Document ID: EPA-HQ-OPP-2008-0276-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-22T05:00Z

UNITED STAES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

 PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		October 20, 2009 

SUBJECT:	Prosulfuron.  REVISED Human Health Risk Assessment for the
Proposed Establishment of Permanent Tolerances for Uses in/on Cereal
Grains (Crop Group 15), Except Rice.

PC Code:  	129031	DP Barcode:	370557

Decision No.:	299767	Registration No.:	100-763

Petition Nos.:	5F4469	Regulatory Action:	Section 3

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

TXR No.:	‘None’	CAS No.:	94125-34-5

MRID No.:	‘None’	40 CFR:	§180.481

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:	John Redden, Team Leader 

		ARIA Team

RIMUERB/RD (7505P)

TO:		Christina Swartz, Branch Chief

		Registration Action Branch 2 (RAB 2)

Health Effects Division (HED) (7509P)

AND:		Kathryn Montague, RM 25

Herbicide Branch, RD

Susan Stanton

RIMUERB/RD (7505P)

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc243371170"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc243371170 \h  4  

  HYPERLINK \l "_Toc243371171"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc243371171 \h  8  

  HYPERLINK \l "_Toc243371172"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc243371172 \h  8  

  HYPERLINK \l "_Toc243371173"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc243371173 \h  9  

  HYPERLINK \l "_Toc243371174"  3.1.1	Database Summary	  PAGEREF
_Toc243371174 \h  9  

  HYPERLINK \l "_Toc243371175"  3.1.1.1	Studies Available and Considered
  PAGEREF _Toc243371175 \h  9  

  HYPERLINK \l "_Toc243371176"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc243371176 \h  9  

  HYPERLINK \l "_Toc243371177"  3.1.2	Toxicological Effects	  PAGEREF
_Toc243371177 \h  9  

  HYPERLINK \l "_Toc243371178"  3.1.3	FQPA	  PAGEREF _Toc243371178 \h 
11  

  HYPERLINK \l "_Toc243371179"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc243371179 \h  11  

  HYPERLINK \l "_Toc243371180"  3.3	FQPA Considerations	  PAGEREF
_Toc243371180 \h  11  

  HYPERLINK \l "_Toc243371181"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc243371181 \h  11  

  HYPERLINK \l "_Toc243371182"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc243371182 \h  12  

  HYPERLINK \l "_Toc243371183"  3.3.3	Developmental/Reproductive
Toxicity Studies	  PAGEREF _Toc243371183 \h  12  

  HYPERLINK \l "_Toc243371184"  3.3.4	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc243371184 \h  12  

  HYPERLINK \l "_Toc243371185"  3.3.4.1	Determination of Susceptibility	
 PAGEREF _Toc243371185 \h  12  

  HYPERLINK \l "_Toc243371186"  3.3.4.2	Degree of Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility	 
PAGEREF _Toc243371186 \h  13  

  HYPERLINK \l "_Toc243371187"  3.3.5	Recommendation for a Developmental
Neurotoxicity (DNT) Study	  PAGEREF _Toc243371187 \h  13  

  HYPERLINK \l "_Toc243371188"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc243371188 \h  13  

  HYPERLINK \l "_Toc243371189"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc243371189 \h  13  

  HYPERLINK \l "_Toc243371190"  3.5.1	Acute Reference Dose (aRfD)	 
PAGEREF _Toc243371190 \h  13  

  HYPERLINK \l "_Toc243371191"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc243371191 \h  14  

  HYPERLINK \l "_Toc243371192"  3.5.3	Dermal Absorption	  PAGEREF
_Toc243371192 \h  16  

  HYPERLINK \l "_Toc243371193"  3.5.4	Dermal Exposure (All Durations)	 
PAGEREF _Toc243371193 \h  16  

  HYPERLINK \l "_Toc243371194"  3.5.5	Inhalation Exposure (All
Durations)	  PAGEREF _Toc243371194 \h  16  

  HYPERLINK \l "_Toc243371195"  3.5.6	Level of Concern for Margin of
Exposure	  PAGEREF _Toc243371195 \h  17  

  HYPERLINK \l "_Toc243371196"  3.5.7	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc243371196 \h  17  

  HYPERLINK \l "_Toc243371197"  3.5.8	Classification of Carcinogenic
Potential	  PAGEREF _Toc243371197 \h  17  

  HYPERLINK \l "_Toc243371198"  3.5.9	Summary of Toxicological Doses and
Endpoints for Prosulfuron for Use in Human Risk Assessments	  PAGEREF
_Toc243371198 \h  17  

  HYPERLINK \l "_Toc243371199"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc243371199 \h  19  

  HYPERLINK \l "_Toc243371200"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc243371200 \h  19  

  HYPERLINK \l "_Toc243371201"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc243371201 \h  19  

  HYPERLINK \l "_Toc243371202"  5.1.1   Metabolism in Primary Crops	 
PAGEREF _Toc243371202 \h  19  

  HYPERLINK \l "_Toc243371203"  5.1.2   Metabolism in Rotational Crops	 
PAGEREF _Toc243371203 \h  19  

  HYPERLINK \l "_Toc243371204"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc243371204 \h  19  

  HYPERLINK \l "_Toc243371205"  5.1.4	Analytical Methodology	  PAGEREF
_Toc243371205 \h  19  

  HYPERLINK \l "_Toc243371206"  5.1.5	Environmental Degradation	 
PAGEREF _Toc243371206 \h  20  

  HYPERLINK \l "_Toc243371207"  5.1.6	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc243371207 \h  20  

  HYPERLINK \l "_Toc243371208"  5.1.7	  Drinking Water Residue Profile	 
PAGEREF _Toc243371208 \h  22  

  HYPERLINK \l "_Toc243371209"  5.1.8	Food Residue Profile	  PAGEREF
_Toc243371209 \h  23  

  HYPERLINK \l "_Toc243371210"  5.1.9	International Residue Limits	 
PAGEREF _Toc243371210 \h  24  

  HYPERLINK \l "_Toc243371211"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc243371211 \h  24  

  HYPERLINK \l "_Toc243371212"  5.2.1   Acute Dietary Exposure/Risk	 
PAGEREF _Toc243371212 \h  24  

  HYPERLINK \l "_Toc243371213"  5.2.2   Chronic Dietary Exposure/Risk	 
PAGEREF _Toc243371213 \h  25  

  HYPERLINK \l "_Toc243371214"  5.2.3   Cancer Dietary Risk	  PAGEREF
_Toc243371214 \h  26  

  HYPERLINK \l "_Toc243371215"  5.3  Anticipated Residue and Percent
Crop Treated (%CT) Information	  PAGEREF _Toc243371215 \h  26  

  HYPERLINK \l "_Toc243371216"  6.0   RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc243371216 \h  26  

  HYPERLINK \l "_Toc243371217"  7.0   AGGREGATE RISK AND RISK
CHARACTERIZATION	  PAGEREF _Toc243371217 \h  26  

  HYPERLINK \l "_Toc243371218"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc243371218 \h  26  

  HYPERLINK \l "_Toc243371219"  7.2	Short/Intermediate-Term Aggregate
Risk	  PAGEREF _Toc243371219 \h  27  

  HYPERLINK \l "_Toc243371220"  7.3	Chronic Aggregate Risk	  PAGEREF
_Toc243371220 \h  27  

  HYPERLINK \l "_Toc243371221"  7.4	Cancer Aggregate Risk	  PAGEREF
_Toc243371221 \h  27  

  HYPERLINK \l "_Toc243371222"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc243371222 \h  27  

  HYPERLINK \l "_Toc243371223"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc243371223 \h  27  

  HYPERLINK \l "_Toc243371224"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc243371224 \h  31  

  HYPERLINK \l "_Toc243371225"  10.1	Toxicology	  PAGEREF _Toc243371225
\h  31  

  HYPERLINK \l "_Toc243371226"  Appendix A:  TOXICOLOGY ASSSESSMENT	 
PAGEREF _Toc243371226 \h  33  

  HYPERLINK \l "_Toc243371227"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc243371227 \h  33  

  HYPERLINK \l "_Toc243371228"  A.2	Toxicity Profiles	  PAGEREF
_Toc243371228 \h  34  

  HYPERLINK \l "_Toc243371229"  A.3	Executive Summaries	  PAGEREF
_Toc243371229 \h  34  

  HYPERLINK \l "_Toc243371230"  A.4	References ( in MRID order)	 
PAGEREF _Toc243371230 \h  46  

  HYPERLINK \l "_Toc243371231"  Appendix B.  DCI Rationales for Required
Toxicology Studies.	  PAGEREF _Toc243371231 \h  50  

 

1.0	EXECUTIVE SUMMARY

A petition has been submitted by Syngenta for the establishment of
permanent tolerances for the herbicide prosulfuron in/on cereal grain
(except rice) (PP# 5F4469).  Expired, time-limited tolerances were
established in 40CFR §180.481 for residues of prosulfuron
(1-(4-methoxy-6-methyl-triazin-2-yl)-3-[2-(3,3,3-trifluoropropyl)-phenyl
sulfonyl]-urea) in/on corn (grain and fresh), grain, cereal (except
rice), milk and livestock commodities.  

In this revised document, ARIA has conducted an assessment of the human
exposure and health risks resulting from the conversion of the expired,
time-limited cereal grain tolerance of 0.01 ppm to a permanent
tolerance.  ARIA has determined that the tolerances proposed under
PP#4F4336 (corn and livestock commodity tolerances) are not required. 
Corn uses are covered by the cereal grain tolerance and there is no
reasonable expectation of residues in livestock commodities
(40CFR§6(a)(3)).

The most recent human health risk assessment for prosulfuron was
conducted in conjunction with a Section 3 request for the establishment
of tolerances for residues of parent prosulfuron in/on field corn (grown
for grain, silage, or seed), pop corn, and sweet corn (B. Madden,
5/1/1995).  The proposed end-use product for this 1995 risk assessment
was Exceed WG Herbicide® EPA Reg. No. 100-763, also known as Peak®.

Use Profile

Prosulfuron is a selective herbicide to be used for ground or aerial
spray treatment for weed control in several crops. Prosulfuron may be
applied to field corn (grown for grain, silage, or seed), popcorn, grain
sorghum (milo), wheat, barley, rye, oats, triticale, proso millet, and
following small grain harvest.  Prosulfuron is applied after emergence
of both crop and weeds for the control of broadleaf weeds and
post-emergence to weeds following small grain harvest.  In addition,
pre-emergence applications can be used in some areas for broadleaf weed
control in sorghum. There are no residential uses for prosulfuron at
this time.

Human Health Risk Assessment

Toxicology/Hazard

HED previously provided updated hazard characterization and revised
endpoint selections for risk assessment (DP Number: 331656, L. Taylor,
TXR No. 0054301, 8/16/2006).   Additionally, the rationale for not
requiring a developmental neurotoxicity study in rats and reduction of
the FQPA safety factor to 1X from 3X was provided.  

Since the 2006 updated assessment, there have been revisions to the
toxicology data requirements outlined in 40 CFR Part 158.  Based on the
revised guidelines, an immunotoxicity study (§870.7800) is required for
prosulfuron.  

For acute dietary exposure, the toxicological endpoint was selected from
an acute neurotoxicity study in rats in which the NOAEL of 10 mg/kg is
based on abnormal gait.  For the chronic dietary exposure and short- or
intermediate-term occupational exposure, the endpoint was selected from
a subchronic oral toxicity study in dogs in which the NOAEL of 5.3
mg/kg/day is based on decreased body-weight gain and feed efficiency,
hematological findings and hepatotoxicity in both sexes.  

The toxicological database indicates that neurological effects are seen
after exposure to prosulfuron following gavage, but not dietary, dosing.
 Effects consistent with neurotoxicity (primarily gait and sensorimotor
effects) were observed in rabbits in the developmental toxicity
range-finding study and in rats in the acute neurotoxicity screening
study.  However, there was no evidence from the developmental and
reproductive studies of increased susceptibility in rat or rabbit
fetuses or pups.  In the chronic and subchronic dietary studies with
prosulfuron, decreased body weight, decreased RBC parameters and liver
effects were observed.  The evidence available shows that prosulfuron is
not mutagenic.  

Prosulfuron is classified as “Not Likely to Be Carcinogenic to
Humans” based on the lack of evidence of carcinogenicity in mice and
rats and no concern for mutagenicity. 

In the absence of specific immunotoxicity studies, EPA has evaluated the
available prosulfuron toxicity database to determine whether an
additional database uncertainty factor is needed to account for
potential immunotoxicity.  No evidence of immunotoxicity was found.  Due
to the lack of evidence of immunotoxicity for prosulfuron, EPA does not
believe that conducting immunotoxicity testing will result in a NOAEL
less than the chronic reference dose (cRfD) NOAEL of 5.3 mg/kg bw/day
already established for prosulfuron and an additional factor for
database uncertainties (UFDB ) is not needed to account for potential
immunotoxicity.

Reduction of the Food Quality Protection Act (FQPA) safety factor from
10X to 1X is recommended, based on: (1) the lack of evidence of
increased pre- and/or postnatal susceptibility; (2) the evidence of
neurotoxicity found only after gavage dosing at dose levels in excess of
those where systemic toxicity occurred and at a dose at least 15-fold
higher than the NOAELs used for risk assessment; (3) no neurotoxicity
was observed in the subchronic neurotoxicity study in rats or other
dietary studies; (4) the neuropathology observed in pregnant rabbits
only occurred at dose levels causing mortality and abortions and showed
no dose-response; and (5) lack of evidence of immunotoxicity in the
available studies.

Dietary Exposure (Food/Water)

Residue Chemistry and Risk:  No new residue chemistry data were
submitted with this action.  Residue chemistry data pertaining to the
proposed use of prosulfuron on cereal grains (PP# 5F04469) were
previously noted in the 1995 risk assessment.  Since that assessment was
conducted, amendments concerning analytical methods and product
chemistry have been submitted to address deficiencies noted in the risk
assessment (DP Number: 242049, G. J. Herndon, 4/4/2000).  All
deficiencies for residue chemistry data have been resolved.  The nature
of the residue in plants is sufficiently understood.  The residue to be
regulated is prosulfuron.

Adequate corn metabolism, field trial, rotational crop, storage
stability and ruminant studies have been reviewed. 

Water Exposure and Risk:  The Environmental Fate and Effects Division
(EFED) provided a drinking water assessment (DP Number: 326831, Barrett,
M., 11/20/2006).  The exposure assessment was performed for prosulfuron
parent on ground and surface waters under the assumption that only
parent contributes to the total toxic residues in drinking water.  Based
on the modeling results using the SCI-GROW model for sorghum, wheat,
barley, and other small grain uses, groundwater concentrations of
prosulfuron are 0.655 ppb for both the acute and chronic assessments.  
To estimate surface water concentrations, the PRZM-EXAMS model was used
based on aerial application of prosulfuron.  The acute estimate is 1.872
ppb and the chronic is 0.583 ppb.   

Acute and Chronic Dietary Exposure Results and Characterization:  Acute
and chronic dietary risk assessments were conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID™, Version 2.03).  Both the acute
and chronic assessments were based on the assumption of recommended
tolerance-level residues and 100% crop treated (%CT) for all
commodities.  The highest drinking water concentrations for acute
exposure (1.872 ppb) and chronic exposure (0.655 ppb) were used in the
analysis.  The results of the analyses indicate that acute and chronic
risk from dietary exposure to prosulfuron will not exceed HED’s level
of concern for the general U.S. population and all population subgroups.

Residential Exposure/Risks

There are no residential uses for prosulfuron at this time.

Aggregate Exposure/Risks

Acute and chronic aggregate risk estimates do not exceed HED's level of
concern.  Since the acute and chronic aggregate risk exposures include
only food and water, and the acute and chronic dietary analyses included
both, no further calculations are necessary.  Since both the acute and
chronic dietary risks do not exceed HED’s level of concern, the acute
and chronic aggregate risks do not exceed HED’s level of concern.

Occupational Exposure/Risks

No new occupational exposure or risk data were submitted with this
action since no new uses are being proposed.  Previously, OREB provided
an assessment for the use of prosulfuron on small grains (DP Number:
219775, C. Lewis, 10/30/1995).  OREB estimates of exposure for aerial
application to small grains were considered pertinent to corn uses

Margins of Exposure (MOEs) were calculated based on a NOEL of 5.3
mg/kg/day from a 90-day dog feeding study. 

The Agency is not generally concerned unless the MOE is below 100. 
Since the estimated MOEs are > 100, the proposed uses do not exceed
HED’s level of concern. 

Worker Protection Standard (WPS) and Restricted Entry Interval (REI)
statements were considered adequate. 

Environmental Justice Consideration

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

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

Review of Human Research

This risk assessment does not rely on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.

Additional Data Needs

Based on the toxicity study guidelines as outlined in the recently
revised 40 CFR Part 158, an immunotoxicity study (§870.7800) is
required for prosulfuron (see Appendix B). ARIA/HED notes that new uses
should be made conditional pending receipt of these required studies.  

RECOMMENDATIONS

There are no residue chemistry, toxicology or occupational issues that
would preclude the establishment of permanent tolerances for prosulfuron
residues in cereal grain commodities.  The submitted data support
tolerances for residues of prosulfuron
1-(4-methoxy-6-methyl-triazin-2-yl)-3-[2-(3,3,3-trifluoropropyl)-phenyls
ulfonyl]-urea, including its metabolites and degradates, in or on cereal
grains, at the levels listed below. Compliance with the tolerance levels
specified below is to be determined by measuring prosulfuron only.  

Commodity	Parts per million

Grain, cereal, forage, fodder and straw, group 16, except rice; forage
0.10

Grain, cereal, forage, fodder and straw, group 16, except rice; hay	0.20

Grain, cereal, forage, fodder and straw, group 16, except rice; stover
0.01

Grain, cereal, forage, fodder and straw, group 16, except rice; straw
0.02

Grain, cereal, group 15, except rice 	0.01

Corn uses are covered by the cereal grain tolerance and there is no
reasonable expectation of residues in livestock commodities; therefore,
tolerances are not required for those commodities.

2.0	INGREDIENT PROFILE

Prosulfuron is a colorless, odorless, crystalline solid. The melting
point of the technical grade of the active ingredient (TGAI) is 155 NC
with decomposition. The density at 20°C is 1.45. Using the gas
saturation method, the vapor pressure of the analytical grade a.i. was
found to be <2.6 x 10-8 mm Hg at 25°C. The pH of a 1% aqueous
dispersion of the TGAI was found to be 4-5.

Table 2.0  Nomenclature of Prosulfuron.

Common name	Prosulfuron

Chemical name
1-(4-methoxy-6-methyl-triazin-2-yl)-3-(2-(3,3,3-trifluoropropyl)-

phenylsulfonyl)-urea

Molecular weight	348.742

CAS #	94125-34-5

PC Code	129031

End-use product/EP	Exceed Herbicide, EPA Reg. No. 100-774

Peak Herbicide, EPA Reg. No. 100-763

Spirit Herbicide, EPA Reg. No. 100-911

3.0	HAZARD CHARACTERIZATION

The hazard characterization of prosulfuron was previously updated by HED
(L. Taylor, DP Number: 331656, TXR No. 0054301, 8/16/2006).  The current
hazard characterization reflects this update, and in addition, updates
to the toxicology data requirements as designated by the recent
revisions to CFR 40 Part 158 published after the 2006 update.

Based on current data requirements, the toxicological database on
prosulfuron is lacking an immunotoxicity study in rats which is required
under the current EPA regulations (40 CFR Part 158).  In the absence of
specific immunotoxicity studies, EPA has evaluated the available
prosulfuron toxicity database to determine whether an additional
database uncertainty factor is needed to account for potential
immunotoxicity.  No evidence of immunotoxicity was found.  Due to the
lack of evidence of immunotoxicity for prosulfuron, EPA does not believe
that conducting immunotoxicity testing will result in a NOAEL less than
the chronic reference dose (cRfD) NOAEL of 5.3 mg/kg bw/day already
established for prosulfuron, and an additional factor for database
uncertainties (UFDB ) is not needed to account for potential
immunotoxicity.

3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary

3.1.1.1	Studies Available and Considered 

The toxicology database for prosulfuron is nearly complete based on
reviewed developmental, reproduction, acute/sub-chronic/chronic (rodent
and canine), neurotoxicity, mutagenicity, oncogenicity and metabolism
studies.  The data provided no indication of increased susceptibility of
rats or rabbits to in utero and/or post-natal exposure to prosulfuron.
The toxicological database on prosulfuron is lacking an immunotoxicity
study in rats which is required under the current EPA regulations (40
CFR Part 158).  The scientific and regulatory quality of the prosulfuron
database is high, and so is the confidence in hazard assessments based
on these data.  

3.1.1.2	Mode of action, metabolism, toxicokinetic data

Prosulfuron belongs to the sulfonylurea class of pesticides.  G.W. Ware
(The Pesticide Book; 4th Edition; 1994; pages 187-188) states that,
sulfonylurea compounds “are essentially meristematic inhibitors
applied to soil and to foliage. Inhibition of cell division at the root
tips was the most pronounced effect, with the inhibition of
branched-chain amino acid biosynthesis as the primary mode of action." 
WSSA's Herbicide Handbook (7th Edition; 1994; pages 50-52) also provides
information specific to prosulfuron.  Growth is rapidly inhibited in
susceptible species with compete plant death occurring 14-21 days
post-application.  Plant death results from events occurring in response
to acetolactate synthase (ALS) inhibition.  

Toxicological Effects

Acute studies show that prosulfuron has minimal toxicity under acute
exposure conditions.  Prosulfuron has a toxicity category of III for
acute oral and dermal toxicity. Its toxicity category is IV for primary
irritations of the eye and skin (non- to minimal-irritant). This
chemical is not a dermal sensitizer. No significant treatment-related
findings were observed in the 21-day repeated-dose dermal study in
rabbits.

Evidence of neurotoxicity was observed in gavage dosing studies. 
Staggered gait, lacrimation and hyposensitivity to touch and sound were
seen in an acute oral study in rats. In addition, evidence of
neurotoxicity (transiently decreased motor activity, ataxia and abnormal
gait, impaired righting reflex, decreased body temperature) was observed
at doses of 250 mg/kg and above in the acute neurotoxicity acute study
in rats. The neurological effects were consistent with transient
neurotoxicity affecting primary sensorimotor and gait functions.
Further, there is evidence of neurotoxicity and neuropathology in a
developmental range-finding study in rabbits at all doses tested,
starting with a dose of 150 mg/kg/day, in which ataxia, hypoactivity and
neuropathology were observed.  However, the 90-day neurotoxicity study
in rats did not result in any significant neurotoxicity (highest dose
tested, 628 mg/kg/day); other dietary studies in the rat, mouse and dog
also did not show evidence of neurotoxicity.

Chronic and subchronic studies with prosulfuron indicated some
treatment-related effects.  Most commonly the effect seen across studies
was on body weight. In a subchronic oral toxicity study in rats,
starting at 31-35 mg/kg/day prosulfuron, there were reductions in body
weights.  Subchronic oral toxicity study in dogs showed that prosulfuron
treatment at 69.3 mg/kg/day and above resulted in not only decreased
body weights but also hematological and hepatic toxicity.  Similar
findings were also found in the 1-year chronic feeding study in dogs at
a dose of 18.6 mg/kg/day and above and the 2-year rat chronic
toxicity/oncogenicity study.   

HED classified prosulfuron as a Group D Chemical; “Not Classifiable as
to Human Carcinogenicity” (4/2/1995), under the old cancer guideline
classification system.  HED has since reaffirmed this classification
(12/2/1999).  This classification was based on the lack of evidence of
carcinogenicity in male or female mice at the limit dose and equivocal
evidence of carcinogenicity in female rats.  In female rats, there was
suggestive evidence of a possible treatment-related increase in the
incidence of adenocarcinomas of the mammary glands at the mid dose but
not at the high dose.  This lack of dose-response (i.e. the relatively
limited response in the high dose group and a more pronounced response
in the middle-dose group) along with the lack of evidence of
carcinogenicity in mice and the lack of evidence for in vivo or vitro
mutagenicity lowered the concern for the carcinogenic potential of
prosulfuron.  Thus, in accordance with the 2005 Guidelines for
Carcinogen Risk Assessment, prosulfuron is classified as “Not Likely
to Be Carcinogenic to Humans” based on the lack of evidence of
carcinogenicity in mice and rats and no concern for mutagenicity. 

Developmental and reproductive studies were conducted with prosulfuron.
In one of two rabbit developmental studies there were no signs of
maternal or developmental toxicity in the earlier study testing up to
100 mg/kg/day.  However, in the rabbit range-finding study that used
higher doses of 150 mg/kg/day and above, not only were neurotoxicity
effects in evidence (as noted above), but also decreased body weights
and increased skeletal malformations were observed. The rat and the
later rabbit developmental studies showed dose-related increases in
small fetuses and skeletal effects. Decreases in body weights were noted
in the reproductive study for both the adults of the P0 and P1
generations and for the F1 and F2 offspring as pups.  However, there was
no evidence from the developmental and reproductive studies of increased
susceptibility in rat or rabbit fetuses.

3.1.3	FQPA

In 2000, HED reviewed prosulfuron and assessed neurotoxicity, the need
for a developmental neurotoxicity (DNT) study and the FQPA safety
factor.  Based on their review, reduction of the FQPA safety factor for
prosulfuron to 1X is recommended, supported by the following
considerations: (1) the lack of evidence of increased pre- and/or
postnatal sensitivity; (2) the evidence of neurotoxicity found only
after gavage dosing at dose levels in excess of those where systemic
toxicity occurred and at a dose at least 15-fold higher than the NOAELs
selected for risk assessment; (3) no neurotoxicity was observed in the
subchronic neurotoxicity study in rats; (4) the neuropathology observed
in pregnant rabbits only occurred at dose levels where mortality and
abortions were observed; and (5) the lesions in the spinal cord and
sciatic nerve showed no dose-response. Although an immunotoxicity study
is now required for prosulfuron, a 10x factor database uncertainty
factor is not required, based on lack of evidence of immunotoxicity in
the available toxicology data and lack of increased pre- and/or
postnatal susceptibility.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

Prosulfuron is readily absorbed by foliage and roots, with extensive
translocation in both xylem and phloem.  Metabolism is rapid in corn
with hydroxylation of the phenyl ring to produce the 5-hydroxy
metabolite.  The 5-hydroxy phenyl derivates are conjugated to sugars to
produce water-soluble metabolites.  Unmetabolized parent prosulfuron is
not detectable in corn 30 days post-application.  Metabolism studies
have been conducted with prosulfuron in rats.  In both rat studies,
approximately 90% of the administered dose was excreted during the first
48 hours. At higher doses a greater proportion of the administered dose
was excreted in the feces compared to urine. Females usually excreted
more of the dose in the urine than males in both instances.  The major
routes of metabolism occurred via hydroxylation at side chains and
phenyl ring positions, and O-demethylation of the triazyl methoxy group
or O-demethylation of the methoxy group, and hydroxylation of the
triazinyl methyl group.  Minor routes of metabolism included
unsaturation of the trifluoropropyl side chain, hydrolysis of the
phenyl-sulfonylurea link, and oxidative/hydrolytic cleavage of the
triazine ring system.  

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

Acceptable neurotoxicity, developmental and reproductive toxicity
studies conducted with prosulfuron are available in rats and rabbits. 
The toxicology database is considered complete for the purposes of FQPA
assessment.   The lack of an immunotoxicity study is not expected to
affect assessment of pre- and/or postnatal toxicity, based on the lack
of evidence of immunotoxicity or increased susceptibility in the
available studies, As discussed below (Section 3.3.5), a DNT study is
not required (L. Taylor, DP Number: 331656, 8/16/2006).

3.3.2	Evidence of Neurotoxicity

Evidence of neurotoxicity observed in oral gavage studies on prosulfuron
was consistent with transient neurotoxicity affecting primary
sensorimotor and gait functions..  In the acute neurotoxicity study in
rats, neurological effects included decreased motor activity, abnormal
gait and decreased body temperature after single gavage doses of 250
mg/kg/day or higher; ataxia and impaired righting reflex were also
observed in females at or above 500 mg/kg/day.  However, the 90-day
neurotoxicity study in rats did not result in any significant
neurotoxicity. In a developmental range-finding study in rabbits,
hypoactivity, muscle weakness and incoordination of limbs/ataxia were
observed at all doses tested.  Sciatic nerve degeneration and white
matter degeneration of the spinal cord were observed at higher dose
levels.   Staggered gait, lacrimation and hyposensitivity to touch and
sound were observed in an acute oral LD50 study.  There was no evidence
of neurotoxicity to offspring observed in the developmental or
reproductive toxicity studies.

3.3.3	Developmental/Reproductive Toxicity Studies

In one of two rabbit developmental studies there were no signs of
maternal or developmental toxicity in the earlier study testing doses as
high as 100 mg/kg/day. However, in the rabbit range-finding study that
used higher doses of 150 mg/kg/day and above, not only were
neurotoxicity effects in evidence (as noted above), but also decreased
body weights and increased skeletal malformations were observed. The rat
and the later rabbit developmental studies showed dose-related increase
in small fetuses and skeletal effects.  Fetal effects in both studies
were observed only in the presence of maternal toxicity.

Decreases in body weights were noted in the reproductive study in rats
for both the adults of the Po and P1 generations and for the F1 and F2
offspring as pups. However, there was no evidence of increased
susceptibility in offspring because effects were observed at doses that
caused parental toxicity. 

3.3.4	Pre-and/or Postnatal Toxicity

3.3.4.1	Determination of Susceptibility

Based on the available developmental toxicity studies in rats and
rabbits and reproductive toxicity study in rats, there is no increased
susceptibility to fetuses exposed in utero.  Fetal toxicity was observed
only at dose levels that also caused maternal or parental toxicity.

3.3.4.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility

	

There is no evidence of increased susceptibility in rat fetuses or pups
following pre/post natal exposure.  In the rat and rabbit developmental
studies and the rat reproduction study, developmental effects were
observed only at or above the maternal NOAEL.  Although neurotoxicity
was observed in the rat and rabbit following gavage administration of
relatively high doses, there is low concern for neurotoxicity. 

3.3.5	Recommendation for a Developmental Neurotoxicity (DNT) Study  

A DNT study is not required.  Although there was evidence of
neurotoxicity following gavage exposure to prosulfuron in the rat
(ataxia, decreased motor activity, decreased body temperature, impaired
gait and righting reflex) and in the pregnant rabbit (ataxia,
hypoactivity, neuropathology), the findings were observed only at high
doses (at or above 250 mg/kg/day) following gavage dosing and were not
observed from dietary exposure to levels up to 628 mg/kg/day.  The
neurotoxicity findings in the pregnant rabbit were observed at a dose
causing death, abortions and systemic toxicity and the neuropathology
did not show a dose-response.  Furthermore, there was no evidence for
neurotoxicity in offspring in the developmental studies or in the rat
reproduction study and increased pre- and/or postnatal susceptibility
was not observed.  HED reviewed the neurotoxicity of prosulfuron (2000)
and determined that a DNT was not required, based on (1) neurotoxicity
was observed only after gavage dosing at dose levels 15-fold higher than
the NOAEL used for risk assessment (not in the dietary studies,
including subchronic neurotoxicity in the rat) and (2) neuropathology in
the rabbit developmental toxicity range-finding study occurred only at
dose levels that caused significant maternal toxicity, including
mortality and the lesions observed did not show a dose-response.

3.4	FQPA Safety Factor for Infants and Children

Reduction of the FQPA safety factor to 1X is recommended, see Section
3.1.3 above.   

3.5	Hazard Identification and Toxicity Endpoint Selection

3.5.1	Acute Reference Dose (aRfD) 

Study Selected: Acute neurotoxicity - Rat. 

MRID No.: 43387703

Executive Summary:  In an acute neurotoxicity study (MRID 43387703) 10
or 11 Hsd:Sprague-Dawley rats/sex/dose group received 0, 10, 250, 500 or
1000 mg CGA-152005 (technical, 99.1% a.i.)/kg body weight by gavage in
aqueous 3% corn starch/-0.5% Tween 80 (20 ml/kg). Functional
observational battery and motor activity tests were conducted
pretreatment, on the day of dosing (peak effect, 3 hr post-dosing) and
on Day 7 and 14 post-dosing. Neural tissues from 5 control and high dose
animals/sex and brain levels 4 and 5 from all animals were examined
microscopically.

At 250 mg/kg on Day 0 (peak effect), slightly decreased mean body
temperature (2% lower than controls) and decreased motor activity (27%
less than controls) were observed in males, and abnormal gaits (5/11,
vs. 0/11 controls) was observed in females. At 500 and 1000 mg/kg,
dose-dependent, significant increases in the incidence of ataxia and/or
abnormal gaits (all animals affected), reduced rearing, decreased motor
activity and decreased body temperature were observed in both sexes.
Possible autonomic effects (stereotypical behavior, nasal staining,
soiled fur) were also observed. All surviving animals were normal by Day
7 neurobehavioral evaluations. Mortality occurred in females (3/11) at
1000 mg/kg; however, one death may have been due to gavage error. 
Transiently decreased body weight gains (16% less than controls) were
observed in males at day 7. The observed effects are consistent with
transient neurotoxicity affecting primarily sensorimotor and gait
functions. The LOAEL is 250 mg/kg/day, based on reduced motor activity
and body temperature in males and abnormal gait in females. The NOAEL is
10 mg/kg. 

This study is classified as Core-minimum and satisfies the guideline
requirements (§81-8) for acute neurotoxicity study in rats.

Dose and Endpoint for Risk Assessment: 10 mg/kg based on reduced motor
activity and body temperature in males and abnormal gait in females.

Uncertainty Factor (UF): 100

Acute RfD = 10 mg/kg (NOAEL) = 0.1 mg/kg

		      100 (UF)

Comments about Study/Endpoint/Uncertainty Factor:  The acute
neurotoxicity study in rat was used for the acute reference dose because
this study provides a single dose with the lowest NOAEL. The effects of
concern are neurotoxic in nature.

3.5.2	Chronic Reference Dose (cRfD) 

Study Selected: Subchronic oral toxicity - Dog. 

MRID No.: 42685230

Executive Summary: In a subchronic oral toxicity study (MRID 42685230),
prosulfuron technical was administered to 4 beagle dogs/sex/dose via the
diet at dose levels of 0, 15, 150, 1500, or 3000 ppm for 90 days. The
equivalent average daily intake of test material was 0, 0.54, 5.3, 57,
or 110 mg/kg/day (males) and 0, 0.59, 6.5, 54, or 120 mg/kg/day
(females).     

There were no deaths during the study, and clinical signs were
comparable among the groups (both sexes). Mean body weight of the 3000
ppm males was approximately 10% lower than control from week 7 on.
Overall (weeks 0-13) body-weight gain was negative for the males at 3000
ppm (-0.1 kg) compared to the control (1.15 kg). Females at 3000 ppm
displayed a decrease in body-weight gain (48% of control). At 1500 ppm,
both males (63% of control) and females (31%) displayed a decrease in
overall body-weight gain compared to the controls. Feed efficiency was
decreased for both sexes at the 1500 ppm and 3000 ppm dose levels.

Hematotoxicity was observed in both sexes at the two highest dose levels
and was manifested as decreased mean corpuscular hemoglobin
concentration, increased appearance of target cells in the blood,
erythrocyte phagocytosis in the lymph nodes, and compensatory increases
in erythroid hyperplasia in the bone marrow and extramedullary
hematopoiesis in the spleen. Males also showed decreased erythrocyte
count and hemoglobin, ineffective erythropoiesis in the bone marrow, and
increased numbers of anisocytes in the blood. Females showed increases
in the numbers of poikilocytes and burr cells in the blood, red
discoloration of the bone marrow, and hemosiderin pigmentation in the
spleen and stomach. Additionally, a few dogs of both sexes displayed
decreased numbers of platelets and leukocytes in the blood. At the
highest dose tested, additional hematological effects were observed,
which included decreased hematocrit in both sexes, decreased erythrocyte
count and hemoglobin, and increased nucleated red blood cells,
reticulocytes, mean corpuscular volume, and hemosiderin pigmentation in
the lymph nodes in females; and increased incidence of burr cells in the
blood, red discoloration of the bone marrow, and hemosiderin
pigmentation in the stomach of males. 

Hepatotoxicity was observed in both sexes at the two highest dose levels
and consisted of decreased serum albumin, grossly enlarged liver, and
increases in the liver-to-body weight ratio. Male dogs displayed an
increased incidence of fatty liver and decreased total protein,
albumin:globulin ratio, and glucose. Female dogs displayed an increased
absolute liver weight and relative-to-brain liver weight ratio. At the
highest dose tested, increased alkaline phosphatase was observed in both
sexes, increased absolute liver weight and aspartate and alanine
aminotransferases were observed in males, and decreased total protein
and increased globulin were observed in females.

At the highest dose tested, two males displayed myocardial necrosis with
fibrosis and dystrophic mineralization in the ventricular and papillary
muscles and one female displayed myocardial degeneration.  The NOAEL is
150 ppm (5.3 mg/kg/day) and the LOAEL is 1500 ppm (54 mg/kg/day) based
on decreased bodyweight gain and feed efficiency as well as
hematological and hepatic toxicity in both males and females.

This study is classified as Core-guideline and satisfies the guidelines
requirements

for a subchronic oral toxicity study in a non-rodent species (§82-1).

Dose/Endpoint for Risk Assessment: The NOAEL is 5.3 mg/kg/day based on
decreased bodyweight gain and feed efficiency as well as hematological
and hepatic toxicity in both males and females.

Uncertainty Factor (UF): 100

Chronic RfD = 5.3 mg/kg (NOAEL) = 0.053 mg/kg

		      100 (UF)

Comments about Study/Endpoint: Findings in the 90-day dog study are
supported by the findings in the 1-year dog study.

3.5.3	Dermal Absorption

A dermal absorption study is not required, a dermal study was used.

3.5.4	Dermal Exposure (All Durations)

No  SEQ CHAPTER \h \r 1  short-term, intermediate-term, or long-term
dermal risk assessment is required, based on the fact that no hazard was
identified in the dermal study (MRID 42685235) at dose levels as high as
the limit dose [1000 mg/kg/day]. Although reproductive toxicity was
observed in the 2-generation reproduction study, it occurred only at the
high-dose level, and systemic toxicity was observed at lower dose
levels. Thus, regulating at dose levels that protect against systemic
effects will be protective of any reproductive toxicity.  

3.5.5	Inhalation Exposure (All Durations) 

Study Selected: 90-Day subchronic oral toxicity - Dogs. 

MRID No.: 42685230

Executive Summary:   See section 3.5.2, above.

Dose/Endpoint for Risk Assessment: The NOAEL is 5.3 mg/kg/day based on
decreased bodyweight gain and feed efficiency as well as hematological
and hepatic toxicity in both males and females.

Comments about Study/Endpoint: Since an oral NOAEL was selected the

onent (i.e., μg a.i./day) using 100% absorption rate

(default value) and application rate should be converted to an
equivalent oral dose (mg/kg/day) and this dose should be compared to the
NOAEL of 5.3 mg/kg/day to calculate the MOEs.  Findings in the 90-day
dog study are supported by the findings in the 1-year dog study.

3.5.6	Level of Concern for Margin of Exposure

A MOE of 100 is adequate for occupational exposure

3.5.7	Recommendation for Aggregate Exposure Risk Assessments

For acute aggregate risk assessment, combine the high end values from
food and water and compare that value to the acute RfD.

For short and intermediate-term aggregate risk assessments, the dermal
and inhalation pathways cannot be combined due to the lack of a common
toxicological endpoint via the dermal (no systemic toxicity) and the
inhalation (hematopoietic and hepatotoxicity via the oral route) routes.
 Long-term aggregate risk assessment is not required since there is no
long-term exposure potential.

3.5.8	Classification of Carcinogenic Potential 

Prosulfuron is classified as “Not Likely to Be Carcinogenic to
Humans” based on the lack of evidence of carcinogenicity in mice and
rats and no concern for mutagenicity. 

3.5.9	Summary of Toxicological Doses and Endpoints for Prosulfuron for
Use in Human Risk Assessments

Table 3.5.9  Summary of Toxicological Endpoints Prosulfuron for Use in
Human Health Risk Assessment

Exposure

Scenario	Dose Used in Risk Assessment,

UF	FQPA SF and Level of Concern for Risk Assessment	Study and
Toxicological Effects

Acute Dietary

All populations	NOAEL = 10 mg/kg

UF = 100

Acute RfD = 0.1 mg/kg/day	FQPA SF = 1X

aPAD =  0.1 mg/kg/day	Acute Neurotoxicity Study - Rat

LOAEL = 250 mg/kg/day, based on abnormal gait in females.

Chronic Dietary

All populations	NOAEL= 5.3 mg/kg/day

UF = 100

Chronic RfD = 0.053 mg/kg/day	FQPA SF = 1X

cPAD = 0.053 mg/kg/day	Subchronic Oral Toxicity Study - Dog

LOAEL = 54 mg/kg/day, based on decreased body-weight gain and feed
efficiency, hematological findings and hepatotoxicity in both sexes.

Short- (1-30 days) Intermed-Term

(1-6 months) and Long-Term (>6 months) Dermal 	Not required based on the
fact that no hazard was identified in the dermal study at dose levels as
high as the limit dose (1000 mg/kg/day).

Short- (1-30 days), 

Intermed-(1- 6 months) and Long-Term (> 6 months) Inhalation	NOAEL = 5.3
mg/kg/day	FQPA SF = 1X

	Subchronic Oral Toxicity Study - Dog

LOAEL = 54 mg/kg/day, based on decreased body-weight gain and feed
efficiency, hematological findings and hepatotoxicity in both sexes.

Cancer

(oral, dermal, inhalation)	Prosulfuron is classified as “Not Likely to
Be Carcinogenic to Humans” based on the lack of evidence of
carcinogenicity in mice and rats and no concern for mutagenicity. 

1 UF = uncertainty factor, FQPA SF = Special FQPA SF, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose

3.6 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 recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the 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.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

Based on reproductive (decreases in fertility index, gestation index,
and parturition index) alterations observed in the 2-generation
reproduction study, it is possible that prosulfuron causes endocrine
disruption. However, the endocrine effects associated with prosulfuron
have been well characterized in an acceptable 2-generation reproduction
study with a clear NOAEL/LOAEL, and the chronic reference dose (cRfD)
selected for prosulfuron risk assessments is considered protective of
endocrine effects. As a result, there are no additional/specific studies
being requested at this time. To the extent that new or revised tests
are developed in connection with the endocrine disruption screening
program that can provide more information on endocrine effects, EPA will
consider whether further testing of prosulfuron is appropriate. Because
the toxicity database for prosulfuron is complete (i. e., there are no
data gaps), there is no evidence of susceptibility, and all adverse
effects have been well-characterized and are addressed by at least a
safety factor of 100X, the 10X FQPA safety factor has been reduced to
1X.  

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

No public health/epidemiology data were used in developing this risk
assessment.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

5.1	Pesticide Metabolism and Environmental Degradation

Field trial and residue data were originally included in the 1995 risk
assessment (B. Madden).  Since then, all deficiencies noted in that
assessment have been resolved.  Because all deficiencies have been
resolved and no new uses are being proposed, ARIA is not revisiting the
residue chemistry data.  

5.1.1   Metabolism in Primary Crops

The nature of the residue in plants is adequately understood based on
corn metabolism data.   The TRR of all direct human food items was below
the limit of detection.  The available storage stability data support
the storage conditions and durations for samples from the field trials
and processing studies.  

5.1.2   Metabolism in Rotational Crops

Based on the results of the rotational crop study, the appropriate crop
rotation interval is 30 days for root and leafy vegetables and 300 days
for small grains and all other crops.  A shorter interval for small
grains can not be considered as wheat was not planted at 30 days and
wheat grain and straw from the 90 DAT samples were not analyzed.  In the
absence of storage stability data, rotational crop intervals were
determined by using the TRR rather than the levels of residues of
potential regulatory concern.  Although storage stability data have
since been reviewed and accepted, ARIA is not revisiting this issue.

5.1.3	Metabolism in Livestock

	

Studies of prosulfuron metabolism in ruminants and poultry have been
reviewed, although no livestock tolerances are required.  There is no
reasonable expectation of residues in livestock commodities
(40CFR§6(a)(3)).

5.1.4	Analytical Methodology		

	

Adequate high-performance liquid chromatography (HPLC) methods are
available for enforcing tolerances for prosulfuron residues in plant
commodities.  A standard for prosulfuron is available from the Ft. Meade
laboratory (personal communication between C. Stafford and J. Herndon on
3/15/2000).

5.1.5	Environmental Degradation

The environmental fate database for prosulfuron is fairly complete in
terms of laboratory and field dissipation data.  However, there are no
monitoring data available for prosulfuron in surface or ground waters. 
Limited environmental fate data are available for degradates, but the
data imply that the degradate CGA-159902
{2-(3,3,3-trifluoropropyl)-benzenesulfonamide} hereafter referred to as
3F benzenesulfonamide  is particularly likely to impact water resources.
 Degradate fate data are reviewed herein as well, however, at this time
it does not appear to be necessary to include degradate exposure in the
Drinking Water Assessment for prosulfuron.

Parent prosulfuron is extremely persistent in soil with half-lives
generally of 151 to >730 days in the root zone.  Prosulfuron has the
potential to hydrolyze rapidly in acidic soils (based on measurement of
a 10-day half-life in pH 5 sterile, distilled water), but none of the
laboratory or field data show transformation anywhere near this rapid
with the exception of the single anaerobic aquatic study (prosulfuron
has a pKa of 3.76 indicating a preference for the anionic form at
relevant environmental pH range of about 5.5 to 9).  At least two
published studies confirm that prosulfuron can be subject to significant
hydrolysis under acidic conditions in water or moist soil but otherwise
is often persistent for months or longer. Label restrictions also
acknowledge this property when addressing concerns/use restrictions
because of possible carryover of residue levels toxic to rotational
crops:

Peak herbicide is broken down in the soil primarily by chemical
hydrolysis and microbial degradation. Several factors influence
degradation of Peak herbicide, including soil pH, moisture, temperature,
and soil friability. In general the higher the soil pH, the less Peak is
degraded due to chemical hydrolysis with little hydrolysis occurring
when soil pH levels are above 7.8.  [Source: Peak label; EPA Reg. No.
100-763 EPA Est. 70992-FRA-001]

Prosulfuron is also very mobile in soil with Kd values of 0.074 to 0.293
and Koc values of 18 to 41 in four American test soils with measured pH
values ranging from 6.5 to 7.7 (Table 4).  Similar results were obtained
in studies to support registration in Europe.

5.1.6	Pesticide Metabolites and Degradates of Concern

There are multiple degradates of prosulfuron, several of which have
occurred at much greater than 10% of applied material in one or more of
the laboratory or field dissipation studies.  The most persistent and
consistently found degradate in laboratory soil metabolism and field
studies is 3F benzenesulfonamide; occurring, for example, at up to 58
percent in the aerobic aquatic metabolism study.

A brief summary of the major degradates of prosulfuron identified in
soil and water in laboratory studies follows.

	1.  CGA-159902 (phenyl ring cleavage product)

Aerobic Kickapoo sandy loam - maximum of 48% at end of study, 12 months
posttreatment (21% parent remaining).

Aerobic Huntington sandy loam - maximum of 49% at end of study, 12
months posttreatment (12% parent remaining).

Anaerobic Aquatic silt loam sediment from Fayette Co., KY pond - Up to
58% by 12 months posttreatment (<1% parent remaining).

The Freundlich Kd values in four test soils were 0.4 to 1.24 ml/g (Soils
ranged from 0.8 to 3.4% organic matter and pH 6.5 to 7.8).  Koc values
were 48 to 96, with a median value of 82 ml/g.

	2.  CGA-150829 (s-triazine ring cleavage product)

Aerobic Kickapoo sandy loam - maximum of 31% at end of study, 12 months
posttreatment (18% parent remaining).

Aerobic Huntington sandy loam - maximum of 12% at end of study, 12
months posttreatment (27 to 37% parent remaining).

Anaerobic Aquatic silt loam sediment from Fayette Co., KY pond - Up to
37% by 6 months, declined to 18% at 12 months (<1% parent remaining).

	3.  CGA-325030 or Desmethoxyamino prosulfuron (sulfonylurea bridge not
cleaved)

Aerobic Huntington sandy loam - maximum of 22% at end of study, 12
months posttreatment in triazine-ring label study; however, only trace
amounts detected in the phenyl-ring labelled study.	

Aerobic Kickapoo sandy loam - <6% in triazine- and <13% in
phenyl-labelled study; in both cases residues were declining at end of
study, 12 months posttreatment.

Anaerobic Aquatic silt loam sediment from Fayette Co., KY pond - Up to
15% by 1 month, declining substantially by 12 months posttreatment (<1%
parent remaining).

	

	4.  CGA-325026 (phenyl ring with sulfonylurea bridge to fragment of
triazine)

Anaerobic Aquatic silt loam sediment from Fayette Co., KY pond - Up to
27% by 12 months posttreatment (<1% parent remaining).

This degradate was not identified in aerobic soil metabolism studies.

	5.  CGA-325028 (phenyl ring with sulfonylurea bridge to open triazine
chain)

Anaerobic Aquatic silt loam sediment from Fayette Co., KY pond - Up to
25% by 12 months posttreatment (<1% parent remaining).

This degradate was not important (maximum 3% of applied) in aerobic soil
metabolism studies.

Laboratory batch-equilibrium studies showed that the degradates
CGA-159902, CGA-150829, and two other minor degradates not discussed in
this assessment were similarly mobile / weakly adsorbed in soil compared
to parent prosulfuron.

None of these degradates were found as greater than 3% (for CGA-159902)
of the applied material on a molar basis in the leachate of either the
unaged or aged (30 days) soil column leaching studies; parent
prosulfuron was always the dominant component of the leachate.

EFED concludes that the available data on prosulfuron shows that the
compound is mobile and persistent, has potential to leach to ground
water, and also presents concerns for transport to surface water by
runoff.  Under some circumstances exposure to degradates could be quite
significant; this is particularly true for CGA-159902, which appears to
be the major aerobic soil degradate and is extremely persistent and
mobile.

5.1.7	  Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were
provided by EFED and summarized in the following memorandum: “Drinking
Water Exposure Assessment for Prosulfuron Usage on Small Grains and
Corn,” (DP Number: 326831, Barrett, M., 11/20/2006) and incorporated
directly into this dietary assessment.  Water residues were incorporated
in DEEM-FCID into the food categories “water, direct, all sources”
and “water, indirect, all sources.” 

Parent prosulfuron is extremely persistent in soil with half-lives
generally of 151 to >730 days in the root zone and has the potential to
hydrolyze rapidly in acidic soils (based on measurement of a 10-day
half-life in pH 5 sterile, distilled water).  Label restrictions also
acknowledge this property when addressing concerns/use restrictions
because of possible carryover of residue levels toxic to rotational
crops.  Prosulfuron is also very mobile in soil with Kd values of 0.074
to 0.293 and Koc values of 18 to 41 in four American test soils with
measured pH values ranging from 6.5 to 7.7.

The exposure assessment was performed for prosulfuron parent on ground
and surface waters under the assumption that only parent contributes to
the total toxic residues in drinking water.  However, prosulfuron does
have persistent and mobile degradates.   The degradate fate data were
reviewed as well, however, because the degradates have not been
established to be a human health concern, EFED concluded that it did not
appear necessary to include degradate exposure in the Drinking Water
Assessment for prosulfuron at this time.  

The Screening Concentration in Ground Water (SCI-GROW) model was used to
estimate ground water concentrations and the Pesticide Root Zone Model
(PRZM) and Exposure Analysis Modeling System (EXAMS) models were used to
estimate surface water concentrations.

Based on the modeling results using the SCI-GROW model for sorghum,
wheat, barley, and other small grain uses, groundwater concentrations of
prosulfuron are 0.655 ppb for both the acute and chronic assessments.  
This value represents the maximum estimated drinking water concentration
of parent prosulfuron alone that might be found in groundwater from the
use of prosulfuron at the maximum application rate.  

To estimate surface water concentrations, the PRZM-EXAMS model was used
based on aerial application of prosulfuron.  The acute estimate is 1.872
ppb and the chronic is 0.583 ppb.  The application rate used in the
surface water assessment represents the maximum single application rate
on the proposed label for the relevant crops. 

Prosulfuron may be applied on grain sorghum (milo), wheat, barley, rye,
oats, triticale, proso millet, and following small grain harvest up to a
maximum single application rate of 0.0356 lb ai/A and a maximum seasonal
application rate of 0.0356 lb ai/A.  

The most conservative estimates for acute exposure (1.872 ppb) and
chronic exposure (0.655 ppb) were used in this analysis (Table 5.1.7,
below).

Table 5.1.7  Water Numbers Used in the Prosulfuron Dietary Risk
Assessment Based on SCI-GROW and PRZM-EXAMS Models

	Acute

(ppb)	Chronic

(ppb)

SCI-GROW

(Ground water)	0.655	0.655

PRZM-EXAMS

(Surface water)	1.872	0.583

5.1.8	Food Residue Profile

Field trial and residue data were originally included in the 1995 risk
assessment.  Since then, all deficiencies noted in that assessment have
been resolved.  Because all deficiencies have been resolved and no new
uses are being proposed, ARIA is not revisiting the residue chemistry
data.  

The nature of the residue in plants is adequately understood based on
corn metabolism data.   The TRR of all direct human food items was below
the limit of detection.  The nature of the residue in ruminants is
adequately understood based on lactating goat ruminant metabolism data. 
The nature of the residue in livestock commodities is adequately
understood based on the results of poultry metabolism studies in which
laying hens were treated orally.  The dietary risk assessment was based
on the assumption that the residue of concern in plants is parent
prosulfuron.  The available storage stability data support the storage
conditions and durations for samples from the field trials and
processing studies.  

Based on the results of the study, the appropriate crop rotation
interval is 30 days for root and leafy vegetables and 300 days for small
grains and all other crops. A shorter interval for small grains can not
be considered as wheat was not planted at 30 days and wheat grain and
straw from the 90 DAT samples were not analyzed.  In the absence of
storage stability data, rotational crop intervals were determined by
using the TRR rather than the levels of residues of potential regulatory
concern.  

Freezer storage stability data were submitted and addressed in the 2000
G. Herndon memorandum.  The data demonstrated the stability of
prosulfuron residues in frozen silage stage corn (about 13 months). 
Also, prosulfuron and its metabolites were found to be stable in corn
homogenates.  

5.1.9	International Residue Limits

No Codex MRLs have been established for residues of prosulfuron.

5.2	Dietary Exposure and Risk

Acute and chronic dietary risk assessments were conducted using the
Dietary Exposure Evaluation Model (DEEM-FCID™, Version 2.03) which
uses food consumption data from the U.S. Department of Agriculture’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.  The dietary exposure analyses were performed by ARIA (B.
Hanson, DP Number: 336488, 2/20/2007).

5.2.1   Acute Dietary Exposure/Risk

An acute dietary assessment assuming tolerance level residues and 100%
crop treated was performed for prosulfuron.  The highest estimate of
acute surface water exposure (1.872 ppb) was used for drinking water in
this analysis.  The acute dietary risk assessment for prosulfuron shows
that for all included commodities, the acute dietary risk estimates are
below HED’s level of concern (i.e. <100% acute population adjusted
doses (aPAD)).  For the U.S. population, exposure to food and water
utilized <1% of the aPAD at the 95th percentile.  The acute dietary risk
estimate for the highest reported exposed population subgroup, children
1-2 years old, is <1 % of the aPAD.  

Table 5.2.1  Summary of Acute Dietary (Food and Drinking Water) Exposure
Risk for Prosulfuron

Population Subgroup	Acute Dietary

(95th Percentile)

	Dietary Exposure (mg/kg/day)	% aPAD*

General U.S. Population	0.000176	<1

All Infants (< 1 year old)	0.000233	<1

Children 1-2 years old	0.000306	<1

Children 3-5 years old	0.000284	<1

Children 6-12 years old	0.000209	<1

Youth 13-19 years old	0.000146	<1

Adults 20-49 years old	0.000139	<1

Adults 50+ years old	0.000112	<1

Females 13-49 years old	0.000133	<1

* Values for the population with the highest risk are in bold type.  

5.2.2   Chronic Dietary Exposure/Risk

A chronic dietary assessment assuming tolerance level residues and 100%
crop treated was also conducted.  The highest estimate of chronic
surface water exposure (0.655 ppb) was used for drinking water in this
analysis.  The chronic dietary risk assessment shows that for all
included commodities, the chronic dietary risk estimates are below
HED’s level of concern (i.e. <100% chronic population adjusted doses
(cPAD).  For the U.S. population the exposure for food and water
utilized <1% of the cPAD.  The chronic dietary risk estimate for the
highest reported exposed population subgroup, children 1-2 years old, is
<1% of the cPAD.

Table 5.2.2  Summary of Chronic Dietary (Food and Drinking Water)
Exposure Risk for Prosulfuron

Population Subgroup	Chronic Dietary

	Dietary Exposure (mg/kg/day)	% aPAD*

General U.S. Population	0.000054	<1

All Infants (< 1 year old)	0.000086	<1

Children 1-2 years old	0.000110	<1

Children 3-5 years old	0.000114	<1

Children 6-12 years old	0.000082	<1

Youth 13-19 years old	0.000057	<1

Adults 20-49 years old	0.000046	<1

Adults 50+ years old	0.000036	<1

Females 13-49 years old	0.000044	<1

* Values for the population with the highest risk are in bold type.

5.2.3   Cancer Dietary Risk

Prosulfuron is classified as “Not Likely to Be Carcinogenic to
Humans” based on the lack of evidence of carcinogenicity in mice and
rats and no concern for mutagenicity; therefore, prosulfuron is not
expected to pose a cancer risk. 

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

No anticipated residue or %CT information was considered in the acute
and chronic dietary analyses.  

6.0   RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

There are no registered residential uses of prosulfuron at this time and
so a non-occupational risk assessment is not required.

7.0   AGGREGATE RISK AND RISK CHARACTERIZATION

In accordance with the FQPA, ARIA must consider and aggregate pesticide
exposures and risks from non-occupational sources, including; food,
drinking water, and residential pathways.  In an aggregate assessment,
exposures from relevant sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, ARIA considers both the route and duration of exposure.

7.1	Acute Aggregate Risk

Since the acute aggregate risk exposure includes only food and water and
the acute dietary analysis included both, no further calculations are
necessary.  Since the acute dietary risk does not exceed HED’s level
of concern, the acute aggregate risk does not exceed HED’s level of
concern.

7.2	Short/Intermediate-Term Aggregate Risk 

There are no residential uses associated with prosulfuron; therefore,
short and intermediate-term aggregate risk assessments are not
performed.

7.3	Chronic Aggregate Risk

Since the chronic aggregate risk exposure includes only food and water
and the chronic dietary analysis included both, no further calculations
are necessary.  Since the chronic dietary risk does not exceed HED’s
level of concern, the chronic aggregate risk does not exceed HED’s
level of concern.

7.4	Cancer Aggregate Risk

Prosulfuron is classified as “Not Likely to Be Carcinogenic to
Humans” based on the lack of evidence of carcinogenicity in mice and
rats and no concern for mutagenicity.  Therefore, prosulfuron is not
expected to pose a cancer risk.  

8.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to prosulfuron and any other
substances and prosulfuron 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 prosulfuron 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   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

No new occupational exposure or risk data were submitted with this
action since no new uses are being proposed.  Previously, OREB provided
an assessment for the use of prosulfuron on small grains (DP Number:
219775, C. Lewis, 10/30/1995).  OREB estimates of exposure for aerial
application to small grains were considered pertinent to the corn use
which is now considered covered under the grain tolerance.  OREB used
assumptions provided by Dr. Yuen-shaung Ng, Biological and Economic
Analysis Division (BEAD) and the Pesticide Handlers Exposure Database,
Version 1.1 (PHED) to develop the exposure assessment.

MOEs were calculated for systemic toxicity (decreased weight gain and
feed efficiency as well as hematological and hepatic toxicity) based on
a NOEL of 5.3 mg/kg/day from a 90-day dog feeding study. For this
analysis ARIA calculated the MOE as the ratio of the NOEL to the
exposure (NOEL/exposure = MOE).  

Below are the results noted in the 1995 OREB assessment for small
grains.

Applications are to be made with ground and aerial equipment.  The
number of acres expected to be treated is not known.  Maximum rate of
application is 0.0356 lb ai/A.  Precise information is not available on
how many farms a professional applicator will treat with this chemical
during the proposed use season.  Consequently, OREB has assumed 10 farms
will be treated during the season.

Average number of acres per farm, based on the state having the largest
acreage for each crop, are as follows: grain sorghum (Texas), 286 acres;
forage sorghum (Kansas), 52 acres; wheat, all (North Dakota), 464 acres;
barley (North Dakota), 171 acres; rye (North Dakota), 78 acres; oats
(South Dakota), 69 acres; triticale (Washington), 68 acres; and proso
millet (South Dakota), 136 acres.  OREB based its exposure estimates on
the crop having the largest average farm size (North Dakota, wheat). 

	Ground Equipment 

	Application rate 0.0356 lb ai/A (from Ciba-Geigy);

	81 acres treated per day;

	2.88 lb ai applied per day ;

	Average farm size = 464 acres.

	Aerial Equipment 

	Application rate 0.0356 lb ai/A (from Ciba-Geigy);

	464 acres treated per day;

	16.5 lb ai applied per day;

	Average farm size = 464 acres.

Mixer-loaders

Minimum clothing required by the WPS for Peak® includes: long pants,
long-sleeved shirt, waterproof gloves, and shoes plus socks.    

Relying on PHED, estimated Absorbed Daily Dose (ADD) for mixer/loaders
of ground equipment, based on treating 81 acres/day, is 3.9 μg ai/kg
bw/day.  For aerial equipment, ADD is 22.2 μg ai/kg bw/day, based on
treating 464 acres/day.  Annual Average Daily Dose (AADD) is 605.9 ng
ai/kg bw/day for ground equipment and 584.4 ng ai/kg bw/day for aerial
equipment.

Please note the PHED estimates of exposure are based on use of a dry
flowable formulation with open mixing.  Peak® is a water dispersible
granule packaged in water soluble packets.  Currently, PHED does not
contain sufficient data entries to quantify the degree of protection
provided by the use of water soluble packets.  Consequently, because
water soluble packets should reduce mixer exposure, actual exposure
should be less than that estimated by OREB.

Applicators

μg ai/kg bw/day. For aerial equipment, ADD is 1.3 μg ai/kg bw/day. 
AADD is 92.1 ng ai/kg bw/day for ground equipment and 34.9 ng ai/kg
bw/day for aerial equipment.   Applicator exposure would not be affected
by use of water soluble packets.

Please note, OREB previously conducted an exposure assessment for the
use of Peak® on corn.  This review was dated March 24, 1995 (C.
Lewis/OREB to R. Taylor/RD).  At the time, the registrant only requested
application by ground equipment.  In this recent submission requesting
addition of small grains to the label, aerial application has been
added.  OREB estimates of exposure for aerial application to small
grains are pertinent to the corn use.  

CALCULATIONS:

Mixer/loaders

	Ground Equipment 

	94.2790 µg/lb ai handled (PHED 1.1, DF.OPEN.AIR.AB.MLOD, for
mixer/loader, open loading, long-sleeved shirt, long pants, wearing
gloves) x 2.88 lb ai/day ÷ 70 kg bw = 3.88 µg ai/kg bw/day, ADD; 3.88
µg ai/kg bw/day x 5.7 (days required to treat 464 acres at 81/day) x 10
(number of farms a professional applicator is expected to treat/season)
÷ 365 = 605.92 ng ai/kg bw/day, AADD. 

	Aerial Equipment 

	94.2790 µg/lb ai handled (PHED unit of exposure value, run # CHARLIEA.
OPEN. EC. MLOD, for mixer/loader, open loading, long-sleeved shirt, long
pants, wearing gloves) x 16.5 lb ai/day ÷ 70 kg bw = 22.22 µg ai/kg
bw/day, ADD; 22.22 µg ai/kg bw/day x 0.96 (days required to treat 464
acres at 482/day) x 10 (number of farms a professional applicator is
expected to treat/season) ÷ 365 = 584.42 ng ai/kg bw/day, AADD. 

Applicators

	Ground Equipment 

	14.219 µg/lb ai applied (PHED unit of exposure value, run # CHARLIEA.
APPL, for ground-boom applicator, open cab, long-sleeved shirt, long
pants, wearing gloves) X 2.88 lb ai/A ÷ 70 kg bw = 0.59 µg ai/kg
bw/day, ADD; 0.59 µg ai/kg bw/day x 5.7 (days required to treat 464
acres at 81/day) x 10 (number of farms a professional applicator is
expected to treat/season) ÷ 365 = 92.14 ng ai/kg bw/day, AADD. 

	Aerial Equipment 

	5.654 µg/lb ai applied (PHED unit of exposure value, run #
CHARLIEB.APPL.APPL., for fixed-wing aerial applicator, long-sleeved
shirt, long pants, no gloves) X 16.5 lb ai/A ÷ 70 kg bw = 1.33 µg
ai/kg bw/day, ADD; 1.33 µg ai/kg bw/day x 0.96 (days required to treat
464 acres at 482/day) x 10 (number of farms a professional applicator is
expected to treat/season) ÷ 365 = 34.98 ng ai/kg bw/day, AADD. 

OREB estimated the total exposure for mixer/loaders and applicators
using Peak® on corn (Table 9.0). The calculated values are based on a
single application of 0.0356 lb ai/A.

Table 9.0  Estimated Absorbed Daily Dose & Annual Average Daily Dose for
Mixer/Loaders & Applicators of Ground and Aerial Equipment using Peak®
on Small Grains. 

	Absorbed Daily Dose (ADD)

	Annual Average Daily Dose (AADD)

Equipment 	Mixer/loader

(mg ai/kg bw/day)	Applicator

(mg ai/kg bw/day)	Mixer/loader

(ng ai/kg bw/day)	Applicator

(ng ai/kg bw/day)

Ground

	3.9 x 10-3	0.6 x 10 -4	6.1 x 10-4	9.2 x 10-5

Aerial

	2.2 x 10 -2	1.3 x 10-3	5.8 x 10-4	3.5 x 10-5

MOEs were calculated for systemic toxicity (decreased weight gain and
feed efficiency as well as hematological and hepatic toxicity) based on
a NOAEL of 5.3 mg/kg/day from a 90-day dog feeding study (MRID
42685230).   The MOE was calculated as the ratio of the NOAEL to the
exposure (NOAEL/exposure = MOE).  The Agency is not generally concerned
unless the MOE is below 100 when based upon data generated in animal
studies. Using the toxicology endpoints and the occupational exposure
noted above, the following MOEs were calculated for occupational risk.

Table 9.1 Margin or Exposure for Mixer/Loaders and Applicators

Use

	Worker Scenario

	Endpoint

NOEL

(mg/kg/day)

	Daily

Exposure

(mg/kg/day)

	MOE

Mixer/Loader

Ground

	water dispersible granule in water soluble packets 	

5.3	3.9 x 10-3

	1359

Aerial

	2.2 x 10-3

	1000

Applicator

Ground	water dispersible granule in water soluble packets	

5.3	0.6 x 10-4

	8833

Aerial

	1.3 x 10-3

	4077

Since the Agency is not generally concerned unless the MOE is below 100
when based upon data generated in animal studies, the MOE values of 1000
- 8833 demonstrates no concern for mixers, loaders and applicators when
Peak® is applied according to label directions.

WPS and REI label statements are considered adequate. 

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

10.1	Toxicology

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

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.

REFERENCES:

Dietary Exposure Memorandum

	Prosulfuron: AMENDED Acute and Chronic Dietary (Food and Drinking
Water) Exposure Assessment for the Expired Tolerances for Residues of
Prosulfuron on Grains, Cereal (Except Rice) (PP#5F4469).; D336488; B.
Hanson; 2/20/2007.

Drinking Water Memorandum

	Drinking Water Exposure Assessment for Prosulfuron Usage on Small
Grains and Corn.  D326831; M. Barrett, 11/20/2006).  

Residue Chemistry Data Review Memorandums

	PP# 4F04336 New Chemical - Prosulfuron in or on corn and animal
commodities. Evaluation of residue data and analytical methods; G.F.
Kramer; Memo to Robert Taylor; 2/22/1995.

	PP# 4F04336 New Chemical - Prosulfuron in or on corn and animal
commodities; G.F. Kramer; Memo to Robert Taylor; 3/29/1995.

Occupational and Residential Exposure Memorandum

	Exposure Assessment for Use of Prosulfuron on Small Grains; C. Lewis;
10/30/1995.

Risk Assessment Document

	Prosulfuron - 129031: Health Effects Division Risk Assessment for Use
of Prosulfuron in/on Corn; B. Madden, 5/1/1995.

	

Appendix A:  TOXICOLOGY ASSSESSMENT

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use of prosulfuron are in
Table 1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

no

yes

yes

yes	yes

-

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes	yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

yes

yes

no	-

-

yes

yes

-

870.7485    General Metabolism	

870.7600    Dermal Penetration	

870.7800   
Immunotoxicity…………………………….………….	yes

no

yes	yes

-

no

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		no

no

no

no	-

-

-

-

A.2	Toxicity Profiles

Table A.2.1  Acute Toxicity of Prosulfuron Technical

Guideline No.	Study Type	MRID #	Results	Toxicity Category

870.1100	Acute Oral	42685215	LD50 = 986 mg/kg	III

870.1200	Acute Dermal	42685216	LD50 > 2000 mg/kg	III

870.1300	Acute Inhalation	42685217	LC50  = 5.467 mg/L	IV

870.2400	Primary Eye Irritation	42685218	Minimal irritant	IV

870.2500	Primary Skin Irritation	42685219	Non-irritant	IV

870.2600

	Dermal Sensitization	42685220	Non-sensitizer	N/A

A.3	Executive Summaries

A.3.1	Subchronic Toxicity

870.3100	90-Day Oral Toxicity – Rat

A subchronic oral toxicity study in rats (MRID 42685232) was conducted
with prosulfuron technical.  Prosulfuron was administered orally to rats
for 3 months at dietary levels of 0, 5, 50, 500, 4,000 or 8,000 ppm. 
Mean daily doses were 0, 0.31, 3.1, 31, 255, or 522 mg/kg/day for males
and 0, 0.32, 3.4, 35, 268, or 512 mg/kg/day for females. The LEL is 500
ppm for males, based on reduced body weight and body weight gain (13%);
and 4,000 ppm for females, based on reduced body weight, body weight
gain, food consumption, and food efficiency. In addition, statistically
significant reductions in 5'nucleotidase activity at > 4,000 ppm and
reduced triglycerides at 8,000 were observed in males, although it was
unclear whether these changes were related to treatment. The NOEL is 50
ppm (3.1 mg/kg/day) for males and 500 ppm (35 mg/kg/day) for females.

870.3100	90-Day Oral Toxicity – Mouse

A 90-day feeding study in mice (MRID 42685234) was conducted in which
prosulfuron technical was administered orally mice for 3 months at
dietary levels of 0, 15, 500, 1750, 3500, or 7000 ppm. Mean daily doses
were 0, 2.0, 69.3, 234, 504, 969 mg/kg/day for males and 0, 2.9, 91.3,
293, 606, and 1400 mg/kg/day for females.

At higher dose levels, degenerative vacuolation of the heart was
observed in males at > 3500 ppm and in females at 7000 ppm. The
incidence of centrilobular hypertrophy observed in the liver was
statistically significant at > 1750 in males and > 3500 in females. The
histopathological findings in the liver correlated with the
statistically

significant increased relative liver (to brain and/or body) weight
observed in both sexes at > 1750 ppm. The LEL is 500 ppm (69.3
mg/kg/day) for males, based on statistically significant decreased
albumin and total bilirubin and statistically significant increased
absolute and relative liver (to brain and/or body) weights. The LEL is
1750 for females, based on statistically significant increased relative
liver (to brain and body) weights, statistically significant increased
hematocrit and mean corpuscular volume, and decreased mean corpuscular
hemoglobin concentration. The NOEL is 15 ppm (2.0 mg/kg/day) for males;
500 ppm (91.3 mg/kg/day) for females.

870.3150	 90-Day Oral Toxicity – Dog

Study Selected: subchronic oral toxicity - dog. 

MRID No.: 42685230

Executive Summary: In a subchronic oral toxicity study (MRID 42685230),
prosulfuron technical was administered to 4 beagle dogs/sex/dose via the
diet at dose levels of 0, 15, 150, 1500, or 3000 ppm for 90 days. The
equivalent average daily intake of test material was 0, 0.54, 5.3, 57,
or 110 mg/kg/day (males) and 0, 0.59, 6.5, 54, or 120 mg/kg/day
(females).     

There were no deaths during the study, and clinical signs were
comparable among the groups (both sexes). Mean body weight of the 3000
ppm males was approximately 10% lower than control from week 7 on.
Overall (weeks 0-13) body-weight gain was negative for the males at 3000
ppm (-0.1 kg) compared to the control (1.15 kg). Females at 3000 ppm
displayed a decrease in body-weight gain (48% of control). At 1500 ppm,
both males (63% of control) and females (31%) displayed a decrease in
overall body-weight gain compared to the controls. Feed efficiency was
decreased for both sexes at the 1500 ppm and 3000 ppm dose levels.

Hematotoxicity was observed in both sexes at the two highest dose levels
and was manifested as decreased mean corpuscular hemoglobin
concentration, increased appearance of target cells in the blood,
erythrocyte phagocytosis in the lymph nodes, and compensatory increases
in erythroid hyperplasia in the bone marrow and extramedullary
hematopoiesis in the spleen. Males also showed decreased erythrocyte
count and hemoglobin, ineffective erythropoiesis in the bone marrow, and
increased numbers of anisocytes in the blood. Females showed increases
in the numbers of poikilocytes and burr cells in the blood, red
discoloration of the bone marrow, and hemosiderin pigmentation in the
spleen and stomach. Additionally, a few dogs of both sexes displayed
decreased numbers of platelets and leukocytes in the blood. At the
highest dose tested, additional hematological effects were observed,
which included decreased hematocrit in both sexes, decreased erythrocyte
count and hemoglobin, and increased nucleated red blood cells,
reticulocytes, mean corpuscular volume, and hemosiderin pigmentation in
the lymph nodes in females; and increased incidence of burr cells in the
blood, red discoloration of the bone marrow, and hemosiderin
pigmentation in the stomach of males. 

Hepatotoxicity was observed in both sexes at the two highest dose levels
and consisted of decreased serum albumin, grossly enlarged liver, and
increases in the liver-to-body weight ratio. Male dogs displayed an
increased incidence of fatty liver and decreased total protein,
albumin:globulin ratio, and glucose. Female dogs displayed an increased
absolute liver weight and relative-to-brain liver weight ratio. At the
highest dose tested, increased alkaline phosphatase was observed in both
sexes, increased absolute liver weight and aspartate and alanine
aminotransferases were observed in males, and decreased total protein
and increased globulin were observed in females.

At the highest dose tested, two males displayed myocardial necrosis with
fibrosis and dystrophic mineralization in the ventricular and papillary
muscles and one female displayed myocardial degeneration.  The NOAEL is
150 ppm (5.3 mg/kg/day) and the LOAEL is 1500 ppm (54 mg/kg/day) based
on decreased bodyweight gain and feed efficiency as well as
hematological and hepatic toxicity in both males and females.

This study is classified as Core-guideline and satisfies the guidelines
requirements

for a subchronic oral toxicity study in a non-rodent species.

Dose/Endpoint for Risk Assessment: The NOAEL is 5.3 mg/kg/day based on
decreased bodyweight gain and feed efficiency as well as hematological
and hepatic toxicity in both males and females.

Comments about Study/Endpoint: Findings in the 90-day dog study are
supported by the findings in the 1-year dog study.

870.3200	21/28-Day Dermal Toxicity – Rabbit

Study Selected: 21-day dermal study in rabbit.

 

MRID No.: 42685235

Executive Summary: In a 21-day dermal toxicity study (MRID 42685235),
doses

of 0, 10, 100, 500 or 1,000 mg/kg/day CGA-152005 Technical, were applied
to

the clipped backs of Chbb:NZW rabbits for 6 hours/day, 7 days/week, for
3

weeks. No significant treatment-related toxicity was reported with the
possible

exception of the lung lesions (edema and intestinal pneumonia) which may

suggest a slight treatment-related decline in the general health of the
high dose

males, and increased absolute and relative liver weights in both sexes
at 500 and

1000 mg/kg/day. However, these findings were not considered sufficient
to

establish a systemic toxicity LOAEL. The increased liver weights,
however, were

considered indicative of dermal absorption of CGA-152005. Based on the

absence of any significant dermal or systemic effects at the highest
dose

tested (1000 mg/kg/day), the NOAEL's for dermal and systemic effects are

established at 1000 mg/kg/day. An LOAEL was not determined.

This study is classified as Core-guideline and satisfies the guidelines
requirements

for a repeated dose dermal toxicity OPPTS 870.3200.

Dose and Endpoint for Risk Assessment: 1000 mg/kg/day based on the
absence of any significant effects.

Comments about Study/Endpoint: The 21-day dermal study in rabbit is the

appropriate route and duration. No dermal or systemic toxicity was
observed in rabbits following dermal application at 1000 mg/kg/day
(highest dose tested) in a 21-day dermal study. Also, neurotoxicity was
not seen in feeding studies (effects only noted in gavage studies at
high dose > 250 mg/kg/bw), so affects are not expected in the dermal
study.

870.3465	90-Day Inhalation – Rat

Study Selected: 90-Day subchronic oral toxicity in dogs. 

MRID No.: 42685230

Executive Summary:  See section above for detailed information.

Dose/Endpoint for Risk Assessment: The NOAEL is 5.3 mg/kg/day based on
decreased bodyweight gain and feed efficiency as well as hematological
and hepatic toxicity in both males and females.

Comments about Study/Endpoint: Since an oral NOAEL was selected the

lation exposure component (i.e., μg a.i./day) using 100% absorption
rate

(default value) and application rate should be converted to an
equivalent oral dose (mg/kg/day) and this dose should be compared to the
NOAEL of 5.3 mg/kg/day to calculate the MOEs.  Findings in the 90-day
dog study are supported by the findings in the 1-year dog study.

A.3.2	Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

Developmental Toxicity Study in Rats: In a 1992 developmental toxicity

study (MRIDs 43159317, 42700001), 26/sex/dose group of the

Sprague Dawley rats received either 0, 5, 50, 200 or 400 mg of CGA-

152005/kg/day by gavage (technical, 96% a.i.), from gestation days 6
through 15,

inclusive. There was a marginal but statistically significant decrease
in body

weight gain at the high dose of 400 mg/kg/day during the treatment
period. No

other maternal toxicity was observed at any dose level in this study.
Note that the range-finding data demonstrated that a higher dose level
of 450 mg/kg/day would have been tolerated. The LOAEL for maternal
toxicity = 400 mg/kg/day

(highest dose level tested), based on decrease body weight gain. The
NOAEL

for maternal toxicity = 200 mg/kg/day. The incidence of skeletal
alterations per

litter, which included the incidence of extra full and rudimentary ribs
(increase in

findings of 14th ribs) seen in the high dose group of 400 mg/kg/day
versus

controls, gives evidence of developmental toxicity. Thus, the LOAEL for

developmental toxicity = 400 mg/kg/day based on skeletal findings
(increase

in findings of 14th ribs). The NOAEL for developmental toxicity = 200

mg/kg/day.

This study is classified as Core-supplementary data and satisfies the
guideline

requirement for a developmental toxicity study in the rat.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

Developmental Toxicity Study in Rabbits: In a 1992 developmental
toxicity study (MRIDs 42685239, 42685238, 43159318), 19/sex/dose group
of the New Zealand White rabbits receive either 0, 1, 10, or 100 mg of
CGA-152005/kg/day by gavage (96% a.i.), from gestation days 7 through
19, inclusive.  No maternal toxicity was observed at any dose level in
this study. The range finding data demonstrated that a high dose level
of 150 mg/kg/day would have been tolerated. Therefore, the LOAEL for
maternal toxicity is > 100 mg/kg/day (highest dose level tested) and the
NOAEL for maternal toxicity > 100 mg/kg/day (HDT). A developmental
toxicity LOAEL has not been determined in this study. Therefore, the
LOAEL for developmental toxicity is > 100 mg/kg/day (highest dose level
tested) and the NOAEL for developmental toxicity > 100 mg/kg/day (HDT). 
No effects were noted at the highest dose level tested, 100 mg/kg/day,
but this should not be considered a definitive NOAEL since the maternal
animals were not adequately challenged, and a limit dose was not
utilized in this study. 

Thus, the dose levels in this study were inadequate to fully assess the
developmental toxicity potential of CGA-152005 in the rabbit, thus the
study is classified as Core-supplementary data.

In a 1996 developmental study in rabbit (MRID # 43953506), New Zealand

14 White rabbits received dosages of CGA-152005 technical (96% a.i.) by
gavage at dose levels of 0, 20, 100 and 200 mg/kg/day on gestation days
7 to 19. Available data support an LOAEL for maternal toxicity of 100
mg/kg/day based on increases in abortion, decreases in food consumption,
and in mean body weight gain. The NOAEL is 20 mg/kg/day.  A dose-related
increase in runts and small fetuses was observed in the 100 and 200
mg/kg/day groups. Fetal weights were reduced and skeletal
anomalies/delayed ossification increased. Based upon the dose-related
increase in runts and small fetuses and the skeletal effects, an LOAEL
for developmental toxicity can be established at 200 mg/kg/day. An NOAEL
for developmental toxicity can be established at 100 mg/kg/day.

The HIARC (meeting 12/02/1999) revised the DER (10/28/1999) and

recommended that the study be upgraded to acceptable. Therefore, this
study is

classified as Core-guideline data and satisfies the guideline
requirement for a

developmental toxicity study in the rabbit.

A.3.3	Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In a 2-generation reproduction study (MRID 42700002) in rats
(Sprague-Dawley) complete in 1992, 30 rats/sex/dose received either 0,
10, 200, 2000, or 4000 ppm (0, 0.67, 13.3, 136, and 278 mg/kg/day for P0
males and 0, 0.76, 15.3, 152, and~3l1 mg/kg/day for P0 females during
the premating growth periods, respectively) of CGA-152005 (99.1% a.i.)
mixed in the feed. Note that organ weights were not obtained in this
study.

At 2000 ppm and 4000 ppm, male and female P0 mean body weights were

consistently and significantly lower (p < 0.01) than controls. These
reduced mean

body weights persisted through the lactation period. P1 mean body
weights were

also reduced (p < 0.01) at the 2,000 (6 to 8% in males and 7 to 9% in
females)

and 4,000 ppm levels. Therefore, the NOAEL for parental toxicity is 200
ppm

(13.3 mg/kg/day for males and 15.3 mg/kg/day for females). The LOAEL for

parental toxicity is 2000 ppm (136 mg/kg/day for males and 152 mg/kg/day

for females), based upon decreased mean body weights and body weight
gain

observed in the P0 and P1 generation animals.  Reproductive performance
of the P0 generation to produce the Fl litters did not appear affected
at any dose level. Fl pups had reduced mean body weights at both the
2000 and 4000 ppm dose levels. These effects on mean pup weight were
first observed by day 7 of lactation at 4000 ppm, and at both the 2000
and 4000 ppm dose levels at days 14 (36.7 grams in the controls versus
34.2 grams at 2000 ppm and 32.5 grams at 4000 ppm, p < 0.01, two-tailed)
and day 21 (58.4 grams in the controls versus 54.5 grams at 2,000 ppm
and 52.7 grams at 4000, p < 0.01).

Reproductive performance of the P1 generation to produce the F2 litters
was

slightly affected at the 4,000 ppm dose level with decreases noted in
the Fertility,

Gestation and Parturition Indices. On day 4 of lactation, mean litter
size was

reduced to a statistically significant level (p < 0.05) with a mean of
13 pups per

litter at 4000 ppm versus 14.7 in the controls. By day 14 of lactation,
pups at both the 2000 and 4000 ppm levels had statistically
significantly reduced mean pup weights. Therefore, in both generations,
an effect during lactation was apparent.

No histopathological examination of the mammary gland was performed in
this

study. The NOAEL for reproductive toxicity is established at 200 ppm
(13.3

mg/kg/day for males and 15.3 mg/kg/day for females). The LOAEL for

reproductive toxicity is established at 2000 ppm (136 mg/kg/day for
males

and 152 mg/kg/day for females), based upon decreased pup weights
observed

in both the Fl and F2 offspring.

The study is classified as Core Minimum Data and satisfies the guideline

requirement for a reproduction study.

A.3.4	Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

MRID No. 42700003, 43159321

Discussion of Tumor Data: In a 1994 feeding/carcinogenicity study (MRID
#

43159321) in rats (CrL:CD(SD)BR), groups of 60 rats/sex/dose group were
administered 0,10, 200, 2000 or 4000 ppm(0.4, 7.9, 79.9 and 160.9
mg/kg/day for males and 0.5, 9.2, 95.7 and 205.8 mg/kg/day for females,
respectively) of technical CGA-152005 (a.i. 99.1%) in the diet for a
2-year period. Males at 2000 ppm and 4000 ppm exhibited decreased body
weights (6-8% less than controls) and body weight gain (4-12%) during
the first 11 weeks at 2000 ppm and through the first 61 weeks at 4000
ppm. Females at 2000 ppm and 4000 ppm had decreased body weights (up to
8%, 2000 ppm and 20%, 4000 ppm) and body weight gain (up to 15%, 2000
ppm and 33%, 4000 ppm) during the first year at 2000 ppm and throughout
the study at 4000 ppm, decreased food consumption (approximately 7-8% at
1 year). Feed efficiency was lower in females at 2000 ppm and 4000 ppm
during the first year of the study. WBC counts were decreased in males
at 2000 ppm and 4000 ppm during the first 18 months of treatment
(16-23%).  RBC counts were slightly but significantly decreased in males
in the 2000 ppm and 4000 ppm groups (3-4%) during the first 6 months.
HGB was also slightly decreased in males in the 4000 ppm group at 12
months (4%). GGT was decreased in males in the 2000 ppm and 4000 ppm
groups and in females in the 2000 ppm and 4000 ppm groups at numerous
time intervals (>33% of controls). The adrenal weight and adrenal to
brain weight ratio were decreased in females in the 4000 ppm group at 24
months. Liver weight and liver to body weight were also decreased in
males in the 4000 ppm group.  Kidney weight and kidney to brain weight
ratio were decreased in females in the 4000 ppm groups. Extra-medullary
hematopoiesis was decreased in males and females in the 4000 ppm group,
which, taken into consideration with the results of the hematology data,
indicate adverse effect (depression) of the hematopoietic system. 

The systemic NOAEL is 200 ppm (7.9 mg/kg/day, males and 9.2 mg/kg/day,
females). The systemic LOAEL is 2000 ppm (79.9 mg/kg/day, males and 95.7
mg/kg/day, females), based on decreased body weight and body weight gain
during the first months to 1 year of the study, decreased food
consumption (females), hematopoietic system effects (males), and
possibly increased GGT with decreases in liver, kidney and adrenal
weight (females).

Increases in the incidence of mammary adenocarcinomas in females was
observed at 2000 ppm (31.9%; p < 0.5) and 4000 ppm (26.3%; NS) compared
to controls (17.5%).  Mammary gland adenomas were also slightly
increased at 2000 ppm and 4000 ppm (4.3% and 2.5% vs. 0%, controls).
Slight increases in the incidence of benign testicular interstitial cell
tumors (significant trend only) were also observed at 2000 ppm (8.6%)
and 4000 ppm (5.0%) compared to controls (1.6%). 

The HED RfD/Peer Review Committee determined (03/25/1999) dosing was
considered adequate to assess carcinogenicity of CGA-152005 in rats.

This study is classified as Core-minimum data and satisfies the data
requirement for the guideline OPPTS 870.4300 for a chronic
toxicity/carcinogenicity study in rats.

Adequacy of the Dose Levels Tested: The RfD Committee (report of
04/20/1995 from the 03/23/1995 meeting) considered the carcinogenicity
phase (83-5, MRID 43159321) of the combined chronic
toxicity/carcinogenicity study in rats to be acceptable and the data
evaluation record (HED Doc. No. 011444) to be adequate.  The Committee
questioned the adequacy of the dose levels tested in this study because
of the limited overall toxicity (hematological effects, hematopoietic
effects, organ weight changes, and limited body weight and body weight
gain decreases in the first three to six months of the study) observed
at 4000 ppm, the highest dose level tested. However, the subchronic
toxicity study in the same strain of rats (§82-1a, MRID No. 42685231,
42685232, HED Doc. No. 010755) provided some support to the dose
selection for the carcinogenicity phase of the combined chronic
toxicity/carcinogenicity study in rats. In the subchronic toxicity
study, mean body weights were reduced by about 19-20% in both males and
females of the 8000 ppm group, the highest dose level tested in this
study, and by about 15% and 12% in males and females, respectively, in
the 4000 ppm group. The RfD Committee, therefore, concluded that the
high dose level tested in the carcinogenicity study was, at least,
approaching an adequate dose level.

870.4100b Chronic Toxicity – Dog

In a 1-year chronic feeding study (MRIDs 43159314 & 43387705) beagle
dogs were administered prosulfuron technical in the diet at 0, 10, 60,
600 or 1200 ppm (0.3, 2.0, 18.6 or 41.0 mg/kg/day, males and 0, 0.3,
1.8, 20.2 or 48.8 mg/kg/day, females). At 600 ppm, slightly decreased
erythrocyte values (10% less than controls), decreased serum albumin
(-12%) and A/G ratio (-15 to -30%) were observed in females and
lipofuscin accumulation in liver was observed in males (3/4, slight) and
females (1/4, mild). Renal lipofuscin accumulation (males, 3/4) and
fatty accumulation (4/4 males and 3/4 females) may have been related to
treatment. At 1200 ppm, decreased body weight gain (23 and 22% less than
controls in males and females, respectively), slightly

decreased erythrocyte values (-10%) and calcium levels (-6 to -7%) in
males, increased absolute and relative liver weight in females (+34 to
+44%) and increased alkaline phosphatase (51 to 303%) in both males and
females were observed. The LEL is 600 ppm (18.6 mg/kg/day, males), based
on hematologic and clinical chemistry effects

(females) and incidence of lipofuscin accumulation in liver (both
sexes). The NOEL is 60 ppm (1.8 mg/kg/day, females).

A.3.5	Carcinogenicity

870.4200a Carcinogenicity Study - Rat

870.4200b Carcinogenicity (feeding) – Mouse

MRID No.: 43159316, 43387706

Discussion of Tumor Data: In a 1995 feeding/carcinogenicity 18-month
study in mouse (Crl:CD-1(ICR)BR), groups of 50 mice/sex/group (6 weeks
old) were administered 0, 15, 700, 3500 or 7000 ppm of CGA-152005
technical in the diet for 18 months. Compound consumption was: 0, 1.71,
81.4, 410 and 832 mg/kg/day in males; 0, 2.11, 100, 508, and 1062
mg/kg/day in females.  At 3500 ppm, slight decreases in mean body weight
gains were observed in females which were statistically significant
during the first 12 weeks (-15%, 3 months to -8%, 18

10 months). Males and females in the 7000 ppm groups exhibited decreases
in body weight throughout the study; 96.3% of controls for males and
90.1% for females at 78 weeks.  Similarly, body weight gain was
decreased in males and females in the 7000 ppm group at 18 months, by 7%
and 18%, respectively. The absolute liver weight, liver to body weight
and liver to brain weight were increased in males in the 3500 ppm group
by 10%, 13% and 8%, respectively, and in males in the 7000 ppm group by
23%, 27% and 19%, respectively. Females in the 7000 ppm group had
increases in absolute liver weight, liver to body weight and liver to
brain weight of 13%, 26% and 13%, respectively. Males in the 3500 ppm
and 7000 ppm groups each had decreases in absolute kidney weights of 11%
and decreased kidney to brain weights (12% and 13%, respectively).
Females exhibited a decrease in absolute kidney weight and kidney to
brain weight at 7000 ppm of 9% and 10%, respectively. There was an
increase in the incidence of prominent lobular structure of the liver in
males in the 3500 and 7000 ppm groups (8% and 26%) compared to controls
(0%) and in females in the 7000 ppm group (26%) when compared to
controls (2%). There were increases in the incidence of centrilobular
hepatocellular hypertrophy in males in the 700, 3500 and 7000 ppm groups
of 39%, 84%, and 92% compared to 6% in the controls. Females in the 3500
and 7000 ppm groups had increases in centrilobular hepatocellular
hypertrophy of 57% and 76% compared to 0% for controls. The degree of
severity also showed a dose-dependent increase. 

The systemic toxicity LOAEL is 3500 ppm (410 mg/kg/day in males and 508
mg/kg/day in females), based on slightly decreased body weight gain in
females. The systemic toxicity NOAEL is 700 ppm (81.4 mg/kg/day in males
and 100 mg/kg/day in females). There appeared to be no increase in the
incidence of neoplasia in treatment groups when compared to controls.
The oncogenic toxicity NOAEL is > 7000 ppm (832 mg/kg/day in males and
1062 mg/kg/day in females).

This study is classified as Core-guideline and satisfies the data
requirement for guideline OPPTS 870.4200 for a carcinogenicity study in
mice.

Adequacy of the Dose Levels Tested: Dosing in this study was considered
adequate to assess carcinogenicity in mice. The RfD Committee (meeting
on 03/23/1995) considered the mouse carcinogenicity study (83-2b, MRID
43159316, 43387706) to be acceptable and the data evaluation record (HED
Doc. No. 011444) to be adequate. The dose selection was based on the
results of a subchronic toxicity study in mice (MRID 42685233,
42685234). The high dose of 7000 ppm (1000 mg/kg/day) was considered to
be the limit dose for carcinogenicity testing in this species. The
treatment did not alter the spontaneous tumor profile in this strain of
mouse.

A.3.6	Mutagenicity

Several mutagenicity studies are summarized below. Data requirements for
these guidelines (under the old mutagenicity guidelines) are satisfied
by these submissions; no further studies need be submitted at this time.
The studies were initiated prior to institution of the revised
mutagenicity guidelines.

Study Type

(MRID No.)

	Title

(Report No.)

	Reported

Results

	TB

Evaluation

Mutagenicity (bacterial

reverse gene mutation)

(MRID# 426852-40)

DOC # 010755

	CGA-152005 Technical: Gene Mutations

Test Salmonella and Escherichia/Liver -

Microsome Test

(Study # 911231)

	Negative for inducing a reverse gene mutations in two independent
assays with Salmonella typhimurium strains

TA1535, TA1537, TA98, and TA100 or E. coli WP2 uvrA exposed in either
the presence or absence of mammalian

metabolic activation.	Acceptable

Gene mutation -

mammalian

(MRID# 426852-41)

DOC # 010755,

New Doc. #

	CGA-152005 Technical: Gene Mutations

Test with Chinese Hamster Cells V79 (OECD Conform.) In vitro

(Study# 901473)

	Negative in two independently conducted assays for inducing

levels up to 1400μg/mL.  However, doses were not high enough to produce
cytotoxicity and there was no evidence that the compound was insoluble
at the highest dose.	Unacceptable

Structural

Chromosome

Aberrations

(MRID# 426852-42)

DOC # 010755

	CGA-152005 Technical: Gene Mutations

Cytogenetic Test on Chinese Hamster Cells

In vitro

(Study # 901472)

	Negative for inducing structural chromosome damage in Chinese hamster
ovary cells exposed to the test material at levels up to 500μg/mL + S9
and harvested either at 18 or 42

hrs post-treatment. However, higher dose levels could be achieved.
Unacceptable

Other Mutagenic

Mechanisms,

(MRID# 426852-44)

DOC # 010755

	CGA-152005 Technical: Tests for Other

Genotoxic Effects Autoradiographic DNA

Repair Test on Rat Hepatocytes

(Study Number 901470)	Negative for inducing unscheduled DNA synthesis
(UDS) in

primary rat hepatocytes exposed to CGA-152005 technical.

	Acceptable

Structural Chromosome

Aberrations,

(MRID# 42685243)

DOC # 010755

	CGA-152005 Technical: Structural Chromosomal Aberration Micronucleus
Test, Mouse

(Study # 901469)

	Negative for inducing micronuclei in polychromatic erythrocytes from
male or female mice at dose levels up to

1842 mg/kg.

	Acceptable

A.3.7	Neurotoxicity

870.6200a Acute Neurotoxicity Screening Battery – Rats

In an acute neurotoxicity study (MRID 43387703) 10 or 11
Hsd:Sprague-Dawley rats/sex/dose group received 0, 10, 250, 500 or 1000
mg CGA-152005 (technical, 99.1% a.i.)/kg body weight by gavage in
aqueous 3% corn starch/-0.5% Tween 80 (20 ml/kg). Functional
observational battery and motor activity tests were conducted
pretreatment, on the day of dosing (peak effect, 3 hr post-dosing) and
on Day 7 and 14 post-dosing. Neural tissues from 5 control and high dose
animals/sex and brain levels 4 and 5 from all animals were examined
microscopically.

At 250 mg/kg on Day 0 (peak effect), slightly decreased mean body
temperature (2% lower than controls) and decreased motor activity (27%
less than controls) were observed in males, and abnormal gaits (5/11,
vs. 0/11 controls) was observed in females. At 500 and 1000 mg/kg,
dose-dependent, significant increases in the incidence of ataxia and/or
abnormal gaits (all animals affected), reduced rearing, decreased motor
activity and decreased body temperature were observed in both sexes.
Possible autonomic effects (stereotypical behavior, nasal staining,
soiled fur) were also observed. All surviving animals were normal by Day
7 neurobehavioral evaluations. Mortality occurred in females (3/11) at
1000 mg/kg; however, one death may have been due to gavage error. 
Transiently decreased body weight gains (16% less than controls) were
observed in males at day 7. The observed effects are consistent with
transient neurotoxicity affecting primarily sensorimotor and gait
functions. The LOAEL is 250 mg/kg/day, based on reduced motor activity
and body temperature in males and abnormal gait in females. The NOAEL is
10 mg/kg. 

This study is classified as Core-minimum and satisfies the guideline
requirements (§81-8) for acute neurotoxicity study in rats.

870.6200b Subchronic Neurotoxicity Screening Battery - Rats

In a 90-day neurotoxicity study (MRID 43387704) rats were fed diets
containing 0, 10, 200, 2500, 5000 (high dose, females only) or 10,000
(high dose, males only) ppm prosulfuron technical. The equivalent
average daily test material intakes were 0, 0.6, 12.1, 147 or 628
mg/kg/day, males; 0, 0.6, 12.5, 157 or 313 mg/kg/day, females). At 2500
ppm, body weight gain was slightly reduced in males (-12%; data
interpretation was complicated by incidences of dehydration). At 5000
ppm, body weight gain was decreased in females (22% less than controls)
in females. At 10,000 ppm, body weight gain was decreased (-25%) and
food consumption/feed efficiency were occasionally reduced in males. A
slight reduction (-14%) in mean forelimb grip strength in males was
probably secondary to reduced body weight.

The LEL for systemic toxicity is 2500 ppm, based on slightly reduced
body weight gain in males. The NOEL is 200 ppm.  The NOEL for
neurotoxicity is >10,000 ppm (males) or >5000 ppm (females).

870.6300 Developmental Neurotoxicity Study

Not required.

A.3.8	Metabolism

870.7485	Metabolism – Rat

In a metabolism study (MRID 43159326) rats were administered
[phenyl-14C] prosulfuron as a single oral dose of 0.5 mg/kg, a single
i.v. dose of 0.5 mg/kg, a single oral dose of 400 mg/kg and a single
oral dose of [phenyl-14C] prosulfuron following 14 days of repeated
dosing with 0.5 mg/kg of nonlabeled compound.

Approximately 90% of the administered dose was excreted during the first
48 hours. Over the 168 hour collection period, rats in the 0.5 mg/kg
group excreted 71-83% of the administered dose in the urine and 10-23%
in the feces. At 400 mg/kg, a greater proportion of the administered
dose was excreted in the feces (33-36%) compared to urine (61-71%).
Females usually excreted more of the dose in the urine (79-91%) than
males (66-79%). The parent compound represented 8-27% of the total
activity in the urine of females and 5-9% in males, whereas in the feces
there was 10-16% of the parent compound in females and 5-6% in males.
Fifteen urinary metabolites were determined and 13 similar metabolites
were confirmed in feces. 90-99% of the urinary radioactivity was
identified and 75-90% of the fecal radioactivity was identified. Tissue
levels were low. At 400 mg/kg, the tissue containing the most
radioactivity was the skin (0.04-0.46%). Bone contained the smallest
amount of radioactivity (0.00031%-0.00050%). No measurable amount of
radioactivity was found in most tissues 168 hours post-dosing in animals
at 0.5 mg/kg. The major routes of metabolism occurred via hydroxylation
at side chains and phenyl ring positions and O-demethylation of the
triazyl methoxy group. Minor routes of metabolism included unsaturation
of the trifluoropropyl side chain, hydrolysis of the phenyl-sulfonylurea
link and oxidative/hydrolytic cleavage of the triazine ring system. The
major metabolite (47% to 60% of urinary radioactivity at 0.5 mg/kg) was
formed by hydroxylation of the triazinyl methyl group. At the 0.5 mg/kg
level, metabolism was not affected by route of administration.

In another metabolism study (MRIDs 43159322 & 43159323) rats were
administered [triazine-4-14C] prosulfuron as a single oral dose of 0.5
mg/kg, a single i.v. dose of 0.5 mg/kg, a single oral dose of 400 mg/kg
and a single oral dose of [triazine-4-14C] prosulfuron following 14 days
of repeated dosing with 0.5 mg/kg of nonradiolabeled compound.

Approximately 90% of the administered dose was excreted within 48 hours
post-dosing. Over a 168 hour period, urinary excretion of radioactivity
ranged from 61.19-83.36% of the administered radioactivity and fecal
excretion of radioactivity ranged from 10.46-35.84%. Tissue
radioactivity was low, less than 0.91% of the

administered dose. The metabolite profile for each sex was similar
regardless of the route of administration.  However, females tended to
excrete more radioactivity in the urine and less in the feces than
males. The metabolites in the greatest concentration in the urine were
#2 (hydroxylation of triazinyl methyl group) and #11 (parent compound)
along with #1 (O-demethylated methoxy group) and #3 (hydroxylation of
trifluoropropyl group). Females excreted more parent compound than
males. Males excreted more of the hydroxylated metabolites and more
metabolites with a double bond on the trifluoropropyl group. At 0.5
mg/kg, the metabolites were not affected by the route or frequency of
administration. The proportion of administered radioactivity in the
feces increased in the 400 mg/kg group. Urinary metabolite #3 was
greater at 400 mg/kg than 0.5 mg/kg, especially in males. It is believed
that O-demethylation of the methoxy group and hydroxylation of the
triazinyl methyl group are the primary metabolic pathways; while
hydroxylation at various sites of the trifluoropropylbenzene moiety is a
slower process that increases in importance as the primary pathways
approach saturation.

870.7600	Dermal Absorption – Rat

Not required, dermal study used.  Dermal Absorption Factor: Not
applicable.

A.4	References ( in MRID order)

42685215	Glaza, S. (1991) Acute Oral Toxicity Study of CGA-152005
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42685216	Glaza, S. (1991) Acute Dermal Toxicity Study of CGA-152005
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42685217	Hartmann, H. (1991) Acute Inhalation Study in Rats: Lab Project
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42685218	Glaza, S. (1991) Primary Eye Irritation Study of CGA-152005
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prepared by Hazleton Wisconsin, Inc. 32 p.

42685219	Glaza, S. (1991) Primary Dermal Irritation Study of CGA-152005
Technical in Rabbits: Lab Project Number: 10302703. Unpublished study
prepared by Hazleton Wisconsin, Inc. 26 p.

42685220	Glaza, S. (1991) Dermal Sensitization Study of CGA-152005
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42685230	Chow, E.; Richter, A. (1992) 90-day Dietary Toxicity Study with
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 Unpublished study prepared by Ciba-Geigy Corp., Env. Health Ctr.  275
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42685231	Pettersen, J.; Morrissey, R. (1991) 4-week Dietary Rangefinding
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42685232	Chow, E.; Morrissey, R. (1991) 90-day Dietary Rangefinding
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42685233	Macaskill, S. (1991) 4-Week Dietary Rangefinder Toxicity Study
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42685234	Chow, E.; Turnier, J. (1991) 90-Day Dietary Toxicity Study with
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42685235	Hagemann, C. (1992) 21-Day Dermal Toxicity Study in Rabbits:
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42685238 	Minor, J. (1991) A Rangefinding Teratology Probe in Rabbits
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42685239	Minor, J. (1992) Teratology Study in Rabbits: CGA-152005
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42685240	Hertner, T. (1991) Gene Mutations Test: Salmonella and
Escheria/Liver--Microsome Test: Lab Project Number: 911231. Unpublished
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42685241	Geleick, D. (1991) Gene Mutations Test with Chinese Hamster
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42685242	Meyer, A. (1991) Gene Mutations Test: Cytogenetic Test on
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42685243	Ogorek, B. (1991) Structural Chromosomal Aberration Test:
Micronucleus Test, Mouse: CGA-152005 Technical: Lab Project Number:
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42685244	Geleick, D. (1991) Tests for Other Genotoxic Effects:
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42700001	Meyer, L. (1991) A Rangefinding Teratology Probe in CD Rats
with CGA-152005 Technical: Volume 1: Final Report: Lab Project Number:
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42700002	Greci, L.; Turnier, J. (1992) A Two-Generation Reproduction
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42700003	Pettersen, J.; Morrissey, R. (1992) Two-Year Dietary Chronic
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43159314	Chow, E.; Hart, S. (1993) 1-Year Dietary Toxicity Study with
CGA-152005 Technical in Beagle Dogs: Lab Project Number: F-00063.
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43159316	Chow, E.; Wyand, D. (1993) 18-Month Dietary Oncogenicity Study
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43159317	Gilles, P. (1994) Addendum 1 to Final Report: A Teratology
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43159318 	Gilles, P. (1994) Addendum 2 to Final Report: A Teratology
Study in Rabbits with CGA-152005 Technical: Lab Project Number: F-00077.
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43159321	Pettersen, J.; Morrissey, R.; Wyand, D. (1994) Two-Year Dietary
Chronic Toxicity/Oncogenicity Study with CGA-152005 Technical in Rats:
Final Report: Lab Project Number: F-00059. Unpublished study prepared by
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43159322	Ritter, J. (1992) Metabolism of (triazine-4-(carbon 14))
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43159323	Ritter, J. (1993) Metabolism of (triazine-4-(carbon
14))CGA-152005 in the Rat: Addendum 1 to the Final Report: Lab Project
Number: F-00106. Unpublished study prepared by Environmental Health
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43159326	Doweyko, A. (1993) Metabolism of (phenyl-(carbon 14))
CGA-152005 in the Rat: Lab Project Number: F-00112. Unpublished study
prepared by Environmental Health Center. 123 p.

43387703	Chang, J.; Hart, S. (1994) Acute Neurotoxicity study with
CGA-152005 in Rats: Final Report: Lab Project Number: F-00133.
Unpublished study prepared by Ciba-Geigy Corp.  414 p.

43387704	Chow, E.; Hart, S. (1994) 90-Day Subchronic Neurobehavioral
Toxicity study with CGA-152005 Technical in Rats: Lab Project Number:
F-00129. Unpublished study prepared by Ciba-Geigy Corp. 605 p.

43387705	Chow, E.; Hart, S. (1994) 1-Year Dietary Toxicity study with
CGA-152005 Technical in Beagle Dogs: Amendment 1 to Final Report: Lab
Project Number: F-00063. Unpublished study prepared by Ciba-Geigy Corp.
17 p.

43387706	Chow, E.; Wyand, S. (1994) 18-Month Dietary Oncogenicity Study
with CGA-152005 Technical in Mice: Amendment Number 1 to Final Report:
Lab Project Number: F-00060. Unpublished study prepared by Ciba-Geigy
Corp. 21 p.

43953506	Gilles, P. (1996) A Teratology Study in Rabbits with CGA-152005
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prepared by Ciba-Geigy Corp. 236 p.

Appendix B.  DCI Rationales for Required Toxicology 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). 

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s 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.

    Dinelli, G., A. Vicari, A. Bonetti, and P. Catizone. 1997.
Hydrolytic dissipation of four sulfonylurea herbicides: J. Agric. Food
Chem. 45: 1940–1945.

     Hultgren, R. P.; Hudson, R. J. M.; Sims, G. K. 2002. Effects of
soil pH and soil water content on Prosulfuron dissipation . J. Agric.
Food Chem. 50: 3236-3243. 

  Prosulfuron SANCO/3055/99-FINAL 2 July 2002; EUROPEAN COMMISSION
HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate E – Food
Safety: plant health, animal health and welfare, international questions
E1 - Plant health.

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