Document ID: EPA-HQ-OPP-2010-1017-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-02-25T05:00Z

Docket ID #:  EPA-HQ-OPP-2010-1017

COMPANY NOTICE OF FILING FOR RIMSULFURON TOLERANCE PETITION 

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

I.E.I. du Pont de Nemours and Company (DuPont), and

Interregional Research Project Number 4 (IR-4) 

PP No. 0E7809

 

EPA has received a pesticide petition (PP No. 0E7809) from the IR-4,
Rutgers, The State University of New Jersey, 500 College Road East,
Suite 201W. Princeton, NJ 08540, proposing pursuant to section 408 (d)
of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a (d), to
amend 40 CFR Part 180.478 by establishing a tolerance for residues of
the herbicide rimsulfuron N-((4,6-dimethoxypyrimidin-2-yl)
aminocarbonyl)-3-(ethylsulfonyl)-2-pyridinesulfonamide in or on the raw
agricultural commodities caneberry subgroup 13-07A at 0.01 parts per
million (ppm) and bushberry subgroup 13-07B at 0.01 ppm.  This summary
was prepared by the registrant, DuPont. 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
support granting 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 rimsulfuron tolerances in field corn
and potato, the EPA determined that the nature of plant residues was
adequately understood for the purposes establishing those tolerances. A
metabolism study in tomatoes was conducted to support establishment of
tolerances for Rimsulfuron in tomato. Based on these studies, the Agency
previously concluded that only rimsulfuron needs to be regulated and
assessed for dietary assessment. Further, the nature of the residue in
corn and potatoes is adequately understood. The nature of the residue in
animals is adequately understood based on acceptable ruminant and
poultry metabolism studies. The pathways of rimsulfuron metabolism in
ruminants and poultry are consistent with those demonstrated in plants. 

2. Analytical method. 

Adequate analytical methodology, high-pressure liquid chromatography
(HPLC) with electrospray ionization tandem mass spectrometry (ESI-MS/MS)
detection, is available for enforcement purposes.  

3. Magnitude of residues.

a. Magnitude of the residue in plants: 

i. Caneberry

The results from six trials show that the maximum residue in caneberry
is <0.01 ppm following a single application of approximately 0.0625
pound active ingredient per acre (lb ai/A) rimsulfuron when the
application is made 21-24 days prior to harvest. 

ii. Bushberry

The results from eight trials show that the maximum residue in blueberry
is <0.01 ppm following a single application of approximately 0.0625 lb
ai/A rimsulfuron when the application is made 19-23 days prior to
harvest.

b. Magnitude of the residue in animals: 

EPA determined, upon granting field corn and potato tolerances, that
there is no reasonable expectation of residues occurring in meat, milk,
poultry, or eggs from these tolerances. Of the commodities for which
tolerances are being proposed, only wet apple pomace, citrus dried pulp,
and almond hulls are considered possible animal feed items. However, the
worst-case animal dietary burden is comprised of only field corn and/or
potato commodities. Therefore, there remains a reasonable expectation
that no residues of rimsulfuron will occur in meat, milk, poultry, or
eggs from the current, and proposed, rimsulfuron tolerances.

B. Toxicological Profile 

1. Acute toxicity. 

Technical rimsulfuron 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 (lethal dose (LD)50
> 2,000 milligram per kilogram (mg/kg); rabbits) and eye irritation
(effects reversible within 72 hours; rabbits). Acute oral toxicity (LD50
> 5,000 mg/kg; rats), acute inhalation toxicity (lethal concentration
(LC)50 > 5.4 mg/liter (L), rats) and skin irritation (no observed
irritation; rabbits) results were assigned toxicology category IV.
Technical rimsulfuron is not a dermal sensitizer.

2. Genotoxicty. 

Technical rimsulfuron was negative for genotoxicity in a battery of in
vitro and in vivo tests. These tests included the following:
mutagenicity in bacterial (Ames test) and mammalian (CHO/HGPRT assay)
cells; in vitro cytogenetics (chromosomal aberration in human
lymphocytes); in vivo cytogenetics (bone marrow micronucleus assay in
mice); and unscheduled DNA synthesis in rat primary hepatocytes.

3. Reproductive and developmental toxicity. 

A two-generation reproduction study was conducted in rats with dietary
technical rimsulfuron concentrations of 0, 50, 3,000 or 15,000 ppm. The
study was negative for reproductive toxicity and there was no indication
that offspring were more susceptible to rimsulfuron administration than
parents. The NOAEL was 3,000 ppm (or 165 to 264 mg/kg/day for P1 and F1
males and females and their offspring). This was based on the following
effects at 15,000 ppm (830 to 1,316 mg/kg/day): lower food consumption
and/or food efficiency in P1 males and females and F1 females; decreased
mean body weights and/or body weight gain by P1 and F1 males and
females; lower mean body weights and increased incidence of small body
size for F2 pups during lactation.

A developmental study was conducted in rats administered technical
rimsulfuron by gavage at 0, 200, 700, 2,000 or 6,000 mg/kg/day. There
were no systemic or developmental effects observed up to and including
the highest dose tested. The NOAEL was therefore > 6,000 mg/kg/day.

    

A developmental study was conducted in rabbits administered technical
rimsulfuron by gavage at 0, 25, 170, 500 or 1,500 mg/kg/day. The NOAELs
for maternal and offspring toxicity were 170 and 500 mg/kg/day,
respectively. The maternal NOAEL was based on reduced body weight and
mortality at higher doses. These maternal effects precluded any
evaluation of adverse effects in fetuses at 1,500 mg/kg/day; however,
there were no systemic or developmental effects observed among fetuses
at 500 mg/kg/day and below.

4. Subchronic toxicity. 

A 90-day study in mice was conducted at dietary concentrations of 0, 50,
375, 1,500 or 7,500 ppm. The NOAELs were 375 ppm (56.0 mg/kg/day) for
male mice and 7,500 ppm (1,575 mg/kg/day) for female mice. The NOAEL for
males was based on slight reductions in mean body weight gain and food
efficiency at 1,500 ppm (228 mg/kg/day).

    

Technical rimsulfuron was administered in the diets of rats at 0, 50,
1,500, 7,500 or 20,000 ppm for 90 days. The NOAEL was 1,500 ppm (102 and
120 mg/kg/day for males and females, respectively) based on reduced mean
body weights and body weight gains and increased relative liver weights
at 7,500 ppm (495 and 615 mg/kg/day for males and females,
respectively).

    

Dogs were administered technical rimsulfuron in their diets at 0, 250,
5,000 or 20,000 ppm for 90 days. The NOAEL was 250 ppm (9.63 and 10.6
mg/kg/day for males and females, respectively). This was based on slight
increases in liver and/or kidney weights, increased urine volume and
decreased urine osmolarity at 5,000 ppm (193 and 189 mg/kg/day for males
and females, respectively).

5. Chronic toxicity. 

An 18-month mouse study was conducted with dietary concentrations of 0,
25, 250, 2,500 or 7,500 ppm technical rimsulfuron. This product was not
oncogenic in mice. The systemic NOAEL was 2,500 ppm (351 and 488
mg/kg/day for males and females, respectively) based on decreased mean
body weights in both sexes and increased incidence of spontaneous,
age-related artery and tunica degeneration in the testes for this mouse
strain at the highest dose tested, 7,500 ppm (1,127 and 1,505 mg/kg/day
for males and females, respectively). The latter was observed in the
absence of any effect on spermatogenesis. An increased incidence of
dilation and cysts in the glandular stomach of males was also observed
at 7,500 ppm.

    

A 2-year chronic toxicity/oncogenicity study was conducted in rats fed
diets that contained 0, 25, 300, 3,000 or 10,000 ppm technical
rimsulfuron. This product was not oncogenic in rats. The systemic NOAELs
were 300 ppm (11.8 mg/kg/day) for males and 3,000 ppm (163 mg/kg/day)
for females. The NOAELs were defined by decreased body weight gain and
increased relative liver weights at 3,000 ppm (121 mg/kg/day) and 10,000
ppm (569 mg/kg/day) for males and females, respectively.

    

Technical rimsulfuron was administered for one year to dogs at dietary
concentrations of 0, 50, 2,500 or 10,000 ppm. The NOAELs were 50 ppm
(1.6 mg/kg/day) for males and 2,500 ppm (86.5 mg/kg/day) for females.
The NOAEL for males was based on the following effects, which the Agency
has previously determined were of questionable biological significance,
observed at 2,500 ppm (81.8 mg/kg/day): increased absolute liver and
kidney weights; and increased incidence of seminiferous tubule
degeneration and increased numbers of spermatid giant cells present in
the epididymides. The NOAEL for females was based on the following
effects observed at 10,000 ppm (358.5 mg/kg/day): decreased body weight
and body weight gain; increased serum cholesterol levels and alkaline
phosphatase activity, increased absolute liver weight and increased
relative liver and kidney weights. 

6. Animal metabolism. 

The metabolism of rimsulfuron in animals (rat, goat and hen) is
adequately understood and is similar among the species evaluated.
Rimsulfuron was rapidly eliminated via urinary and fecal excretion in
the rat. Approximately 60 to 70% of the administered dose to rats was
excreted within 24 hours. There were no volatile metabolites detected
and unmetabolised rimsulfuron was the major component in the urine (42 -
55%) and feces (5 - 16%). The major metabolic pathway in rats involved a
contraction of the sulfonylurea bridge followed by dealkylation,
hydroxylation and/or conjugation reactions. Cleavage of the sulfonylurea
bridge was observed; however, it was considered to be a minor pathway.
Elimination of administered rimsulfuron was similarly rapid for the goat
and hen. Tissue residue levels were generally less than 0.3% of the
administered dose for the rat, goat and hen. There was no evidence of
accumulation of rimsulfuron or its metabolites in tissues of any of the
species or in milk and eggs.

7. Metabolite toxicology. 

Common metabolic pathways for rimsulfuron were demonstrated in the rat,
goat and hen as well as plants (corn, tomatoes and potatoes). When
evaluated for acute toxicity and mutagenicity, two of the major
metabolites, i.e., one resulting from contraction of the sulfonylurea
bridge and one from the cleavage of this bridge, were found to be of low
toxicity and were negative in the Ames test. The existing metabolism
studies indicate that the metabolites formed are unlikely to accumulate
in humans or in animals that may be exposed to these residues in the
diet. The fact that no quantifiable residues were found in treated crops
further indicates that exposures to and accumulation of metabolites are
unlikely. Because of the above, toxicology studies on metabolites were
not required.

8. Endocrine disruption. 

No special studies investigating potential estrogenic or other endocrine
effects of rimsulfuron have been conducted.  However, the standard
battery of required toxicology studies has been completed. These include
an evaluation of the potential effects on reproduction and development,
and an evaluation of the pathology of the endocrine organs following
repeated or long-term exposure to doses that far exceed likely human
exposures.  Based on these studies there is no evidence to suggest that
rimsulfuron has an adverse effect on the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. 

When tolerances were established on field corn and potatoes, EPA
determined that the residue of concern was rimsulfuron. Therefore, for
the commodities for which new tolerances are being proposed, the residue
of concern continues to be rimsulfuron.

No acute dietary risk assessment was needed since there is no acute tox
endpoint.

The chronic risk assessments (food only and food + water) for
rimsulfuron were conducted using DEEM-FCIDTM software, version 2.16
(Exponent, Inc.).  A chronic reference dose of 0.818 mg/kg/day, from a
systemic NOAEL of 81.8 mg/kg/day from a one-year beagle dog tox study,
was used.  Tolerance values were used for residue inputs, no processing
factors were employed, and 100% crop treated was assumed.  All
commodities for a given crop were included, ie, orange juice (citrus),
wine, almond oil, and field corn flour.

a. Food. 

i. Acute

For the general U.S. population, acute dietary exposure assessments were
not considered relevant for rimsulfuron for the following reasons:
rimsulfuron presents very low acute toxicity based on animal testing;
and no detectable residues have been demonstrated in edible portions of
treated crops.

ii. Chronic

There is no population in the chronic risk assessment for rimsulfuron,
either dietary (food only) or aggregate (food and water), with an
exposure greater than 0.1% of the chronic reference dose.

b. Drinking water.

Chronic drinking water exposure analyses were calculated for rimsulfuron
based on the First Index Reservoir Screening Tool (FIRST) and Screening
Concentration in Ground Water (SCI-GROW) models.  Results indicate that
a reasonable certainty exist that rimsulfuron residues in drinking water
will not contribute significantly to the aggregate human risk.

The predicted chronic concentration for rimsulfuron maximum surface
water value was 0.74 parts per billion (ppb), and a maximum ground water
value was 0.0522 ppb.  When the surface water concentration was included
in the chronic dietary risk assessment, no population including the
general U.S. population and all subpopulations had an exposure greater 
0.1% of the chronic reference dose (cRfD), indicating a significant
margin of safety.   

No acute dietary endpoint was identified. Therefore, an acute drinking
water risk assessment is not considered necessary. One can conclude with
reasonable certainty that residues of Rimsulfuron in drinking water do
not contribute significantly to the aggregate acute human health risk.

2. Non-dietary exposure. 

Rimsulfuron is not registered for any use that could result in
non-occupational, non-dietary exposure to the general population.

D. Cumulative Effects

Rimsulfuron belongs to the sulfonylurea class of crop protection
chemicals. Other structurally similar compounds in this class are
registered herbicides. However, the herbicidal activity of sulfonylureas
is due to the inhibition of acetolactate synthase (ALS), an enzyme found
only in plants. This enzyme is part of the biosynthesis pathway leading
to the formation of branched chain amino acids. Animals lack ALS and
this biosynthetic pathway. This lack of ALS contributes to the
relatively low toxicity of sulfonylurea herbicides in animals. There is
no reliable information that would indicate or suggest that rimsulfuron
has any toxic effects on mammals that would be cumulative with those of
any other chemical.

E. Safety Determination

1. U.S. population. 

Based on the completeness and reliability of the toxicology database and
using the conservative assumptions presented earlier, EPA has
established a chronic RfD of 0.818 mg/kg/day. This RfD is based on the
systemic NOAEL of 81.8 mg/kg/day for males in a 1-year toxicity study in
beagle dogs. It has been concluded that the aggregate exposure for
existing crops plus the tolerances being proposed would utilize less
than 0.1% of the RfD. Generally, exposures below 100% of the RfD are of
no concern because it represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risk to human health. Thus, there is reasonable certainty that no harm
will result from aggregate exposures to rimsulfuron residues. 

 

2. Infants and children. 

In assessing the potential for additional sensitivity of infants and
children to residues of rimsulfuron, data from the previously discussed
developmental and multigeneration reproductive toxicity studies were
considered.

Developmental studies are designed to evaluate adverse effects on the
developing organism resulting from pesticide exposure during pre-natal
development. Reproduction studies provide information relating to
reproductive and other effects on adults and offspring from pre-natal
and post-natal exposures to the pesticide. The studies with rimsulfuron
demonstrated no evidence of developmental toxicity at exposures below
those causing maternal toxicity. This indicates that developing animals
are not more sensitive to the effects of rimsulfuron administration than
adults.

    

FFDCA section 408 provides that EPA may apply an additional uncertainty
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on current toxicological data requirements, the database
for rimsulfuron relative to pre- and post-natal effects for children is
complete. In addition, the NOAEL upon which the RfD is based is much
lower than the NOAELs defined in the reproduction and developmental
toxicology studies. Conservative assumptions utilized to estimate
aggregate dietary exposures of infants and children to rimsulfuron
demonstrated that only 0.1% of the RfD would be utilized for the highest
exposed group, Children 1-2 years old. Based on these exposure estimates
and the fact that the current database demonstrates that the developing
offspring or young animals are not uniquely susceptible to rimsulfuron
administration, the extra 10-fold uncertainty factor is not warranted
for these groups. Therefore, it may be concluded that there is
reasonable certainty that no harm will result to infants and children
from aggregate exposures to rimsulfuron.

F. International Tolerances

A number of international tolerances (or Maximum Residue Levels (MRLs))
have been established for rimsulfuron including the following:

Countries	Crop	Tolerance/MRL

Austria, Italy	Corn	0.1 ppm

Austria, Italy, Canada	Potatoes	0.1 ppm

Belgium, Denmark, Germany, Spain	Potatoes	0.05 ppm

Germany, Spain, Portugal, Canada	Tomatoes	0.05 ppm

 

Pesticide Petition for Tolerances		AGRICULTURAL COMMODITIES

for Rimsulfuron	Caneberry Subgroup 13-07A, Bushberry Subgroup 13-07B