Document ID: EPA-HQ-OPP-2009-0004-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-18T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

September 8, 2009

MEMORANDUM

SUBJECT:	Rimsulfuron.  Human Health Risk Assessment for Proposed Section
3 Uses on Genetically Modified Field Corn and Soybean.  

PC Code:  	129009	DP Barcode:	D358866

Decision No.:	400402	Registration No.:	352-748

Petition No.:	8F7431 and 8F7440	Regulatory Action:	Section 3

Assessment Type:	Single Chemical Aggregate	Registration Case No.:	None

TXR No.:	None	CAS No.:	122931-48-0

MRID No.:	None	40 CFR:	§180.478

FROM:	Debra Rate, Ph.D., Biologist

			Alternative Risk Integration and Assessment (ARIA) Team

			Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)

			Registration Division (RD) (7505P)

			AND

		Alan Levy, Ph.D., Toxicologist

		Risk Assessment Branch II (RABII)

		Health Effects Division (HED) (7509P)

THROUGH:	William Cutchin, Acting Senior Branch Scientist

				ARIA

				RIMUERB/RD (7505P)

				Douglas Dotson, Ph.D., Chemist

			RABII/HED (7509P)

					AND

				Christina Swartz, Branch Chief

			RABII/HED (7509P)

TO:	Jim Tompkins, RM 25

	Herbicide Branch (HB)/RD (7505P)

The ARIA Team of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that ARIA evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from proposed and registered uses of the pesticide rimsulfuron (N
-((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)-3-(ethylsulfonyl)-2-pyridi
nesulfonamide)as a result of the proposed Section 3 uses on genetically
modified field corn and soybean.  A summary of the findings and an
assessment of human risk resulting from the registered and proposed
tolerances for rimsulfuron is provided in this document.  The overall
risk assessment was provided by Debra Rate.  The dietary risk assessment
was provided by Doug Dotson (RABII/HED) and the occupational/residential
exposure assessment by Mark Dow (ARIA).  Residue chemistry by Debra Rate
(ARIA), hazard assessment/toxicology by Alan Levy (RABII/HED) and
drinking water assessments by José Meléndez (Environmental Fate and
Effects Division; EFED) were also incorporated. 

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc239646322"  1.0	Executive
Summary	  PAGEREF _Toc239646322 \h  5  

  HYPERLINK \l "_Toc239646323"  2.0	Ingredient Profile	  PAGEREF
_Toc239646323 \h  9  

  HYPERLINK \l "_Toc239646324"  2.1	Proposed Use Directions	  PAGEREF
_Toc239646324 \h  10  

  HYPERLINK \l "_Toc239646325"  2.2	Structure and Nomenclature	  PAGEREF
_Toc239646325 \h  10  

  HYPERLINK \l "_Toc239646326"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc239646326 \h  11  

  HYPERLINK \l "_Toc239646327"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc239646327 \h  11  

  HYPERLINK \l "_Toc239646328"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc239646328 \h  11  

  HYPERLINK \l "_Toc239646329"  3.1.1	Database Summary	  PAGEREF
_Toc239646329 \h  12  

  HYPERLINK \l "_Toc239646330"  3.1.2	Toxicological Effects	  PAGEREF
_Toc239646330 \h  12  

  HYPERLINK \l "_Toc239646331"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc239646331 \h  13  

  HYPERLINK \l "_Toc239646332"  3.3	FQPA Considerations	  PAGEREF
_Toc239646332 \h  13  

  HYPERLINK \l "_Toc239646333"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc239646333 \h  13  

  HYPERLINK \l "_Toc239646334"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc239646334 \h  13  

  HYPERLINK \l "_Toc239646335"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc239646335 \h  14  

  HYPERLINK \l "_Toc239646336"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc239646336 \h  14  

  HYPERLINK \l "_Toc239646337"  3.3.5	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc239646337 \h  14  

  HYPERLINK \l "_Toc239646338"  3.3.6	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc239646338 \h  15  

  HYPERLINK \l "_Toc239646339"  3.3.7	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc239646339 \h  15  

  HYPERLINK \l "_Toc239646340"  3.4	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc239646340 \h  15  

  HYPERLINK \l "_Toc239646341"  3.4.1	Acute Reference Dose (aRfD) –
Females Ages 13-49 and General Population	  PAGEREF _Toc239646341 \h  15
 

  HYPERLINK \l "_Toc239646342"  3.4.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc239646342 \h  15  

  HYPERLINK \l "_Toc239646343"  3.4.3	Dermal Absorption	  PAGEREF
_Toc239646343 \h  16  

  HYPERLINK \l "_Toc239646344"  3.4.4	Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc239646344 \h  17  

  HYPERLINK \l "_Toc239646345"  3.4.5	Inhalation Exposure (Any Time
Period)	  PAGEREF _Toc239646345 \h  17  

  HYPERLINK \l "_Toc239646346"  3.4.6	Level of Concern for Margin of
Exposure	  PAGEREF _Toc239646346 \h  17  

  HYPERLINK \l "_Toc239646347"  3.4.7	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc239646347 \h  17  

  HYPERLINK \l "_Toc239646348"  3.4.8	Classification of Carcinogenic
Potential	  PAGEREF _Toc239646348 \h  18  

  HYPERLINK \l "_Toc239646349"  3.4.9	Summary of Toxicological Doses and
Endpoints for Rimsulfuron for Use in Human Risk Assessments	  PAGEREF
_Toc239646349 \h  18  

  HYPERLINK \l "_Toc239646350"  3.5	Endocrine disruption	  PAGEREF
_Toc239646350 \h  18  

  HYPERLINK \l "_Toc239646351"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc239646351 \h  19  

  HYPERLINK \l "_Toc239646352"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc239646352 \h  19  

  HYPERLINK \l "_Toc239646353"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc239646353 \h  19  

  HYPERLINK \l "_Toc239646354"  5.1.1	Metabolism in Primary Crops and
Livestock	  PAGEREF _Toc239646354 \h  19  

  HYPERLINK \l "_Toc239646355"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc239646355 \h  19  

  HYPERLINK \l "_Toc239646356"  5.1.3	Analytical Methodology	  PAGEREF
_Toc239646356 \h  19  

  HYPERLINK \l "_Toc239646357"  5.1.4	Magnitude in Plants	  PAGEREF
_Toc239646357 \h  20  

  HYPERLINK \l "_Toc239646358"  5.1.5	Environmental Degradation	 
PAGEREF _Toc239646358 \h  21  

  HYPERLINK \l "_Toc239646359"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc239646359 \h  21  

  HYPERLINK \l "_Toc239646360"  5.1.7	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc239646360 \h  22  

  HYPERLINK \l "_Toc239646361"  5.1.8	Drinking Water Residue Profile	 
PAGEREF _Toc239646361 \h  22  

  HYPERLINK \l "_Toc239646362"  5.1.9	Food Residue Profile	  PAGEREF
_Toc239646362 \h  22  

  HYPERLINK \l "_Toc239646363"  5.1.10	International Residue Limits	 
PAGEREF _Toc239646363 \h  23  

  HYPERLINK \l "_Toc239646364"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc239646364 \h  23  

  HYPERLINK \l "_Toc239646365"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc239646365 \h  23  

  HYPERLINK \l "_Toc239646366"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc239646366 \h  23  

  HYPERLINK \l "_Toc239646367"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc239646367 \h  24  

  HYPERLINK \l "_Toc239646368"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc239646368 \h  24  

  HYPERLINK \l "_Toc239646369"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc239646369 \h  24  

  HYPERLINK \l "_Toc239646370"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc239646370 \h  24  

  HYPERLINK \l "_Toc239646371"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc239646371 \h  24  

  HYPERLINK \l "_Toc239646372"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc239646372 \h  25  

  HYPERLINK \l "_Toc239646373"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc239646373 \h  25  

  HYPERLINK \l "_Toc239646374"  9.1	Short-Term Handler Risk	  PAGEREF
_Toc239646374 \h  25  

  HYPERLINK \l "_Toc239646375"  9.2	Postapplication Exposure and Risk	 
PAGEREF _Toc239646375 \h  26  

  HYPERLINK \l "_Toc239646376"  9.3	Restricted Entry Interval (REI)	 
PAGEREF _Toc239646376 \h  26  

  HYPERLINK \l "_Toc239646377"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc239646377 \h  26  

  HYPERLINK \l "_Toc239646378"  10.1	Toxicology	  PAGEREF _Toc239646378
\h  26  

  HYPERLINK \l "_Toc239646379"  10.2	Residue Chemistry	  PAGEREF
_Toc239646379 \h  26  

  HYPERLINK \l "_Toc239646380"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc239646380 \h  27  

  HYPERLINK \l "_Toc239646381"  References:	  PAGEREF _Toc239646381 \h 
27  

  HYPERLINK \l "_Toc239646382"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc239646382 \h  28  

  HYPERLINK \l "_Toc239646383"  A.1  Toxicity Profiles	  PAGEREF
_Toc239646383 \h  28  

  HYPERLINK \l "_Toc239646384"  A.2  Rationale for Toxicology Data
Requirements.	  PAGEREF _Toc239646384 \h  31  

  HYPERLINK \l "_Toc239646385"  Appendix B: Tolerance Setting	  PAGEREF
_Toc239646385 \h  34  

  HYPERLINK \l "_Toc239646386"  Appendix C: Review of Human Research	 
PAGEREF _Toc239646386 \h  34  

 

1.0	Executive Summary

Rimsulfuron is a sulfonylurea herbicide (Group 2) that works via
inhibition of acetolactate synthase (ALS).  Inhibition of the enzyme
leads to rapid cessation of growth and visual symptoms such as
chlorosis, necrosis, leaf malformation and discoloration.  These effects
appear a few days after treatment in sensitive species.  

DuPont has submitted petitions supporting the use of rimsulfuron on
field corn and soybeans that are genetically tolerant to sulfonylurea
herbicides (PP#s 8F7440 and 8F7431).  These petitions have been
submitted in conjunction with related petitions for use of tribenuron
methyl and chlorimuron ethyl on genetically modified field corn and
soybeans in support of an end-use product containing all three
sulfonylurea herbicides.  The petitioner is proposing the establishment
of the following permanent tolerances for residues of rimsulfuron:

Corn, aspirated grain fraction	1.02 ppm

Corn, field, forage	0.4 ppm

Corn, field, grain	0.01 ppm

Corn, field, stover	2.5 ppm

Soybean, aspirated grain fractions 	4.51 ppm

Soybean, forage	0.25 ppm

Soybean, hay	1.2 ppm

Soybean, hulls	0.035 ppm

Soybean, seed 	0.01 ppm

Toxicity/Hazard

≥ 125 mg/kg bw/day after 90 days.  Chronic exposure led to increased
absolute liver and kidney weights and increased incidence of
seminiferous tubule degeneration and increased numbers of spermatid
giant cells present in epididymides in males at ≥ 81.8 mg/kg bw/day in
males.  At 342.4/358.5 mg/kg bw/day (M/F), decreased mean 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 were observed.

In the developmental toxicity study in rats, no developmental toxicity
was seen at the highest dose tested.  In the developmental toxicity
study in rabbits, and in the two generation study in rats,
developmental/offspring toxicity was seen in the presence of
maternal/systemic toxicity and at similar dose levels.  Consequently,
there is no quantitative or qualitative evidence of increased
susceptibility following pre- and/or postnatal exposures, and there are
no concerns or residual uncertainties.  Although the acute and
subchronic neurotoxicity studies are now required, there was no evidence
of potential neurotoxicity in the submitted studies, and HED has
concluded that a developmental neurotoxicity study is not needed.  Based
on the low concerns for pre- and/or postnatal susceptibility and the
lack of potential immunotoxic effects, HED has concluded that the FQPA
Safety Factor should be reduced to 1X.

It was determined that rimsulfuron should be classified as “Not Likely
a Human Carcinogen,” based on the lack of evidence for carcinogenicity
in studies conducted in rats and mice.  

Residue Chemistry

The nature of the residue in plants and livestock is adequately
understood based on acceptable metabolism studies conducted with
rimsulfuron, labeled in the pyridine or pyrimidine ring, in field corn,
potatoes, tomatoes, lactating goat, and laying hen. 

HED previously concluded that rimsulfuron is the residue of concern for
both regulatory and risk assessment purposes in both plant and animal
commodities.  

  SEQ CHAPTER \h \r 1 An adequate method (HPLC/UV with column switching)
is available to enforce the established tolerances.  The method,
AMR-1241-88, has a limit of quantitation (LOQ) of 0.05 ppm.  DuPont has
proposed two methods based on LC/MS/MS for tolerance enforcement: Method
DuPont-15033 for watery and dry crop matrices, and Method DuPont-15027
for oily crop matrices.  Both methods involve extraction with potassium
phosphate buffer and methanol or acetonitrile, acidification of the
extract, solid-phase extraction cleanup, and LC/MS/MS analysis.  The
validated LOQ is 0.010 ppm in each matrix.  Adequate independent
laboratory validation (ILV) data were submitted for both methods.  

Adequate field trial data have been submitted for genetically modified
field corn and soybean reflecting treatment at 1x the proposed rate. 
The submitted crop field trial data were collected using the proposed
enforcement methods and are supported by adequate storage stability
data.  Residues of rimsulfuron were <LOQ (<0.01 ppm) in/on all samples
of corn grain and soybean seed collected at the appropriate preharvest
interval (PHI).  The data indicate that the proposed tolerances for
field corn and soybean commodities are adequate; however, the current
tolerance in/on corn, field, grain at 0.1 ppm will be maintained for
residue harmonization.  As such, a revised Section F will be required to
remove the request for a tolerance of 0.01 ppm in/on corn, field, grain.

The available corn and soybean processing data for rimsulfuron are
adequate to support the proposed/recommended tolerances and the proposed
use patterns.  A revised Section F will be required to remove the
requested tolerances on corn, aspirated grain fractions (AGF) and
soybean AGF and to request the recommended grain, aspirated fractions of
4.5 ppm based on the soybean data.  Adequate confined rotational crop
data are available to support minimum plant-back intervals up to 18
months, depending on the end-use product.  As the labels for rimsulfuron
currently specify minimum plantback intervals compatible with these
plantback intervals, data requirements for rotational crops are
fulfilled and tolerances are not required for rotational crops.  

Dietary Exposure (food/water)/Risk Characterization:

The Environmental Fate and Effects Division (EFED) determined estimated
drinking water concentrations (EDWCs) of rimsulfuron in surface and
groundwater.  The EDWCs were calculated based on the maximum application
rate of 0.0625 lb ai/A/season (for citrus, pome and stone fruits, ground
broadcast application, wetted in).  For rimsulfuron, the cancer/chronic
surface water value is 0.120 ppb.  The groundwater screening
concentration is 0.016 ppb of rimsulfuron, which is suitable for acute
and chronic (refer to Table 5.1.8).  EFED evaluated the new uses for
rimsulfuron on DUPONT™ OPTIMUM® GAT® herbicide tolerant corn and
soybean for pre-emergence and post-emergence control of certain annual
grass and broadleaf weeds.  Aerial applications are allowed for these
uses and the maximum application rate is 0.0625 lb ai/A for both crops
(same as the rate previously assessed for citrus, pome and stone
fruits).  The results of a FIRST run showed lower EDWCs than the
previously assessed scenarios, as listed above.  Therefore, ARIA/HED
used the EDWC of 0.120 ppb, for the dietary exposure and analysis and,
as a result, for this human health risk assessment as well.  

The unrefined chronic dietary assessment is based on the assumption that
rimsulfuron residues are present at tolerance levels in all commodities
for which tolerances have been established and that 100% of those crops
are treated.  DEEM™ Version 7.81 default processing factors were
applied to all processed commodities for which they were available.  The
resulting chronic dietary exposure estimates for food and water combined
are well below ARIA/HED’s level of concern for the general U.S.
population and all population subgroups.  Using the DEEM-FCID software,
dietary exposure is estimated at 0.000428 mg/kg/day for the U.S.
population (<1% of the cPAD) and 0.001063 mg/kg/day (<1% of the cPAD)
for children 1 to 2 years old, the population subgroup with the highest
estimated chronic dietary exposure to rimsulfuron.  

An acute dietary assessment was not performed, as a toxicological
endpoint attributable to a single dose has not been identified for
rimsulfuron.  Also, rimsulfuron is classified as “not likely” to be
carcinogenic; therefore, a cancer assessment was not performed.

Residential Exposure

There are currently no residential uses for rimsulfuron, therefore no
non-occupational exposure is expected to result from the proposed and
labeled uses.

Aggregate Risk

There are no registered residential uses for rimsulfuron at this time
and therefore no resulting residential exposure.  Because there is no
residential exposure and no acute dietary endpoints were identified, the
aggregate risk for rimsulfuron is equivalent to chronic dietary (food
and drinking water) risk.  As with the chronic dietary risk, the
aggregate risk associated with the proposed and registered uses of
rimsulfuron is below the ARIA’s level of concern. 

Occupational Exposure/Risk

No dermal or inhalation toxicological endpoints were identified for use
in risk assessment for rimsulfuron.  Therefore a quantification of
post-application exposure and risk to workers is not necessary.

The currently registered product label lists a restricted entry interval
(REI) of 4 hours.  Rimsulfuron meets the reduced risk criteria as per PR
Notice 95-03 (See Section 9.3), which allows a 4-hour REI.

Environmental Justice Considerations:

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, ”Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations,”   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, ARIA estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Surveys of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research:

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (listed in Appendix C) have been determined to
require a review of their ethical conduct.  The listed studies have
received the appropriate review and were determined to be ethically
conducted.

Additional Data Needs:

The following toxicity studies are required: acute and subchronic
neurotoxicity, immunotoxicity, and a 21/28 day dermal toxicity study.

Recommendations:

G) formulation; DuPont™ Resolve ® SG Herbicide (EPA No. 352-748)) on
DuPont™ Optimum® GAT® herbicide-tolerant corn and soybeans.  ARIA
recommends for the following permanent tolerances:

Corn, field, grain	0.1 ppm

Corn, field, forage	0.4 ppm

Corn, field, stover	2.5 ppm

Soybean, hay	1.2 ppm

Soybean, forage	0.25 ppm

Soybean, seed 	0.01 ppm

Soybean, hulls	0.04 ppm

Grain, aspirated fractions	4.5 ppm

In addition, in order to ensure that legal uses of rimsulfuron under
FIFRA do not result in illegal residues in food under the FFDCA, ARIA
recommends for the following tolerance expression to be implemented for
rimsulfuron under 40 CFR 180.478:

(a) General. Tolerances are established for residues of the herbicide
rimsulfuron, including its metabolites and degradates, in or on the
commodities in the table below.  Compliance with the tolerance levels
specified below is to be determined by measuring only rimsulfuron (N
-((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)-3-(ethylsulfonyl)-2-pyridi
nesulfonamide). 

Residue Chemistry Deficiencies

860.1550 Proposed Tolerances

A revised Section F must be submitted to reflect the recommended
tolerance levels in/on corn, field, grain at 0.1 ppm and request a
tolerance in/on grain, aspirated fractions at 4.5 ppm as specified below
in Table B.1 (Appendix B).  Also, the requested tolerances for corn,
aspirated grain fraction and soybean, aspirated grain fractions are not
necessary and must be removed from the revised Section F.

Ingredient Profile

Rimsulfuron is a sulfonylurea herbicide (Group 2) that works via
inhibition of acetolactate synthase (ALS).  Inhibition of the enzyme
leads to rapid cessation of growth and visual symptoms such as
chlorosis, necrosis, leaf malformation and discoloration.  These effects
appear a few days after treatment in sensitive species.  

2.1	Proposed Use Directions

DuPont has submitted a proposed label for a 25% WDG formulation,
DuPont™ Resolve ® SG Herbicide (EPA No. 352-748), proposed for use on
DuPont™ Optimum® GAT® herbicide-tolerant corn and soybeans.  A
summary of the proposed use directions is presented in Table 2.1.  

Table 2.1.  Summary of Directions for Use of Rimsulfuron.

Applic. Timing	Form.

	Applic. Rate

lb ai/A	Max. No. Applic. per Season	RTI1

(days)	Max. Seasonal Applic. Rate

lb ai/A	PHI

(days)	Use Directions and Limitations

Soybean

Preplant burndown, preemergence, postemergence and/or post harvest	25%
WDG	0.06	1	--	0.06	14 – forage and hay	Apply using a crop oil
concentrate at 1.0 % v/v, or a nonionic surfactant at 0.25% v/v.

Field Corn

Preplant burndown, preemergence, postemergence and/or post harvest	25%
WDG	0.06	2	--	0.06	7	Apply using a crop oil concentrate at 1.0 % v/v, or
a nonionic surfactant at 0.25% v/v.

1  RTI = Retreatment interval

Conclusions.  The label directions are adequate to allow evaluation of
the residue data relative to the labeled uses.  The available field corn
and soybean data support the proposed 7-day PHI for all corn commodities
and the proposed 14-day PHI for soybean forage and hay.  A separate PHI
is not required for soybean seeds, as the application must be made on or
before flowering (stage R2).

2.2	Structure and Nomenclature

 (Resolve ™ SG Herbicide; EPA Reg. No. 352-748)

Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of Rimsulfuron

Parameter	Value	Reference

Melting point	176-178(C	Reviewed in DP# 193018, M. Nelson, 23/NOV/1993; 
All product chemistry requirements reported to be fulfilled.

Also, MRID No. 4752805.

pH	4.32 to 5.89 (1% dilution in water)

	Density	0.784 ± 0.0016 g/mL

	Water solubility	pH 5:  0.135 ± 0.005 g/L (25°C)

pH 7:  7.3 ± 0.03 g/L (25(C)

pH 9:  5.56 ± 0.05 g/L (25(C)

pH 4-4.5:  0.024 ± 0.001 g/L (20(C)

	Solvent solubility (25°C)	N,N-dimethylformamide	241 ± 1 g/L

Dimethyl sulfoxide		113 ± 3 g/L

Methylene chloride		35.5 ± 0.4 g/L

Acetonitrile		17.2 ± 0.5 g/L

Acetone		14.8 ± 0.5 g/L

Ethyl acetate		2.85 ± 0.17 g/L

Methanol		1.55 ± 0.11 g/L

Toluene		0.363 ± 0.022 g/L

Xylenes		0.093 ± 0.008 g/L

n-Hexane		<0.01 g/L

	Vapor pressure (25°C)	1.1 X 10-8 torr

	Dissociation constant, pKa	4

	Octanol/water partition coefficient, Log(KOW)	pH 5:  1.94

pH 7:  0.0342

pH 1.80 at 230 nm, ε = 1.78 x 104 (log ε = 4.25) and at 290 mm, ε =
1.81x 102 (log ε = 2.26)

pH 2.10 at 290 nm, ε = 2.03 x102 (log ε = 2.31)

pH 5.03 at 240 nm, ε = 2.24 x 104 (log ε = 4.35) and at 290 nm, ε =
4.81 x 102 (log ε = 2.68)

	

Hazard Characterization/Assessment

3.1	Hazard and Dose-Response Characterization

The toxicological database indicates that technical grade rimsulfuron is
a moderate eye irritant.  Rimsulfuron falls into Toxicity Category IV
for acute oral, dermal, and inhalation toxicity.  Rimsulfuron is not a
dermal sensitizer.  The acute toxicity of rimsulfuron technical is
summarized in Appendix A. 

3.1.1	Database Summary

3.1.1.1	Studies available and considered (animal, human, general
literature)

Studies available for hazard characterization include three 90-day oral
toxicity feeding studies (rats, mice, dog); two prenatal developmental
toxicity studies (rat, rabbit); a reproduction and fertility effects
study in rats; a chronic dog feeding study; two gene mutation assays
(bacterial or mammalian cells in culture); an in vivo mammalian
cytogenetics study in mouse; an in vitro mammalian cytogenetics study in
human lymphocytes; an unscheduled DNA synthesis (UDS) assay in primary
rat hepatocyte cultures; a metabolism study; a combined chronic
toxicity/carcinogenicity study in rats and a carcinogenicity study in
mice.

Sufficiency of studies/data

The toxicological database is adequate to select endpoints for the
current risk assessment.  However, the following studies which have not
been submitted are considered to be data gaps and are required: acute
and subchronic neurotoxicity, immunotoxicity and a 21/28 day dermal
toxicity study. 

Toxicological Effects

Rimsulfuron has low acute toxicity orally, dermally or by inhalation,
but is a moderate eye irritant.  It is not a dermal sensitizer.  As part
of the new part 158 guidelines, the following studies are needed to
complete the toxicity database: acute and subchronic neurotoxicity,
immunotoxicity and a 21/28 day dermal toxicity study.  The toxicology
database for rimsulfuron does not show any evidence of treatment-related
effects on the immune system.  The overall weight of evidence suggests
that this chemical does not directly target the immune system.  Although
an immunotoxicity study is required as a part of new data requirements,
the Agency does not believe that conducting a functional immunotoxicity
study will result in a lower POD than that currently being used for
overall risk assessment, and therefore, a UFDB is not needed to account
for the lack of this study.

 was observed at ≥ 125 mg/kg bw/day after 90 days.  Chronic exposure
led to increased absolute liver and kidney weights and increased
incidence of seminiferous tubule degeneration and increased numbers of
spermatid giant cells present in epididymides in males at ≥ 81.8 mg/kg
bw/day in males.  At 342.4/358.5 mg/kg bw/day (M/F) decreased mean 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 were observed.

In the developmental toxicity study in rats, no developmental toxicity
was seen at the highest dose tested.  In the developmental toxicity
study in rabbits, and in the two generation study in rats,
developmental/offspring toxicity was seen in the presence of
maternal/systemic toxicity and at the same dose levels.  Consequently,
there is no quantitative or qualitative evidence of increased
susceptibility following pre- and/or postnatal exposures and there are
no concerns or residual uncertainties.

In the available toxicity studies on rimsulfuron there was no evidence
of estrogen, androgen, and/or thyroid mediated toxicity.

HED classified rimsulfuron as “Not Likely to be Carcinogenic to
Humans” based on the lack of evidence for carcinogenicity in rats and
mice in the long term carcinogenicity studies.  

3.1.3	FQPA

The database is considered adequate to characterize any potential for
prenatal or postnatal susceptibility for infants and children.

Absorption, Distribution, Metabolism, Excretion (ADME)

The metabolism of 14C-labeled rimsulfuron was studied in male and female
rats.  The low dose groups were treated once by oral gavage with 25
mg/kg 14C -pyridine-labeled compound and the high dose groups with 250
mg/kg of either 14C -pyridine- or 14C-pyrimidine-labeled compound.  The
repeat dose groups were gavaged orally with unlabeled test compound (25
mg/kg) for 14 consecutive days, followed on the 15th day by 25 mg/kg of
14C -pyridine-test compound.  Excretion accounted for 93 to 96% of the
administered radioactivity, with 58 to 67% appearing in the urine and 20
to 33% in the feces.  Tissue distribution of labeled residues was low. 
Males showed slightly higher hepatic accumulation than females within
each test group.  Animals in the repeat dose groups also showed a slight
accumulation in the spleen.  The metabolic profiles were determined
using pooled urinary and fecal samples.  The highest percentage of the
urinary (42 to 55%) and fecal (5 to 16%) radioactivity was attributed to
unmetabolized parent compound.  The parent compound is metabolized by
cleavage or contraction of the sulfonylurea bridge, leading to the
formation of 3- (ethylsulfonyl)-2-pyridinesulfonamide (IN-E9260) or
N-(4, 6-dimethoxy-2-pyrimidinyl)-N-((3-ethylsulfonyl)-2-pyridinyl) urea
(IN-70941).  IN-70941 is deamidated to form IN-70942, which is
sequentially demethylated and hydroxylated.

3.3	FQPA Considerations

Adequacy of the Toxicity Database

The toxicology database for rimsulfuron is adequate to characterize
potential pre- and/or post-natal susceptibility for infants and
children.  Acceptable/guideline studies for developmental toxicity in
rats and rabbits and a 2-generation reproduction study in rats were
available for FQPA assessment.

3.3.2	Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in the available
developmental, reproduction, subchronic or chronic studies.  Acute and
subchronic neurotoxicity studies are required based on the latest
guidelines.  

3.3.3	Developmental Toxicity Studies

In a prenatal developmental study, pregnant rats were given rimsulfuron
(98.8 %) by gavage at dose levels of 0, 200, 700, 2000 or 6000 mg/kg
bw/day during gestation days 7 through 16.  A NOAEL was not established
for either maternal or developmental toxicity, as no maternal or
offspring effects were observed at the highest dose tested of 6000 mg/kg
bw/day.

In a prenatal developmental toxicity study, pregnant New Zealand White
rabbits received rimsulfuron (98.8 %) by gavage at dose levels of 0, 25,
170, 500, or 1500 mg/kg bw/day during gestation days 7 through 19.  In
the rabbit study, maternal toxicity was observed at a lower dose than
that which caused developmental toxicity.  The NOAEL for maternal
toxicity was 170 mg/kg bw/day and the LOAEL was 500 mg/kg bw/day based
on mortality, abortion and decreased body weight.  For developmental
toxicity, the NOAEL was 500 mg/kg bw/day and the LOAEL was 1500 mg/kg
bw/day as there were only 2 viable pups at 1500 mg/kg bw/day.

3.3.4	Reproductive Toxicity Study

In a two-generation reproduction study, Crl:CD-BR rats were fed diets
containing rimsulfuron (98.8%) at dose levels equivalent to 0, 2.8, 165
or 830 mg/kg bw/day for F0 males; 0; 3.4, 204 or 1021 mg/kg bw/day for
F0 females; 0, 3.7, 217 or 1316 mg/kg bw/day for F1 males; and 0, 4.3,
264 or 1316 mg/kg bw/day for F1 females, respectively.

For parental systemic toxicity, the NOAEL was 165/204 mg/kg bw/day in
males/females and the LOAEL was 830/1021 mg/kg bw/day in males/females
based on decreased body weight gain.

Similar effects were observed in offspring at similar or slightly higher
doses.  For offspring toxicity, the NOAEL was 217/264 mg/kg bw/day in
males/females and the LOAEL was 1316 mg/kg bw/day based on decreased
mean body weight in F1 males, decreased body weight gain in F1 females,
decreased mean pup weight of the F2 females, decreased daily food
consumption in F1 males, and decreased mean number of male F1 pups. 
Decreased weight was also the key finding for systemic effects.  Thus,
the toxic effects in offspring occurred at the same dose level as the
systemic parental effects.

3.3.5	Pre-and/or Postnatal Toxicity

3.3.5.1	Determination of Susceptibility

In the developmental toxicity study in rats, no developmental toxicity
was seen at the highest dose tested.  In the developmental toxicity
study in rabbits, and in the two generation study in rats,
developmental/offspring toxicity was seen in the presence of
maternal/systemic toxicity.  Consequently, there is no quantitative or
qualitative evidence of increased susceptibility following pre- and/or
postnatal exposures.

3.3.5.2	Degree of Concern Analysis and Residual Uncertainties for Pre
and/or Post-natal Susceptibility

There are no concerns, nor residual uncertainties for pre- and/or
postnatal toxicity since there was no indication of increased
susceptibility of rats or rabbits to in utero and/or postnatal 

exposure to rimsulfuron in the data provided.  

3.3.6	Recommendation for a Developmental Neurotoxicity Study

There is no evidence to support requiring a developmental neurotoxicity
study.  Neither the subchronic or chronic toxicity studies in rats and
dogs, the developmental toxicity studies in rats and rabbits, nor the
2-generation reproduction study indicated that the nervous system was
specifically affected by treatment with rimsulfuron.  Acute and
subchronic neurotoxicity studies are required by the most recent
guidelines and are considered to be data gaps.  

FQPA Safety Factor for Infants and Children 

Based on the hazard and exposure data, it is determined that the FQPA SF
can be reduced to 1x because: 

There is no evidence of increased susceptibility following in utero
and/or postnatal exposure in the developmental toxicity studies in rats
or rabbits, and in the 2-generation rat reproduction study; and there
are no residual uncertainties concerning pre- and postnatal toxicity and
no neurotoxicity concerns (based on the submitted studies).  

The chronic and cancer dietary food exposure assessments utilize
tolerance level residues calculated from field trial data and 100
percent crop treated data for all commodities. 

Conservative surface water modeling estimates were used. 

The assessments are based on reliable data and will not underestimate
exposure/risk for rimsulfuron.  There is no potential for residential
exposure.

Despite the need for immunotoxicity and neurotoxicity studies, there is
no evidence that rimsulfuron either causes neurotoxic effects or
directly targets the immune system, and therefore an additional
uncertainty factor is not needed to account for the lack of these
studies.

 

3.4	Hazard Identification and Toxicity Endpoint Selection

3.4.1	Acute Reference Dose (aRfD) – Females Ages 13-49 and General
Population

Study Selected: 	None  

MRID. Nos.		None

Executive Summaries:  None

Dose and Endpoint for Risk Assessment:  Not Applicable.

Comments about Study and Endpoint:  There were no toxicological effects
attributable to a single dose observed in oral toxicity studies
including the developmental toxicity studies in rats and rabbits. 
Therefore, a dose and endpoint were not selected for this risk
assessment.

3.4.2	Chronic Reference Dose (cRfD)

Study Selected:  	Chronic Toxicity - Dog					870.4100

MRID No.  		41931643

Dose/Endpoint for establishing the RfD:  The dose selected for risk
assessment is the NOAEL of 81.8 mg/kg bw/day based on statistically
significant increases in liver and kidney weights observed at the LOAEL
of 342.4 mg/kg bw/day.

Executive Summary: In a chronic toxicity study, groups of beagle dogs
(5/sex/dose) were fed diets containing rimsulfuron (98.8%) at 0, 50,
2500, or 10000 ppm for one year.  These dose levels were equivalent to
approximately 0, 1.6, 81.8, and 342.4 mg/kg bw/day for males and; 0,
1.6, 86.5, and 358.5 mg/kg bw/day for females, respectively.  For males,
the NOAEL was 1.6 mg/kg bw/day and the LOAEL was 81.8 mg/kg bw/day based
on increased absolute liver and kidney weights as well as increased
incidence of seminiferous tubule degeneration and increased numbers of
spermatid giant cells present in the epididymides.  For females, the
NOAEL was 86.5 mg/kg bw/day and the LOAEL was 358.5 mg/kg bw/day based
on decreased mean 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.

Comments about Study and Endpoint:  The original review of the submitted
study established a NOAEL of 1.6 mg/kg bw/day in males.  It was
determined that the increased kidney and liver weights in males only at
the next dose (81.8 mg/kg bw/day) was of questionable biological
significance since the increases showed statistical significance only
for the absolute values and not for relative; in addition, there were no
corroborative histopathological lesions in the liver or kidneys at this
dose.  Histopathological lesions at 81.8 mg/kg bw/day in males in the
seminiferous tubules were characterized as unilateral degeneration (2/5)
and in the epididymides as spermatid giant cells (3/5) compared to 0/5
(for each lesion) in the controls.  The seminiferous tubule lesion was
not considered to be toxicologically significant since the occurrence
was unilateral and there was no dose-response.  The epididymidal lesions
were also not considered to be toxicologically significant since they
are often associated with infection and/or old age.  Consequently, HED
determined that this dose (81.8 mg/kg bw/day) is the NOAEL to be used
for risk assessment purposes.  

The dog was shown to be the most sensitive species for
rimsulfuron-induced toxicity among subchronic and chronic studies.  In
subchronic toxicity studies the NOAEL/LOAEL in dogs was lower than in
rats.  Also, the NOAEL of 81.8 mg/kg bw/day used for risk assessment
purposes is still lower than the NOAEL of 165 mg/kg bw/day established
for parental systemic toxicity in the two generation reproduction study.
 HED also concluded that a NOAEL of 1.6 mg/kg bw/day is not supported by
the toxicity observed in any of the other studies in the database.

Uncertainty Factor (UF):  100X (10X for inter-species extrapolation and
10X for intra-species variation).  Because the FQPA Safety Factor has
been reduced to 1X, the reference dose and the chronic population
adjusted dose (cPAD) are the same.

Chronic Reference Dose (cRfD)  =   81.8 mg/kg bw/day (NOAEL)  = 0.818
mg/kg bw/day 

100 (UF)

3.4.3	Dermal Absorption

No dermal absorption studies are available.  A dermal absorption factor
is not applicable, since dermal risk assessments are not required.

3.4.4	Dermal Exposure (Short-, Intermediate- and Long-Term) 

	Short-Term Dermal - (1-7 days)

Study Selected:  	None

MRID No.  		None

Executive Summary:  None 

Dose and Endpoint for Risk Assessment:  Not Applicable.

Comments about Study and Endpoint:  The toxicity profile of rimsulfuron
indicated that there are no toxicological concerns based on the low
toxicity observed in studies conducted in mice, rats, rabbits and dogs. 
The NOAELs and LOAELs are tabulated below:

Study/Species	NOAEL (mg/kg bw/day)	LOAEL (mg/kg bw/day)

90-Day-Dog	6.25	125

90-Day-Rat	75	375

1-Year-Dog 	81.8 (M)    86.5 (F)	342.4 (M)    358.5 (F)

Developmental-Rabbit	170	500

Developmental-Rat	6000	Not Established

Two-Gen. Repro.-Rat	165	830

Carcinogenicity-Mouse	351 (M)    488 (F)	1127 (M)    1505 (F)

Carcinogenicity-Rat	11.8 (M)     163 (F)	121 (M)    568 (F)

Historically, the low toxicity, the use pattern (2 oz ai/A or 0.125 lbs
ai/A) and the number of applications (2/year) did not indicate a concern
for potential dermal exposure and risk.  These conclusions have not
changed, and therefore HED has not selected a dermal endpoint and dose
for occupational risk assessment.

3.4.5	Inhalation Exposure (Any Time Period) 

Except for an acute inhalation toxicity study, there are no other
inhalation toxicity studies available for use in selecting the dose and
endpoint for this risk assessment.  However, based on the formulation of
the product (dry flowable granule containing 25% ai), the low
application rate (0.125 lbs ai/acre), the application method (sprinkler
irrigation), and the low acute toxicity (LC50 ≥ 5 mg/L, Tox. Cat. IV),
there is minimal concern for potential inhalation exposure/risk for the
proposed use.

3.4.6	Level of Concern for Margin of Exposure

Due to the lack of toxicological endpoints of concern for dermal and
inhalation routes of exposure, Margins of Exposure (MOEs) are not
applicable for occupational exposure and risk assessments.

3.4.7	Recommendation for Aggregate Exposure Risk Assessments

There is no residential exposure associated with rimsulfuron nor is
there an acute dietary dose and endpoint; therefore, the only aggregate
risk scenario is chronic dietary (food and water) exposure.

3.4.8	Classification of Carcinogenic Potential

The doses used in the two-year rat and 18-month mouse studies were
adequate.  No evidence of carcinogenicity was observed.  Therefore, HED
determined that rimsulfuron should be classified as “Not Likely to be
Carcinogenic to Humans.”  As such, there is no cancer risk associated
with registered or proposed uses of rimsulfuron.

3.4.9	Summary of Toxicological Doses and Endpoints for Rimsulfuron for
Use in Human Risk Assessments

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
3.4.9.

Table 3.4.9.  Toxicological Doses and Endpoints for Rimsulfuron for Use
in Human Health Risk Assessments.

Exposure

Scenario	Point of Departure 	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

(females 13-49)

Acute Dietary

(general population)	

No appropriate endpoint attributable to a single dose is available.

Chronic Dietary

(all populations)

   	NOAEL= 81.8 mg/kg bw/day

	UFA=10x

UFH=10x	

FQPA SF=1x	Chronic RfD = chronic NOAEL

                          Safety Factors

= 0.818 mg/kg bw/day

cPAD = Chronic RfD

                FQPA SF

= 0.818 mg/kg bw/day	Chronic Toxicity –Dog

Increases in liver and kidney weights at a LOAEL of 342.4 mg/kg bw/day.

Incidental Oral 	

No appropriate endpoint available; use pattern does not indicate a need
for this risk assessment.

Dermal 

(All Durations)	No appropriate endpoint available; use pattern does not
indicate a need for this risk assessment.

Inhalation 

All Durations	

The low toxicity, use pattern and application method and rate do not
indicate a need for risk assessment via this route.

Cancer (oral, dermal, inhalation)	Rimsulfuron is considered “not
likely” to be carcinogenic to humans.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).  RfD = reference dose.  

Endocrine disruption		

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there were
scientific bases for including, as part of the program, androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  When the appropriate
screening and/or testing protocols being considered under the Agency’s
Endocrine Disrupter Screening Program (EDSP) have been developed and
vetted, rimsulfuron may be subjected to additional screening and/or
testing to better characterize effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data

There are no new public health data or pesticide epidemiology data to
report at this time.

5.0	Dietary Exposure/Risk Characterization

5.1	Pesticide Metabolism and Environmental Degradation

Metabolism in Primary Crops and Livestock

  SEQ CHAPTER \h \r 1 MARC Decision Memo, L. Cheng, G. Herndon,
11//FEB/1998; and DP# 200158, M. Nelson, 29/MAR/1994

MARC Briefing Memo, L. Cheng, 04/FEB/1998; and DP# 200157, M. Nelson,
17/MAR/1994

The nature of the residue in plants and livestock is sufficiently
understood based on adequate metabolism studies conducted with
rimsulfuron, labeled in the pyridine or pyrimidine ring, in field corn,
potatoes, tomatoes, lactating goat, and laying hen. 

The metabolic pathways were found to be similar in plants and livestock.
 The major route of rimsulfuron metabolism/degradation involves
sulfonylurea bridge contraction, with sulfonylurea bridge cleavage as a
minor metabolic route.  The metabolites detected were IN-70941,
IN-70942, IN-E9260, IN-J290, IN-69190 (goat), IN-H1043 (goat), IN-T5831
(potato), IN-JF999 (hen, tomato), and unresolved polar/nonpolar
products.  Based on the results of the studies, HED concluded that the
residue of concern in plant and livestock commodities is the parent
compound, rimsulfuron.  

5.1.2	Metabolism in Rotational Crops

DP# 200157, M. Nelson, 17/MAR/1994

The nature of rimusulfuron residues in rotational crops is adequately
understood based on the previously submitted confined accumulation study
in wheat.  Rimsulfuron is extensively metabolized in rotational crops. 
Metabolites 1N-70941, IN-E9260, and IN-Hl043 were identified in the
straw of wheat planted into aged (30 days and 120days), 14C-E9636
treated soil and grown to maturity.  No undegraded rimsulfuron was
detected in the straw of wheat at maturity.  

5.1.3	Analytical Methodology

DP# 330813, S. Hummel, 08/AUG/2006

DP# 326655, D. Rate, 15/MAY/2007

Enforcement methods:  Currently, an HPLC/UV method exists for the
enforcement of tolerances for residues of rimsulfuron in/on corn,
potato, and tomato commodities.  The method, AMR-1241-88, involves
extraction of samples with pH 7 potassium phosphate buffer and methanol
(75:25, v:v).  The extract is acidified to pH 2.5-3.5 (using
concentrated phosphoric acid) and filtered for analysis by HPLC/UV with
column switching, using a phenyl column for clean-up chromatography
followed by an Rx column for analytical chromatography.  The LOQ is 0.05
ppm.

Data-Collection methods:  Samples were analyzed for all sulfonylurea
residues (chlorimuron-ethyl, rimsulfuron and tribenuron-methyl) using an
LC/MS/MS method, DuPont-13412 RV1, “Analytical Method for the
Determination of Nicosulfuron, Thifensulfuron Methyl, Ethametsulfuron
Methyl, Rimsulfuron, Tribenuron Methyl, and Chlorimuron Ethyl in Oil
Crop Matrices Using SPE Purification and LC/MS/MS Detection.”

The submitted LC/MS/MS method (Method 13412, Revision 1) is adequate for
enforcing tolerances.  No new DER was written for the submitted method
(MRID 47562001), as it has been previously reviewed in conjunction with
a petition for thifensulfuron-methyl (DP# 330813, S. Hummel,
08/AUG/2006).  The current submission incorporates the ILV comments as
previously requested by HED, and since methodology does do not differ
significantly from the existing enforcement methods, petition method
validation (PMV) at the Biological and Economic Analysis Division
(BEAD)/Analytical Chemistry Branch (ACB) is not required.

5.1.4	Magnitude in Plants

DP# 360852, D. Rate, 13/AUG/2009

Adequate field trial data have been submitted for genetically modified
field corn and soybean reflecting treatment at 1x the proposed rate. 
The submitted crop field trial data were collected using the proposed
enforcement methods and are supported by adequate storage stability
data.  Residues of rimsulfuron were <LOQ (<0.01 ppm) in/on all samples
of corn grain and soybean seed collected at the appropriate PHI.  The
data indicate that the proposed tolerances for field corn and soybean
commodities are adequate.  

The available corn and soybean processing data for rimsulfuron are
adequate.  As residues did not concentrate in corn grits, meal, starch
or refined oil and concentrated only slightly in corn flour, separate
tolerances are not required for processed corn commodities.  For
soybeans, residues did not concentrate in meal or refined oil; therefore
separate tolerances are not required for these processed fractions. 
However, residues did concentrate in hulls.  Based on the highest
average field trial (HAFT) residues for soybeans (0.01 ppm) and the
processing factor for hulls (3.5x), the maximum expected residues in
hulls are 0.04 ppm.  Rimsulfuron residues were shown to concentrate in
AGF from both corn grain (102x) and soybean seeds (454x).  Based on the
HAFT residues of field corn grain (0.01 ppm) and soybean seeds (0.01
ppm), the maximum expected residues in AGF would be 1.0 ppm for corn
grain and 4.5 ppm for soybean seeds.  The recommended AGF tolerance of
4.5 ppm is based on soybean data.

5.1.5	Environmental Degradation

DP#s 358869 and 358875, J. Meléndez, 23/JAN/2009

Rimsulfuron is expected to transform/degrade into a number of
transformation/degradation products under different environmental
conditions.  The three major degradates of rimsulfuron result from
contraction or cleavage of the sulfonurea-bridge (IN-70941 and IN-70942
from contraction while IN-J9260 from cleavage).  In contrast, the minor
degradates are cleavage degradates (IN-J9260 is a minor degradate in
systems other than aerobic soil, IN-J290 and IN-T5831). A summary of the
degradation profiles in various laboratory systems is included in Table
5.1.5.

Table 5.1.5.  Transformation/degradation profiles of rimsulfuron in
various systems.

Degradate

Name 	Max Degradate Concentration in % of applied  and (Time in Days to
Max Concentration; Does it Decline Y/N)

	Hydrolysis @ pH7	Aerobic Soil	Anaerobic Soil	Other Studies

IN-70941	17%

(3 days; Y to 1%)	55%

(10 days; Y to 30%)	32%

(10 days; Y to 6%)	H2OPhotolysis: Similar to hydrolysis with reduction
in transformation of IN-70941 into IN-70942 and/or increase in the
degradation of IN-70942. Plus enhanced formation of IN-J920 and IN-E9260

Aerobic Aquatic Data: May not represent the natural environment as the
system was exposed to light

TFD (Terrestrial Field Dissipation) Data: None Identified possibly due
to inappropriate LOD/LOQ (limits of detection/quantification)

IN-70942	84%

(30 days; N)	30%

(360 days; N)	56%

(360 days; N)

	IN-E9290	10%

(30 days; N)	19%

(30 days; Y to 16%)	23%

(360 days; N)

	IN-J290	7%

(14 days; Y to 6%)	3%

(30 days; Y to 1%)	8%

(28 days; Y to 6%)

	

5.1.6	Comparative Metabolic Profile

In rats, rimsulfuron is excreted within the first 72 hours following
dosing in the urine (~64%) and the feces (~30%).  Low, but detectable
amounts of radioactivity were found in the heart, lung, liver, kidney,
and muscle; animals in the repeat dose groups also showed some
accumulation in the spleen.  Hepatic accumulation, although low, was
slightly higher than other organs; within each treatment group, the
males showed more accumulation in the liver than the females.  The
highest percentage of the urinary (42 to 55%) and fecal (5 to 16%)
radioactivity was attributed to unmetabolized parent compound. 
Metabolism involves either the contraction or cleavage of the
sulfonylurea bridge.  While the cleavage of the bridge to form the
pyridinesulfonamide metabolite is expected, the contraction reaction is
not.  

Metabolism of rimsulfuron in plants and other animals (poultry and
ruminants) appears to be similar to its metabolism in rats.  Metabolism
involves either the contraction or cleavage of the sulfonylurea bridge. 
While the cleavage of the bridge to form the pyridinesulfonamide
metabolite is expected, the contraction reaction is not.  The major
residue found in plants is the parent compound, rimsulfuron.  

5.1.7	Pesticide Metabolites and Degradates of Concern

Table 5.1.7.  Summary of Metabolites and Degradates to be Included in
the Risk Assessment and Tolerance Expression.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	rimsulfuron	rimsulfuron

	Rotational Crop	rimsulfuron	Not Applicable

Livestock

	Ruminant	rimsulfuron	Not Applicable

	Poultry	rimsulfuron	Not Applicable

Drinking Water

	rimsulfuron	Not Applicable

5.1.8	Drinking Water Residue Profile

DP#s 358869 and 358875, J. Meléndez, 23/JAN/2009

The residue of concern in drinking water is parent rimsulfuron only (HED
MARC decision memo; 29/MAR/1994).  EFED estimated the residues of
rimsulfuron in surface water and groundwater using the FQPA Index
Reservoir Screening Tool (FIRST) and Screening Concentrations in
Groundwater (SCIGROW) models, respectively.  The models and their
descriptions are available at the EPA internet site:   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  The maximum EDWCs are
presented below in Table 5.1.8.

Table 5.1.8.  Summary of Estimated Surface Water and Groundwater
Concentrations of Rimsulfuron1.

Maximum Surface Water EDWC (ppb)	Maximum Groundwater Acute/Chronic EDWC
(ppb)

Acute Value	Chronic/Cancer Value

	5.596	0.120	0.016

1 Degradates are not included as recommended by HED Metabolism
Committee.  The EDWCs were calculated based on the maximum application
rate of 0.0625 lb ai/A/season (for citrus, pome and stone fruits, ground
broadcast application, wetted in).

The chronic surface water EDWC was higher than the groundwater EDWC;
therefore, the surface water value of 0.120 ppb was used in the chronic
dietary assessment.  The acute surface water value is not relevant to
this dietary assessment, as a toxic effect attributable to a single dose
has not been identified for rimsulfuron.

5.1.9	Food Residue Profile

DP#365798, D. Dotson, 13/AUG/2009

Permanent tolerances have been established under 40 CFR §180.478(a) for
residues of rimsulfuron at 0.01 ppm in/on citrus fruit, pome fruit,
stone fruit, grapes, tree nuts, and pistachios; 0.05 ppm in/on tomatoes,
0.09 ppm in/on almond hulls, and 0.1 ppm in/on field corn grain, forage,
and stover.  The recommended tolerances associated with the new uses of
rimsulfuron on genetically modified soybeans and field corn are the
following:  0.4 ppm in/on field corn forage, 2.5 ppm in/on field corn
stover, 0.1 ppm in/on field corn grain, 0.01 ppm in/on soybean seed, 1.2
ppm in/on soybean hay, 0.25 ppm in/on soybean forage, 0.04 ppm in/on
soybean hulls and 4.5 ppm in/on aspirated grain fractions (based on the
soybean data).  

The unrefined chronic dietary assessment is based on the assumption that
rimsulfuron residues are present at tolerance levels (established or
recommended) in all commodities for which tolerances have been
established and that 100% of those crops are treated.  DEEM™ Version
7.81 default processing factors were applied to all processed
commodities for which they were available.  

5.1.10	International Residue Limits

There are no established or proposed Codex maximum residue limits (MRLs)
for residues of rimsulfuron.  However, there are Canadian MRLs for
rimsulfuron residues on tomatoes and blueberries and Mexican tolerances
for residues on potatoes, tomatoes and corn.  The Mexican tolerance for
corn (0.1 mg/kg) is identical to the existing U.S. tolerance for corn
grain and harmonization will be maintained.  

5.2	Dietary Exposure and Risk

5.2.1	Acute Dietary Exposure/Risk

An acute dietary assessment was not performed, since a toxicological
endpoint attributable to a single dose has not been identified for
rimsulfuron.

5.2.2	Chronic Dietary Exposure/Risk

DP#365798, D. Dotson, 13/AUG/2009

Rimsulfuron chronic dietary (food + water) exposure estimates using the
DEEM-FCID™ software are well below ARIA/HED’s level of concern for
the U.S. population and each of the population subgroups.  Dietary
exposure was estimated to be 0.000428 mg/kg bw/day for the U.S.
population (<1% of the cPAD) and 0.001063 mg/kg bw/day (<1% of the cPAD)
for the most highly exposed population subgroup (children, 1-2 years
old).  The estimated exposures and risks from residues of rimsulfuron in
food and water are summarized in Table 5.2.

Table 5.2.  Chronic Aggregate Dietary (Food + Drinking Water) Exposure
and Risk for Rimsulfuron.

Population Subgroup	Chronic Dietary	Cancer

	Dietary Exposure

(mg/kg bw/day)	% cPAD	Dietary Exposure

(mg/kg bw/day)	Risk

General U.S. Population	0.000428	<1	N/A	N/A

All Infants (< 1 year old)	0.000544	<1

Children 1-2 years old	0.001063	<1

Children 3-5 years old	0.001002	<1

Children 6-12 years old	0.000686	<1

Youth 13-19 years old	0.000504	<1

Adults 20-49 years old	0.000342	<1

Adults 50+ years old	0.000254	<1

Females 13-49 years old	0.000336	<1

The values for the highest exposed population for each type of risk
assessment are in bold text.

  TOC \o "1-3" \h \z \u   5.2.3	Cancer Dietary Risk

HED classified rimsulfuron as “not likely to be carcinogenic.” 
Therefore, there a cancer risk assessment was not required. 

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

The unrefined chronic assessment assumed that rimsulfuron residues are
present in all commodities at tolerance levels and that 100% of all
crops are treated.  

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

There are currently no residential uses for rimsulfuron, therefore no
non-occupational exposure is expected to result from the proposed and
labeled uses.

Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for rimsulfuron.
 The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices.  On
a chemical by chemical basis, the Agency is now requiring interim
mitigation measures for aerial applications that must be placed on
product labels/labeling.  The Agency has completed its evaluation of the
new database submitted by the Spray Drift Task Force, a membership of
U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

7.0	Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate rimsulfuron
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED and ARIA have considered both the route and duration of
exposure.  The only exposure identified for rimsulfuron is chronic (food
and water).  Because there are currently no registered residential uses
for rimsulfuron and chronic exposures due to residential use are not
expected, chronic risk is solely due to dietary risk from food and
water.  Section 5.2.2 describes the chronic aggregate risk.

8.0	Cumulative Risk Characterization/Assessment

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 for rimsulfuron and any other
substances, and rimsulfuron does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
action, therefore, EPA has assumed that rimsulfuron does not have a
common mechanism of toxicity with other substances.  For information
regarding EPA’s efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

9.0	Occupational Exposure/Risk Pathway

DP# 365801, M. Dow, 23/JUN/2009

9.1	Short-Term Handler Risk

applicators and other handlers to wear long-sleeved shirt, long pants,
shoes plus socks and chemical-resistant gloves in Category A (such as
butyl rubber, natural rubber, neoprene rubber or nitrile rubber), all
≥14 mils.

The rimsulfuron risk assessment team determined that there were no
dermal or inhalation toxicological endpoints identified for use in risk
assessment for rimsulfuron.  Therefore a quantification of
post-application exposure and risk to workers is not necessary

Postapplication Exposure and Risk

Typically, it is possible for agricultural workers to have
post-application exposure to dislogeable pesticide residues.  In this
case, since no dermal toxicological endpoint has been identified, an
assessment of post-application exposure and risk is not necessary.

9.3	Restricted Entry Interval (REI) 

The currently registered product label lists a REI of 4 hours.  PR
Notice 95-03 on the Reduced REI policy (3-May-1995) does not list
rimsulfuron as an active ingredient approved for a 4-hour REI.  However,
PR 95-03 allows a 4-hour REI provided that end-use products meet the
following reduced risk criteria:

1) The end-use product is in Toxicity Category III or IV for all of the
following acute toxicity studies: acute dermal toxicity, acute
inhalation toxicity, primary skin irritation, and primary eye
irritation.

2) Based on the required sensitization or hypersensitivity studies, the
end use product is not a sensitizer, and there have been no reports of
hypersensitivity.

3) The registrant has no data indicating, and is not aware of, adverse
health effects associated with the end use product, e.g.,
carcinogenicity, neurotoxicity, developmental effects or reproductive
effects.

4) The registrant is not aware and has not been informed of incident
information (illness or injury reports) that are “definitely” or
“probably” (as defined by the California Incident Reporting System)
related to post application exposures to the product.

Based on the toxicity criteria discussed above, rimsulfuron meets the
criteria for a reduced (4-hour) REI.

10.0	Data Needs and Label Recommendations

Toxicology			

As part of the new part 158 guidelines, the following studies are needed
to complete the toxicity database: acute and subchronic neurotoxicity,
immunotoxicity and a 21/28 day dermal toxicity study 

10.2	Residue Chemistry

A revised Section F must be submitted to reflect the recommended
tolerance levels in/on corn, field, grain at 0.1 ppm and request a
tolerance in/on grain, aspirated fractions at 4.5 ppm as specified below
in Table B.1.  Also, the requested tolerances for corn, aspirated grain
fraction and soybean, aspirated grain fractions are not necessary and
must be removed from the revised Section F.

10.3	Occupational and Residential Exposure

None.

References:

DP# 365798, D. Dotson, 13/AUG/2009

DP# 360852, D. Rate, 13/AUG/2009

  SEQ CHAPTER \h \r 1 MARC Decision Memo, L. Cheng, G. Herndon,
11//FEB/1998; and DP# 200158, M. Nelson, 29/MAR/1994

MARC Briefing Memo, L. Cheng, 04/FEB/1998; and DP# 200157, M. Nelson,
17/MAR/1994

DP# 200157, M. Nelson, 17/MAR/1994

DP# 330813, S. Hummel, 08/AUG/2006

DP# 326655, D. Rate, 15/MAY/2007

DP#s 358869 and 358875, J. Meléndez, 23/JAN/2009

DP# 365801, M. Dow, 23/JUN/2009

Appendix A:  Toxicology Assessment

A.1  Toxicity Profiles

Table A.1.1	Acute Toxicity Profile – Rimsulfuron

Guideline No.	

Study Type	

MRID(s)	

Results	

Toxicity Category

870.1100	

Acute oral Rat

Acute oral Mouse	

41356311,  41356310,41931634

41931623	

LD50 = > 5000 mg/kg

LD50 = > 5000  mg/kg	

IV

IV

870.1200	

Acute dermal Rabbit	

41356312, 41356313, 41931624,41931635	

LD50 = > 2000 mg/kg	

IV

870.1300	

Acute inhalation Rat	

41356314; 41931625;41931637;41931636;	

LC50 = >5.4; > 5.0; > 7.5; > 5.4 mg/L	

IV

870.2400	

Acute eye irritation Rabbit	

41931626, 41356315, 41356316, 41931638 	

Moderate eye irritant	

III

870.2500	

Acute dermal irritation Rabbit	

41931627, 41356318,41931639, 41356317 	

No irritation	

IV

870.2600	

Skin sensitization Guinea Pig	

41931628, 41356320, 41931641, 41931640,41356319	

Not a sensitizer	

IV

Table A.1.2   Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity (rat)	

41356321 (1989)/ ACCEPTABLE-GUIDELINE 

0, 50, 1500, 7500, 2000 ppm  (0, 2.5, 75, 375, 1000 mg/kg bw/day)	

NOAEL = 75 mg/kg bw/day

LOAEL = 375 mg/kg bw/day based on reduced body wt. gains.

870.3100

90-Day oral toxicity (mouse)

	

41356323 ((1989)/ ACCEPTABLE-NONGUIDELINE  (90-day oral toxicity in the
mouse is not required under the 1884 Subdivision F guideline
requirements.)

0, 50, 375, 1500, 7500 ppm (0, 7.5, 56.25, 225, 1125 mg/kg bw/day)	

NOAEL = M: 56.25 ;  F: >1125 mg/kg bw/day

LOAEL = M: 225 mg/kg bw/day based on increased RBC and hemoglobin and
decreased body weight gain and food efficiency.   F: LOAEL not
established.

870.3150

90-Day oral toxicity (dog)

	41356322 (1989)/ ACCEPTABLE-GUIDELINE 

0, 250, 5000, 20000 ppm (0, 6.25, 125, or 500 mg/kg bw/day). 	NOAEL =
6.25 mg/kg bw/day

≥ 6000 mg/kg bw/day

LOAEL = not established

Developmental NOAEL ≥ 6000 mg/kg bw/day

LOAEL = not established

870.3700b

Prenatal developmental in (rabbit)	

41356325 (1989)/ ACCEPTABLE-GUIDELINE 

0, 25, 170, 500, 1500 mg/kg bw/day	

Maternal NOAEL = 170 mg/kg bw/day

LOAEL = 500 mg/kg bw/day based on based death and reduced weight gain.

Developmental NOAEL = 500 mg/kg bw/day

Developmental LOAEL = 1500 mg/kg bw/day based on production of only two
viable fetuses.

870.3800

Reproduction and fertility effects

(rat)	

41931644 (1990)/ ACCEPTABLE-GUIDELINE 

 0, 50, 3000, 15000 ppm ( 0, 2.76, 165, 830 mg/kg bw/day (F0 males);

 0, 3.38, 204, 1021 mg/kg bw/day (F0 females); 0, 3.66, 217, 1316 mg/kg
bw/day (F1 males); and 0, 4.29, 264, 1316 mg/kg bw/day (F1 females)
respectively).

	

Parental/Systemic NOAEL = 165 mg/kg bw/day in males, 204 mg/kg bw/day in
females

Parental/Systemic LOAEL = M: 830; F: 1021mg/kg bw/day based on decreased
body weight gain in males and females

Reproductive NOAEL =1316 mg/kg bw/day (HDT)

Reproductive LOAEL = Not Established.

Offspring NOAEL =  M: 217; F; 264 mg/kg bw/day

LOAEL = 1316 mg/kg bw/day based on decreased mean body weight in F1
males, decreased body weight gain in F1 females and decreased daily food
consumption in F1 males.

870.4100b

Chronic toxicity (dog)	41931643(1991)/ ACCEPTABLE-GUIDELINE 

0, 50, 2500, 10,000 ppm (0, 1.6, 81.8, 342.4 mg/kg bw/day (males);
0,1.6, 86.5, 358.5 mg/kg bw/day (females) respectively)	Following
re-evaluation (HED DOC. NO.  012501, HIARC, 19/FEB/1998):

NOAEL = in males 81.8 mg/kg/day and in females 86.5 mg/kg bw/day.

LOAEL = 342.4 mg/kg/day) based on increased absolute liver and kidney
weights and increased incidence of seminiferous tubule degeneration and
increased numbers of spermatid giant cells present in epididymides in
males.   The LOAEL in females is 358.5 mg/kg/day based on decreased mean
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.

870.4200

Carcinogenicity

(rat)	42047701(1991)/ ACCEPTABLE-GUIDELINE 

0, 25, 300, 3000, 10,000 ppm [0, 1.0, 11.8, 121, 414  mg/kg bw/day
(males); 1.38, 17.1, 163, 568 mg/kg bw/day (females)]	NOAEL = 11.8 mg/kg
bw/day for males and 163 mg/kg/day for females.

LOAEL = 121 mg/kg bw/day for males and 568 mg/kg bw/day for females,
based on decreased body weight gain and increased relative liver
weights.  

No evidence of carcinogenicity.

870.4300

Carcinogenicity

(mouse)	41931642 (1991)/ ACCEPTABLE-GUIDELINE 

0, 25, 250, 2500, or 7500 ppm [0, 3.47, 35.5, 351, or 1127 mg/kg bw/day
(males) 0, 4.99, 50.5, 488, or 1505 mg/kg bw/day (females)]	

NOAEL = 351 mg/kg bw/day (males); 488 mg/kg bw/day (females).

LOAEL = 1127 mg/kg bw/day for males; and 1505 mg/kg bw/day, females,
based on decreased mean body weight in males and females, increased
incidence of dilation and cysts in the glandular stomach and
degeneration of the testicular artery and tunica albuginea in males.    
                                   No evidence of carcinogenicity.

870.5100

In vitro Bacterial Gene Mutation Assay 	42471310 (1992)/
ACCEPTABLE-GUIDELINE 

5000, 1000, 750, 500, 100, 75, 50, 25, 10, 0 µg/plate and (Trial 2)
5000, 2500, 1000, 750, 500, 100, 0 µg/plate in the presence and absence
of mammalian metabolic activation with 0.5 ml S-9 mix.	

There was no evidence of induced mutant colonies over background.

870.5300

In Vitro Mammalian Cells in Culture Gene Mutation assay in CHO	41356328
(1989)/ ACCEPTABLE-GUIDELINE 

0, 10, 100, 250, 750, 1300 µg/mL in the presence and absence of
mammalian metabolic activation with S/9.

41356327 (1989)/ ACCEPTABLE-GUIDELINE 

0, 0.0008, 0.004, 0.008, 0.04, 0.08, 0.4, 0.8, or 1.1 mg/mL	There was no
evidence of induced mutant colonies over background.

There was no evidence that unscheduled DNA synthesis, as determined by
radioactive tracer procedures [nuclear silver grain counts] was induced.

A.2  Rationale for Toxicology Data Requirements.

 	

Table A.2.1.  Guideline Number:  870.6200

Study Title:  Acute & Subchronic Neurotoxicity

Rationale for Requiring the Data

The acute and subchronic neurotoxicity studies are a new data
requirement under 40 CFR Part 158 as a part of the data requirements for
registration of a pesticide (food and non-food uses). 

The Neurotoxicity Test Guideline (OPPTS 870.6200) prescribes functional
and structural neurotoxicity testing and is designed to evaluate the
potential of a repeated chemical exposure to produce adverse effects on
the nervous system.  Although some information on neurotoxicity may be
obtained from standard guideline toxicity study data, studies not
specifically conducted to assess neurotoxic endpoints may be inadequate
to characterize a pesticide’s potential neurotoxicity.  While data on
clinical signs of toxicity or histopathology in routine chronic or
subchronic toxicity studies may offer useful information on potential
neurotoxic effects, these endpoints alone may be insufficient to detect
more subtle neurological effects.  

Practical Utility of the Data

How will the data be used?

Neurotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the nervous
system from pesticide exposure.  Since epidemiologic data on the effects
of chemical exposures on neurologic parameters are limited and may be
inadequate to characterize a pesticide’s potential neurotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation.

How could the data impact the Agency's future decision-making? 

If the neurotoxicity studies show that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.

Table A.2.2.  Guideline Number:  870.7800

Study Title:  Immunotoxicity 

Rationale for Requiring the Data

The immunotoxicity study is a new data requirement under 40 CFR Part 158
as a part of the data requirements for registration of a pesticide (food
and non-food uses). 

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chemical exposure to produce adverse effects (i.e., suppression) on the
immune system. Immunosuppression is a deficit in the ability of the
immune system to respond to a challenge of bacterial or viral infections
such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS),
or neoplasia.  Because the immune system is highly complex, studies not
specifically conducted to assess immunotoxic endpoints are inadequate to
characterize a pesticide’s potential immunotoxicity.  While data from
hematology, lymphoid organ weights, and histopathology in routine
chronic or subchronic toxicity studies may offer useful information on
potential immunotoxic effects, these endpoints alone are insufficient to
predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation. For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.

Guideline Number: 870.3250

Study Title:   21/28-Day Dermal Toxicity 

Rationale for Requiring the Data

The subchronic (21/28-day) dermal toxicity study is a new data
requirement under 40 CFR Part 158 as a part of the data requirements for
registration of a pesticide for food use.

The dermal toxicity Test Guidelines (OPPTS.870.3250) is intended to
evaluate the toxic effects associated with continuous or repeated
exposures to a test substance for a period of 21/28-days. 

The Agency needs a 21/28-day dermal toxicity study for food use
pesticides because a route-specific study eliminates the uncertainties
associated with use of an oral study and dermal absorption factors for
dermal risk assessments

Practical Utility of the Data

How will the data be used?  

A route specific (i.e., dermal) study will provide critical scientific
information needed to characterize potential hazard to the human
population exposed to the pesticide by the dermal route.  This study
will provide a dose and a toxicological endpoint of concern for
quantification of risks for dermal exposures. This study would eliminate
the uncertainties associated with the use of an oral study with a
default (100% oral equivalent) dermal absorption factor.  

In many cases, toxicity observed via the dermal route will be different
than toxicity observed via oral exposure,  due to absorption and
distribution of the toxic agent after exposure or differences in
metabolism (i.e., systemic versus local).  This means that the
route-to-route extrapolation (i.e., use of an oral dose/endpoint) in
risk assessment could result in under or over estimation of risks from
the dermal route.  

How could the data impact the Agency’s future decision-making?

If the dermal toxicity study indicates that the test material poses
either a greater or lesser risk than that calculated using an oral dose,
(as used in the interim decision), the risk assessment would be revised
to reflect the magnitude of potential risk derived from the new data.
Also, the requested data would allow the Agency to determine if the
risks were over-estimated or under-estimated.  If the risks were
under-estimated, additional risk mitigation measures could be required. 
If the risks were over-estimated, risk mitigation measures could be
reduced.

Appendix B: Tolerance Setting

Table B.1.  Tolerance Summary for Rimsulfuron.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

Corn, field, grain	0.01	0.1	Maintained at 0.1 ppm to stay harmonized
with the MRL in Mexico.

Corn, field, forage	0.4	0.4

	Corn, field, stover	2.5	2.5

	Corn, aspirated grain fractions	1.02	None

	Soybean, hay	1.2	1.2

	Soybean, forage	0.25	0.25

	Soybean, seed	0.01	0.01

	Soybean, hulls	0.035	0.04

	Soybean, aspirated grain fractions	4.51	None

	Grain, aspirated fractions	None	4.5

	

Appendix C: Review of Human Research

The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database,
Version 1.1.  Task Force members Health Canada, U.S. Environmental
Protection Agency, and the National Agricultural Chemicals Association,
released February, 1995.

Rimsulfuron	Risk Assessment Document	DP# 358866

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