Document ID: EPA-HQ-OPP-2008-0065-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-03-04T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDES

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

DATE:  	10-DEC-2008

SUBJECT:	Propoxycarbazone-sodium; Human-Health Risk Assessment for
Proposed Section 3 New Use on Pasture and Rangeland Grasses.

PC Code:  122019	DP Barcode:  348510

Decision No.:  387740	Registration No.:  264-RNTU

Petition No.:  7F7304	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical/Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  181274-15-7 (sodium salt);

                  145026-81-9 (acid)

MRID No.:  NA 	40 CFR:  180.600

FROM:	Sarah J. Levy, Chemist

		Registration Action Branch 1 (RAB1)/Health Effects Division (HED;
7509P)

 

		P.V. Shah, Ph.D., Branch Chief

Inert Ingredient Assessment Branch/Registration Division (RD; 7505P)

Mark I. Dow, Ph.D., Biologist

Alternate Risk Integration Assessment Team (ARIA)/RD (7505P)

THROUGH:	Dana M. Vogel, Branch Chief

		George F. Kramer, Ph.D., Senior Chemist

		RAB1/HED (7509P)

TO:		Jim Stone/Joanne Miller, RM 23

		Herbicide Branch/RD (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational/residential, and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from the registered and proposed uses of the herbicide
propoxycarbazone-sodium [methyl
2-[[[(4,5-dihydro-4-methyl-5-oxo-3-propoxy-1H-1,2,4-triazol-1-yl)carbony
l]amino]sulfonyl]benzoate].  The last risk assessment conducted by HED
was for Section 3 use on wheat forage (Memo, G. Kramer, 15-JUN-2006;
DP#: 335364).

A summary of the findings and an assessment of human-health risk
resulting from the proposed uses of propoxycarbazone-sodium are provided
in this document.  The risk assessment, residue chemistry data review,
and dietary exposure assessment were provided by Sarah Levy (RAB1/HED),
the occupational/residential exposure assessment by Mark Dow (RD), the
hazard characterization by P.V. Shah (RD), and the drinking water
assessment by Ibrahim Abdel-Saheb of the Environmental Fate and Effects
Division (EFED).

Table of Contents

  TOC \o "1-4" \u  1.0     EXECUTIVE SUMMARY	  PAGEREF _Toc216684543 \h 
3 

2.0     PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	  PAGEREF
_Toc216684544 \h  9 

2.1	Identification of Active Ingredient	  PAGEREF _Toc216684545 \h  9 

2.2	Physical and Chemical Properties	  PAGEREF _Toc216684546 \h  10 

3.0     HAZARD CHARACTERIZATION	  PAGEREF _Toc216684547 \h  10 

3.1	Hazard Profile	  PAGEREF _Toc216684548 \h  10 

3.2	FQPA Considerations	  PAGEREF _Toc216684549 \h  11 

3.3	Dose-Response Assessment	  PAGEREF _Toc216684550 \h  12 

3.4	Endocrine Disruption	  PAGEREF _Toc216684551 \h  14 

4.0     EXPOSURE ASSESSMENT AND CHARACTERIZATION	  PAGEREF _Toc216684552
\h  15 

4.1	Summary of Uses	  PAGEREF _Toc216684553 \h  15 

4.2	Dietary Exposure/Risk Pathway	  PAGEREF _Toc216684554 \h  16 

4.2.1	Residue Profile	  PAGEREF _Toc216684555 \h  16 

4.2.2	Water Exposure/Risk Pathway	  PAGEREF _Toc216684556 \h  22 

4.2.3	Dietary Exposure Analyses	  PAGEREF _Toc216684557 \h  23 

4.2.3.1	 Acute-Dietary Exposure Analysis	  PAGEREF _Toc216684558 \h  23 

4.2.3.2	 Chronic-Dietary Exposure Analysis	  PAGEREF _Toc216684559 \h 
24 

4.3	Residential Exposure/Risk Pathway	  PAGEREF _Toc216684560 \h  24 

5.0     AGGREGATE-RISK ASSESSMENTS AND RISK CHARACTERIZATION	  PAGEREF
_Toc216684561 \h  25 

6.0     CUMULATIVE RISK	  PAGEREF _Toc216684562 \h  25 

7.0     OCCUPATIONAL EXPOSURE	  PAGEREF _Toc216684563 \h  25 

7.1	Occupational Handler	  PAGEREF _Toc216684565 \h  26 

7.2	Occupational Post-Application Exposure	  PAGEREF _Toc216684566 \h 
27 

8.0     DATA DEFICIENCIES/LABEL REVISIONS	  PAGEREF _Toc216684567 \h  28

8.1	 Toxicology	  PAGEREF _Toc216684568 \h  28 

8.2	 Residue Chemistry	  PAGEREF _Toc216684569 \h  28 

8.3	 Occupational/Residential	  PAGEREF _Toc216684570 \h  28 

APPENDICES	  PAGEREF _Toc216684571 \h  28 

 

1.0	EXECUTIVE SUMMARY

 to Bayer CropScience.  These products are registered for use only on
wheat and include a 70% water-dispersible granule (WDG; Olympus™ 70%
WDG Herbicide, EPA Reg. No. 264-809) and two other WDGs that are
multiple-active-ingredient (MAI) formulations containing 6.75% or 8.14%
propoxycarbazone-sodium with 4.50% or 2.03% mesosulfuron-methyl
(Olympus™ Flex Herbicide, EPA Reg. No. 264-833; Rimfire™ Herbicide,
EPA Reg. No. 264-847).  Propoxycarbazone-sodium may be applied to wheat
using ground or aerial spray equipment at a rate of 0.026-0.039 lb
ai/A/application, with a maximum of 0.053 lb ai/A/year and a minimum
preharvest interval (PHI) of 71 days for grain and straw.  There are no
proposed or registered uses of propoxycarbazone-sodium that would result
in residential exposures.

Tolerances for propoxycarbazone-sodium are currently established for the
combined residues of propoxycarbazone-sodium and its Pr-2-OH metabolite
[methyl
2-[[[(4,5-dihydro-3-(2-hydroxypropoxy)-4-methyl-5-oxo-1H-1,2,4-triazol-1
-yl)carbonyl]amino]sulfonyl]benzoate], expressed as parent, in/on wheat,
forage at 17 ppm, wheat, grain at 0.02 ppm, wheat, hay at 0.15 ppm and
wheat, straw at 0.05 ppm [40 CFR §180.600(a)(1)].  In addition,
tolerances are currently established for residues of propoxycarbazone
per se in selected livestock commodities at 0.03-0.3 ppm [40 CFR
§180.600(a)(2)].

mpus™ Rangeland Herbicide; EPA File Symbol 264-RNTU).  The proposed
use is for postemergence broadcast application(s) in the fall and/or
spring at 0.039-0.053 lb ai/A/application, with a maximum seasonal rate
of 0.053 lb ai/A. No PHI is specified for grass forage or hay. 
Applications can be made using ground or aerial equipment in a minimum
of 5 or 3 gal/A, respectively, and can include the addition a non-ionic
surfactant (NIS).

In conjunction with the proposed use on pasture and rangeland grasses,
Bayer has proposed the following:



Tolerances for combined residues of propoxycarbazone and metabolite
Pr-2-OH MKK 6561:

Commodity	Proposed Tolerance (ppm)

Grass, forage	20

Grass, hay	25

	Tolerances for combined residues of propoxycarbazone per se:

Commodity	Proposed Tolerance (ppm)

Cattle, meat	0.1

Cattle, meat byproducts	1.0

Goat, meat	0.1

Goat, meat byproducts	1.0

Horse, meat	0.1

Horse, meat byproducts	1.0

Milk	0.05

Sheep, meat	0.1

Sheep, meat byproducts	1.0

Hazard Assessment

Propoxycarbazone-sodium has low acute toxicity via the oral, dermal, and
inhalation routes (Toxicity Category IV).  It is not an eye or dermal
irritant or a dermal sensitizer.  No toxicity was seen at the limit dose
in a 28-day dermal toxicity study in rats.  The main target organ
appears to be the gastrointestinal (GI) tract (gastric irritation), with
irritation observed in the 2-generation reproduction toxicity study in
rats, developmental toxicity study in rabbits, and the 90-day feeding
study in rats.  In the 64-day and 1-year toxicity studies in dogs, no
toxicity was observed at doses (1181 mg/kg/day and (605 mg/kg/day,
respectively.  Increased incidence of gastric irritation was observed at
a very high-dose (limit dose) in a 90-day feeding study in rats.  While
in a combined chronic toxicity/carcinogenicity study in rats, decreased
body weight, increased urinary pH and histopathological changes in the
kidney, indicate the kidney as the target organ.  Effect on body weight
was evident in both subchronic and chronic toxicity studies in mice. 

There was no evidence of neurotoxicity in any study.  No quantitative or
qualitative evidence of increased susceptibility was seen following in
utero exposure to rats or rabbits in developmental toxicity studies.  No
quantitative or qualitative evidence of increased susceptibility was
seen following the pre/post natal exposure to rats in a 2-generation
reproduction toxicity study in rats. No evidence of carcinogenicity was
observed in a carcinogenicity study in mice at doses up to the limit
dose.  In a chronic toxicity/carcinogenicity study in rats, there was an
increase in the incidence of mononuclear cell leukemia (MNCL) in mid-
and high-dose males.  The Cancer Assessment Review Committee (CARC)
concluded that MNCL in male Fischer 344 rats was not treatment-related. 
In accordance with the EPA Proposed Guidelines for Carcinogen Risk
Assessment (JUL-1999), the CARC classified propoxycarbazone-sodium as
“not likely to be carcinogenic to human” based on lack of
carcinogenicity in mice and rats and negative findings in various
mutagenicity assays.  Quantification of human cancer risk is not
required; propoxycarbazone-sodium and its selected metabolites were
negative for mutagenicity in various mutagenic assays.

Dose-Response Assessment and Food Quality Protection Act (FQPA) Decision

The HED Hazard Identification Assessment Review Committee (HIARC) met on
15-JAN-2004 to select endpoints for risk assessment and to evaluate the
potential for increased susceptibility of infants and children from
exposure to propoxycarbazone-sodium according to the FEB-2002 OPP 10X
guidance document.  The FQPA Safety Factor (SF) was reduced to 1X based
on toxicological considerations evaluated by HIARC (TXR # 0052481), no
new data since the HIARC meeting, the conservative assumptions used in
the dietary and exposure risk assessments, and the completeness of the
residue chemistry and environmental fate databases (evaluated by the
risk assessment team).

Risk assessments were conducted for the following specific exposure
scenarios listed below.  The acute dietary risk was not calculated since
an effect of concern attributable to a single exposure (dose) was not
identified from the oral toxicity studies including the developmental
toxicity studies in rats and rabbits.  The chronic reference dose (RfD)
was calculated by dividing the no-observed-adverse-effect-level (NOAEL)
by 100 (10X for interspecies extrapolation, 10X for intraspecies
variation).  Since the FQPA SF has been reduced to 1X, the chronic
population-adjusted dose (cPAD) is equal to the cRfD.  The short- and
intermediate-term dermal risks were not calculated since there are no
developmental concerns and no evidence of systemic toxicity at the limit
dose of 1000 mg/kg/day in a 28-day dermal toxicity study.  Since oral
studies were used to calculate inhalation risk, 100% inhalation
absorption factor was used for extrapolation of an oral dose to
inhalation-equivalent dose.  The level of concern (LOC) for residential
dermal exposures and occupational dermal and inhalation exposures are
for margins of exposure (MOEs) <100.

Exposure Scenario	Dose	LOC (PAD/MOE)	Study/Effect

Acute dietary (general U.S. population, including infants and children)
N/A	N/A	An effect of concern attributable to a single exposure (dose)
was not identified from the oral toxicity studies including the
developmental toxicity studies in rats and rabbits.

Chronic dietary	NOAEL = 74.8 mg/kg/day	cRfD and cPAD = 0.748 mg/kg/day
Reproduction and Fertility Effects Study - Rat.  Based on microscopic
lesions of the stomach in males seen at the LOAEL of 297.1 mg/kg/day

Short-, and intermediate-term dermal	N/A	N/A	No developmental concerns
and no evidence of systemic toxicity at the limit dose of 1000 mg/kg/day
in a 28-day dermal toxicity study.

Short-term inhalation	Oral maternal NOAEL = 100 mg/kg/day	MOE = 100
Developmental toxicity study in rabbits based on GI toxicity (enlarged
cecum, reduced and light-colored feces).

Intermediate-term inhalation	Oral NOAEL = 74.8 mg/kg/day	MOE = 100
Reproduction and Fertility Effects Study - Rat.  Based on microscopic
lesions of the stomach in males seen at the LOAEL of 297.1 mg/kg/day

Note that while the new 40 CFR revised Part 158 requirement for an
immunotoxicity study has not yet been fulfilled, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under FQPA.  Further, the data
requirements pertaining to immunotoxicity (see Section 8.1) should be
fulfilled as a condition of registration.

Residential Exposure Estimates

Currently, there are no registered or proposed uses of
propoxycarbazone-sodium that would result in residential exposures.

Occupational Exposure and Risk Assessment

Since there were no compound specific data available with which to
assess pesticide handler exposure, the exposure estimates are based upon
surrogate exposure data in the Pesticide Handler Exposure Database
(PHED) Surrogate Exposure Guide (AUG-1998).  Since no dermal endpoints
were identified, only short- and intermediate-term inhalation exposures
and risks are estimated.  MOEs of at least 100 are adequate to protect
occupational pesticide handlers.  The calculated MOEs are greater than
100; therefore, the proposed use does not exceed HED’s LOC.

There is a potential for post-application exposure to agricultural
workers during the course of typical agricultural activities.  However,
in this case, since the HIARC did not identify short- or
intermediate-term dermal endpoints and there is a 12-hour
post-application restricted-entry interval (REI), the proposed use does
not exceed HED’s LOC.  With the 12-hour REI, HED expects
post-application inhalation exposure to be negligible.  A toxicological
endpoint was identified for long-term dermal exposures but is not
relevant for purposes of this petition as long-term exposures are not
expected.

Dietary Risk Estimates (Food + Water)

™, 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.  For the unrefined chronic
dietary risk assessment, HED assumed that propoxycarbazone-sodium
residues are present in all commodities at tolerance levels and that
100% of all crops are treated.  Drinking water was incorporated directly
into the dietary assessment using the estimated drinking water
concentration (EDWC) for surface water of 1.79 ppb generated by the Tier
1 FQPA Index Reservoir Screening Tool (FIRST) model.

The resulting chronic dietary exposure estimates for combined food and
drinking water are well below HED’s level of concern (i.e., <100% of
the cPAD of 0.748 mg/kg bw/day) for the overall U.S. population and all
population subgroups.  Using the DEEM-FCID™ software, dietary exposure
is estimated to be <1.0% of the cPAD for the U.S. population and all
population subgroups, including children 1-2 years old, the population
subgroup with the highest estimated exposure.

Aggregate-Risk Estimates

Aggregate exposure risk assessments were assessed by incorporating the
drinking water directly into the dietary exposure assessment for the
following scenario:  chronic aggregate exposure (food + drinking water);
therefore, the chronic dietary exposure analysis represents chronic
aggregate risk for propoxycarbazone-sodium.  The chronic exposure
estimates were <1.0% cPAD for all population subgroups, and are
therefore not of concern to HED. 

Short-, intermediate-, and long-term aggregate-risk assessments were not
performed because there are no registered or proposed uses of
propoxycarbazone-sodium which result in residential exposures.  Acute
and cancer aggregate-risk assessments were not performed because no
appropriate endpoint was available to determine the aRfD for the general
population or any population subgroup and propoxycarbazone-sodium is not
carcinogenic.

Environmental-Justice Considerations

Potential areas of environmental-justice concerns, to the extent
possible, were considered in this human-health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations," (  HYPERLINK
"http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.
pdf_" 
http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.p
df ).

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 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 post-application are evaluated.  Further
considerations are currently in development as OPP has committed
resources and expertise to the development of specialized software and
models that consider exposure to bystanders and farm workers as well as
lifestyle and traditional dietary patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from PHED studies in which
adult human subjects were intentionally exposed to a pesticide or other
chemical.  These studies have been determined to require a review of
their ethical conduct, and have received that review.

Recommendations for Tolerances/Registration

Provided revised Sections B and F are submitted and an analytical
standard for the regulated Pr-2-OH metabolite is provided to the EPA
National Pesticide Standards Repository, HED concludes there are no
residue chemistry or toxicology data requirements that would preclude
the establishment of permanent tolerances for the combined residues of
propoxycarbazone-sodium and its Pr-2-OH metabolite, expressed as parent,
in/on the following raw agricultural commodities (RACs):

Grass, forage	20 ppm

  Grass, hay	25 ppm

Note that the tolerance on grass hay will be reassessed once the
requested residue data on grass hay are available.  

Registration of Olympus™ 70% WDG should be made conditional upon the
submission of additional residue chemistry data in order to resolve the
following data gaps:

Guideline immunotoxicity study (OPPTS 780.7800).  An immunotoxicity
study is now a data requirement in the 40 CFR revised Part 158.

As a condition of registration, new grass field trials are required
reflecting a specific PHI for hay.  The number and location of the
required trials depends on what PHI the petitioner intends to support
for hay and what data are currently available.  If the petitioner
intends to support a 0-day PHI, then residue data on hay are required
from ten additional grass field trials conducted in Zones 1, 2, 3, 4, 5
(2 trials), 6, 10, 11, and 12.  If the petitioner intends to support a
7-day PHI, then residue data on hay are required from seven additional
grass field trials conducted in Zones 1, 2, 3, 5, 10, 11, and 12.  If
the petitioner intends to support a 21-day PHI, then residue data on hay
are required from seven additional grass field trials conducted in Zones
2, 3, 4, 5, 10, 11, and 12.

For the proposed liquid chromatography/mass spectroscopy/mass
spectroscopy (LC/MS/MS) enforcement method, the instructions should be
modified to clearly state that propoxycarbazone-sodium as the free acid
is the compound to be used for preparation of standard and fortification
solutions.

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

2.1	Identification of Active Ingredient

Common Name	2-OH Propoxycarbazone

Company Experimental Name	AE 1364270, Pr-2-OH

2.2	Physical and Chemical Properties

Table 2.2.1.  Physicochemical Properties of Propoxycarbazone-sodium
(salt).

Parameter	Value	Reference

Boiling range	230-240ºC	MRID#: 46580801

pH (at 24ºC)	6.6

	Density (g/mL at 20ºC)	1.42

	Water solubility (mg/L at 20°C)	42

	Solvent solubility (g/L at 25°C)	DMSO	190

Acetonitrile	0.90

Acetone	0.50

PEG	5.2

Methylene Chloride	1.5

Heptane	<1

Zylene	<1

Isopropanol	<1

Octanol	<1

Ethyl Acetate	<1

	Vapor pressure (Torr at 20°C)	7.50 x 10-11

	Dissociation constant (pKa)	2.1

	Octanol/water partition coefficient (KOW) at 20ºC	0.028

	UV/visible absorption spectrum ((max, nm)	Primary: 	200

Secondary:  232

Tertiary:  	275

	

3.0	HAZARD CHARACTERIZATION

The existing toxicological database for propoxycarbazone-sodium is
adequate to support the establishment of conditional tolerances for
residues of propoxycarbazone-sodium in/on the RACs resulting from the
proposed uses.

3.1	Hazard Profile

Propoxycarbazone-sodium has low acute toxicity via the oral, dermal, and
inhalation routes (Toxicity Category IV).  It is not an eye or dermal
irritant or a dermal sensitizer.  No toxicity was seen at the limit dose
in a 28-day dermal toxicity study in rats.  The main target organ
appears to be the GI tract (gastric irritation), with irritation
observed in the 2-generation reproduction toxicity study in rats,
developmental toxicity study in rabbits, and the 90-day feeding study in
rats.  In the 64-day and 1-year toxicity studies in dogs, no toxicity
was observed at doses (1181 mg/kg/day and (605 mg/kg/day, respectively. 
Increased incidence of gastric irritation was observed at a very
high-dose (limit dose) in a 90-day feeding study in rats.  While in a
combined chronic toxicity/carcinogenicity study in rats, decreased body
weight, increased urinary pH and histopathological changes in the kidney
(foci of mineralization of pelvis, dilated and cystic renal tubules
filled with proteinaceous material, regenerative tubular epithelium,
glomerular and interstitial fibrosis, and hyperplasia of the pelvic
epithelium) were observed.  These effects are indicative of the kidney
as a target organ.  Effect on body weight was evident in both subchronic
and chronic toxicity studies in mice. 

There is no evidence of neurotoxicity in any study.  No quantitative or
qualitative evidence of increased susceptibility was seen following in
utero exposure to rats or rabbits in developmental studies.  No
quantitative or qualitative evidence of increased susceptibility was
seen following pre/post natal exposure to rats in 2-generation
reproduction toxicity study in rats.  No evidence of carcinogenicity was
observed in a carcinogenicity study in mice at doses up to the limit
dose.  In a chronic toxicity/carcinogenicity study in rats, there was an
increase in the incidence of MNCL in mid- and high-dose males.  The CARC
concluded that MNCL in male Fischer 344 rats was not treatment-related. 
In accordance with the EPA Proposed Guidelines for Carcinogen Risk
Assessment (JUL-1999), the CARC classified propoxycarbazone-sodium as
“not likely to be carcinogenic to humans” based on lack of
carcinogenicity in mice and rats and negative findings in various
mutagenicity assays.  Quantification of human cancer risk is not
required; propoxycarbazone-sodium and its selected metabolites were
negative for mutagenicity in various mutagenicity assays.

3.2	FQPA Considerations

There is no evidence of increased susceptibility of rat or rabbit
fetuses to in-utero exposure to propoxycarbazone-sodium.  In the rat
developmental toxicity study, no developmental or maternal toxicity was
observed at doses up to 1000 mg/kg/day (limit dose).  In the
developmental toxicity study in rabbits, developmental effects
(abortion, post-implantation loss) were seen at a higher dose (limit
dose) than the maternally toxic dose.  There is no qualitative and/or
quantitative evidence of increased susceptibility to
propoxycarbazone-sodium following pre/post-natal exposure in a
2-generation reproduction study in rats.  Although
propoxycarbazone-sodium caused increased postimplantation loss and
decreased live litter size in the F2 litters at a dose level of
1230.7-1605.3 mg/kg/day, the HIARC did not consider it as an evidence
for increased susceptibility since it occurred in the presence of severe
maternal toxicity (histopathological lesions in the stomach) and only at
doses above the limit dose. 

Since there is no evidence of increased susceptibility, there are no
concerns or residual uncertainties for pre and/or post-natal toxicity.

HED has determined that reliable data show the safety of infants and
children would be adequately protected if the FQPA SF were reduced to
1X.  That decision is based on the following findings:

The toxicity database for propoxycarbazone-sodium is complete, except
for immunotoxicity testing.  EPA began requiring functional
immunotoxicity testing of all food and non-food use pesticides on
26-DEC-2007.  Since this requirement went into effect well after the
tolerance petition was submitted, these studies are not yet available
for propoxycarbazone-sodium.  In the absence of specific immunotoxicity
studies, EPA has evaluated the available propoxycarbazone-sodium
toxicity data to determine whether an additional database uncertainty
factor is needed to account for potential immunotoxicity.  There was no
evidence of adverse effects on the organs of the immune system in any
study with propoxycarbazone-sodium.  In addition,
propoxycarbazone-sodium does not belong to a class of chemicals (e.g.,
the organotins, heavy metals, or halogenated aromatic hydrocarbons) that
would be expected to be immunotoxic.  Based on these considerations, EPA
does not believe that conducting a special series 870.7800
immunotoxicity study will result in a point of departure less than the
NOAEL of 74.8 mg/kg/day used in calculating the cPAD for
propoxycarbazone-sodium; therefore, an additional database uncertainty
factor is not needed to account for potential immunotoxicity.

There is no indication that propoxycarbazone-sodium is a neurotoxic
chemical and there is no need for a developmental neurotoxicity study or
additional uncertainty factors (UFs) to account for neurotoxicity.

There is no evidence that propoxycarbazone-sodium results in increased
susceptibility in in utero rats or rabbits in the prenatal developmental
studies or in young rats in the 2-generation reproduction study.

There are no residual uncertainties identified in the exposure
databases.  The dietary food exposure assessments were based on 100%
crop treated and tolerance-level residues.  EPA made conservative
(protective) assumptions in the ground and surface water modeling used
to assess exposure to propoxycarbazone-sodium in drinking water. 
Residential exposure to propoxycarbazone-sodium is not expected.  These
assessments will not underestimate the exposure and risks posed by
propoxycarbazone-sodium.

3.3	Dose-Response Assessment

The doses and toxicological endpoints selected for various exposure
scenarios are summarized in Table 3.3.1.

Table 3.3.1.  Summary of Toxicological Dose and Endpoints for
Propoxycarbazone-Sodium for Use in Human Health Risk Assessment.1

Exposure Scenario	Dose Used in Risk Assessment, UF 	FQPA SF* and LOC for
Risk Assessment	

Study and Toxicological Effects

Acute Dietary

	Not applicable	None	An endpoint of concern attributable to a single
dose was not identified.  An acute RfD was not established.

Chronic Dietary

(All populations)	NOAEL= 74.8 mg/kg/day

UF = 100X

Chronic RfD = 

0.748 mg/kg/day

	FQPA SF = 1X

cPAD = 

chronic RfD

 FQPA SF

= 0.748 mg/kg/day	Two-generation Reproduction Study in Rats

LOAEL = 297.1 mg/kg/day based on microscopic lesions of the stomach in
parental male rats

Short-Term 

Incidental Oral

(1-30 days)

	Maternal NOAEL= 100 mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Developmental Study in Rabbits

LOAEL = 500 mg/kg/day based on GI toxicity (enlarged cecum, reduced and
light-colored feces)

Intermediate-Term 

Incidental Oral

(1-6 months)	Parental NOAEL= 74.8 mg/kg/day	Residential LOC for MOE =
100

Occupational LOC for MOE = 100	Two-generation Reproduction Study in Rats

LOAEL = 297.1 mg/kg/day based on microscopic lesions of the stomach in
parental male rats

Short-Term Dermal

(1-30 days)	Dermal NOAEL= N/A	Residential LOC for MOE = N/A

Occupational LOC for MOE = N/A 	Since there are no developmental
concerns and no evidence of systemic toxicity at the limit dose of 1000
mg/kg/day in a 28-day dermal toxicity study, quantification of dermal
risk for this exposure scenario is not required.  In addition, GI
effects (stomach lesions) seen in the oral study are not expected to
occur following a dermal exposure.

Intermediate-Term

Dermal

(1-6 months)	Dermal NOAEL = N/A 	Residential LOC for MOE = N/A

Occupational LOC for MOE = N/A 	Since there are no developmental
concerns and no evidence of systemic toxicity at the limit dose of 1000
mg/kg/day in a 28-day dermal toxicity study, quantification of dermal
risk for this exposure scenario is not required.  In addition, GI
effects (stomach lesions) seen in the oral study are not expected to
occur following a dermal exposure.

Long-Term Dermal (>6 months)

	Oral NOAEL= 

74.8 mg/kg/day

(dermal- absorption rate = 25%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Two-generation Reproduction Study in
Rats

LOAEL = 297.1 mg/kg/day based on microscopic lesions of the stomach in
parental male rats.

Short-Term Inhalation

(1-30 days)

	Oral NOAEL= 100 mg/kg/day

(inhalation- absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Developmental Study in Rabbits

LOAEL = 500 mg/kg/day based on GI toxicity (enlarged cecum, reduced and
light-colored feces).

Intermediate-Term Inhalation

(1-6 months)

	Oral NOAEL = 74.8 mg/kg/day

(inhalation- absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Two-generation Reproduction Study in Rats

LOAEL = 297.1 mg/kg/day based on microscopic lesions of the stomach in
parental male rats.

Long-Term Inhalation

(>6 months)

	Oral NOAEL= 74.8 mg/kg/day

(inhalation- absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Two-generation Reproduction Study in
Rats

LOAEL = 297.1 mg/kg/day based on microscopic lesions of the stomach in
parental male rats.

Cancer	Not likely to be carcinogenic to humans

Quantification of cancer risk is not required.

1  UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed-adverse-effect-level, LOAEL =
lowest-observed-adverse-effect-level, PAD = population-adjusted dose (a
= acute, c = chronic) RfD = reference dose, MOE = margin of exposure,
LOC = level of concern, NA = Not Applicable.

3.4	Endocrine Disruption

EPA is required under the Federal Food, Drug and Cosmetic Act (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).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, there may be additional
screening and/or testing required to better characterize effects related
to endocrine disruption.

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION

4.1	Summary of Uses

There are currently three end-use products containing
propoxycarbazone-sodium that are registered to Bayer CropScience for use
on food/feed crops in the U.S.  These products are registered for use
only on wheat and include a 70% WDG (Olympus™ 70% WDG Herbicide, EPA
Reg. No. 264-809) and two other WDGs that are MAI formulations
containing 6.75% or 8.14% propoxycarbazone-sodium with 4.50% or 2.03%
mesosulfuron-methyl (Olympus™ Flex Herbicide, EPA Reg. No. 264-833;
Rimfire™ Herbicide, EPA Reg. No. 264-847).  There are no proposed or
registered uses of propoxycarbazone-sodium that would result in
residential exposure.

For this petition, Bayer is proposing use of a 70% WDG on pasture and
rangeland grasses for the control of annual grasses and broadleaf weeds
(Olympus™ Rangeland Herbicide; EPA File Symbol 264-RNTU).  An example
label for this formulation was provided, and the proposed use directions
are summarized below in Table 4.1.

Table 4.1.  Summary of Proposed Directions for Use of
Propoxycarbazone-sodium.

Applic. Timing, Type, and Equip.	Formulation

[EPA File Symbol]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations1

Rangeland and Pastures

Broadcast foliar application(s) in fall and/or spring to actively
growing weeds; 

Ground or air equipment	WDG

[264-RNTU]	0.039-0.053	2	0.053	NS	Apply in a minimum of 3 and 5 gal/A
using aerial and ground equipment, respectively.  

A NIS should be used at 0.25-0.5% v/v in the spray solution.

Do not use organosilicone-based surfactants.

llet and soybeans (STS™); 12 months for cotton, sorghum, sunflower,
field peas, and soybeans (conventional); 18 months for corn
(conventional in OK, KS, NE, and TX), spring barley, and lentils; and 22
months for canola, potato (WA, OR and ID) and corn (conventional in CO,
MT, WY and SD).   In all areas, 24 inches of rainfall and a 24-month
interval are required before replanting with buckwheat, onions, oats,
sugar beets, potatoes, and dry beans.

NS – not specified.

Conclusions:  The proposed use directions are adequate to allow for
evaluation of the grass field trial data.  The available field data
support the proposed use of propoxycarbazone-sodium (WDG) on pasture and
rangeland grasses.  However, the label should be amended to specify a
minimum PHI of 7 days for the cutting of treated hay in order to ensure
that residues in/on hay do not exceed the proposed 25 ppm tolerance.  A
revised Section B should be submitted.

4.2	Dietary Exposure/Risk Pathway

The residue chemistry data submitted in support of proposed petitions
were evaluated by HED on 08-OCT-2008 (Memo, S. Levy, DP#: 348513).  The
drinking water assessment was completed by EFED on 05-AUG-2008 (Memo, I.
Abdel-Saheb, DP#: 348511).  The dietary exposure assessment was
completed in a HED memorandum dated 10-DEC-2008 (S. Levy, DP#: 356507).

4.2.1	Residue Profile

Background

™ 70% WDG Herbicide, EPA Reg. No. 264-809) and two other WDGs that are
MAI formulations containing 6.75% or 8.14% propoxycarbazone-sodium with
4.50% or 2.03% mesosulfuron-methyl (Olympus™ Flex Herbicide, EPA Reg.
No. 264-833; Rimfire™ Herbicide, EPA Reg. No. 264-847). 
Propoxycarbazone-sodium may be applied to wheat using ground or aerial
equipment at 0.026-0.039 lb ai/A/application, with a maximum of 0.053 lb
ai/A/year and a minimum PHI of 71 days for grain and straw.

Tolerances for propoxycarbazone-sodium are currently established for the
combined residues of propoxycarbazone-sodium and its Pr-2-OH metabolite
[methyl
2-[[[(4,5-dihydro-3-(2-hydroxypropoxy)-4-methyl-5-oxo-1H-1,2,4-triazol-1
-yl)carbonyl]amino]sulfonyl]benzoate], expressed as parent, in/on wheat,
forage at 17 ppm, wheat, grain at 0.02 ppm, wheat, hay at 0.15 ppm and
wheat, straw at 0.05 ppm [40 CFR §180.600(a)(1)].  In addition,
tolerances are currently established for residues of propoxycarbazone
per se in selected livestock commodities at 0.03-0.3 ppm [40 CFR
§180.600(a)(2)].

™ Rangeland Herbicide; EPA File Symbol 264-RNTU).  The proposed use is
for postemergence broadcast application(s) in the fall and/or spring at
0.039-0.053 lb ai/A/application, with a maximum seasonal rate of 0.053
lb ai/A. No PHI is specified for grass forage or hay.  Applications can
be made using ground or aerial equipment in a minimum of 5 or 3 gal/A,
respectively, and can include the addition a NIS.

In conjunction with the proposed use on pasture and rangeland grasses,
Bayer has proposed the following:



Tolerances for combined residues of propoxycarbazone and metabolite
Pr-2-OH:

Commodity	Proposed Tolerance (ppm)

Grass, forage	20

Grass, hay	25

	Tolerances for combined residues of propoxycarbazone per se:

Commodity	Proposed Tolerance (ppm)

Cattle, meat	0.1

Cattle, meat byproducts	1.0

Goat, meat	0.1

Goat, meat byproducts	1.0

Horse, meat	0.1

Horse, meatbyproducts	1.0

Milk	0.05

Sheep, meat	0.1

Sheep, meat byproducts	1.0

Nature of the Residue in Plants and Livestock

The nature of the residues in wheat and livestock is adequately
understood (PP#0F6094; Memo, G. Kramer, 22-APR-2004; DP#: 284670). 
Based on the submitted wheat metabolism study, the primary metabolic
pathway in wheat is hydroxylation of the propoxy side chain to form
Pr-2-OH.  Subsequent hydrolysis of Pr-2-OH yields Pr-2-OH NMT MKH 6561
(containing the triazolone ring) and, probably, a sulfonamide methyl
ester intermediate, which undergoes hydrolysis to yield a sulfonamide
acid (containing the benzene ring).  The sulfonamide acid may exist in
equilibrium with saccharin.  The metabolite N-desmethyl MKH 6561 is
formed by demethylation of propoxycarbazone-sodium in a minor pathway. 
As grasses are similar to wheat and the use patterns are similar for the
two crops, the available wheat metabolism data will support the proposed
use on grasses.

 

The available livestock data indicate that metabolism is similar in
ruminants and poultry, and that metabolism of propoxycarbazone-sodium
proceeds by hydrolysis of the sulfonylurea to form the methyl ester (MKH
6561 sulfonamide methyl ester) and saccharin, hydroxylation to form
Pr-2-OH and Pr-2-OH NMT MKH 6561, and/or cleavage of the sulfonylurea
bridge to form NMPT MKH 6561.  

The MARC has determined that the residues of concern in wheat and
rotational crop commodities are propoxycarbazone-sodium and Pr-2-OH and
that the residue of concern in livestock commodities is
propoxycarbazone-sodium per se.  Due to the fact that wheat and grass
are closely related crops, and for the purposes of this petition, the
residue of concern in grass commodities is propoxycarbazone-sodium per
se.  Chemical names and structures for these metabolites are presented
in Appendix I.

Residue Analytical Methods

An adequate analytical method is available for enforcing tolerances of
regulated residues in/on wheat and livestock commodities.  Bayer has
provided an LC/MS/MS method (Bayer Method No. 108817) for determining
residues of propoxycarbazone-sodium and its Pr-2-OH metabolite in/on
wheat commodities.  The same LC/MS/MS method is proposed for enforcing
tolerances for residues of propoxycarbazone-sodium per se in ruminant
tissues and milk.  The validated LOQs for propoxycarbazone-sodium and
its Pr-2-OH metabolite are 0.05 ppm each in/on wheat grain, forage, hay
and straw, 0.05 ppm in ruminant tissues (parent only), and 0.002 ppm in
milk (parent only).

The LC/MS/MS method has undergone a petition method validation (PMV) at
Analytical Chemistry Laboratory/Biological and Economics Analysis
Division (ACL/BEAD) (Memo, G. Kramer, 13-OCT-2005; DP#: 322202).  Based
on the submitted method validation data and the successful independent
laboratory validation (ILV), ACL concluded that an Agency laboratory
validation was not required and that the proposed method appears to be
suitable for food tolerance enforcement in wheat, bovine tissues (meat
and meat byproducts) and milk.  Given the similarly in grass and wheat
commodities, the proposed LC/MS/MS method will be acceptable of
enforcing tolerances for the regulated residues in/on grass forage and
hay.

 

Although the method has been deemed acceptable, HED concluded the method
instructions should be modified to clearly state that
propoxycarbazone-sodium as the free acid is the compound to be used for
preparation of standard and fortification solutions.  Because the
petitioner appears to use the code MKH 6561 interchangeably for both
propoxycarbazone-sodium and propoxycarbazone free acid and because the
method description does not specify any chemical information for the
standards, it is not obvious which compound is to be used (Memo, G.
Kramer, 22-APR-2004; DP#: 284670).  Once the revised method is received,
HED will forward the method to the Food and Drug Administration (FDA)
for publication in Pesticide Analytical Manual, Volume II (PAM II).

Multiresidue Methods (MRM)

Propoxycarbazone-sodium (as the free acid) and its Pr-2-OH metabolite
were analyzed according to the FDA MRM Test Guidelines in Pesticide
Analytical Manual (PAM) Vol. I, Appendix II (1/94). 
Propoxycarbazone-sodium and its Pr-2-OH metabolite were not adequately
recovered from any of the MRMs (Memo, G. Kramer, 22-SEP-2003; DP#:
293677).  Therefore, the MRM are not adequate for enforcement of
tolerances for residues of propoxycarbazone-sodium and its Pr-2-OH
metabolite.

Magnitude of Residues in Plants

Bayer has submitted field trial data on grasses to support the proposed
use of propoxycarbazone-sodium (70% WDG) on pasture and rangeland
grasses.    SEQ CHAPTER \h \r 1 The results from these field trials are
discussed below and the residue data are summarized in Table 4.2.1.1.



Table 4.2.1.1.  Summary of Residue Data from Grass Field Trials with
Propoxycarbazone-sodium (WDG).

Crop matrix	Total Applic. Rate (lb ai/A)	PHI (days)	Combined Residue
Levels (ppm)1

	n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

Grasses (proposed use rate = 0.053 lb ai/A total application rate)

Forage	0.051-0.056	0	24	1.69	12.22	11.97	6.65	6.57	2.89

Hay

0-81	24	0.64	11.36	11.33	2.55	3.77	3.39

1 	Combined residues include propoxycarbazone-sodium and its Pr-2-OH
metabolite, expressed as parent.  The validated LOQ for each analyte is
0.05 ppm in forage and hay, for a combined LOQ of 0.1 ppm.

2	HAFT = Highest-Average Field Trial.

Twelve field trials were conducted in Zones 1, 3, 4, 5, 10, 11 and 12
during 2006 on a variety of grass species, including: Bahia grass,
Bermuda grass, bromegrass, orchard grass, rye grass, fescue and wheat
grass.  At each site, propoxycarbazone-sodium (70% WDG) was applied as a
single broadcast foliar application to grass during stem elongation at
rates of 0.051-0.056 lb ai/A (1X proposed maximum rate).  Each
application was made using ground equipment at 7-10 gal/A, and included
the use of an unspecified NIS at 0.25%-0.5% v/v.  Single control and
duplicate treated samples of grass forage and hay were harvested from
each site.  Forage samples were collected as soon as the spray had dried
(0 days after treatment, DAT).  Hay samples were cut at the earliest
possible commercial harvest; however, this covered harvest intervals
from 0-81 DAT, with most hay samples (14 of 24) being cut from 10-28
DAT.  At one trial site, duplicate forage samples were collected a 0, 6,
12, 21 and 27 DAT and hay samples were collected at 0, 6, 16, 21 and 27
DAT to assess residue decline.

ntervals (≤7 DAT).  Combined residues of propoxycarbazone-sodium and
the Pr-2-OH metabolite were 1.69-12.22 ppm in/on grass forage at 0 DAT
and 0.64-11.36 ppm in/on grass hay cut from 0-81 DAT.  Average combined
residues were 6.57 ppm for forage and 3.77 ppm for hay.

Conclusions:  The grass field trial data are provisionally adequate,
provided that the label is amended to specify a 7-day PHI for hay and
additional grass hay data are submitted.  An adequate number of trials
were conducted in the appropriate geographic regions on grass species
representative of the respective regions.  The trials were conducted at
1x the maximum proposed rate, and the appropriate commodities (forage
and hay) were collected from each trial.  The forage samples were
collected at 0 DAT, according to Agency guidance; however, the hay
samples were not cut at similar PHIs.  Although all hay samples were cut
around a similar stage of maturity, the PHIs at cutting varied greatly
from trial to trial (0-81 DAT).  As the decline data indicate that
residue levels in/on hay are dependent on the post-treatment interval,
the residue values for hay cannot be pooled to determine an appropriate
tolerance.  Therefore, an insufficient number of hay samples were
collected at any given PHI.

The residue data for forage are adequate and will support the proposed
20-ppm tolerance.  Although the residue data on grass hay are
incomplete, the available data will support the proposed 25-ppm
tolerance provided that a 7-day PHI is specified for hay, as hay is not
a human food and the 25-ppm tolerance will not alter the current
tolerances of livestock commodities.  Once the requested residue data
are available, the tolerance for grass hay will be reassessed.

 

As a condition of registration, new grass field trials are required
reflecting a specific PHI for hay. The number and location of the
required trials depends on what PHI the petitioner intends to support
for hay and what data are currently available.  Three possible scenarios
are listed below reflecting possible PHIs of 0, 7, or 21 days:  

	•	Residue data on hay are available from 2 trials (Zones 5 and 11)
reflecting a 0-DAT harvest.  Therefore, to support a 0-day PHI for hay,
ten additional field trials are required in Zones 1, 2, 3, 4, 5 (2
trials), 6, 10, 11, and 12.

	•	Residue data on hay are available from 5 trials (Zones 3, 4, 5, 10
and 11) at reflecting approximately a 7-day PHI (6-10 DAT).  Therefore,
to support a 7-day PHI for hay, seven additional field trials are
required in Zones 1, 2, 3, 5, 10, 11, and 12.

	•	Residue data are available from 5 trials (Zones 3, 4, 5, 10 and 11)
at reflecting approximately a 21-day PHI for hay (19-28 DAT). 
Therefore, to support a 21-day PHI for hay, seven additional field
trials are required in Zones 2, 3, 4, 5, 10, 11, and 12.

Magnitude of Residues in Processed Commodities

Data requirements pertaining to this guideline topic are not relevant to
this petition because there is no processed food/feed item associated
with grass.

Magnitude of Residues in Meat, Milk, Poultry and Eggs (MMPE)

As the recalculated maximum reasonable dietary burden (MRDB) for cattle
(35.4 ppm) is lower than the level (41 ppm) previously used to assess
livestock tolerances, no changes are required in the tolerances on milk
and ruminant commodities for the current petition.  However, as
previously noted by HED, if additional uses are proposed on feed crops
which result in a higher dietary burden, a new feeding study may be
required.

With regards to tolerances on poultry and hog commodities, HED has
previously concluded that quantifiable residues are unlikely to occur in
eggs, poultry, and hog commodities based on the low dietary exposure of
poultry and hog to propoxycarbazone-sodium residues and the results from
the available livestock metabolism studies and cattle feeding study [40
CFR §180.6(a)(3)].

Confined and Field Accumulation in Rotational Crops

An adequate confined rotational crop study is available (Memo, G.
Kramer, 22-APR-2004; DP#: 284670).  As the metabolites that were
identified in rotational crop commodities, with the exception of the
glucose conjugates, were consistent with those identified in the wheat
metabolism study, HED concluded that the residues of concern in
rotational crop commodities are the same as in primary crops,
propoxycarbazone-sodium and its Pr-2-OH metabolite.

Adequate limited rotational crop field trials are available (Memo, G.
Kramer, 22-APR-2004; DP#: 284670).  Based on these data, HED has
determined that rotational crop tolerances are not needed for
propoxycarbazone-sodium uses on annual crops with the following PBIs:  1
month for cereal grains (except wheat, anytime); and 4 months for all
other rotatable crops.  The proposed label for the 70% WDG specifies a
minimum PBI of 4 months for any rotated crop, except wheat (0-month
PBI).  

Tolerance Summary

HED has determined that the residues of concern are
propoxycarbazone-sodium and its Pr-2-OH metabolite in wheat commodities
and propoxycarbazone-sodium per se in livestock.  Tolerances for
propoxycarbazone-sodium are established for the combined residues of
propoxycarbazone-sodium and its metabolite Pr-2-OH, expressed as parent,
in/on wheat forage at 17 ppm, wheat grain at 0.02 ppm, wheat hay at 0.15
ppm and wheat straw at 0.05 ppm [40 CFR §180.600(a)(1)]. Tolerances are
also established for residues of propoxycarbazone-sodium per se at 0.03
ppm in milk, 0.05 ppm in meat of cattle, goats, horses and sheep, and at
0.3 ppm in meat byproducts of cattle, goats, horses and sheep [40 CFR
§180.600(a)(2)].  No tolerances have been established for poultry or
hog commodities.  For the current petition, Bayer is proposing
tolerances of 20 ppm in/on grass forage and 25 ppm in/on grass hay
(Table 4.2.1.2).  Bayer is also proposing increases in the current
tolerances on livestock commodities.

The grass field trial data are acceptable for assessing the proposed
tolerances on grass forage and hay.  An adequate number of field trials
were conducted in the appropriate regions at 1X the maximum proposed use
rate.  Forage samples were collected at the appropriate PHI (0-day), but
the hay samples were collected over a wide range of post-treatment
intervals.  As residues were quantifiable in/on forage samples from all
trials and the samples represented a single PHI, the Agency’s
Guidelines for Setting Pesticide Tolerances Based on Field Trial Data
were utilized for determining the appropriate tolerance level for
forage.  Based on the 0-DAT residue data, the calculated tolerance for
grass forage is 20 ppm.

Because the hay samples were collected at widely different
post-treatment intervals (0-81 days), and the decline trial indicates
that residues levels are dependent on the post-treatment interval, the
residue values for hay samples from the various sampling intervals
represent distinct populations of residue values.  Therefore, the
Tolerance Harmonization Spreadsheet could not be utilized to determine a
tolerance for hay.  However, it is apparent that Bayer calculated the
proposed hay tolerance (25 ppm) using the Tolerance Harmonization
Spreadsheet. 

Although additional grass hay residue data are being requested as a
condition of registration, HED is recommending establishing a 25-ppm
tolerance on grass hay provided the label is amended to specify a 7-day
PHI for cutting of hay.  Based on the available field trial data,
residues in/on hay cut at 7-DAT are unlikely to exceed 25 ppm.  If the
25-ppm tolerance is considered to be a worst-case scenario, then
residues in/on grass hay will have no impact on the dietary exposure of
humans, as grass hay is not a human food and residues in/on hay at up to
25 ppm will have no impact on the dietary burden or tolerances for
livestock.  Once the requested grass hay field trial data are available,
the tolerance for grass hay will be reassessed.

No changes are required in the current tolerances on livestock
commodities for this petition.  A revised Section F should be submitted.

There are currently no established Codex, Canadian, or Mexican maximum
residue limits (MRLs) for propoxycarbazone-sodium.

Table 4.2.1.2.  Tolerance Summary for Propoxycarbazone-sodium.

Commodity	Current Tolerance

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

Grass, forage	--	20	20	Adequate data are available.

Grass, hay	--	25	25	The available will support the proposed tolerance;
however, additional residue data on hay are required as a condition of
registration.

Cattle, meat	0.05	0.1	0.05	No changes are necessary to livestock
tolerances as the proposed use on grass will not increase the MRDB for
livestock.

Cattle, meat byproducts	0.3	1.0	0.30

	Goat, meat	0.05	0.1	0.05

	Goat, meat byproducts	0.3	1.0	0.30

	Horse, meat	0.05	0.1	0.05

	Horse, meat byproducts	0.3	1.0	0.30

	Milk	0.03	0.05	0.03

	Sheep, meat	0.05	0.1	0.05

	Sheep, meat byproducts	0.3	1.0	0.30

	

4.2.2	Water Exposure/Risk Pathway

The physical properties of propoxycarbazone-sodium (high solubility and
low soil sorption coefficients) indicate a high likelihood that residues
will reach surface drinking water sources.  However, the low application
rates result in estimated concentrations in the low ppb range.  The
stability of the degradate, propoxycarbazone-carboxylic acid, in aerobic
aquatic metabolism studies indicates that it may persist in reservoirs. 
Raw drinking water concentrations from surface sources may therefore be
higher than indicated by the Tier 1 assessment.  A waiver of a
monitoring requirement for reservoirs based on the previously registered
wheat use was approved in an EFED memo of 05-APR-2005 (DP#: 310048).

Tier I EDWCs for propoxycarbazone-sodium were generated for surface
water (parent + propoxycarbazone-carboxylic acid (MKH 7018 or MKH 8394)
and groundwater (parent only) using FIRST and SCI-GROW, respectively
(Memo, I. Abdel-Saheb, 05-AUG-2008; DP#: 348511).  The models and their
descriptions are available at the EPA internet site:   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  The EDWCs were based on the
rangeland use pattern, which allows for up to two applications and a
yearly application rate of 0.0525 lbs. ai/A. For surface water, the
chronic (average annual) EDWC is 1.79 ppb.  The chronic groundwater EDWC
is 0.36 ppb.  The chronic surface water value of 1.79 ppb (0.00179 ppm)
is higher than the groundwater EDWC and was incorporated directly into
this dietary assessment under the DEEM-FCID food categories “water,
direct, all sources” and “water, indirect, all sources.”  As
stated previously, this updated EDWC value is the only change to the
last dietary assessment.

4.2.3	Dietary Exposure Analyses

™ Version 2.03, which incorporates consumption data from USDA’s
CSFII, 1994-1996 and 1998.  The 1994-96 and 1998 data are based on the
reported consumption of more than 20,000 individuals over two
non-consecutive survey days.  Foods “as consumed” (e.g., apple pie)
are linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA.  For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events.  Based on analysis of the 1994-96 and
1998 CSFII consumption data, which took into account dietary patterns
and survey respondents, HED concluded that it is most appropriate to
report risk for the following population subgroups: the general U.S.
population, all infants (<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For chronic dietary exposure assessments, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate. The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

4.2.3.1		Acute-Dietary Exposure Analysis

An acute-dietary exposure assessment was not performed because there
were no toxic effects attributable to a single dose.  Thus, an endpoint
of concern was not identified to quantitate acute-dietary risk to the
general population or to any population subgroup.

4.2.3.2		Chronic-Dietary Exposure Analysis

An unrefined chronic assessment assumed that propoxycarbazone-sodium
residues are present in all commodities at tolerance levels and that
100% of all crops are treated.  Drinking water was incorporated directly
into the dietary assessment using the EDWC for surface water of 1.79 ppb
generated by the Tier 1 FIRST model.

™ software, dietary exposure is estimated to be less than 1% of the
cPAD for the U.S. population and all population subgroups, including
children 1-2 years old, the population subgroup with the highest
estimated exposure.

Table 4.2.3.2.1.  Summary of Dietary Exposure and Risk for
Propoxycarbazone-sodium.

Population Subgroup	Chronic Dietary1

	Dietary Exposure (mg/kg/day)	% cPAD

U.S. Population (total)	0.000317	<1.0

All Infants (< 1 year old)	0.000540	<1.0

Children 1-2 years old	0.001327*	<1.0

Children 3-5 years old	0.000924	<1.0

Children 6-12 years old	0.000567	<1.0

Youth 13-19 years old	0.000276	<1.0

Adults 20-49 years old	0.000201	<1.0

Adults 50+ years old	0.000187	<1.0

Females 13-49 years old	0.000199	<1.0

1  Chronic dietary endpoint of 0.748 mg/kg/day applies to the general
U.S. population and all population subgroups.

*  The highest dietary exposure value is bolded. 

4.3	Residential Exposure/Risk Pathway

There are no products containing propoxycarbazone-sodium proposed or
registered that would result in residential exposure.  Therefore, a
residential exposure assessment was not performed.

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

 

5.0	AGGREGATE-RISK ASSESSMENTS AND RISK CHARACTERIZATION

Aggregate exposure risk assessments were assessed by incorporating the
drinking water directly into the dietary exposure assessment for the
following scenario:  chronic aggregate exposure (food + drinking water).
 The chronic aggregate risk assessment considered exposure from food and
drinking water; therefore, the dietary exposure analysis presented in
Section 4.2.3.2 represents chronic aggregate risk for
propoxycarbazone-sodium.  The chronic analysis was an unrefined
assessment assuming tolerance-level residues, 100% CT, and DEEM( ver.
7.81 default processing factors.  As can be seen in Table 4.2.3.2.1, the
DEEM-FCID™ chronic exposure estimates were <1.0% cPAD for all
population subgroups, and are therefore not of concern to HED. 

Short-, intermediate-, and long-term aggregate-risk assessments were not
performed because there are no registered or proposed uses of
propoxycarbazone-sodium which result in residential exposures.  Acute
and cancer aggregate-risk assessments were not performed because no
appropriate endpoint was available to determine the aRfD for the general
population or any population subgroup and propoxycarbazone-sodium is not
carcinogenic.  

6.0	CUMULATIVE RISK

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

7.0 	OCCUPATIONAL EXPOSURE

An occupational exposure assessment for the proposed uses of
propoxycarbazone-sodium on pasture and rangeland grasses was prepared in
an ARIA/RD memorandum dated 17-MAR-2008 (M. Dow, DP#: 349694).  Based on
the proposed use on grasses, handler exposure and post-application
exposure are possible.  HED conducted conservative assessments for all
potential exposure pathways. 

Occupational Handler

In view of the proposed use pattern, RD believes the most highly exposed
occupational pesticide handlers will mixer/loaders using open-pour
loading of dry flowable (surrogate for WDG), applicators using open-cab,
groundboom sprayers and aerial applicators.  

For ground applications, it is expected that some private (i.e., grower)
applicators may perform all tasks; that is, mix, load and apply the
material.  However, HED Science Advisory Council for Exposure (ExpoSAC)
draft Standard Operating Procedure (SOP) (29-MAR-2000) directs that
although the same individual may perform all tasks, in some cases they
shall be assessed separately.  

The available exposure data for combined mixer/loader/applicator
scenarios are limited in comparison to the monitoring of these two
activities separately.  These exposure scenarios are outlined in the
PHED Surrogate Exposure Guide (AUG-1998).  HED has adopted a methodology
to present the exposure and risk estimates separately for the job
functions in some scenarios and to present them as combined in other
cases.  Most exposure scenarios for hand-held equipment (such as hand
wands, backpack sprayers, and push-type granular spreaders) are assessed
as a combined job function.  With these types of hand held operations,
all handling activities are assumed to be conducted by the same
individual.  The available monitoring data support this and HED presents
them in this way.  Conversely, for equipment types such as fixed-wing
aircraft, groundboom tractors, or air-blast sprayers, the applicator
exposures are assessed and presented separately from those of the mixers
and loaders.  By separating the two job functions, HED determines the
most appropriate levels of personal-protective equipment (PPE) for each
aspect of the job without requiring an applicator to wear unnecessary
PPE that may be required for a mixer/loader (e.g., chemical-resistant
gloves may only be necessary during the pouring of a liquid
formulation).  

The HIARC did not identify dermal toxicological endpoints for short-term
duration and intermediate-term duration exposures stating that there
were no developmental concerns and no evidence of systemic toxicity at
the limit dose of 1,000 mg ai/kg bw/day in a 28-day dermal toxicity
study.  A toxicological endpoint was identified for long-term dermal
exposures but is not relevant for purposes of this petition as long-term
exposures are not expected.  

The HIARC identified short-term duration (1-30 days) and
intermediate-term duration (1-6 months) inhalation toxicological
endpoints.  Typically, HED expects handler exposures to be short-term
(1-30 days).  However, according to guidance from the ExpoSAC, it might
be possible for commercial applicators to experience intermediate-term
exposures (1-6 months).  Therefore, although short-term exposures are
typically expected, the estimated exposures and risks for
intermediate-term exposures are also presented.  See Table 7.1 for a
summary of estimated exposures and risks.



Table 7.1.  Summary of Inhalation Exposure & Risk for Occupational
Handlers Applying Propoxycarbazone-Sodium to Pasture and Rangeland.

Unit Exposure1

(mg ai/lb handled)	Application Rate2

(lb ai/unit)	Units Treated3	Avg. Daily Exposure4

(mg ai/kg bw/day)	MOE5

Short-term	MOE6

Intermed.-Term

Mixer/Loader – WDG (Dry Flowable) – Open Pour

Inhal.  0.00077	0.053 lb ai/A	200 A/day by ground

1200 A/day by air	Inhal.

Ground  0.000117

Aerial     0.0007	

850,000

140,000	

640,000

107,000

Applicator – Groundboom – Open-cab

Inhal.  0.00074	0.053 lb ai/A	200 A/day	Inhal.     0.000112	890,000
670,000

Aerial Applicator

Inhal.  0.000068	0.053 lb ai/A	1200 A/day	Inhal.     0.0000619	1,600,000
1,200,000

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

2.  Application Rate = Taken from proposed OLYMPUS label (EPA File
Symbol 264-RNTU).

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP No. 9.1.  Science Advisory Council for
Exposure; Revised 05-JUL-2000; PHED v 1.1, MAY-1997.   

4.  Average Daily Dose = Unit Exposure * Application Rate * Units
Treated assume 100% inhalation absorption ( Body Weight (70 kg).  

5.  MOE = Margin of Exposure = No-Observed-Adverse-Effect-Level (NOAEL)
( ADD.  Short-term (1-30 days) inhalation NOAEL = 100 mg ai/kg bw/day.

6.   MOE = Margin of Exposure = No-Observed-Adverse-Effect-Level (NOAEL)
( ADD.  Intermediate-term (1-6 months) inhalation NOAEL = 74.8 mg ai/kg
bw/day.

A MOE (100 is sufficient to protect occupational pesticide handlers. 
Since the estimated MOEs are all >100, the proposed uses do not exceed
HED’s level of concern.  

7.2	Occupational Post-Application Exposure

There is a potential for agricultural workers to experience
post-application exposure to pesticides during the course of typical
agricultural activities.  However, the HIARC did not identify short- or
intermediate-term dermal toxicological endpoints.  There is a 12 hour
REI for propoxycarbazone-sodium.  A toxicological endpoint was
identified for long-term dermal exposures but is not relevant for
purposes of this petition as long-term exposures are not expected.  HED
believes post-application inhalation exposure will be negligible.  The
proposed uses do not exceed HED’s LOC and post-application exposure is
not assessed.

REI

The proposed label lists a REI of 12 hours.  Propoxycarbazone-sodium is
classified in Toxicity Category IV for acute dermal, acute inhalation,
primary eye irritation and primary skin irritation.  It is not a dermal
sensitizer.  Therefore the interim worker protection standard (WPS) REI
of 12 hours is adequate to protect agricultural workers from
post-application exposures to propoxycarbazone-sodium. 

8.0	DATA DEFICIENCIES/LABEL REVISIONS

8.1		Toxicology

The HED HIARC has identified an acceptable/guideline 28-day inhalation
toxicity study in rats as the only toxicological data gap for
propoxycarbazone-sodium; however, based on the low exposure and overall
low oral toxicity of propoxycarbazone-sodium, HED’s Risk Assessment
Review Committee (RARC) recommended removing this data gap.

Immunotoxicity Study.  An immunotoxicity study is now a data requirement
in the 40 CFR revised Part 158.

8.2	Residue Chemistry

The proposed label should be amended to specify a minimum 7-day PHI for
the cutting of hay, in order to assure that residues in/on hay do not
exceed the recommended 25-ppm tolerance.

An analytical standard for the regulated Pr-2-OH metabolite should be
provided to the EPA National Pesticide Standards Repository.

As a condition of registration, new grass field trials are required
reflecting a specific PHI for hay.  The number and location of the
required trials depends on what PHI the petitioner intends to support
for hay and what data are currently available.  If the petitioner
intends to support a 0-day PHI, then residue data on hay are required
from ten additional grass field trials conducted in Zones 1, 2, 3, 4, 5
(2 trials), 6, 10, 11, and 12.  If the petitioner intends to support a
7-day PHI, then residue data on hay are required from seven additional
grass field trials conducted in Zones 1, 2, 3, 5, 10, 11, and 12.  If
the petitioner intends to support a 21-day PHI, then residue data on hay
are required from seven additional grass field trials conducted in Zones
2, 3, 4, 5, 10, 11, and 12.

For the proposed LC/MS/MS enforcement method, the instructions should be
modified to clearly state that propoxycarbazone-sodium as the free acid
is the compound to be used for preparation of standard and fortification
solutions.

A revised Section F should be submitted with the removal of proposed
livestock commodity tolerances.  No changes are required in the current
tolerances on livestock commodities.

8.3		Occupational/Residential

None.

  SEQ CHAPTER \h \r 1 APPENDICES

Appendix 1:  Chemical Names and Structures of Propoxycarbazone-Sodium
Transformation Products.

Appendix 2:  Acute Toxicity of Propoxycarbazone-Sodium.

Appendix 3:  Toxicity Profile of Propoxycarbazone-Sodium.

RDI: D.Vogel (10-DEC-2008); Branch (03-DEC-2008), RAB1 Chemists
(10-DEC-2008)

S. Levy: S-10953: PY1: (703)305-0783: 7509P: RAB1

Petition#: 7F7304; DP#: 348510; PC Code: 122019

Appendix 1

Chemical Names and Structures of Propoxycarbazone-Sodium Transformation
Products.

Common name/code

Matrix	

Chemical name	

Chemical structure

N-Desmethyl MKH 6561

Wheat	

Methyl 2-[[[(4,5-dihydro-5-oxo-3-

propoxy-1H-1,2,4-triazol-1-yl)-carbon-yl]amino]sulfonyl]benzoate	

Pr-2-OH NMT MKH 6561

Wheat

Goat

Hen

Rotated turnip tops and wheat
2,4-Dihydro-5-(2-hydroxypropoxy)-4-methyl-3H-1,2,4-triazol-3-one	

Sulfonamide acid

Wheat	2-(Aminosulfonyl)benzoic acid	

Saccharin

Wheat

Goat

Hen

Rotated kale, turnip tops, and wheat	1,2-Benzoisothiazol-3-(2H)-one,
1,1-dioxide	

NMPT MKH 6561

Goat

Hen	2,4-dihydro-4-methyl-5-propoxy-3H-1,2,4-triazole-3-one	

MKH 6561 sulfonamide methyl ester

Goat

Hen	2-carbomethoxybenzenesulfonamide	

  SEQ CHAPTER \h \r 1 Appendix 2

Acute Toxicity of Propoxycarbazone-Sodium.

Guideline

 No.	

Study Type	

MRID(s)	

Results	

Toxicity Category

870.1100

(81-1)	

Acute Oral (rat)	

45012509	

LD50 > 5000 mg/kg	

IV

870.1200

(81-2)	

Acute Dermal	

45012507/45012508 	

LD50 > 5000 mg/kg	

IV

870.1300

(81-3)	

Acute Inhalation	

45012505	

LC50 > 5.03 mg/L	

IV

870.2400

(81-4)	

Primary Eye Irritation	

45012504 	

Minimally irritating	

IV

870.2500

(81-5 )	

Primary Skin Irritation	

45012504	

Slightly irritating	

IV

87.2600

(81-6)	

Dermal Sensitization	

45012510 	

Not a dermal sensitizer	

N/A

Appendix 3

Toxicity Profile of Propoxycarbazone-Sodium.

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity (rat)	

45012610  (1998)

Acceptable/guideline

0, 250, 1000, 4000 or 20,000 ppm

M: 0, 21.6, 81.6, 350.6 or 1769.9 mg/kg/d

F: 0, 17.4, 73.0, 286.4 or 1507.5 mg/kg/d	

NOAEL = 286.4 (M) and 350.6 (F) mg/kg/day

LOAEL = 1507.5 (M) and 1769.9 (F) mg/kg/day based on gastric irritation.

870.3100

90-Day oral toxicity (mouse)	

45012521 (1997)

Acceptable/guideline

0, 625, 2500 or 10,000 ppm

M: 0, 205, 860 or 3926 mg/kg/d

F: 0, 307, 1159 or 5109 mg/kg/d	

NOAEL = 205 (M) and 1159 (F) mg/kg/day

LOAEL = 860 (M) and 5109 (F) mg/kg/day based on decreased body weight,
body weight gain and food efficiency.

870.3150

64-Day oral toxicity (dog)

(range-finding)	

45012511 (1997)

Acceptable/guideline

0, 1000, 5000, 10,000 or 40,000 ppm 

M: 0, 28, 140, 332, and 1407 mg/kg bw/d

F: 0, 32, 134, 286 or 1181 mg/kg/d 	

NOAEL = 1407 (M) and 1181 (F) mg/kg/day   

LOAEL = not determined

870.3200

21/28-Day dermal toxicity	

45012530 (1997)

Unacceptable/guideline

0 or 1000 mg/kg/d	

NOAEL = 1000 mg/kg/day

LOAEL = not determined

870.3700a

Prenatal developmental rodent (rat)	

45012515 (1997)

Acceptable/guideline

0, 100, 300, or 1000 mg/kg/d	

Maternal NOAEL ( 1000 mg/kg/day

LOAEL = not determined

Developmental NOAEL ( 1000 mg/kg/day

LOAEL = not determined

870.3700b

Prenatal developmental in nonrodents (rabbit)	

45012608 (1998)

Acceptable/guideline

0, 20, 100, 500 or 1000 mg/kg/d 	

Maternal NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on reduced body weight gain and food
consumption, GI toxicity and decreased water consumption and urination. 

Developmental NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day based on an abortion, decrease in mean fetal
weights, and elevated pre- and post-implantation loss.

870.3800

Reproduction and fertility effects	

45012529 (1999)

Acceptable/guideline

 0, 1000, 4000, or 16,000 ppm

F0(M):  0, 74.8, 297.1, or 1230.7 mg/kg/d 

F0(F): 0, 92.7, 373.5, or 1605.3 mg/kg/d

F1(M): 0, 79.6, 322.9, or 1313.9 mg/kg/d

 F1(F):  0, 103.8, 413.5, or 1907.5 mg/kg/d	

Parental/Systemic NOAEL = M: 74.8-79.6 mg/kg/day and F: 373.5-413.5
mg/kg/day

LOAEL = M: 297.1-322.9 mg/kg/day and F: 1605.3-1907.5 mg/kg/day based on
microscopic lesions of the stomach.

Reproductive NOAEL = M: 1230.7-1313.9 mg/kg/day and F: 373.5-413.5 mg/kg
/day 

LOAEL = M: not observed and F: 1605.3-1907.5 mg/kg/day based on
increased in diestrous/metestrous.

Offspring NOAEL = M: 297.1-322.9 mg/kg/day and F: 373.5-413.5 mg/kg/day

LOAEL = M: 1230.7-1313.9 mg/kg/day and F: 1605.3-1907.5 mg/kg/day based
on increased postimplantation loss and decreased live litter size in the
F2 litters.

870.4100a

Chronic toxicity (rodent)	

45012514 (1999)

Acceptable/guideline

0, 1000, 10,000 and 20,000 ppm

M: 0, 43,
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LOAEL = M: 459 mg/kg/day and F: 525 mg/kg/day based on decreased body
weight and increased urinary pH (preceding histological changes in the
kidney of rats in the mid- and high-dose groups such as:  foci of
mineralization of pelvis, dilated and cystic renal tubules filled with
proteinaceous material, regenerative tubular epithelium, glomerular and
interstitial fibrosis, and hyperplasia of the pelvic epithelium).

870.4100b

Chronic toxicity (dog)	

45012513 (1998)

0, 2000, 10,000 or 25,000 ppm 

M: 0, 52.2, 258.0 or 630.7 mg/kg/d

F: 0, 55.7, 235.5, or 605.4 mg/kg/d	

NOAEL =  630.7 mg/kg/day

LOAEL >  630.7 mg/kg/day 

870.4200

Carcinogenicity (rat)	

45012514 (1999)

Acceptable/guideline

0, 1000, 10,000 and 20,000 ppm

M: 0, 43, 459 or 924 mg/kg/d 

F: 0, 49, 525 or 1049 mg/kg/d  	

NOAEL = M: 43 mg/kg/day and F: 49 mg/kg/day 

LOAEL = M: 459 mg/kg/day and F: 525 mg/kg/day based on decreased body
weight and increased urinary pH (preceding histological changes in the
kidney of rats in the mid- and high-dose groups such as:  foci of
mineralization of pelvis, dilated and cystic renal tubules filled with
proteinaceous material, regenerative tubular epithelium, glomerular and
interstitial fibrosis, and hyperplasia of the pelvic epithelium).

no evidence of carcinogenicity

870.4300

Carcinogenicity (mouse)	

45012614 (1999)

Acceptable/guideline

0, 280, 1400, or 7000 ppm 

M: 0, 74.6, 369.0, or 1880.9 mg/kg/

F: 0, 126.2, 626.9, or 3106.1 mg/kg/d	

NOAEL = M: established369.0 mg/kg/day and F: 3106.1 mg/kg/day 

LOAEL = M: 1880.9 mg/kg/day based on decreased body weight gain combined
with lower food efficiency and F: not established.

no evidence of carcinogenicity

Gene Mutation

870.5100

1) Ames

2) Ames

3) Ames

870.5300

4)In vitro Chinese hamsterV79-HPRT

	

1) 45012506 (1994)

Accept扡敬术極敤楬敮

0, 1.6, 8, 40, 200, 1000 or 5000 μg/plate 

2) 45012516 (1999)

Acceptable/guideline

0, 16, 50, 158, 500, 1581 or 5000 μg/plate 

3) 45012528 (1999)

Acceptable/guideline

0, 0.25, 0.5, 1, 2, 4, or 8 μg/plate

4) 45012522 (1996)

Acceptable/guideline

0, 500, 1000, 2000, 3000 or 4000 μg/mL	

1) Negative

2) Negative

3) Negative

4) Negative

Cytogenetics 

870.5375

1) In vitro Chinese hamster

2) In vitro Chinese hamster

870.5395

3) Hsd/Win: NMRI mouse bone marrow micronucleus 	

1) 45012527 (1999)

Acceptable/guideline

0, 625, 1250 or 2500 μg/mL

2) 45012613 (1996)

Acceptable/guideline

0, 500, 2500 or 5000 μg/mL 

3) 45012603 (1995)

Acceptable/guideline

2500 mg/kg	

1) Negative

2) Negative

3) Negative

Other Effects 

870.5550

UDS	

45012607 (1996)

Acceptable/guideline

0, 25, 100, 250, 500, 1000, 2000 or 4000 μg/mL	

Negative

870.6200a

Acute neurotoxicity screening battery	

45012512 (1997)

Acceptable/guideline

2000 mg/kg	

NOAEL = M: 2000 mg/kg and F: 800 mg/kg

LOAEL = M: not established and F: 2000 mg/kg based on a decrease in body
weight gain s was 800 mg/kg.

870.6200b

Subchronic neurotoxicity screening battery	

45012609 (1998)

Acceptable/guideline

0, 1000, 4000, or 20,000 ppm M: 0, 64, 252, or 1321 mg/kg/d

F: 0, 79, 312, or 1651 mg/kg/d	

NOAEL ( M: 1321 mg/kg/day and F ( 1651 mg/kg/day 

LOAEL = not established

870.7485

Metabolism and pharmacokinetics	

45012631 (1999)

Acceptable/guideline

2 or  200 mg/kg

		

 labeled in the phenyl position.  No metabolites were found in the urine
of rats that received propoxycarbazone-sodium labeled in the triazol
position.  One metabolite, STJ 4934, was recovered in the feces of rats
that received propoxycarbazone-sodium labeled in the phenyl position and
accounted for 2-9% of the fecal radioactivity.  The primary fecal
metabolite found from rats treated with the triazol-labeled test
material was identified as MKH 7017 and accounted for ~3% of the
recovered radioactivity.  The metabolite Pr-2-OH MKH 6561, a product of
wheat metabolism, was essentially not found in the urine or feces of
treated rats.

Propoxycarbazone-sodium	                       Human-Health Risk
Assessment		DP#: 348510

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