesticide petition is given below. The petitioner
prepared the summary of the petition. 

EPA Registration Division contact: Mindy Ondish, Risk Manager 25, (703)
605-0723

 E. I. DuPont de Nemours and Company, DuPont Crop Protection 

[PP 8F7501]

	EPA has received a pesticide petition ([PP8F7501]) from E. I. DuPont de
Nemours and Company, DuPont Crop Protection, Wilmington, Delaware,
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 to
establish tolerances for residues of nicosulfuron,
[3-pyridinecarboxamide,
2-((((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)aminosulfonyl))-N,N-dime
thyl] in or on grass forage at 9.0 parts per million (ppm), grass hay at
25.0 ppm, fat (of cattle, goat, hog, horse and sheep) at 0.05 ppm, meat
(of cattle, goat, hog, horse and sheep) at 0.05 ppm,  meat byproducts
(of cattle, goat, hog, horse and sheep) at 0.05 ppm, milk at 0.05 ppm
and milk, fat at 0.02 ppm.  EPA has determined that the petition
contains data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; 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 and animal metabolism. With the initial establishment of
nicosulfuron tolerances in field corn and subsequent establishment of
tolerances on sweet corn, the EPA determined that the nature of plant
residues was adequately understood for the purposes establishing those
tolerances. A metabolism study in canola has also been conducted.  Based
on these studies, the Agency previously concluded that only nicosulfuron
needs to be regulated and assessed for dietary assessment. Further, the
nature of the residue in corn and canola is adequately understood. The
nature of the residue in animals is adequately understood based on an
acceptable ruminant study. The pathways of nicosulfuron metabolism in
ruminants is consistent with those demonstrated in plants.

2. Analytical method.  Adequate analytical methodology, high-pressure
liquid chromatography with ESI-MS/MS detection, is available for
enforcement purposes. The two methods are “Analytical Method for the
Determination of Nicosulfuron (DPX-V9360) And Its Metabolite IN-V9367 In
Pasture Grass By HPLC/ESI-MS/MS”, DuPont Report 17928 and
“Analytical Method for the Determination of Nicosulfuron (DPX-V9360)
And Its Metabolite IN-V9367 In Animal Tissues By HPLC/ESI-MS/MS”,
DuPont Report 17927. The limit of quantitation for nicosulfuron with
these methods, in raw agricultural commodities and in processed
fractions, is 0.01 ppm. EPA offers enforcement methodology to anyone
interested in pesticide enforcement when requested by mail from: Public
Response and Program Resources Branch, Field Operations Division
(7506C), Office of Pesticide Programs, Environmental Protection Agency,
401 M St., SW., Washington, DC 20460. Office location CM#2, 1801 South
Bell Street, Arlington, VA 22202.

3, Magnitude of residues

i. Plant residues. 

Grass crop group 17 - Residue trials were conducted on bermudagrass,
brome grass and fescue at 12 locations distributed across the U.S.  The
nature of nicosulfuron residue in grass is adequately understood through
the corn and canola metabolism studies.    These residue data were the
basis for establishing tolerances for grass forage and grass hay.

ii. Animal residues. EPA determined, upon granting field corn
tolerances, that there was no reasonable expectation of residues
occurring in meat, milk, poultry, or eggs from these tolerances. Of the
commodities for which tolerances are being proposed, grass hay and grass
forage are possible animal feed items. Therefore, a cattle feeding study
was conducted to establish tolerances on meat, meat by-products and
milk.  

B. Toxicological Profile

1. Acute toxicity. Technical nicosulfuron has been placed in acute
toxicology category III based on overall results from several studies.
This compound was placed in toxicology category III for acute dermal
toxicity (LD50 > 2,000 mg/kg; rabbits) and eye irritation (effects
reversible within 72 hours; rabbits). Acute oral toxicity (LD50 > 5,000
mg/kg; rats), acute inhalation toxicity (LC50 > 5.4 mg/L, rats) and skin
irritation (no observed irritation; rabbits) results were assigned
toxicology category IV. Technical nicosulfuron is not a dermal
sensitizer.

2. Genotoxicty.  Technical nicosulfuron was negative for genotoxicity in
a battery of in vitro and in vivo tests.  These tests included the
following: Bacterial Reverse Mutation Assay, Unscheduled DNA Synthesis
In Primary Rat Hepatocytes, In Vitro Cho Mammalian Cells Gene Mutation
Assay, Mammalian Cells In Culture Cytogenic Assay In Human Lymphocytes,
In Vivo Micronucleus Assay – Mouse

3. Reproductive and developmental toxicity. 

i. Rat developmental study.  A developmental study was conducted in rats
administered technical nicosulfuron by oral gavage at dose levels of 0,
186, 930, 2325 or 5581 mg/kg/day. No treatment-related effects were
noted on maternal or developmental toxicity up to and including the
highest dose tested of 5581 mg/kg (the limit of the suspension
capability). The LOAEL for maternal and developmental toxicity could not
be determined and the NOAEL is at least 5581 mg/kg/day for both maternal
and developmental toxicity.

ii. Rabbit developmental study.  In developmental study was conducted in
rabbits administered technical nicosulfuron by oral gavage at dose
levels of 0, 93, 465, 930 or 1860 mg/kg/day.  The LOAEL for maternal
toxicity is 465 mg/kg/day and the NOAEL is 93 mg/kg/day. The LOAEL for
developmental toxicity is 465 mg/kg/day (based on an apparent increase
in percent post implantation loss) and the NOAEL is 93 mg/kg/day. There
were no external on visceral anomalies in the fetuses. Fetal toxicity
was manifested by reduced mean fetal body weight at 930 mg/kg/day and
above. Therefore, the LOAEL for fetal toxicity is 930 mg/kg/day and the
NOAEL is 465 mg/kg/day.

iii. Two-generation rat reproduction study.  A two generation
reproduction study was conducted in rats administered continuously with
technical nicosulfuron in the diet at 0,250, 5000 or 20000 ppm.   There
were no treatment related effects observed in the parental animals
except for lower body weight gain (p<0.05) in the F1 (first mating)
females at the high dose during the last (third) week of gestation. A
lower body weight gain was also seen, but not statistically significant
in the F0 females during the last week of gestation. Therefore, the
LOAEL for parental systemic toxicity is 20,000 ppm (1265 mg/kg/day) and
the NOAEL is 5000 ppm (287 mg/kg/day).  Reproductive parameters were
unaffected in the low- and mid-dose groups. There was a statistically
significant (p<0.05) decrease in litter size at birth (reproductive
effects) and in pup (offspring effects) weights at postpartum day 14
through 21 in the F2a high dose group. The other litters showed a
similar tendency, but not a statistically significant difference.
Therefore, the NOAEL for both reproductive and offspring toxicity is
5000 ppm (287 mg/kg/day) and the LOAEL is 20,000 ppm (1265 mg/kg/day).

4.  Subchronic toxicity.    

i. 90-Day rat feeding study. A 90 day study in rats was conducted at
dose levels of 0, 300, 1500, 7500 or 20,000 ppm.  No treatment-related
signs of toxicity or mortality were attributed to the test material. No
compound effects on organ weights, gross and microscopic pathology were
seen. A LOAEL for subchronic toxicity of this test material is >20,000
ppm (1495/1830 mg/kg/day for males/females) and a NOAEL is 20,000 ppm
(1495/1830 mg/kg/day for males/females). 

ii. 90-Day mouse study.  A 90 day study in mice was conducted at dose
levels of 0, 300, 1500, 7500 or 10000 ppm. No treatment-related signs of
toxicity or mortality were attributed to the test material. The LOAEL
derived from this study is 1500 ppm (234.0 / 323.0 mg/kg/day for males/
females) based on decreased hematological parameters, particularly the
circulating neutrophils, and the NOAEL is 300 ppm (43.9/ 62.0 mg/kg/day
for males/ females).

	

iii. 90-Day dog study Technical nicosulfuron was administered to dogs at
dose levels of 0, 250, 5000, or 20000 ppm. Based on hematological
findings (reduction of neutrophils in females), the LOAEL is 20000 ppm
(710/ 683 mg/kg/day in males/females) and the NOAEL is 5000 ppm (172/
171 mg/kg/day in males/females).

5. Chronic toxicity and oncogenicity 

i. 18-Month mouse oncogenicity study.  An 18-month carcinogenicity study
with mice fed dosages of 0, 3.3/4.4, 32.7/44.8, 327/438, and 993/1,312
mg/kg/day (males/females) demonstrated that no carcinogenic effects up
to the highest dose tested. The systemic NOAEL is 993/1,312
(males/females) mg/kg/ day.

ii. 1-Year chronic dog study. A 1-year feeding study with dogs fed
dosages of 0, 6.25, 125, and 500 mg/kg/day resulted in a systemic NOAEL
of 125 mg/kg/day in males based upon a decrease in body weight gains and
a concomitant increase in relative liver and kidney weights in males.
The NOAEL for females was 500 mg/kg/day, the highest dose tested.

iii. Two-year combined rat chronic toxicity/oncogenicity study. In a
two-year combined chronic toxicity/oncogenicity study in rats, technical
nicosulfuron was administered in the diet at concentrations of 0, 50,
1500, 7500 or 20000 ppm.  Based on the lack of chronic toxic effects the
NOAEL is the highest dose tested: 20,000 ppm (786 mg/kg/day in males and
1098 mg/kg/day in females). 

6. Rat metabolism. In the rat, nicosulfuron is rapidly and moderately
absorbed and is rapidly eliminated via urinary and fecal excretion. 
Following oral administration of the low dose (10 mg/kg bw), elimination
in the feces accounted for 80 to 87% of the dose, and elimination in the
urine accounted for 13 to 20%. At the high dose (1000 mg/kg bw) fecal
and urinary excretion ranged from 89 – 95% and 5 – 11%,
respectively.  Elimination of 14C-CO2 was negligible. The average
cumulative excretion half-lives were between 12 and 24 hours. Following
intravenous administration, approximately 76 to 80% of the dose was
eliminated in the urine and 27 to 30% in the feces. Residues in tissues
accounted for 0.05 to 0.5% of the dose. The major excretion product in
urine and feces was unchanged parent compound. In addition, pyridine
sulfonamide (N, N-dimethyl-2-sulfonamide pyridine-3-carboxamide or
IN-V9367) was detected in the urine and accounted for 1.1 to 5.7% of the
dose. Pyridine acid sulfonamide (2-sulfonamidepyridine-3- carboxylic
acid, or IN-64859) was tentatively identified as a minor metabolite in
the feces of orally dosed rats and urine of intravenously dosed rats.
These metabolites represent hydrolytic cleavage/oxidation of the parent
molecule. 

7. Metabolite toxicology.  Common metabolic pathways for nicosulfuron
were demonstrated in the rat, goat and in corn.  The major nicosulfuron
metabolites in corn and the goat were the same as those in the rat.  A
minor metabolite in the goat and two in corn differed from those
observed in the rat.  These minor metabolites were only detectable
following exaggerated doses to corn plants and in feed provided to
goats.  Neither of these minor metabolites were detectable in human
dietary components; therefore, exposures to and accumulation of these
minor metabolites are unlikely.  The EPA has previously determined that
the residue to be regulated is nicosulfuron only.

  

8. Endocrine disruption.  In the available toxicity studies on
nicosulfuron, there was no estrogen, androgen, and/or thyroid mediated
toxicity.

C. Aggregate Exposure

	

1. Dietary exposure –

 i. Food.  Because an endpoint attributable to a single dose was not
identified, the dietary exposure assessment considered only chronic
exposure.  

Chronic dietary exposure assessment. Chronic dietary exposure resulting
from the currently approved uses and proposed uses of nicosulfuron is
well within acceptable limits for all sectors of the population. The
chronic module of the Dietary Exposure Evaluation Model with Food
Commodity Intake Database (DEEM-FCIDTM, version 2.14, Exponent, Inc.)
was used to conduct the assessment with the chronic reference dose
(cRfD) of 1.25 mg/kg/ day. This model incorporates nationwide food
consumption data as reported by respondents in the U.S. Department of
Agriculture (USDA) 1994-1996, 1998 Continuing Surveys of Food Intake by
Individuals (CSFII).  The analysis used tolerance values in place of
residue values for relevant crops and meat and milk and assumed 100%
crop treated for all commodities included.  The chronic dietary exposure
of the US population to nicosulfuron is 0.000363 mg/kg/day, and utilizes
<1% of the cRfD for the overall U.S. population. No population subgroup
had an exposure that utilized more than 1% of the cRfD.  There are large
margins of safety for each population subgroup and very low probability
of effects resulting from chronic exposure to nicosulfuron.

ii. Drinking water. Based on the FIRST Tier 1 surface water and SCI GROW
Tier 1 groundwater models under worst-case conditions the chronic
estimated environmental concentrations (EECs) of nicosulfuron are 1.811
parts per billion (ppb) for surface water and 0.078 ppb for ground
water. 

When the higher surface water concentration was included in the chronic
dietary risk assessment, the predicted exposure for the general
population was 0.000401 mg/kg/day, <1% of the cRfD.  No population
subgroup had an exposure that utilized more than 1% of the cRfD.  Thus,
the chronic dietary exposure of nicosulfuron, including the contribution
of drinking water, clearly meets the standard of reasonable certainty of
no harm.  

 

2. Non-dietary exposure. No nicosulfuron product registrations for
residential non food uses have been approved. Therefore, there should be
no non-occupational, non-dietary exposure.

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 Nicosulfuron and any other
substances and Nicosulfuron does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that Nicosulfuron has a
common mechanism of toxicity with other substances 

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 nicosulfuron including all anticipated dietary
exposure and all other non occupational exposures. 

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 that children are more sensitive
than adults to nicosulfuron, 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 nicosulfuron,
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

There is neither a Codex proposal, nor a Canadian or Mexican tolerance
for grass and grass commodities.

E. I. DuPont de Nemours & Company                                       
            	Nicosulfuron

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