Document ID: EPA-HQ-OPP-2007-0301-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-27T04:00Z

EPA Registration Division contact: Sidney Jackson, 703-305-7610

Interregional Research Project Number 4 (IR-4) 

PP No. 6E7153

EPA has received a pesticide petition (PP) [6E7153] from the IR-4, 500
College Road East, Suite 201 W, Princeton, NJ 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 180.429 by establishing a
tolerance for residues of the herbicide, chlorimuron-ethyl, [ethyl
2-[[[[ (4-chloro-6-methoxypyrimidin-2yl) amino]carbonyl] amino]sulfonyl]
benzoate] in or on the raw agricultural commodities cranberry,
bearberry, bilberry, lowbush berry, cloudberry, lingonberry, muntries
and partridgeberry at 0.02 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 [14C]chlorimuron-ethyl is adequately understood
in three diverse crops: maize, peanuts and soybeans.  The results of
these plant metabolism studies indicate that no significant
chlorimuron-ethyl’s residues (<0.05 mg/kg) can be expected in either
food or feed commodities under pre-emergence (via soil application) and
post-emergence (via direct foliage application) when used in accordance
with the maximum label rates.   Chlorimuron ethyl metabolizes
extensively in the tolerant crops, such as maize, peanuts, and soybeans.
 Homo-glutathione conjugation of chlorimuron ethyl is the primary
inactivation pathway in the tolerant crops.  In soybeans, it also
undergoes deesterification to yield
[2-(4-chloro-6-methoxypyrimidin-2-ylcarbamoylsulfamoyl)benzoic acid. The
other metabolic pathways involve hydroxylation in either pyrimidine or
phenyl rings followed by conjugation with glucose. The cleavage of the
sulphonylurea linkage yields the corresponding sulphonamide and
pyrimidine amine.  The fate of chlorimuron ethyl is consistent under
both pre-emergence and post-emergence application scenarios. Similar
results to those obtained in maize have also been observed in soybean
and peanut plant metabolism studies and earlier reported in-vitro maize
plant metabolism investigations.

 

2. Analytical method. 

The nature of residues of chlorimuron-ethyl is adequately understood and
an acceptable analytical method is available for enforcement purposes. 
The limit of quantitation allows monitoring of crops with
chlorimuron-ethyl residues at or above the levels proposed in this
tolerance. 

3. Magnitude of residues.

Magnitude of residue studies were conducted by IR-4 to determine residue
of chlorimuron ethyl in cranberries at five test sites during the 2001
growing season. At each trial, one post emergence foliar application of
chlorimuron-ethyl 25 WG® at a rate of approximately 0.016 lb ai/A was
made for a total of approximately 0.016 lb ai/A.  Either a non-ionic
surfactant at 0.25% or crop oil concentrate at 1% was added to the spray
mixture. Commercially mature cranberries were harvested 57-63 days
following the application.  The results from these trials show that the
residues of chlorimuron ethyl in cranberries from all five trials were
less than the Limit of Quantitation (0.0084 ppm).

B. Toxicological Profile

1. Acute toxicity.  

A battery of acute toxicity tests on technical chlorimuron-ethyl 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 mg/L		Category IV

Eye irritation		Rabbit			Mild irritation		Category III

Dermal irritation	Rabbit			Slight irritant		Category IV

Dermal sensitization	Guinea Pig		Not a sensitizer

2. Genotoxicty. 

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

Bacterial gene mutation           			Salmonella typhimurium    	Negative

Mammalian gene mutation in vitro  		CHO           		Negative

Mammalian chromosome aberrations in vivo 		Rat Bone Marrow		Negative

Unscheduled DNA synthesis in vitro 	    	       Rat Hepatocytes		  
Negative

3. Reproductive and developmental toxicity. 

In a 2-generation rat reproduction study with chlorimuron-ethyl, the
NOAEL for both parents and offspring was 250 ppm (approximately 19
mg/kg/day), based on decreased body weight in parental animals and pup
growth parameters at 195 mg/kg/day.  There were no reproductive or
fertility effects at any dietary level.

In a rat developmental study, the maternal and developmental NOAELs were
both 30 mg/kg/day based on body weight effects in dams and growth
retardation (delayed ossification) in fetuses at higher doses.   In
rabbits, the maternal NOAEL was 48 mg/kg/day based on decreased body
weight gain during compound administration and 13 mg/kg/day in fetuses
based on growth retardation at higher doses.

4. Subchronic toxicity. 

Subchronic (90-day) feeding studies were conducted with rats, mice, and
dogs.  In the rat subchronic toxicity study with chlorimuron-ethyl, the
NOAEL was 7/8 (males/females) mg/kg/day (100 ppm), respectively, based
on effects on body weight gain and liver changes at higher
concentrations.  In the mouse subchronic feeding study, there were no
adverse effects at any level and the NOAEL was 5000 ppm (1030 mg/kg/day
males, 1151 mg/kg/day females), the highest dose tested.  In a
subchronic feeding study in dogs, the NOAEL was 2.8/2.9 (males/females)
mg/kg/day (100 ppm) based on increased liver weight, hematologic
changes, and changes in thymus and prostate at the next highest
concentration, 1500 ppm (45.8mg/kg/day males and 42.7 mg/kg/day
females).  However a higher for dogs was subsequently established in a
chronic dog study which included an intermediate dose level (250 ppm).

5. Chronic toxicity. 

Chronic studies with chlorimuron-ethyl were conducted on rats, mice, and
dogs.   Chlorimuron-ethyl was not oncogenic in rats or mice.  In a
chronic rat study the NOAEL was 250 ppm (12.5 mg/kg/day) based on body
weight changes at 2500 ppm (125 mg/kg/day).  In mice, the NOAEL was 1250
ppm (160 mg/kg/day males and 210 mg/kg/day females), the highest dose
tested.  There was no evidence of carcinogenicity or other
compound-related changes.  In dogs the chronic NOAEL was 250 ppm (10/9
mg/kg/day in males and females, respectively) based on mild hematologic
changes at 1500 ppm (51/55 mg/kg/day).

6. Animal metabolism. 

Metabolism studies in rats showed that chlorimuron-ethyl is absorbed
from the gastro-intestinal tract and is eliminated equally in urine and
feces with a biological half-life of about 50 hours.  Chlorimuron-ethyl
was extensively metabolized oxidation, hydrolysis, or enzymatic
reactions with the major metabolite being a hydroxy-chlorimuron-ethyl. 
The greatest concentration of radioactivity was found in the liver.

7. Metabolite toxicology.

None of the metabolites of chlorimuron-ethyl are considered to be of
toxicological significance to mammals.

8. Endocrine disruption. 

Chlorimuron-ethyl has been evaluated in a battery of chronic, lifespan,
and multi-generational bioassays in mammals and acute and subchronic
studies on aquatic organisms and wildlife.  Based on the available data,
there is no indication that chlorimuron-ethyl exerts a toxic effect on
any endocrine organ.

C. Aggregate Exposure

Chlorimuron ethyl is an herbicide currently registered in the United
States for use on peanuts and soybeans. This tolerance petition proposes
the following new uses in the United States: cranberries. There are no
residential uses.

1. Dietary exposure. 

For the chronic dietary endpoint EPA selected the NOAEL of 9 mg/kg/day
from the chronic dog study based on mild anemia at the LOAEL of 51
mg/kg/day.  With the uncertainty factor of 100, due to inter- and
intraspecies factors, the chronic RfD is 0.09 mg/kg/day.   No acute
dietary endpoint was selected since no effects attributable to a single
oral exposure were identified in toxicology studies with chlorimuron
ethyl.

i. Food. 

a. Chronic Dietary Exposure Assessment 

 

Chronic dietary exposure, resulting from the proposed use of chlorimuron
ethyl on cranberries, as well as on peanuts and soybeans, 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-FCIDTM), Exponent, Inc., Version 2.14 was used to conduct
the assessment with a chronic RfD of 0.09 mg/kg/day. The analysis
employed tolerance-level residues and no further adjustments for
processing or percent of crop treated.

For the general U.S. population and all subpopulations <1% of the
chronic RfD was used.  This chronic dietary risk estimate for
chlorimuron ethyl shows that an adequate margin of safety exists for all
population subgroups, and that no effects would result from dietary
exposure to chlorimuron ethyl.

b. Acute Dietary Exposure

Based on the results of toxicity studies no endpoint attributable to a
single oral dose of chlorimuron ethyl was identified. 

ii. Drinking Food. 

                                                                        
                                                                        
              

Chronic drinking water exposure analyses were calculated for chlorimuron
ethyl using EPA screening concentration models for ground water
(SCI-GROW ver. 2.3) and surface water (FIRST ver. 1.0).  Results
indicate that a reasonable certainty exists that chlorimuron ethyl
residues in drinking water will not contribute significantly to the
aggregate human risk.

The predicted chronic concentration for chlorimuron ethyl under
worst-case conditions was 2.24 parts per billion (ppb) in ground water
(due to soybean uses) and 2.28 ppb in surface water (due to non-crop
uses).  When the surface water concentration was included in the chronic
dietary risk assessment, <1% of the cRfD was used for the general U.S.
population and all population subgroups, indicating a significant margin
of safety.   

2. Non-dietary exposure. 

Chlorimuron ethyl products are not labeled for residential non-food
uses, thereby eliminating the potential for residential exposure.
Non-occupational, non-dietary exposure for chlorimuron ethyl 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 has not made a common mechanism of toxicity finding as to
chlorimuron-ethyl and any other substances and has not assumed that
chlorimuron-ethyl 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
chlorimuron ethyl including all anticipated dietary exposure (including
drinking water) 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 chlorimuron ethyl from all anticipated sources of dietary (including
drinking water) and non-occupational exposure. Accordingly, there is no
need to apply an additional safety factor for infants and children.

F. International Tolerances

There are no Canadian, Mexican or Codex MRLs for chlorimuron-ethyl on
cranberry.

Pesticide Petition for Tolerance                                        
                   	AGRICULTURAL COMMODITIES

for Chlorimuron-ethyl                                                   
                                               Cranberry

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

Wilmington, DE 19880-0038 (September 2006)