Document ID: EPA-HQ-OPP-2009-0005-0008
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

MEMORANDUM

DATE: 		September 28, 2009 

SUBJECT:	Tribenuron methyl.  Human Health Risk Assessment for the
Proposed Use of Tribenuron methyl on Corn and Soybean.	

PC Code:  	128887	DP Barcode:	358876

Decision No.:	400410	Registration No.:	352-632

Petition Nos.:	8F7432 and 8F7441	Regulatory Action:	Section 3

Assessment Type:	Single Chemical Human Health Risk Assessment
Registration Case No.:	‘None’

TXR No.:	‘None’	CAS No.:	101200-48-0

MRID No.:	‘None’	40 CFR:	§180.451

					

FROM:	Breann Hanson, Biologist

			Alternative Risk Integration and Assessment (ARIA) Team

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

			Registration Division (RD; 7505P)

THROUGH:	William Cutchin, Acting Senior Branch Scientist

				ARIA/RIMUERB/RD (7505P)

AND:			Christina Swartz, Branch Chief

			Michael A. Doherty, Ph.D., Senior Chemist

		Risk Assessment Branch (RAB) II

Health Effects Division (HED; 7509P)

TO:		James Tompkins, RM Team 25  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1 

		Herbicide Branch (HB)/RD; 7505P

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc241893459"  1.0	Executive
Summary	  PAGEREF _Toc241893459 \h  4  

  HYPERLINK \l "_Toc241893460"  2.0	Ingredient Profile	  PAGEREF
_Toc241893460 \h  11  

  HYPERLINK \l "_Toc241893461"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc241893461 \h  11  

  HYPERLINK \l "_Toc241893462"  2.2	Structure and Nomenclature	  PAGEREF
_Toc241893462 \h  12  

  HYPERLINK \l "_Toc241893463"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc241893463 \h  12  

  HYPERLINK \l "_Toc241893464"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc241893464 \h  13  

  HYPERLINK \l "_Toc241893465"  3.1	Hazard Characterization	  PAGEREF
_Toc241893465 \h  13  

  HYPERLINK \l "_Toc241893466"  3.2	FQPA Considerations	  PAGEREF
_Toc241893466 \h  14  

  HYPERLINK \l "_Toc241893467"  3.2.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc241893467 \h  14  

  HYPERLINK \l "_Toc241893468"  3.2.2	Evidence of Neurotoxicity	 
PAGEREF _Toc241893468 \h  14  

  HYPERLINK \l "_Toc241893469"  3.2.3	Developmental Toxicity Studies	 
PAGEREF _Toc241893469 \h  15  

  HYPERLINK \l "_Toc241893470"  3.2.4	Reproductive Toxicity Study	 
PAGEREF _Toc241893470 \h  15  

  HYPERLINK \l "_Toc241893471"  3.2.5	Additional Information from
Literature Sources	  PAGEREF _Toc241893471 \h  15  

  HYPERLINK \l "_Toc241893472"  3.2.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc241893472 \h  15  

  HYPERLINK \l "_Toc241893473"  3.3	Safety Factor for Infants and
Children	  PAGEREF _Toc241893473 \h  15  

  HYPERLINK \l "_Toc241893474"  3.4	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc241893474 \h  16  

  HYPERLINK \l "_Toc241893475"  3.4.1.	Acute Reference Dose (aRfD) -
General Population (Including Infants and Children) and Females Age
13-49	  PAGEREF _Toc241893475 \h  16  

  HYPERLINK \l "_Toc241893476"  3.4.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc241893476 \h  16  

  HYPERLINK \l "_Toc241893477"  3.4.3.	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc241893477 \h  17  

  HYPERLINK \l "_Toc241893478"  3.4.4	Dermal Absorption	  PAGEREF
_Toc241893478 \h  17  

  HYPERLINK \l "_Toc241893479"  3.4.5	Dermal Exposure (Short,
Intermediate- and Long-Term)	  PAGEREF _Toc241893479 \h  17  

  HYPERLINK \l "_Toc241893480"  3.4.6	Inhalation Exposure (Short,
Intermediate- and Long-Term)	  PAGEREF _Toc241893480 \h  18  

  HYPERLINK \l "_Toc241893481"  3.4.7	Margins of Exposure	  PAGEREF
_Toc241893481 \h  19  

  HYPERLINK \l "_Toc241893482"  3.4.8	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc241893482 \h  19  

  HYPERLINK \l "_Toc241893483"  3.4.9	Classification of Carcinogenic
Potential	  PAGEREF _Toc241893483 \h  19  

  HYPERLINK \l "_Toc241893484"  3.4.10	Summary of Toxicological Doses
and Endpoints for Use in Human Health Risk Assessment	  PAGEREF
_Toc241893484 \h  19  

  HYPERLINK \l "_Toc241893485"  3.5.	Endocrine disruption	  PAGEREF
_Toc241893485 \h  21  

  HYPERLINK \l "_Toc241893486"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc241893486 \h  21  

  HYPERLINK \l "_Toc241893487"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc241893487 \h  22  

  HYPERLINK \l "_Toc241893488"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc241893488 \h  22  

  HYPERLINK \l "_Toc241893489"  5.1.1 	Metabolism in Primary Crops	 
PAGEREF _Toc241893489 \h  22  

  HYPERLINK \l "_Toc241893490"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc241893490 \h  22  

  HYPERLINK \l "_Toc241893491"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc241893491 \h  22  

  HYPERLINK \l "_Toc241893492"  5.1.4	Analytical Methodology	  PAGEREF
_Toc241893492 \h  22  

  HYPERLINK \l "_Toc241893493"  5.1.5 	Environmental Degradation	 
PAGEREF _Toc241893493 \h  23  

  HYPERLINK \l "_Toc241893494"  5.1.6	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc241893494 \h  23  

  HYPERLINK \l "_Toc241893495"  5.1.7	Drinking Water Residue Profile	 
PAGEREF _Toc241893495 \h  24  

  HYPERLINK \l "_Toc241893496"  5.1.8	Food Residue Profile	  PAGEREF
_Toc241893496 \h  24  

  HYPERLINK \l "_Toc241893497"  5.1.9	International Residue Limits	 
PAGEREF _Toc241893497 \h  25  

  HYPERLINK \l "_Toc241893498"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc241893498 \h  25  

  HYPERLINK \l "_Toc241893499"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc241893499 \h  25  

  HYPERLINK \l "_Toc241893500"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc241893500 \h  25  

  HYPERLINK \l "_Toc241893501"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc241893501 \h  26  

  HYPERLINK \l "_Toc241893502"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc241893502 \h  26  

  HYPERLINK \l "_Toc241893503"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc241893503 \h  26  

  HYPERLINK \l "_Toc241893504"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc241893504 \h  26  

  HYPERLINK \l "_Toc241893505"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc241893505 \h  26  

  HYPERLINK \l "_Toc241893506"  7.3	Long-Term Aggregate Risk	  PAGEREF
_Toc241893506 \h  27  

  HYPERLINK \l "_Toc241893507"  7.4	Cancer Risk	  PAGEREF _Toc241893507
\h  27  

  HYPERLINK \l "_Toc241893508"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc241893508 \h  27  

  HYPERLINK \l "_Toc241893509"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc241893509 \h  27  

  HYPERLINK \l "_Toc241893510"  9.1	Workers’ Exposure/Risk	  PAGEREF
_Toc241893510 \h  28  

  HYPERLINK \l "_Toc241893511"  9.2	Postapplication Exposure/Risk	 
PAGEREF _Toc241893511 \h  29  

  HYPERLINK \l "_Toc241893512"  9.3	Restricted Entry Interval (REI)	 
PAGEREF _Toc241893512 \h  30  

  HYPERLINK \l "_Toc241893513"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc241893513 \h  30  

  HYPERLINK \l "_Toc241893514"  10.1	Toxicology	  PAGEREF _Toc241893514
\h  30  

  HYPERLINK \l "_Toc241893515"  10.2	Residue Chemistry.	  PAGEREF
_Toc241893515 \h  30  

  HYPERLINK \l "_Toc241893516"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc241893516 \h  31  

  HYPERLINK \l "_Toc241893517"  Appendix A.  Toxicity Profile for
Tribenuron Methyl	  PAGEREF _Toc241893517 \h  33  

  HYPERLINK \l "_Toc241893518"  Appendix B.  DCI Rationales for Required
Toxicology Studies.	  PAGEREF _Toc241893518 \h  36  

  HYPERLINK \l "_Toc241893519"  Appendix C.  International Residue Limit
Status.	  PAGEREF _Toc241893519 \h  38  

 

                                                                        
                                                                        
                                                                        
                                                                        
                                                                        
                  SEQ CHAPTER \h \r 1 1.0	Executive Summary

Introduction

Under provisions in Section 3 of the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA), as amended, the E.I. du Pont de Nemours and
Company (herein called “DuPont”) has requested registration of the
herbicide active ingredient (ai) tribenuron methyl,
methyl-2-[[[[[4-methoxy-6-methyl-1,3,5-triazin-2-yl] methylamino]
carbonyl] amino] sulfonyl] benzoate, for use on genetically modified
soybean and corn commodities.

Tribenuron methyl is a triazinylsulfonylurea herbicide that works via
inhibition of acetolactate synthase (ALS).  It is currently registered
for post-emergence application(s) to barley, canola, cotton, flax, oats,
sunflower, wheat, and grasses grown for seed, for the selective control
of broadleaf weeds.  It is also registered for use as a pre-emergence
burndown broadcast application for wheat and barley, and as a preplant
or at-planting burndown application for cotton, field corn, rice, grain
sorghum, and soybeans.  Permanent tolerances are established for
residues of tribenuron methyl at levels ranging from 0.02 ppm in/on
cotton and canola commodities to 0.5 ppm in/on wheat hay (40CFR
§180.451[a] and [c]).  Tolerances have already been established at 0.05
ppm in/on field corn forage, grain and stover.  

The most recent human health risk assessment for tribenuron methyl was
conducted by HED (DP#: 340848, D. Dotson, 4/17/2008).  

Use Profile

DuPont is proposing the establishment of permanent tolerances for
residues of tribenuron methyl in/on soybean commodities (PP# 8E7432) and
field corn commodities (PP# 8E7441) at the levels listed below.  

Soybean, hay	0.25 ppm

Soybean, forage	0.06 ppm

Soybean, seed	0.01 ppm

Soybean, hulls	0.04 ppm

Soybean, aspirated grain fractions	3.46 ppm

Corn, field, grain	0.01 ppm

Corn, field, forage	0.2 ppm

Corn, field, stover	1.1 ppm

Corn, field, aspirated grain fractions	3.55 ppm

 actions is DuPont™ Express®, a water soluble granule (SG)
formulation containing 50% ai tribenuron methyl.  Express® is proposed
for use as one or two foliar spray treatments to genetically modified
soybeans or field corn, at a maximum single (and seasonal) use rate of
0.03125 pounds of ai per acre (lb ai/A), which corresponds to the
proposed label’s stated maximum use rate of 1 ounce of EP per acre per
crop season.  The label specifies pre-harvest intervals (PHIs) of 7 days
for field corn commodities, and 14 days for soybean forage and hay.  As
the label directions for use on soybeans prohibit applications after the
R2 stage, a specific PHI for soybean seeds was not proposed, and is not
required.  Re-treatment intervals (RTIs) for use on soybeans and field
corn were not specified.  

Hazard Characterization/Assessment

The toxicology database is adequate to characterize the toxicity of
tribenuron methyl and to assess risk for the proposed use and amended
tolerance.  However, several newly required toxicity studies are needed
to complete the database.  Tribenuron methyl has low to moderate acute
toxicity via the oral, inhalation, and dermal routes.  It is not a
dermal irritant, but was found to be mildly irritating to the eye and it
is a skin sensitizer. 

Repeated dose oral toxicity studies in rats and dogs resulted primarily
in decreased body weights and body weight gains accompanied by decreased
food consumption.  There is no evidence that tribenuron methyl targets
specific organs following repeated oral exposure. In addition, no
evidence of neurotoxicity or neuropathy was observed in the available
studies.  The chronic dietary (food and water) risk assessment is based
on the no observed adverse effect level (NOAEL) of 0.8 mg/kg/day from a
one-year dog study that demonstrated elevated bilirubin blood levels,
elevated AST blood levels, increased urinary volume, and a reduction in
body weight observed at the lowest observed adverse effect level (LOAEL)
of 8 mg/kg/day.  As no acute toxicological effects have been associated
with a single oral exposure to tribenuron methyl, an acute dietary
endpoint and dose for risk assessment were not identified. 

Developmental and reproductive toxicity studies indicated no increased
susceptibility of offspring to tribenuron methyl.  In the developmental
study in rats, decreased fetal weights were observed in the presence of
decreased maternal body weights.  At the highest dose tested, increased
resorptions, fetal deaths, and incomplete ossifications were observed. 
In the developmental rabbit study, maternal toxicity consisted of
decreased food consumption and abortions.  In a two-generation
reproduction study, reproductive effects of tribenuron methyl were
limited to decreased body weight gain during lactation.  In the
reproduction study, there was no evidence of susceptibility, as
parental, offspring and reproduction NOAELs and LOAELs were established
at similar doses.  HED previously concluded the Food Quality Protection
Act (FQPA) safety factor should be reduced to 1x because the available
data provided no indication of increased susceptibility (quantitative or
qualitative) to rats or rabbits following in utero or pre- and/or
post-natal exposure to tribenuron methyl, due to the lack of
neurotoxicity, and a lack of residual concerns for susceptibility.  Due
to recent changes in the Part 158 data requirements, acute and
subchronic neurotoxicity studies and an immunotoxicity study are now
required for tribenuron methyl.  However, due to a lack of evidence of
neurotoxicity or potentially immunotoxic effects in the available
toxicity studies, HED has concluded no additional database uncertainty
factor is needed in the absence of these studies.

Tribenuron methyl was previously classified as a Group C (possible human
carcinogen) because of the increased incidence of mammary gland
adenocarcinomas in female rats; however, quantitative estimation of
cancer risk with a cancer potency factor was not recommended by HED. 
Tribenuron methyl was not shown to be mutagenic.  Because the
adenocarcinomas were only observed at doses above the maximum tolerated
dose, HED considers the chronic risk assessment to be protective of any
potential risk of carcinogenicity.

For occupational risk assessment, short-term dermal and inhalation
endpoints were based on maternal effects in the developmental rabbit
study, which included decreases in body weight and abortions. 
Intermediate-term dermal and inhalation endpoints were selected from the
90-day rat study where the effects observed included decreased body
weight gain, food consumption and food efficiency, and changes in the
absolute and relative organ weights as well as some clinical chemistry
parameters. The chronic feeding study in dogs was used for long-term
dermal and inhalation endpoints.  The absorption rates were assumed to
be 100% for both dermal and inhalation exposures. 

Dietary Exposure/Risk Characterization

The nature of the residue in plants is adequately understood based on
acceptable metabolism studies with wheat, canola, and cotton.  The
nature of the residue in ruminants is adequately understood based on an
adequate goat metabolism study.  The residue of concern in plants and
livestock is tribenuron methyl. 

Several adequate analytical   SEQ CHAPTER \h \r 1 methods are available
for enforcing tolerances for tribenuron methyl in plant commodities. 
Residues in samples from the soybean and field corn field trials
associated with these petitions (PP#s: 8F7432 and 8F7441) were
determined using a liquid chromatography with tandem mass-spectrometric
detection (LC/MS/MS) method, DuPont Method 13412 (Revision 1).  This
method was adequately validated prior to, and in conjunction with, the
field trial analyses; the validated limit of quantitation (LOQ) is 0.01
ppm for tribenuron methyl in all corn and soybean commodities.  

The available data indicate that residues of tribenuron methyl are not
recovered by the FDA multiresidue methods.  

The available storage stability data adequately support the sample
storage durations and conditions incurred during the corn and soybean
field trial and processing studies.  

The available corn and soybean field trial data are acceptable, and
support the proposed use patterns for tribenuron methyl on genetically
modified soybeans and field corn.  An adequate number of trials were
conducted on each crop in the appropriate geographical regions.  All
samples were analyzed for the residue of concern (ROC) using an adequate
method, and sample storage conditions and durations are supported by the
available storage stability data.  The data support tolerances of 0.01
ppm in/on corn grain, 0.15 ppm in/on corn forage, 1.1 ppm in/on corn
stover, 0.01 ppm in/on soybean seeds, 0.07 ppm in/on soybean forage, and
0.35 ppm in/on soybean hay.  

Available corn and soybean processing data for tribenuron methyl are
adequate.  As residues were <LOQ in corn grain and all corn processed
fractions following an application at 5X the proposed use rate, separate
tolerances are not required in corn grain processed fractions.  For
soybeans, residues concentrated only in hulls (4.05X).  Based on highest
average field trial (HAFT) residues of 0.01 ppm for soybean seeds
(14-day PHI), the tolerance in/on soybean hulls should be set at 0.04
ppm.  

Tribenuron methyl residues were shown to concentrate in aspirated grain
fractions (AGF) from both field corn grain (13X), and soybean seeds
(150X).  Based on the HAFT residues of field corn grain (0.01 ppm), and
soybean seeds (0.01 ppm), the maximum expected residues would be 0.13
ppm in AGF from corn grain, and 1.5 ppm in AGF from soybean seeds.  As
residues in soybean AGF are higher than in corn grain AGF, the
appropriate tolerance in/on AGF is 1.5 ppm.  

There are no established or proposed Codex or Mexican maximum residue
limits (MRLs) for residues of tribenuron methyl (Appendix C).  Canada
has established MRLs for tribenuron methyl in several plant commodities.
 However, no Canadian MRLs for tribenuron methyl have been proposed or
established in the commodities being considered under these petitions.  

An analytical standard for tribenuron methyl is currently available in
the National Pesticide Standards Repository.  

Adequate confined rotational crop data are available to support a
minimum 30-day plantback interval (PBI) for all crops without registered
uses.  As labels for tribenuron methyl currently specify minimum PBIs of
no less than 45 days, data requirements for rotational crops are
fulfilled, and tolerances are not required in rotational crops.  

The petitioner should submit revised Sections F to correct the tolerance
levels in field corn forage (PP#8F7441), and soybean forage and hay
(PP#8F7432), and to correct the commodity definition for AGF (PP#8F7432
and PP#8F7441).

Dietary (Food and Drinking Water) Exposure Analysis  

Food

There was no appropriate endpoint for assessing acute dietary exposure;
therefore, acute dietary risk is not a concern for tribenuron methyl.
Tribenuron methyl is classified as a possible human carcinogen; however,
a separate assessment of cancer risk is not necessary because the
chronic dietary risk assessment is considered protective of any
potential risk due to carcinogenicity.

An unrefined chronic dietary analysis for tribenuron methyl was
conducted using existing and ARIA-recommended tolerance levels, 100%
crop-treated (%CT), and Dietary Exposure Evaluation Model (DEEM; Version
7.81) default processing factors (PFs).  An empirical PF of 0.07x was
used for soybean, oil.  Drinking water was incorporated directly into
the dietary assessment using the chronic concentration for groundwater
generated by the Screening Concentration in Ground Water (SCI-GROW;
Version 2.3) Model at 6.8 ppb.  The results of the analysis indicate
that chronic risk from the dietary (food + drinking water) exposure to
tribenuron methyl will not exceed ARIA’s or HED’s level of concern
for the general U.S. population, and all population subgroups.  The
chronic dietary risk estimate for the highest reported exposed
population subgroup, all infants (<1 year old), is <8% of the cPAD.  The
general U.S. population utilizes <4% of the cPAD.

Water

Since ARIA does not have ground or surface water monitoring data to
calculate quantitative aggregate exposure, estimates of tribenuron
methyl levels in surface and ground water were made using computer
modeling.  The acute estimated drinking water concentrations (EDWCs) in
surface water as predicted by the Food Quality Protection Act (FQPA)
Index Reservoir Screening Tool (FIRST) model ranged from 2.57 – 2.88
ppb.  The chronic EDWCs ranged from 0.76 – 0.86 ppb.  The Screening
Concentration in Ground Water (SCI-GROW) model was used by EFED to
estimate ground water concentrations.  The groundwater EDWC as predicted
by the SCI-GROW model was 4.95E-03 ppb.  These EDWCs are lower than the
EDWCs derived in a 2006 drinking water assessment previously completed
by EFED.  In that assessment the acute and chronic surface water EDWCs
predicted by the FIRST model were 4.1 ppb and 2.7 ppb, respectively. 
The groundwater acute and chronic EDWC as predicted by the SCI-GROW
model was 6.8 ppb.  Therefore, ARIA used the 2006 chronic EDWC of 6.8
ppb to predict potential health risks associated with tribenuron methyl
concentrations in surface and groundwater.  Drinking water was
incorporated directly into the dietary assessment.

Non-Occupational and Residential Exposure

There are no non-occupational/residential registered or proposed uses
currently associated with tribenuron methyl.  Therefore, a
non-occupational/residential assessment is not required. 

Aggregate Risk Assessments and Risk Characterization

An acute aggregate risk assessment was not performed because no acute
dietary endpoint was identified.  As tribenuron methyl has no
residential uses, the chronic aggregate risk assessment is equivalent to
the chronic dietary (food plus drinking water) risk assessment.  The
general U.S. population and all population subgroups have risk estimates
that are below ARIA’s and HED’s level of concern.  Short- and
intermediate-term aggregate risk assessments are not required (again,
because the chemical has no residential uses).

Cumulative Risk Assessments and Risk Characterization

EPA has not made a common mechanism of toxicity finding as to tribenuron
methyl and any other substances, and tribenuron methyl does not appear
to produce a toxic metabolite produced by other substances.  As a
result, for the purposes of this tolerance action, EPA is not assuming
that tribenuron methyl has a common mechanism of toxicity with other
substances.

Occupational Exposure/Risk Pathway

Workers may be exposed to tribenuron methyl during mixing, loading, and
application activities associated with agricultural crops.  No
chemical-specific data were available with which to assess potential
exposure to pesticide handlers, so estimates of exposure to pesticide
handlers are based upon surrogate study data.  

ARIA believes pesticide handlers will be exposed to short-term duration
(1 - 30 days) and intermediate-term (1 - 6 months) duration exposures. 
A margin of exposure (MOE) of 100 or more is sufficient to protect
occupational pesticide handlers.  Occupational handler assessments
indicate that all MOEs are above the levels of concern (MOEs =
197-5,320).  Post-application MOEs are above the levels of concern (MOEs
= 580-1,666), except for detasseling treated corn (MOE = 51).  Due to
the risk associated with intermediate-term post-application exposure,
ARIA recommends that the REI be increased to 7 days (MOE = 110).  

Environmental Justice

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,"
(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pd
f).

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, HED 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
Survey 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, nondietary 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, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review.  The studies in PHED
were considered appropriate (ethically conducted) for use in risk
assessments. 

RECOMMENDATIONS

Pending submission of revised Section F’s and amending the REI on the
label to 7-days, there are no residue chemistry, toxicology or
occupational issues that would preclude the establishment of permanent
tolerances for tribenuron methyl residues in soybean and field corn
commodities.  The submitted data support tolerances for residues of
tribenuron methyl, including its metabolites and degradates, in or on
soybean and field corn commodities, at the levels listed below.
Compliance with the tolerance levels specified below is to be determined
by measuring tribenuron methyl only.  

Commodity	Parts per million

Barley, grain	0.05

Barley, hay	0.4

Barley, straw	0.10

Canola, seed	0.02

Corn, field, forage	0.15

Corn, field, grain	0.01

Corn, field, stover	1.1

Cotton, gin byproducts	0.02

Cotton, undelinted seed	0.02

Flax, seed	0.02

Grain, aspirated fractions	1.5

Oat, forage	0.05

Oat, grain	0.05

Oat, hay	0.05

Oat, straw	0.10

Rice, grain	0.05

Rice, straw	0.05

Sorghum, grain, forage	0.05

Sorghum, grain, grain	0.05

Sorghum, grain, stover	0.05

Soybean, hay	0.35

Soybean, forage	0.07

Soybean, seed	0.01

Soybean, hulls	0.04

Sunflower, seed	0.05

Wheat, forage	0.3

Wheat, grain	0.05

Wheat, hay	0.5

Wheat, straw	0.10

Tolerances with regional registration, as defined in §180.1(n) are
established for residues of the herbicide tribenuron methyl
(methyl-2-[[[[N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl) methylamino]
carbonyl]amino]sulfonyl]  benzoate) in or on the following raw
agricultural commodities:

Commodity	Parts per million

Grass, forage, fodder and hay, group 17, except bermudagrass; forage
0.10

Grass, forage, fodder and hay, group 17, except bermudagrass; hay	0.10

2.0	Ingredient Profile

Summary of Registered/Proposed Uses

There are currently 10 active end use products containing tribenuron
methyl that are registered to DuPont for post-emergence uses on wheat,
barley and oats.  With the current petitions (PP#8F7432 and PP#8F7441),
DuPont provided an amended label for Express®, the SG formulation (EPA
Reg. No. 352-632) containing 50% ai, intended for use on Optimum® GAT®
herbicide-tolerant soybeans and field corn.  The amended use directions
for genetically modified soybeans and field corn are summarized in Table
2.1 (below).  

Table 2.1.  Summary of Directions for Use of Tribenuron Methyl.  

Application Timing; Type; Equipment	Formulation

[EPA Reg. #]	Use Rate

(lb ai/A)	Number of Uses per Season	Maximum Seasonal Use Rate

(lb ai/A)	PHI 1

(Days)	Use Directions and Limitations 2

Soybean

Post-emergence (of crop and weeds); broadcast foliar; ground, air, or
chemigation equipment.  	50% ai SG

[352-632]	0.008-0.03	2	0.03	14	Add a non-ionic surfactant (NIS) at 0.25%
v/v, or a crop oil concentrate (COC) at 1.0% v/v.  

Field Corn

Post-emergence (of crop and weeds); broadcast foliar; ground, air, or
chemigation equipment.  	50% ai SG

[352-632]	0.008-0.03	2	0.03	7	Add an NIS at 0.25% v/v, or a COC at 1.0%
v/v.  

1 PHI = Pre-Harvest Interval.  

2 For applications up to 0.008 lb ai/A, sugar beet, winter rape, and
canola may be planted 60 days after application; other crops may be
planted 45 days after application.  For applications above 0.008 lb
ai/A, non-labeled crops may be planted 4 months after application.  

2.2	Structure and Nomenclature 

Table 2.2.   Tribenuron Methyl Nomenclature.  

Chemical structure	

Common name	Tribenuron methyl

Molecular formula	C15H17N5O6S

Molecular weight	395.4

Company experimental name	DPX-L5300

IUPAC name
Methyl-2-[4-methoxy-6-methyl-1,3,5-triazin-2-yl(methyl)carbamoyl-sulfamo
yl]benzoate

CAS name
Methyl-2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)methylamino]carbonyl
]amino] sulfonyl]benzoate

CAS registry number	101200-48-0

End-use product (EP)	50% ai SG (DuPont Express herbicide; EPA
Registration #352-632)

2.3	Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of Tribenuron Methyl.  

Parameter	Value	Reference

Melting point/range	142ºC	MRID #47138301

pH (at 20ºC)	4.64

	Density  (at 19.6ºC)	1.4594 ± 0.001 g/cm3

	Water solubility (at 20ºC)	pH 5		0.0489 g/L

pH 7		2.04

pH 9		18.3

	Solvent solubility (at 20ºC)	Acetone			39.1 g/L

Acetonitrile		46.4

Dichloromethane		>250

Dimethylformamide	98.2

Ethyl acetate		16.3

n-Heptane		0.02

Methanol		2.59

n-Octanol		0.383

Xylene			13.1

	Vapor pressure (at 25ºC)	2.7 x 10-7 mm Hg

	Dissociation constant (pKa)	5.0

	Octanol/water partition coefficient, Log [KOW] (at 20ºC)	pH 5			2.60

pH 7			0.78

, λ)	pH 1.66		200, 231 nm

pH 7		201, 256 nm

pH 11.72	208, 256 nm

	3.0	Hazard Characterization/Assessment

Studies available and considered for hazard characterization for
tribenuron methyl include subchronic studies conducted in the rat and
the dog, developmental toxicity studies in rats and rabbits, a
reproduction study in rats, a chronic study in dogs, a carcinogenicity
study in mice, and a combined chronic/carcinogenicity study in rats.  In
addition, a number of mutagenicity studies and a metabolism study were
submitted.

3.1	Hazard Characterization

Tribenuron methyl has low to moderate acute toxicity via the oral,
inhalation, and dermal routes of exposure.  It is not a dermal irritant,
but was found to be mildly irritating to the eye.  It is a skin
sensitizer.

In the subchronic toxicity rat study, toxic effects included decreases
in body weight gain, food consumption, and food efficiency; decreases in
absolute heart, liver, and kidney weights; increases in relative organ
weights for heart, liver, kidney, testes, and spleen; and decreases in
serum glucose, globulin, and cholesterol.  However, the subchronic
toxicity study in the dog resulted in no toxic effects at the highest
dose tested (HDT) of 78 mg/kg/day. 

In a developmental toxicity study in the rat, the maternal effects
included decreased body weight gain and food consumption, increased
liver-to-body weight ratios (at the highest dose), and excess salivation
in some animals.  The only developmental effect observed was decreased
mean fetal body weight ((7.4%).  However, both maternal and fetal
toxicity were observed at similar doses, with a LOAEL of 125 mg/kg/day
and a NOAEL of 20 mg/kg/day.  At the HDT (500 mg/kg/day), tribenuron
methyl caused an increased incidence of resorptions (not statistically
significant), fetal deaths, and incomplete ossification, which may have
been the result of maternal toxicity.  In the developmental toxicity
study in rabbits, the maternal NOAEL was 20 mg/kg/day and the maternal
LOAEL was 80 mg/kg/day (HDT), based on decreased feed consumption and
increased incidence of late abortions (GD19-29) at the highest dose.  As
the number of dead fetuses and resorptions per litter were not affected
by treatment, the increased incidence of abortions in the high dose
group is an indicator of maternal toxicity.  The developmental NOAEL and
LOAEL were that same as the maternal NOAEL.  No teratogenicity was
observed.

In the 2-generation reproduction toxicity study in rats, there was no
evidence of susceptibility, as parental, reproductive and offspring
NOAELs and LOAELs were observed at similar doses.  Effects in the
parental animals included decreased body weight gain in the F1A adult
females, while the reproductive effects included decreased body weight
gain in F1B pups on day 7 and in F2B pups on postpartum days 14 and 21. 
The offspring effects included decreased absolute splenic weights
independent of body weight effect in F2B male and female pups.  While
the reduced spleen weight could be considered a potentially immunotoxic
effect, it was observed in the absence of other potential indicators of
immunotoxicity, including histopathology and alterations in hematology;
in addition, there were no accompanying decreases in thymus weights and
therefore HED has decreased concern for potential immunotoxicity for
tribuenuron methyl.

The results of the chronic toxicity study in dogs indicated elevated
bilirubin blood levels at all time points, elevated aspartate
aminotransferase (AST) blood levels at 26 and 52 weeks, increased
urinary volume at 36 weeks, and a 20% reduction in body weight gain at
53 weeks.  In females, elevated serum creatinine levels occurred at all
time points, elevated serum AST levels at 4 weeks, elevated globulin
levels at 12 weeks, elevated blood bilirubin levels at 26 weeks; there
was an 18% decrease in body weight gain at 53 weeks.  These effects
occurred at higher dose levels than those observed in males.  In a
carcinogenicity study in mice, the NOAEL was 3 mg/kg/day in males with a
LOAEL of 30 mg/kg/day, based on an increased incidence of bilateral
seminiferous degeneration and oligospermia in mid- and high-dose group
males.  For females, no LOAEL was established, but the minimal body
weight reductions (10%) in the highest dosed females suggested that the
NOAEL was 30 mg/kg/day.  In the combined chronic toxicity/
carcinogenicity study in rats, the NOAELs were 0.95 and 1.2 mg/kg/day
(M/F, respectively), and the LOAELs were 10 and 13 mg/kg/day (M/F,
respectively), based on decreased body weight gain at the end of the
study.  It should also be noted that there was a significant
statistically increased incidence of adenocarcinomas in the mammary
glands in high dose females (26 of 61, 43%) compared to control females
(9 of 60, 15%).  Althought this effect was only observed in animals
exposed to doses above the maximum tolerated dose (MTD), it was the
basis for HED’s determination that tribenuron methyl is a possible
human carcinogen.

Tribenuron methyl was negative when tested for mutagenic effects in the
following assays: gene mutation in Salmonella typhimurium, Chinese
hamster ovary cells in vitro, an in vitro chromosome aberration test, a
mouse micronucleus test, a rat cytogenetics assay and an unscheduled DNA
synthesis assay in rat primary hepatocytes.

Descriptions of the acute toxicity profile as well as subchronic,
chronic, and other toxicity studies can be found in Appendix A.



FQPA Considerations

Adequacy of the Toxicity Database

The toxicology database for tribenuron methyl is not complete but is
considered adequate to characterize potential pre- and/or post-natal
risk for infants and children for the purpose of this risk assessment. 
Acceptable/guideline developmental toxicity studies in rats and rabbits
and a 2-generation reproduction study in rats are available for
consideration  However, in accordance with 40 CFR Part 158, acute and
subchronic neurotoxicity studies and an immunotoxicity study are now
required for tribenuron methyl (See Appendix B).

Evidence of Neurotoxicity

No evidence of neurotoxicity or neuropathology was observed in the
submitted toxicology studies. A developmental neurotoxicity study is not
required.

Developmental Toxicity Studies 

In a developmental toxicity study in the rat, the maternal NOAEL was 20
mg/kg/day and the maternal LOAEL was 125 mg/kg/day, based on decreased
maternal body weight gain and food consumption, increased liver-to-body
weight ratios, and excess salivation in some animals.  The developmental
NOAEL was 20 mg/kg/day and the LOAEL was 125 mg/kg/day, based on
decreased mean fetal body weight.  At the highest dose tested,
tribenuron methyl caused an increased incidence of resorptions (not
statistically significant), fetal deaths, and incomplete ossification,
which may have been the result of maternal toxicity.  In the
developmental toxicity study in rabbits, the maternal NOAEL was 20
mg/kg/day and the maternal LOAEL was 80 mg/kg/day (HDT), based on
decreased feed consumption and increased incidence of late abortions
(GD19-29).  As the number of dead fetuses and resorptions per litter
were not correlated with the dosing level, the increased incidence of
abortions in the high dose group is likely due to maternal toxicity. 
The developmental NOAEL was 20 mg/kg/day and the developmental LOAEL was
80 mg/kg/day, based on 10% reduction in fetal weights (not statistically
significant).  No teratogenicity was observed.

Reproductive Toxicity Study

In a two-generation reproduction toxicity study in rats, the parental
systemic NOAEL was 2 mg/kg/day in males and females and the LOAEL was 21
mg/kg/day, based on decreased body weight gain in the F1A adult females
(up to 25% less than controls).  The reproductive NOAEL was 2.5
mg/kg/day in males and females, and the LOAEL was 25 mg/kg/day, based on
decreased body weight gain in F1B pups on day 7 (9%) and in F2B pups on
postpartum days 14 (9%) and 21 (9%).  The offspring NOAEL was 2.5
mg/kg/day in males and females, and the LOAEL was 25 mg/kg/day, based on
decreased absolute splenic weights independent of body weight effect in
F2B male (24% mid; 26% high) and female (23% mid; 28% high) pups.

Additional Information from Literature Sources

A literature search of tribenuron methyl studies was not conducted for
the current risk assessment.

Pre-and/or Postnatal Toxicity

Developmental studies in rats and rabbits and a reproductive toxicity
study in rats indicated no increased susceptibility (quantitative or
qualitative) following in utero or post-natal exposure to tribenuron
methyl.  

3.3	Safety Factor for Infants and Children

The toxicology database for tribenuron methyl is considered adequate for
FQPA considerations despite the missing neurotoxicity and immuntoxicity
studies.  There is no concern for pre- and/or post-natal toxicity
resulting from exposure to tribenuron methyl.  The available data from
the developmental and reproductive toxicity studies do not indicate a
potential increase in susceptibility of infants and children to
tribenuron methyl.  In addition, HED has concluded a DNT study is not
required.  Finally, although increase speen weights were observed in the
90-day rat study, and decreased spleen weights were observed in the
reproduction study, these effects occurred in the absence of other
potential indicators of immunotoxicity, and there was no evidency of
susceptibility of the offspring to these effects.  Finally, the
endpoints and doses selected for risk assessment are protective of the
spleetn effects, which occurred at much higher doses.  The dietary
exposure and risk assessment is conservative (including the assumption
of 100% crop treated and tolerance residues) and there are no
residential uses of tribenuron methyl.  Therefore, HED continues to
conclude that the FQPA safety factor can be reduced to 1x for this
chemical.

3.4	Hazard Identification and Toxicity Endpoint Selection

3.4.1.	Acute Reference Dose (aRfD) - General Population (Including
Infants and Children) and Females Age 13-49				

Acute reference doses for the general population and females 13-49 have
not been established because there were no studies that demonstrated
evidence of toxicity attributable to a single dose.

3.4.2	Chronic Reference Dose (cRfD)

Studies Selected:  Chronic Feeding, Dog; Combined
Chronic/Carcinogenicity, Rat

MRID No.:  40245512; 40245511

Dose and Endpoint for Risk Assessment:  NOAEL = 0.8 mg/kg/day.  LOAEL =
8.16 mg/kg/day, based on decreased body weight gain, elevated bilirubin,
AST, and increased urinary volume in males.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

  = 0.008 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:  Two studies in
different species support a toxicity endpoint for chronic dietary
exposure.  The toxicity endpoint was based on a one-year oral feeding
study in dogs because the study encompasses the appropriate duration of
exposure and has the lowest NOAEL.  The NOAEL from this study was 0.8
mg/kg/day and the LOAEL was 8.16 mg/kg/day based on elevated bilirubin
blood levels at all time points, elevated AST blood levels at 26 and 52
weeks, increased urinary volume at 36 weeks, and 20% reduction in body
weight gain at 53 weeks.  The combined chronic/carcinogenicity study in
the rat with NOAELs of 0.95 and 1.2 mg/kg/day (M/F, respectively) was
also considered for a chronic reference dose (decreased body weight gain
of 36/54%, M/F).  The NOAEL in the rat is similar between males and
females and supports the NOAEL of 0.8 mg/kg/day seen in the dog.  

An uncertainty factor of 100 (10x for interspecies extrapolation and 10x
for intraspecies variability) is applied to the chronic toxicity
endpoint resulting in a chronic reference dose (cRfD) of 0.008
mg/kg/day.   As the FQPA safety factor has been reducted to 1X, the
chronic population adjusted dose (cPAD) is also 0.008 mg/kg/day.

Incidental Oral Exposure (Short- and Intermediate-Term)

As there are no current or proposed residential uses for tribenuron
methyl, the incidental oral exposure scenario does not need to be
included in this risk assessment.

3.4.4	Dermal Absorption

A 28-Day dermal toxicity study in rabbits was submitted for tribenuron
methyl.  At the limit dose of 1000 mg/kg/day, systemic toxicity included
decreases in body weight and food consumption, kidney histopathology,
and deaths.  Dermal toxicity was observed as treatment site lesions as
well as hypokinesia.  A dermal absorption study was not available for
tribenuron methyl; therefore, a default dermal absorption factor (DAF)
of 100% was used for risk assessment.

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

Short-Term Dermal Exposure

Study Selected:  Developmental Rabbit Study

MRID No.:  40245514

Dose and Endpoint for Risk Assessment:  Oral NOAEL = 20 mg/kg/day. 
LOAEL = 80 mg/kg/day, based on the maternal effects consisting of
decreased food consumption and increased abortions.

Comments about Study/Endpoint/Uncertainty Factors:  In the absence of an
acceptable dermal study, an oral study was chosen for short-term dermal
risk assessment.  The duration of exposure in the developmental rabbit
study was considered appropriate for short-term risk assessment, and the
maternal effects observed were associated with repeated exposures. 
Similar effects (decreased food consumption and body weight gain) were
observed in the dams in the rat developmental study, but the rat study
had a higher LOAEL, therefore the rabbit study is considered to be more
protective.  Because an oral study was chosen for this risk assessment,
and no dermal penetration study is available, a default assumption of
100% dermal absorption (DA) is considered appropriate.  The level of
concern (LOC) for occupational exposure is a MOE of 100, equivalent to
the combined uncertainty factors of 10X, each, for intraspecies
variability and interspecies extrapolation.

Intermediate-Term Dermal Exposure

Study Selected:  Subchronic Rat Study

MRID No.:  00148638

Dose and Endpoint for Risk Assessment:  Oral NOAEL = 7 mg/kg/day.  LOAEL
= 118 mg/kg/day, based on decreased body weight gain, food consumption
and efficiency; decreased absolute heart, liver, and kidney weights;
increased relative brain, heart, liver, kidney, testes, and spleen
weights; and decreased serum glucose and globulin.

Comments about Study/Endpoint/Uncertainty Factors:  In the absence of an
acceptable dermal study, an oral study was chosen for intermediate-term
dermal risk assessment.  The duration of exposure in the subchronic
study was considered appropriate for intermediate-term risk assessment,
and the NOAEL/LOAEL were the lowest available from studies of similar
durations.  Because an oral study was chosen for this risk assessment,
and no dermal penetration study is available, a default assumption of
100% DA is considered appropriate.  The LOC for occupational exposure is
a MOE of 100, equivalent to the combined uncertainty factors of 10X,
each, for intraspecies variability and interspecies extrapolation.

Long-Term Dermal Exposure

Studies Selected:  Chronic Feeding, Dog; Combined
Chronic/Carcinogenicity, Rat

MRID No.:  40245512; 40245511

Dose and Endpoint for Risk Assessment:  NOAEL = 0.8 mg/kg/day.  LOAEL =
8.16 mg/kg/day, based on decreased body weight gain, elevated bilirubin,
AST, and increased urinary volume in males.

Comments about Study/Endpoint/Uncertainty Factors:  In the absence of an
acceptable dermal study, an oral study was chosen for long-term dermal
risk assessment.  Refer to the discussion for the chronic reference dose
for additional rationale.  Because an oral study was chosen for this
risk assessment, and no dermal penetration study is available, a default
assumption of 100% DA is considered appropriate.  The LOC for
occupational exposure is a MOE of 100, equivalent to the combined
uncertainty factors for intraspecies variability (10X) and interspecies
extrapolation (10X).  However, HED notes that long-term dermal exposure
is not expected based on the use pattern for tribenuron methyl.

Inhalation Exposure (Short, Intermediate- and Long-Term)

 	

Short-Term Inhalation Exposure

Study Selected:  Developmental Rabbit Study

MRID No.:  40245514

Dose and Endpoint for Risk Assessment:  Oral NOAEL = 20 mg/kg/day. 
LOAEL = 80 mg/kg/day, based on the maternal effects consisting of
decreased food consumption and increased abortions.

Comments about Study/Endpoint/Uncertainty Factors:  In the absence of an
acceptable inhalation study, an oral study was chosen for short-term
inhalation risk assessment.  The duration of exposure in the
developmental rabbit study was considered appropriate for short-term
risk assessment, and the maternal effects observed were associated with
repeated exposures.  Similar effects (decreased food consumption and
body weight gain) were observed in the dams in the rat developmental
study, but the rat study had a higher LOAEL, therefore the rabbit study
is considered to be more protective.  Because an oral study was chosen
for this risk assessment, a default assumption of 100% inhalation
absorption is considered appropriate.  The LOC for occupational exposure
is a MOE of 100, equivalent to the combined uncertainty factors of 10X,
each, for intraspecies variability and interspecies extrapolation.

Intermediate-Term Inhalation Exposure

Study Selected:  Subchronic Rat Study

MRID No.:  00148638

Dose and Endpoint for Risk Assessment:  Oral NOAEL = 7 mg/kg/day.  LOAEL
= 118 mg/kg/day, based on decreased body weight gain, food consumption
and efficiency; decreased absolute heart, liver, and kidney weights;
increased relative brain, heart, liver, kidney, testes, and spleen
weights; and decreased serum glucose and globulin.

Comments about Study/Endpoint/Uncertainty Factors:  In the absence of an
acceptable inhalation study, an oral study was chosen for
intermediate-term inhalaton risk assessment.  The duration of exposure
in the subchronic study was considered appropriate for intermediate-term
risk assessment, and the NOAEL/LOAEL were the lowest available from
studies of similar durations.  Because an oral study was chosen for this
risk assessment, a default assumption of 100% inhalation absorption is
considered appropriate.  The LOC for occupational exposure is a MOE of
100, equivalent to the combined uncertainty factors of 10X, each, for
intraspecies variability and interspecies extrapolation.

Long-Term Inhalation Exposure

Studies Selected:  Chronic Feeding, Dog; Combined
Chronic/Carcinogenicity, Rat

MRID No.:  40245512; 40245511

Dose and Endpoint for Risk Assessment:  NOAEL = 0.8 mg/kg/day.  LOAEL =
8.16 mg/kg/day, based on decreased body weight gain, elevated bilirubin,
AST, and increased urinary volume in males.

Comments about Study/Endpoint/Uncertainty Factors:  In the absence of an
acceptable inhalation study, an oral study was chosen for long-term
inhalation risk assessment.  Refer to the discussion for the chronic
reference dose for additional rationale.  Because an oral study was
chosen for this risk assessment, a default assumption of 100% inhalation
absorption is considered appropriate.  The LOC for occupational exposure
is a MOE of 100, equivalent to the combined uncertainty factors of 10X,
each, for intraspecies variability and interspecies extrapolation. 
However, HED notes that long-term inhalation exposure is not expected
based on the use pattern for tribenuron methyl.

3.4.7	Margins of Exposure

The LOC for occupational exposure is a MOE of 100 based on the
conventional uncertainty factors of 10X for intraspecies variation and
10X for interspecies extrapolation.

3.4.8	Recommendation for Aggregate Exposure Risk Assessments

An acute aggregate risk assessment is not necessary because no acute
dietary endpoint was identified for tribenuron methyl.  As tribenuron
methyl has no residential uses, neither a short- or intermediate-term
aggregate risk assessment is required.  The chronic aggregate risk
assessment is equivalent to the chronic dietary (food plus drinking
water) risk assessment.  

3.4.9	Classification of Carcinogenic Potential

Tribenuron methyl was classified as a Group C chemical (possible human
carcinogen) by the HED Cancer Assessment Review Committee (1989).  This
conclusion was based on statistically significant increases in mammary
gland adenocarcinomas in female rats at the highest dose tested. 
However, quantitative cancer risk assessment was not recommended due to
the excessive toxicity at the doses at which the tumors were seen (i.e.,
greater than the maximum tolerated dose), because there was no evidence
of genotoxicity, and because structurally similar compounds were not
known to be carcinogenic in rats and mice.  The NOAEL selected for the
cRfD (and the cPAD) is considered to be protective of any potential
cancer risk.

3.4.10	Summary of Toxicological Doses and Endpoints for Use in Human
Health Risk Assessment

Tables 3.4.10a and 3.4.10b, below, list the toxicological doses and
endpoints used for human health risk assessments for tribenuron methyl.

Table 3.4.10a. Toxicological Doses and Endpoints for Tribenuron methyl
for Use in Dietary 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 (All populations)	N/A

	N/A

	N/A

	No appropriate endpoint identified.

Chronic Dietary (All Populations)	NOAEL = 0.8 mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Chronic RfD = 0.008 mg/kg/day

cPAD = 0.008 mg/kg/day	Chronic-Dog:

LOAEL = 8.16 [M] mg/kg/day based on decreased body weight gain (20%),
elevated bilirubin, AST, and increased urinary volume.

Cancer 	Classified as Group C (possible human carcinogen).  Not
mutagenic.  The chronic RfD is considered to be protective of any
potential cancer risk.

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 (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

Table 3.4.10b.  Toxicological Doses and Endpoints for Tribenuron methyl
for Use in Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal,

Short-term (1-30 days) 	NOAEL = 20 mg/kg/day

DAF=100%	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	Developmental toxicity, Rabbit:

LOAEL = 80 mg/kg/day, based on the maternal effects consisting of
decreased food consumption and increased abortions.

Dermal

Intermediate-term

(1-6 months)	NOAEL = 7 mg/kg/day

DAF=100%	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	Subchronic Rat:

LOAEL = 118 mg/kg/day, based on decreased body weight gain, food
consumption and efficiency; decreased absolute heart, liver, and kidney
weights; increased relative brain, heart, liver, kidney, testes, and
spleen weights; and decreased serum glucose and globulin.

Dermal

Long-term

(> 6 months)	NOAEL = 0.8 mg/kg/day

DAF = 100%	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	Chronic-Dog:

LOAEL = 8.16 [M] mg/kg/day based on decreased body weight gain (20%),
elevated bilirubin, AST, and increased urinary volume.

Inhalation Short-term

(1-30 days)	NOAEL = 20 mg/kg/day

IAF=100%	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	Developmental toxicity, Rabbit:

LOAEL = 80 mg/kg/day, based on the maternal effects consisting of
decreased food consumption and increased abortions.

Inhalation,

Intermediate-term

(1-6 months)	NOAEL = 7 mg/kg/day

IAF=100%	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	LOAEL = 118 mg/kg/day, based on
decreased body weight gain, food consumption and efficiency; decreased
absolute heart, liver, and kidney weights; increased relative brain,
heart, liver, kidney, testes, and spleen weights; and decreased serum
glucose and globulin.

Inhalation, Long-term

(> 6 months)	NOAEL = 0.8 mg/kg/day

IAF = 100%	UFA = 10X

UFH = 10X

	Occupational LOC for MOE = 100	Chronic-Dog:

LOAEL = 8.16 [M] mg/kg/day based on decreased body weight gain (20%),
elevated bilirubin, AST, and increased urinary volume.

Cancer (oral, dermal, inhalation)	Classified as Group C (possible human
carcinogen).  Not mutagenic.  Quantitative estimation of cancer risk is
not recommended.

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 (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

For the purpose of conducting risk assessments for occupational workers,
dermal and inhalation exposures may be combined because the same studies
(with the same effects) were used for each route of exposure for each of
the respective exposure scenarios.

3.5.	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, tribenuron methyl 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

No public health or pesticide epidemiology data were consulted in
conjunction with this risk assessment for the proposed use and amended
tolerance.

5.0	Dietary Exposure/Risk Characterization

ARIA prepared a residue chemistry summary document in which the residue
chemistry issues that impact dietary exposure are discussed.  Reference
may be made to this memo for further details concerning residue
chemistry issues (DP#: 360846, W. Drew, 9/9/2009).

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1 	Metabolism in Primary Crops

The nature of the residue in plants is adequately understood based on
metabolism studies with wheat, canola, and cotton; the residue of
concern (ROC) in plant commodities is tribenuron methyl. 

5.1.2	Metabolism in Rotational Crops

Adequate confined rotational crop data are available to support a
minimum 30-day PBI for all crops without registered uses.  As labels for
tribenuron methyl currently specify minimum PBIs of no less than 60 days
for canola, rape and sugar beets, and 45 days for all other crops not
listed on the label, data requirements for rotational crops are
fulfilled, and tolerances are not required in rotational crops.  

5.1.3	Metabolism in Livestock 

The nature of the residue in livestock is adequately understood based on
an acceptable goat metabolism study; the ROC in plant commodities is
tribenuron methyl.  HED has previously concluded that tribenuron methyl
residues in livestock commodities can be classified under 40CFR
§180.6[a][3], as there is no reasonable expectation of detecting finite
residues of tribenuron methyl in milk, eggs, meat or poultry. 

5.1.4	Analytical Methodology

Plant commodity methods

A high-performance liquid chromatography with photo-conductivity
detection (HPLC/PC) method, Method AMR 337-85 (Revision A), is available
for   SEQ CHAPTER \h \r 1 enforcement of tolerances for residues of
tribenuron methyl in grain, forage and straw commodities.  For this
method, residues are extracted with acetonitrile (ACN), cleaned up using
silica-gel chromatography, and analyzed by HPLC/PC.  

A liquid chromatography with mass-spectrometric detection (LC/MS)
method, DuPont Method 1381, is also available for enforcement of
tolerances for residues of tribenuron methyl in canola, cotton and flax
commodities.  For this method, samples are extracted with an
ACN/ammonium carbonate buffer solution, and the concentrated residues
are reconstituted in methanol for analysis.  

For the current petitions, field trial samples were analyzed for all of
the sulfonylurea residues (chlorimuron ethyl, rimsulfuron, and
tribenuron methyl) in soybeans and field corn using a liquid
chromatography with tandem mass-spectrometric detection (LC/MS/MS)
method, DuPont Method 13412 (Revision 1), 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.  This
method was previously reviewed in conjunction with a petition for
thifensulfuron methyl (DP#: 330813, S. Humme, 8/8/2006).  One of the
comments from that review stated that a new copy of the method was
needed, incorporating the comments from the independent laboratory
validation (ILV) laboratory.  The submitted copy of the method has been
amended to include comments from the ILV, so it can now be forwarded to
FDA for use as an enforcement method.  A PMV trial is not required.  

Animal commodity method

An enforcement method for animal commodities is not currently required,
as there are no tolerances for tribenuron methyl residues in livestock
commodities.  

Multiresidue Methods

The FDA PESTDATA database, dated 6/2005 (PAM Volume I, Appendix I), does
not contain any information regarding the recovery of tribenuron methyl
using multiresidue methods.  Data investigating the behavior of
tribenuron methyl using the FDA Multiresidue Methods have been submitted
by the registrant (MRID #40927202).  These data were apparently not
received by FDA for evaluation, despite being sent to Leon Sawyer, a
chemist with the Pesticides and Industrial Chemicals Branch of FDA’s
Division of Contaminants Chemistry, in a memo dated 22 March 1989.  The
results of the Multiresidue Methods study with tribenuron methyl will be
re-sent to the FDA.  The available data indicate that residues of
tribenuron methyl are not recovered by the FDA multiresidue methods.  

5.1.5 	Environmental Degradation 

Tribenuron methyl is non-persistent but very mobile in soils. The
primary routes of dissipation for tribenuron methyl are acid and neutral
hydrolysis and microbial degradation with half-lives of 1-6 days in acid
environments (shallow wells) and 4-30 days in more basic environments. 
The field dissipation half-lives (based on lysimeters) range from <5
days in acid soils to 19 days in soils with a basic pH.

Pesticide Metabolites and Degradates of Concern

		

Table 5.1.6.  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	Tribenuron methyl	Tribenuron methyl

	Rotational Crop	N/A	N/A

Livestock

	Ruminant	N/A	N/A

	Poultry	N/A	N/A

Drinking Water

	Tribenuron methyl	N/A

Drinking Water Residue Profile

EFED provided ARIA with the results of a Tier 1 drinking water
assessment of EXPRESS and its active ingredient tribenuron methyl for
broadcast spray on OPTIMUM®GAT field corn and OPTIMUM®GAT soybeans for
pre-plant, post-emergence, and post-harvest control of certain broadleaf
weeds (DP#s: 358877, 358880, 358882, 358885, W. Shaughnessy, 6/15/2009).
 The acute EDWCs in surface water as predicted by the FIRST model ranged
from 2.57 – 2.88 ppb.  The chronic EDWCs ranged from 0.76 – 0.86
ppb.  The SCI-GROW model was used by EFED to estimate ground water
concentrations from the use of this herbicide.  The groundwater EDWC as
predicted by the SCI-GROW model was 0.005 ppb.  These EDWCs are lower
than the EDWCs derived in an October 2006 drinking water assessment
completed by EFED for use on sunflower, cotton, field corn, sorghum,
soybean, canola, flax, and rice.  In that assessment the FIRST and
SCI-GROW modeling was based on a use rate of three (3) aerial
applications of 0.015 lb ai/A, 14 days apart.   The acute and chronic
surface water EDWCs predicted by the FIRST model were 4.1 ppb and 2.7
ppb, respectively; the groundwater acute and chronic EDWC as predicted
by the SCI-GROW model was 6.8 ppb.  Therefore, EFED recommended that
ARIA use the 2006 results to predict potential health risks associated
with tribenuron methyl concentrations in surface and groundwater.

Food Residue Profile

DuPont Crop Protection has submitted petitions supporting the use of
tribenuron methyl on soybeans and field corn that are genetically
tolerant to sulfonylurea herbicides (PP#8F7432 and PP#8F7441).  These
petitions have been submitted in conjunction with related petitions for
use of rimsulfuron and chlorimuron ethyl on genetically modified
soybeans and field corn in support of a future EP containing all three
sulfonylurea herbicides.  Please see the residue chemistry memorandum
(DP#:  360846, B. Drew, 9/9/2009) for detailed information pertaining to
the food residue profile.

The available corn and soybean field trial data are acceptable, and
support the proposed use patterns for tribenuron methyl (50% ai SG) on
genetically modified soybeans and field corn.  An adequate number of
trials were conducted on each crop in the appropriate geographical
regions.  All samples were analyzed for the ROC using an adequate
method, and sample storage conditions and durations are supported by the
available storage stability data.  

The field trial data support the proposed 7-day PHI for all corn
commodities, and the proposed 14-day PHI for soybean forage and hay.  As
the label directions for use on soybeans prohibit applications after the
R2 stage, a specific PHI for soybean seeds is not required.  The trials
support the tolerances listed on Page 10.  

The available corn and soybean processing data for tribenuron methyl are
adequate.  As residues were <LOQ in corn grain, and all corn processed
fractions following an application at 5X the proposed use rate, separate
tolerances are not required in corn grain processed fractions.  For
soybeans, residues concentrated only in hulls (4.05X).  Based on HAFT
residues of 0.01 ppm for soybean seeds (14-day PHI), the tolerance in/on
soybean hulls should be set at 0.04 ppm.  Tribenuron methyl residues
were shown to concentrate in AGF from both field corn grain (13X), and
soybean seeds (150X).  Based on the HAFT residues of field corn grain
(0.01 ppm), and soybean seeds (0.01 ppm), the maximum expected residues
would be 0.13 ppm in AGF from corn grain, and 1.5 ppm in AGF from
soybean seeds.  As residues in soybean AGF are higher than in corn grain
AGF, the tolerance in/on AGF should be set at 1.5 ppm.  

Based on the data from the poultry metabolism study, residues in liver
resulting from the 10X dosing level would be 0.012 ppm.  Normally, a
poultry feeding study would be required (due to residues being detected
above 0.01 ppm at the 10X dosing level), but none were previously
requested.  Given the conservative assumptions regarding calculation of
the dietary burden and because no significant poultry feed items are
associated with the current petitions, a poultry feeding study is not
required at this time.  However, should the registrant submit any future
petition proposing use on a commodity (or commodities) associated with
poultry feed items, a poultry feeding study will be required, and that
study should be submitted in conjunction with any such petition.  

International Residue Limits

There are no established or proposed Codex or Mexican MRLs for residues
of tribenuron methyl (Appendix C).  Canada has established MRLs for
tribenuron methyl in several plant commodities.  However, no Canadian
MRLs for tribenuron methyl have been proposed or established in the
commodities being considered under these petitions.  Therefore, there
are no concerns regarding compatibility of the proposed tolerances.  

Dietary Exposure and Risk

A chronic dietary risk assessment was conducted using DEEM software with
the Food Commodity Intake Database (DEEM-FCID™, Version 2.03) which
uses food consumption data from the U.S. Department of Agriculture’s
(USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII)
from 1994-1996 and 1998.  The dietary exposure analysis and its results
are discussed in another ARIA memorandum (DP#: 365813, B. Hanson,
9/9/2009).  

Acute Dietary Exposure/Risk

An acute risk assessment was not performed because no acute dietary
endpoint was identified for tribenuron methyl.

 

5.2.2	Chronic Dietary Exposure/Risk

An unrefined chronic dietary analysis for tribenuron-methyl was
conducted using existing and ARIA-recommended tolerance levels, 100%CT,
and DEEM (Version 7.81) default PFs.  An empirical PF of 0.07x was used
for soybean, oil.  Drinking water was incorporated directly into the
dietary assessment using the chronic concentration for groundwater
generated by SCI-GROW (Version 2.3) Model at 6.8 ppb.  The results of
the analysis indicate that chronic risk from the dietary (food +
drinking water) exposure to tribenuron-methyl will not exceed ARIA’s
level of concern for the general U.S. population, and all population
subgroups.  The chronic dietary risk estimate for the highest reported
exposed population subgroup, all infants (<1 year old), is <8% of the
cPAD.  The general U.S. population utilizes <4% of the cPAD (Table
5.2.2).

Table 5.2.2.   Summary of Dietary Exposure and Risk for Tribenuron
methyl

Population Subgroup	

Acute Dietary	Chronic Dietary	Cancer

	

Dietary Exposure (mg/kg/day)	

% aPAD	

Dietary Exposure

(mg/kg/day)	

% cPAD	

Dietary Exposure

(mg/kg/day)	

Risk

General U.S. Population	N/A	N/A	0.000275	< 4	

Chronic assessment is protective of cancer effects

All Infants (< 1 year old)	N/A	N/A	0.000616	< 8

	

Children 1-2 years old	N/A	N/A	0.000516	< 7

	

Children 3-5 years old	N/A	N/A	0.000501	< 7

	

Children 6-12 years old	N/A	N/A	0.000348	< 5

	

Youth 13-19 years old	N/A	N/A	0.000237	3

	

Adults 20-49 years old	N/A	N/A	0.000244	< 4

	

Adults 50+ years old	N/A	N/A	0.000222	< 3

	

Females 13-49 years old	N/A	N/A	0.000233	< 3

	1 Values for the population with the highest risk for each type of risk
assessment are bolded.  

2 NA = Not Applicable; no acute dietary endpoint was identified for
these population subgroups.

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

In performing the chronic dietary exposure analysis the following
conservative assumptions were made; a) that foods contain tolerance
level residues, and b) that 100% of the crop is treated.  No anticipated
residues or estimates of %CT were used in the analysis.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

There are no non-occupational/residential uses for tribenuron methyl. 
As a result, residential uses (including home and recreational uses,
etc.) are not relevant to this assessment.

7.0	Aggregate Risk Assessments and Risk Characterization

7.1	Acute Aggregate Risk 

No toxic effect attributable to a single dose was observed in any
studies in the toxicology database.  As a result, no acute dietary
endpoint was identified and no acute risk assessment was performed.

7.2	Short- and Intermediate-Term Aggregate Risk

As there are no residential uses for tribenuron methyl, short- and
intermediate-term aggregate risk assessments are not required.

7.3	Long-Term Aggregate Risk 

For tribenuron methyl, chronic aggregate risk consists of risks
resulting from exposure to residues in food, drinking water, and
residues resulting from residential applications.  As there are no
residential uses for tribenuron methyl, chronic aggregate risk consists
of risks resulting from exposure to residues in food and drinking water
alone.  The chronic dietary exposure analysis included both food and
drinking water, and as a result, the chronic aggregate risk assessment
is equivalent to the chronic dietary risk assessment.  Refer to Section
5.2.2, above, for a discussion of the dietary exposure analysis. 

7.4	Cancer Risk 

Tribenuron methyl is a Group C chemical, i.e., a possible human
carcinogen.  The chronic dietary exposure analysis is considered to be
protective of any potential cancer effects, and there is no cancer risk
associated with the proposed use and amended tolerance.

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 as to tribenuron methyl and any
other substances, and tribenuron does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that tribenuron methyl
has 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
http://www.epa.gov/pesticides/cumulative/.

Occupational Exposure/Risk Pathway

There is a potential for exposure to tribenuron methyl during mixing,
loading, application, and post-application activities.  The exposures
are expected to be short- to intermediate-term in duration.  

See Table 9.0 for a summary of the proposed new use patterns.  

Table 9.0 Summary of Proposed Use Pattern for Applying Tribenuron methyl
to Corn and Soybean

Formulation	DuPontTM Express® Herbicide;  Reg. No. 352-632;  50.0% by
weight;  water dispersible granule

Pest	Certain grasses and broadleaf weed species

Method of Applic.	ground-boom, aerial

Applic. Rate	0.0078-0.03125 lb ai/A

Max. No. Applications	1 per year at the high rate

Max. Am't/Yr	0.03125 lb ai/A/yr

Applic. Interval	N/A

Preharvest Interval	7 days for corn harvested for grain

Restricted Entry Interval	12 hours

Manufacturer	DuPont

9.1	Workers’ Exposure/Risk

Based upon the proposed use pattern, ARIA/RD believes the most highly
exposed occupational pesticide handlers will be 1) mixer/loaders using
open-pour loading of water soluble granules, 2) applicators using
open-cab, ground-boom sprayers and 3) aerial applicators.  

The product label directs applicators and other handlers to wear
personal protective equipment (PPE) consisting of: long-sleeved shirt,
long pants, shoes plus socks and chemical-resistant gloves made of any
water proof material such as polyethylene or polyvinyl chloride.   

See Table 9.1, below, for a summary of exposures and risks to
occupational handlers.  Note that the dermal and inhalation
toxicological effects are identified from the same stidues and have the
same NOAELs; therefore, the dermal and inhalation exposures are summed
prior to calculation of the MOEs.  Although the short-term NOAEL was
identified from a developmental study, a 70 kg body weight was used for
calculating exposure since the effects were maternal effects, not fetal
effects.

Table 9.1 Summary of Exposure & Risk to Occupational Handlers From
Applying Tribenuron Methyl to Corn and Soybeans.  

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Short Term	MOE

Intermed

Term

Mixer/Loader - Dry Flowable - Open Pour

Dermal:

SLNoGlove      0.066 SLWithGlove   0.066 

Inhal.            0.00077 	0.03125

lb ai/A	1200 A/day	Dermal:

SLNoGlove    0.035

SLWithGlove 0.035

Inhal.              0.0004125	No Glove

560

With Glove

560	No Glove

197

With Glove

197

Applicator - Ground-boom - Open-cab

Dermal:

SLNoGlove       0.014 

SLWithGlove    0.014 

Inhal.              0.00074 	0.03125

lb ai/A	200 A/day	Dermal:

SLNoGlove    0.00125

SLWithGlove 0.00125

Inhal.              0.0000661	No Glove

15,200

With Glove

15,200	No Glove

5,320

With Glove

5,320

Aerial Applicator (Pilots not required to wear gloves)

Dermal:

SLNoGlove       0.005

Inhal.               0.000068	0.03125

lb ai/A	1200 A/day	Dermal:

SLNoGlove    0.002678

Inhal.              0.00003643	No Glove

7,370	No Glove

2,579

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.    Dermal = Single Layer Work
Clothing No Gloves;  Single Layer  Work Clothing With Gloves;  Inhal. =
Inhalation.  Units = mg ai/pound of active ingredient handled.  

2.  Applic. Rate = Taken from draft supplemental product labeling.  

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; ExpoSAC SOP No. 9.1.   Revised 5 July 2000;

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated (
70 kg Body Weight

5.  MOE = Margin of Exposure = NOAEL  ( ADD.   ADD = dermal plus
inhalation.   Short term NOAEL = 20 mg/kg bw/day; intermediate term
NOAEL = 7.0 mg/kg bw/day

A MOE of 100 is adequate to protect occupational pesticide handlers from
exposures to tribenuron methyl.  The estimated MOEs are all > 100. 
Therefore the proposed new uses do not exceed ARIA’s level of concern.

Postapplication Exposure/Risk 

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  HED in conjunction with the Agricultural Re-entry Task
Force (ARTF) has identified a number of post-application agricultural
activities that may occur and which may result in post-application
exposures to pesticide residues.  HED has also identified transfer
coefficients (TC) (cm²/hr) which express the amount of foliar contact
over time for each of the various activities.  

The post-emergence uses of Express® may occur later in the crop season
i.e., 14-day pregrazing interval for treated soybean hay or a 7-day
preharvest interval for corn.   As such, the highest typical (i.e., most
conservative) TC for the proposed new uses is 1,500 cm2/hr for scouting
late season soybeans has been used in this assessment.

Due to the labeled possibility of late season applications to corn, if
that corn is grown for seed it could result in post-application
exposures to workers detasseling the corn.  Detasseling corn has a TC of
17,000 µg/cm2.  Most post-application exposures are not expected to
involve detasseling.  

The TCs used in this assessment are from an interim TC SOP developed by
HED’s ExpoSAC using proprietary data from the ARTF database (SOP #
3.1).  

Lacking compound-specific dislodgeable foliar residue (DFR) data, HED
assumes 20% of the application rate is available as dislodgeable foliar
residue on day zero after application.  This is adapted from the ExpoSAC
SOP No. 003 (5/7/1998 - Revised 8/7/2000).  

The following convention may be used to estimate post-application
exposure.  

Average Daily Dose (ADD) (mg ai/kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/70 kg bw 

and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.03125 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb * 2.47 x10-8 A/cm²
= 0.07009 µg/cm2 , therefore,

0.07009 µg/cm2 * 1,500 cm2/hr (for scouting) * 8 hr/day * 0.001 mg/µg
( 70 kg bw = 0.012 mg/kg bw/day.

MOE = NOAEL ( ADD then 20.0 mg/kg bw/day ( 0.012 mg/kg bw/day = 1,666
(short term exposure).  Intermediate exposures = 7.0 mg/kg bw/day ÷
0.012 mg/kg bw/day = 580

As noted earlier, detasseling treated corn is a possibility.  Therefore
it is also assessed.

0.07009 µg/cm2 * 17,000 cm2/hr (for detasseling) * 8 hr/day * 0.001
mg/µg ( 70 kg bw = 0.136 mg/kg bw/day.

MOE = NOAEL ( ADD then 20.0 mg/kg bw/day ( 0.136 mg/kg bw/day = 147
(short term exposure).  Intermediate exposures = 7.0 mg/kg bw/day ÷
0.136 mg/kg bw/day = 51.

For post-application activities other than detasseling, MOEs are >100. 
The MOE for intermediate-term duration (1-6 months) exposures from
detasseling is 51.  The Agency does not have any data to depart from the
above default assumptions.  For regulatory purposes an REI of 7 days
(MOE = 110, assuming a loss of dislodgeable foliar residue of 10% per
day based upon the assumption of 100% DA), is recommended for
intermediate-term risk to be acceptable to the Agency.  Therefore, it is
ARIA’s recommendation that the REI appearing on the label be increased
to 7 days.  

9.3	Restricted Entry Interval (REI)

Tribenuron methyl is classified in Acute Toxicity Category III for acute
dermal toxicity and acute inhalation toxicity.  It is classified in
Category IV for eye irritation (rabbit) and dermal irritation (rabbit). 
It is not a dermal sensitizer.  Except for workers involved in
detasseling treated corn grown for seed, the interim worker protection
standard (WPS) REI is adequate to protect agricultural workers from
post-application exposures to tribenuron methyl.  Due to the risk
associated with intermediate-term post-application risk (detassling of
corn), ARIA recommends that the REI be increased to 7 days.  

10.0	Data Needs and Label Recommendations

10.1	Toxicology

The following toxicology studies are now required and must be submitted,
in accordance with 40 CFR Part 158:

870.6200	Acute and Subchronic Neurotoxicity

870.7800	Immunotoxicity

ARIA/HED notes that new uses should be made conditional pending receipt
of these required studies.  The Data Call-In (DCI) language for these
studies is provided in Appendix B.

10.2	Residue Chemistry

The petitioner should submit revised Sections F to correct the tolerance
levels in field corn forage (PP#8F7441), and soybean forage and hay
(PP#8F7432), and to correct the commodity definition for AGF (PP#8F7432
and PP#8F7441).  

Occupational and Residential Exposure 

There are no data needs or label requirements related to occupational
and residential exposure.  Due to risks associated with
intermediate-term post-application risk (detassling of corn), ARIA
recommends that the REI be increased to 7 days.  

References:

Dietary Exposure Memorandum

Tribenuron Methyl.  Chronic Dietary (Food and Drinking Water) Exposure
Assessment for the Petition Proposing Tolerances for Residues in/on Corn
and Soybean. DP#: 365813; B. Hanson, 9/9/2009.

Drinking Water Memorandum

Tier 1 Drinking Water Assessment for the DuPont EXPRESS® Herbicide
Containing the Active Ingredient Tribenuron methyl. DP#s: 358877,
358880, 358882, 358885; W. Shaughnessy; 6/15/2009.  

Residue Chemistry Data Reviews

Tribenuron Methyl.  Petition   SEQ CHAPTER \h \r 1 to Establish New (and
Amend Several Existing) Permanent Tolerances for Residues Associated
with Food/Feed Use of the Herbicide on Genetically Modified Soybeans and
Field Corn.  Summary of Analytical Chemistry and Residue Data.   DP#:
360846; W. Drew; 9/9/2009.  

Occupational and Residential Exposure Memorandum

TRIBENURON METHYL – Human, Occupational Exposure/Risk Assessment for
the Proposed Use of Tribenuron methyl on Corn and Soybean. DP#: 365814;
M. Dow; 6/23/2009.	

Appendix A.  Toxicity Profile for Tribenuron Methyl

Summary of Acute Toxicity Data for Tribenuron Methyl (Technical Grade)

Test	MRID	Results	Category

Oral LD50-rat	

00149670	

LD50>5000 mg/kg (limit test)	

IV

Dermal LD50-rabbit	

00148632	

LD50>2000 mg/kg (limit test)	

III

Inhalation LC50-rat	

00148634	

LC50>6.7 mg/L gravimetric concentration (4-hour nose-only limit test);
MMAD = 3.5 µm	

III

Eye Irritation-rabbit	

40357401	

Mild irritation in washed and unwashed eyes, redness with vessel
injection at 1 and 4 hours.	

IV

Dermal irritation-rabbit	

40357402	

Non-irritating	

IV

Dermal sensitization-guinea pig	

42364302	

Sensitizer	

Not applicable

Subchronic, chronic, and Other Toxicology Profile for Tribenuron Methyl

Type of Study/Guideline	

Study Title	

MRID	

Results

870.3100	90-Day oral toxicity, Rat	00148638	NOAEL=100 ppm (7/8
mg/kg/day, M/F,     respectively)

LOAEL=1750 ppm (118/135 mg/kg/day,    M/F, respectively) for decreased
body       weight gain, food consumption and food

efficiency; decreased absolute heart, liver, and kidney weights;
increase relative brain, heart, liver, kidney, testes, and spleen
weights; decreased serum glucose and globulin; no histopathologic
lesions; likely cachexia

870.3150

	13-week subchronic oral toxicity, Dog	00148639	NOAEL>2500 ppm
(73.3/78.0 mg/kg/day  in M/F, respectively) HDT

870.3200	28-Day Dermal, Rabbit	42243101	Limit dose, 1000 mg/kg/day,
resulted in serious toxicity and death. No NOAEL and LOAEL defined. 
Toxicity included treatment site lesions, hypokinesia, decreased body
weights and food consumption, and kidney pathology, but the cause of
death could not be determined.  Although this study is Core
Supplementary, another study is not needed.  Worker exposure is expected
to be 4-5 orders of magnitude lower than the limit dose.

870.3700a	Developmental Toxicity, Rat	00148640	Maternal NOAEL=20
mg/kg/day

Maternal LOAEL=125 mg/kg/day          (decreased maternal body weight
gain and food consumption)

Developmental NOAEL=20 mg/kg/day

Developmental LOAEL=125 mg/kg/day

(decreased body weight)

At 500 mg/kg/day (HDT) there were increased resorption, fetal deaths,
and incomplete ossifications.

870.3700b	Developmental Toxicity, Rabbit	40245514	Maternal NOAEL=20
mg/kg/day

Maternal LOAEL=80 mg/kg/day (HDT-

decreased food consumption, increased

abortions (GD 19-29)

Developmental NOAEL=20 mg/kg/day

Developmental LOAEL=80 mg/kg/day

(HDT-10% decrease in body weight

compared to controls, not statistically significant) Abortions were
increased at 80 mg/kg/day.  Teratogenicity was not observed.

870.3800	2-Generation Reproduction, Rat	40245515	Parental NOAEL=25 ppm
(2 mg/kg/day)

Parental LOAEL=250 ppm (21

mg/kg/day) -decreased body weight gain in F1a adult females)

Reproductive NOAEL=25 ppm (2.5 mg/kg/day)

Reproductive LOAEL=250 ppm (25     mg/kg/day) - decreased body weight
gain     during lactation for F1b and F2b pups)

Offspring NOAEL= 25 ppm (2.5 mg/kg/day)

Offspring LOAEL= 250 ppm (25 mg/kg/day) - decreased absolute splenic
weights.

870.4100b	Chronic Feeding, Dog	40245512	NOAEL (M) = 25 ppm (0.79
mg/kg/day)

NOAEL (F) = 250 ppm (8.16 mg/kg/day)

LOAEL (M) = 250 ppm (8.18 mg/kg/day)-  elevated serum bilirubin, AST,
and         urinary volume, reduced body weight gain (20%).

LOAEL (F) = 1500 ppm (52.02    mg/kg/day-increased serum creatinine,   
bilirubin, AST, and globulin, decreased    body weight gain of 18.2%)

870.4200b	Carcinogenicity, Mouse	40245513	NOAEL =20 ppm (3 mg/kg/day) M

LOAEL = 200 ppm (30 mg/kg/day) -bilateral seminiferous degeneration

and oligospermia.  Although frank toxicity was not observed in the
females, HED peer review judged the dose levels to be adequate.  There
was no evidence of carcinogenicity.

870.4300	Chronic Feeding/Carcinogenicity, Rat	40245511	NOAEL=25
ppm(0.95/1.2 mg/kg/day, M/F)

LOAEL=250 ppm (10/13 mg/kg/day, M/F-decreased body weight gain in both
sexes.

Statistically significant increase in mammary gland adenocarcinomas in
female rats at 1250 ppm (76 mg/kg/day, HDT)

870.4300	Supplement-Estrogenic Activity in Rats	41181901	Dose levels: 0
and 390 mg/kg/day for 90 days.

Weak estrogenic activity was observed in female rats.  The technical and
7 metabolites may be agonists for the estrogen receptor.

870.5100	Gene Mutation Bacterial Reverse Mutation Assay	00148641
Negative (S. typhimurium).

870.5300	Gene Mutation in vitro Mammalian Cell (Chinese Hamster Ovary)
00149671	Negative.

870.5395	Cytogenetics, Mouse Micronucleus Bone Marrow	00148644	Negative.

870.5395	Cytogenetics, Rat Micronucleus Bone Marrow	00148642	Negative.

870.5550	Other Effects – Unscheduled DNA Rat Hepatocyte	00148643
Negative.

870.7485	Metabolism Study - Rat	40245516	Single oral dose readily
absorbed, low dose (20 mg/kg) single and repeated dose 26-33 hours
(half-life); single high (1700-2000 mg/kg) 51-54 males and 69-96
females.  Major excretion via urine (2-4 x feces).  Tissue levels inc.
with dose.  No accumulation in any particular tissue.  Major metabolites
in urine and feces included metsulfuron methyl, saccharin and O-demethyl
triazine amine.  No evidence of glucuronide or sulfate conjugation. 

Appendix B.  DCI Rationales for Required Toxicology Studies.

Guideline Number: 870.6200

Study Title:  Neurotoxicity Battery (Acute and Subchronic Studies)

Rationale for Requiring the Data

This 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). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to
evaluate the potential adverse effects on the nervous system from
exposure to pesticide chemicals.  The Agency believes that the guideline
studies are inadequate in their assessment of behavioral effects and do
not use optimal methods to evaluate the potential toxicity to the
nervous tissue structure and function. To detect and characterize these
potential effects more fully, a battery of more sensitive testing is
required. The objective of this neurotoxicity battery testing is to
evaluate the incidence and severity of the functional and/or behavioral
effects, the level of motor activity, and the histopathology of the
nervous system. The acute neurotoxicity study is required to detect
possible effects resulting from a single exposure. The subchronic
neurotoxicity study is intended to detect possible effects resulting
from repeated or long-term exposures.

 

Practical Utility of the Data

How will the data be used?

The acute and subchronic neurotoxicity studies provide critical
scientific information needed to characterize potential hazard to the
human population on the nervous system from pesticide exposure. These
studies can provide data on a wide range of functional tests for
evaluating neurotoxicity including sensory effects, neuromuscular
effects, learning and memory and histopathology of the nervous system 
For example, animal studies with organophosphorous chemicals  have shown
neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase
inhibition) of concern in rodents and non-rodents.    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. The Agency has
established an oral reference dose (RfD) for assessing dietary risks for
a number of chemicals (e.g., organophoshates and carbamates) where
neurotoxicity was the most sensitive endpoint of concern.

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

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

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied when conducting a risk assessment using the currently
available studies.

 



Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This 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). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated 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 assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

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 this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

Appendix C.  International Residue Limit Status.

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: Methyl-2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)
methylamino] carbonyl] amino] sulfonyl] benzoate	

Common Name:  

Tribenuron methyl	

X Recommended tolerances

( Reevaluated tolerance

( Other 	

Date: 8 July 2009

Codex Status (Maximum Residue Limits)	US Tolerances

X No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested  	Petition
Numbers:  8F7432, 8F7441

DP Number:  360846

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	Grain, aspirated fractions	1.5

Limits for Canada	Limits for Mexico

( No Limits

X No Limits for the crops requested	X No Limits

( No Limits for the crops requested

Residue definition:
Methyl-2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)methylamino]carbonyl
]amino] sulfonyl]benzoate	Residue definition:  NA

Crop	MRL (mg/kg)	Crop	MRL (mg/kg)

Notes/Special Instructions:  NA = Not Applicable.  Per Steve Funk, 20
July 2009.  

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