Document ID: EPA-HQ-OPP-2010-0865-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-12-30T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

CHEMICAL SAFETY AND

POLLUTION PREVENTION

Date: November 7, 2011

MEMORANDUM

SUBJECT:	Amended:  Tepraloxydim:  Human Health Risk Assessment for New
Tolerances on Imported Dry Bean and Dry Pea Subgroup 6C and Sunflower
Subgroup 20B.

PC Code:  121005	DP Barcode:  D395874

Decision No.:  440435	Registration Nos.:  NA

Petition Nos.:  0E7788	Regulatory Action:  Tolerance Assessment 

Risk Assessment Type:  Single chemical/ aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  149979-41-9

MRID No.:  NA	40 CFR:  §180.573

FROM:	Barry O’Keefe, Senior Biologist

		Amelia Acierto, Chemist

		Sheila Healy, Toxicologist

		Risk Assessment Branch III

		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief

		Risk Assessment Branch III

		Health Effects Division (7509P)

TO:		Susan Stanton, RM 25

		Herbicide Branch

		Registration Division (7505P)

Introduction

This amendment of the recent HED risk assessment (DP384834, B.
O’Keefe, 7/28/11) of tepraloxydim was completed to provide a more
thorough characterization of the toxicological database for
tepraloxydim. 

BASF Corporation, on behalf of Nippon Soda Company, has submitted a
petition (Petition No. 0E7788) proposing the establishment of tolerances
for residues of the herbicide tepraloxydim and its metabolites
convertible to GP [3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid],
calculated as tepraloxydim, in/on the following imported raw
agricultural commodities grown in Canada:

Pea and bean, dried shelled, except soybean, subgroup 6C	0.10 ppm

Sunflower subgroup 20B	0.25 ppm

Tepraloxydim is registered for use in Canada under the trade name
EQUINOX™ EC Herbicide, an emulsifiable concentrate formulation
containing 200 g/L (1.67 lb ai/gal) which is identical to EQUINOX EC
Herbicide, registered in the US (EPA Reg. No. 8033-12) on canola,
cotton, fallow land, non-cropland, and soybeans.  The label was amended
and approved by PMRA in April 2010 to include new uses on additional
crops of Subgroup 6C and on sunflower.  The product was previously
labeled in Canada under the trade name ARAMOTM EC Herbicide (Canadian
Reg. No. 27603).  BASF has no plans to apply to register EQUINOX in the
U.S for the new uses on dried beans and sunflower.  

The Registration Division (RD) requested that the Health Effects
Division (HED) evaluate toxicology and residue chemistry data and
conduct dietary and aggregate exposure and risk assessments, as needed,
to estimate the risk to human health that will result from these new
tolerances on imported commodities.

A summary of the findings and an assessment of human risk resulting from
the registered and proposed new uses of tepraloxydim are provided in
this document.  The risk assessment was provided by Barry O’Keefe, the
hazard characterization by Sheila Healy, and the residue chemistry data
review and the dietary assessment by Amelia Acierto.  The drinking water
assessment was provided by James Breithaupt of the Environmental Fate
and Effects Division (EFED).

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc308438131 \h  5 

2.0	Regulatory Conclusions and Recommendations	  PAGEREF _Toc308438132
\h  6 

2.1	Data Deficiencies	  PAGEREF _Toc308438133 \h  7 

2.2	Tolerance Considerations	  PAGEREF _Toc308438134 \h  7 

2.2.1	Enforcement Analytical Method	  PAGEREF _Toc308438135 \h  7 

2.2.2	International Harmonization	  PAGEREF _Toc308438136 \h  8 

2.2.3	Recommended Tolerances	  PAGEREF _Toc308438137 \h  9 

2.2.4	Revisions to Petitioned-For Tolerances	  PAGEREF _Toc308438138 \h 
10 

3.0	Ingredient Profile	  PAGEREF _Toc308438139 \h  10 

3.1	Summary of Proposed Uses	  PAGEREF _Toc308438140 \h  10 

3.2	Structure and Nomenclature	  PAGEREF _Toc308438141 \h  11 

3.3	Physical and Chemical Properties	  PAGEREF _Toc308438142 \h  13 

3.4	Anticipated Exposure Pathways	  PAGEREF _Toc308438143 \h  13 

3.5	Consideration of Environmental Justice	  PAGEREF _Toc308438144 \h 
13 

4.0	Hazard Characterization/Assessment	  PAGEREF _Toc308438145 \h  14 

4.1	Toxicology Studies Available for Analysis	  PAGEREF _Toc308438146 \h
 14 

4.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc308438147 \h  15 

4.2.1	Dermal Absorption	  PAGEREF _Toc308438148 \h  15 

4.3	Toxicological Effects	  PAGEREF _Toc308438149 \h  15 

4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	 
PAGEREF _Toc308438150 \h  17 

4.4.1	Completeness of the Toxicity Database	  PAGEREF _Toc308438151 \h 
17 

4.4.2	Evidence of Neurotoxicity	  PAGEREF _Toc308438152 \h  18 

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing of Young
Animal	  PAGEREF _Toc308438153 \h  18 

4.4.4	Residual Uncertainty in the Exposure Database	  PAGEREF
_Toc308438154 \h  19 

4.5	Toxicity Endpoint and Point of Departure Selections	  PAGEREF
_Toc308438155 \h  19 

4.5.1	Recommendation for Combing Routes of Exposures for Risk Assessment
  PAGEREF _Toc308438156 \h  19 

4.5.2	Cancer Classification and Risk Assessment Recommendation	  PAGEREF
_Toc308438157 \h  19 

4.5.3	Summary of Points of Departure and Toxicity Endpoints Used in
Human Risk Assessment	  PAGEREF _Toc308438158 \h  20 

4.6	Endocrine Disruption	  PAGEREF _Toc308438159 \h  21 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc308438160 \h 
22 

5.1	Pesticide Metabolism	  PAGEREF _Toc308438161 \h  22 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc308438162 \h  22 

5.1.2	Metabolism in Livestock	  PAGEREF _Toc308438163 \h  22 

5.1.3	Drinking Water Residue Profile	  PAGEREF _Toc308438164 \h  23 

5.1.4	Food Residue Profile	  PAGEREF _Toc308438165 \h  24 

5.2	Dietary Exposure and Risk	  PAGEREF _Toc308438166 \h  27 

5.2.1	Acute Dietary Exposure/Risk	  PAGEREF _Toc308438167 \h  28 

5.2.2	Chronic Dietary Exposure/Risk	  PAGEREF _Toc308438168 \h  29 

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc308438169 \h  29 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc308438170 \h  29 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc308438171 \h  30 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc308438172
\h  30 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc308438173 \h  31 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc308438174 \h  31 

A.1  Toxicology Data Requirements	  PAGEREF _Toc308438175 \h  31 

A.2  Toxicity Profiles	  PAGEREF _Toc308438176 \h  32 

Appendix B:  Physical and Chemical Properties	  PAGEREF _Toc308438177 \h
 36 

Appendix C:  International Residue Limit Status	  PAGEREF _Toc308438178
\h  37 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Tepraloxydim is a herbicidal active ingredient (ai) intended for
postemergence control of certain annual grasses and quackgrass, and is
currently registered and formulated as EquinoxTM (1.67 lb ai/gal EC) for
use on canola, cotton and soybean crops in the US.  BASF Corporation, on
behalf of Nippon Soda Company, submitted a petition (Petition No.
0E7788), proposing the establishment of tolerances for residues of the
herbicide tepraloxydim and its metabolites convertible to GP
[3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid], calculated as
tepraloxydim, in/on the following imported raw agricultural commodities
grown in Canada:  pea and bean, dried shelled, except soybean, subgroup
6C, and sunflower subgroup 20B.

Use Profile

BASF submitted a label for the 200 g/L (1.67 lb ai/gal) EQUINOX EC
Herbicide which was previously labeled in Canada under the trade name
ARAMOTM EC Herbicide (Canadian Reg. No. 27603).  The emulsifiable
concentrate formulation is identical to EQUINOX EC Herbicide, registered
in the U.S. (EPA Reg. No. 8033-12) on canola, cotton, fallow land,
non-cropland, and soybeans.  The label has been amended and approved by
PMRA in April 2010 to include its use on the additional crops in
Subgroup 6C and sunflower subgroup 20B.  BASF noted that they have no
plans to apply for U.S. registration of EQUINOX use on the additional
Subgroup 6C crops or on sunflower subgroup 20B crops at this time. 
Under the registered use pattern in Canada, tepraloxydim is applied as a
broadcast foliar spray to crop subgroup 6C crops at up to 0.045 lb ai/A
(50 g ai/ha), and  to sunflower subgroup 20B crops at up to 0.036 lb
ai/A (40 g ai/ha), with preharvest intervals (PHIs) of 60 days for
crops.

Toxicity/Hazard

The toxicological database for tepraloxydim is sufficient for the
purpose of this risk assessment.  The main target organs for
tepraloxydim toxicity are the liver, the spleen/hematopoietic system and
reproductive system.  The reproductive system was affected at relatively
high doses (in excess of LOAELs).    SEQ CHAPTER \h \r 1 Tepraloxydim
also affected the hematopoietic system.  Prenatal developmental toxicity
studies indicate that, relative to maternal animals, the developing rat
fetus had increased quantitative and qualitative susceptibility to
tepraloxydim while no increased susceptibility was evident in the
developing rabbit fetus or rat pups.  In both the acute and subchronic
rat neurotoxicity studies, there were mild changes in motor activity and
grip strength indices.  None of the studies, including both
neurotoxicity studies, reported treatment-related effects on brain
weight or gross/microscopic lesions in the tissues of the nervous
system.

Data are inadequate for an assessment of human carcinogenic potential
because some evidence is suggestive of carcinogenic effects, but other
equally pertinent evidence does not confirm, therefore, quantification
of human cancer risk is not required.  The Agency, however, has
determined that additional carcinogenicity studies are not required
since the doses tested in both species, mice and rats, were adequate to
assess the carcinogenic potential of tepraloxydim and that the chronic
PAD (0.05 mg/kg/day) will adequately protect for all chronic effects,
including carcinogenicity, likely to result from exposure to
tepraloxydim.

  SEQ CHAPTER \h \r 1 Tepraloxydim has a low acute toxicity based on its
classification in Toxicity Category III via the oral route, Toxicity
Category III by the dermal route, and Toxicity Category IV by the
inhalation route of exposure.  Tepraloxydim produces minimal eye
irritation (Toxicity Category III), is a slight dermal irritant and is
not a dermal sensitizer.

The 10X FQPA Safety Factor was retained for assessing the acute dietary
risk (aRfD) for the general population in the form UFL since a LOAEL was
used as the point of departure (i.e., a NOAEL was not identified in the
critical study).  Since NOAELs are used for assessing acute dietary risk
of Females 13-49 and for chronic dietary exposure scenarios, the FQPA
Safety Factor was reduced to 1X for these scenarios.

Drinking Water

No new estimated drinking water concentrations (EDWCs) were computed for
the new tolerances on imported commodities from this petition.  The
estimated environmental concentrations (EECs) previously computed for
surface water concentrations were used.  Based on FIRST-IR modeling, the
acute and chronic EECs are 1.4 and 0.7 μg/L, respectively.

Dietary Exposure (food and drinking water)

Unrefined dietary (food and drinking water) exposure analyses which were
performed using the Dietary Exposure Evaluation Model (DEEM-FCID™,
Version 2.03) indicate that acute and chronic dietary exposures to
tepraloxydim from food and drinking water are well below HED’s level
of concern (LOC) for tepraloxydim.  Acute dietary exposure from food and
drinking water at the 95th percentile of exposure represents <1% (0.74%)
of the acute Population Adjusted Dose (aPAD) for the general U.S.
population, and for children 1-2 years old, the most highly exposed
subgroup, the exposure represents 2.2% of the aPAD.  Chronic dietary
exposure represents 2.4% of the chronic Population Adjusted Dose (cPAD)
for the general U.S. population and 9.6% of the cPAD for children 1-2
years old, the population subgroup with the highest estimated chronic
dietary exposure to tepraloxydim.

Residential Exposure

This document only presents the assessment of the proposed new tolerance
for imported commodities.  No residential uses are being requested at
this time; therefore, no residential risk assessment has been conducted.

Aggregate Risk

There is no residential exposure expected for tepraloxydim; therefore,
the sources considered in the aggregate assessment are food and drinking
water.  Because the dietary assessment incorporates exposure from both
food and drinking water, the dietary assessment addresses concern from
aggregate exposure.  

2.0	Regulatory Conclusions and Recommendations  TC \l1 "2.0	Regulatory
Conclusions and Recommendations 

Provided a revised Section F (OPPTS 860.1550) is submitted, HED can
recommend for permanent tepraloxydim tolerances for the imported
commodities in pea and bean, dried shelled, except soybean, subgroup 6C
and sunflower subgroup 20B.  Additional data are needed as outlined in
Section 2.1 below.  The specific tolerance recommendations are discussed
in Section 2.2.

Data Deficiencies  TC \l2 "2.1	Data Deficiencies 

The following must be provided prior to a tolerance being established or
registration allowed:

860.1550  Proposed Tolerance

A revised Section F must be submitted to propose a tolerance of 0.20 ppm
for sunflower subgroup 20B to harmonize with the established MRL for
residues of tepraloxydim in/on sunflower in Canada.  

Note to RD:  The petitioner should be notified that the following data
are required for domestic registrations: 

TOXICOLOGY

870.3465  28-Day Inhalation Toxicity Study

A guideline 28 day inhalation toxicity study is required to fulfill
current 40 CFR Part 158 data requirements.

870.7800  Immunotoxicity Study

A guideline immunotoxicity study is required to fulfill current 40 CFR
Part 158 data requirements.  A guideline immunotoxicity submission is
expected by the end of 2011.

RESIDUE CHEMISTRY

860.1650  Submittal of Analytical Reference Standards

The following reference standards for tepraloxydim metabolites in the
National Pesticide Standards Repository have expired and the registrant
is urged to submit new standards with new lot numbers or to recertify
the lot numbers of the standard in the repository.  The new standard or
updated certificate of analysis must be sent to the Pesticide
Repository. 

BH 620-DML  (expired on 10/1/2010)

BH 620-OH-DMP  (expired on 10/1/2010)

Tolerance Considerations  TC \l2 "2.2	Tolerance Considerations 

2.2.1	Enforcement Analytical Method  TC \l3 "2.2.1	Enforcement
Analytical Method 

An adequate gas chromatography/mass spectrometry (GC/MS) enforcement
method, BASF Analytical Method D9701/1, is available for the enforcement
of tolerances for plant commodities.  The method has been reported and
reviewed in detail in conjunction with earlier petitions (PP#8F04945,
D243962, L Cheng, 10/3/2000 and PP#6E7046, D328044, N. Dodd, 6/19/2007).
 The method is designed to determine the total residues of tepraloxydim
and its metabolites.  Parent tepraloxydim and related metabolites
containing the 3-tetrahydropyranylpentane-1,5-dione moiety are converted
by oxidation to GP, and GP residues are subsequently methylated and
determined as DMP (dimethyl 3-(tetrahydropyran-4-yl)pentane-1,5-dioate).
 Residues of 5-OH-DP and related 5-hydroxy-metabolites containing the
3-hydroxy-3-tetrahydropyranylpentane-1,5-dione moiety are oxidized to
OH-GP and are subsequently methylated and quantified as OH-DMP (dimethyl
3-hydroxy-3-(tetrahydroxypyran-4-yl)pentane-1,5-dioate).  Ions 168, 182,
and 213 are monitored for DMP, with ion 182 the typical quantitation
ion.  Ions 143 and 175 are monitored for OH-DMP, with ion 143 the
typical quantitation ion.  Residues are reported in terms of parent
equivalents.  The validated limit of quantitation (LOQ) for each of the
residues of tepraloxydim and 5-OH-DP is 0.05 ppm.  BASF Method D9701/1
has been successfully radiovalidated and has undergone an independent
laboratory validation (ILV).  HED has determined that a tolerance method
validation by the Agency’s analytical laboratory is not necessary. 

Adequate GC/MS enforcement methods, BASF Analytical Method Nos. 389/0
and 975/1, are available for determining residues in livestock.  The
methods have been reported and also reviewed in detail in conjunction
with the earlier petitions for tolerances for residues of tepraloxydim
in or on imported commodities (PP#8F04945, D243962, L Cheng, 10/3/2000
and PP#6E7046, D328044, N. Dodd, 6/19/2007).    SEQ CHAPTER \h \r 1 The
LOQ for residues of tepraloxydim, 5-OH-DP, and DL are 0.01 ppm each in
milk, 0.05 ppm each in eggs, and 0.05 ppm each in livestock tissues.  
HED has determined that based on the successful radiovalidation and ILV
studies on BASF Analytical Method Nos. 389/0 and 975/1, a tolerance
method validation in the Agency’s analytical laboratory is not
necessary.

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method (BASF
Analytical Method D9704) is available for data collection in plant
commodities.  The method is a confirmatory method for the enforcement
method in plants.  It is a common moiety method and determines the
residues of tepraloxydim and its metabolites containing the
3-tetrahydropyranylpentane-1,5-dione moiety which are converted by
oxidation to GP and determined as GP; and residues of metabolite 5-OH-DP
and related hydroxy metabolites containing the
3-hydroxy-3-tetrahydropyranylpentane-1,5-dione moiety which is oxidized
to OH-GP and determined as OH-GP.  Residues of GP and OH-GP are
expressed as the parent using molecular weight conversion factors.  A
slightly modified method (BASF Analytical Method D9704/1) was used to
analyze the residues of tepraloxydim and its metabolites from the
submitted crop field trials in support of the current petition.  The
validated LOQ for the combined residues of tepraloxydim and its
metabolites in both dry bean seeds and sunflower seeds is 0.10 ppm (0.05
ppm for tepraloxydim derived from GP, and 0.05 ppm for 5-OH-DP derived
from OH-GP).

2.2.2	International Harmonization  TC \l3 "2.2.2	International
Harmonization 

There are no Codex MRLs for residues of tepraloxydim.  A Canadian MRL
has been established for residues of tepraloxydim and its metabolites
convertible to 3-perhydropyran-4-ylglutaric acid (GP) and
3-hydroxy-3-perhydropyran-4-ylglutaric acid (OH-GP), expressed as parent
equivalent, in sunflower crop subgroup 20B and dried shelled pea and
bean, except soybean, crop subgroup 6C.  The US tolerance expression for
plants is harmonized with the Canadian expression.  An International
Residue Limit (IRL) status sheet is appended to this document as
Appendix C.

2.2.3	Recommended Tolerances  TC \l3 "2.2.3	Recommended Tolerances 

HED has examined the residue chemistry database for tepraloxydim. 
Pending submission of a revised Section F, there are no residue
chemistry issues that would preclude establishment of tolerances for
residues of tepraloxydim as follows:

Pea and bean, dried shelled, except soybean, subgroup 6C ...........
0.10 ppm

Sunflower subgroup 20B
................................................................0.20 ppm

The tolerances for lentil, seed and pea, dry, seed should be revoked, as
these are covered by the new subgroup 6C tolerance.

The tolerance expression for tepraloxydim in 40 CFR §180.573(a)(1),
(a)(2), and (c) should be stated according to HED’s Interim Guidance
on Tolerance Expression (5/27/09, S. Knizner) as follows:

40 CFR §180.573(a)(1)

“Tolerances are established for residues of tepraloxydim, including
its metabolites and degradates, in or on the commodities in the table
below.  Compliance with the tolerance levels specified below is to be
determined by measuring only the combined residues of tepraloxydim
(2-[1-[[[(2E)-3-chloro-2-propen-1-yl]oxy]imino]propyl]-3-hydroxy-5-(tetr
ahydro-2H-pyran-4-yl)-2-cyclohexen-1-one) and its metabolites
convertible to GP (3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid) and
OH-GP (3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid),
calculated as tepraloxydim.”

40 CFR §180.573(a)(2)

“Tolerances are established for residues of tepraloxydim, including
its metabolites and degradates, in or on the commodities in the table
below.  Compliance with the tolerance levels specified below is to be
determined by measuring only the combined residues of tepraloxydim
(2-[1-[[[(2E)-3-chloro-2-propen-1-yl]oxy]imino]propyl]-3-hydroxy-5-(tetr
ahydro-2H-pyran-4-yl)-2-cyclohexen-1-one) and its metabolites
convertible to GP (3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid),
OH-GP (3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid), and GL
(3-(2-oxotetrahydropyran-4-yl)-1,5-dioic acid), calculated as
tepraloxydim,”

40 CFR §180.573(c)

“A tolerance with regional registration, as defined in §180.1(m), is
established for residues of tepraloxydim, including its metabolites and
degradates, in or on the commodities in the table below.  Compliance
with the tolerance levels specified below is to be determined by
measuring only the combined residues of tepraloxydim
(2-[1-[[[(2E)-3-chloro-2-propen-1-yl]oxy]imino]propyl]-3-hydroxy-5-(tetr
ahydro-2H-pyran-4-yl)-2-cyclohexen-1-one) and its metabolites
convertible to GP (3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid) and
OH-GP (3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid),
calculated as tepraloxydim.”

2.2.4	Revisions to Petitioned-For Tolerances  TC \l3 "2.2.4	Revisions to
Petitioned-For Tolerances 

The proposed tolerance of 0.25 ppm for imported sunflower subgroup 20B
should be modified to 0.20 ppm to harmonize with the established
Canadian MRL.

Table 1. Tolerance Summary for Tepraloxydim.

Commodity	Proposed Tolerance

(ppm)	Recommended Tolerance

(ppm)	Comments

(correct commodity definition)

40 CFR §180.573

Pea and bean, dried shelled, except soybean, subgroup 6C	0.10	0.10

	Sunflower subgroup 20B	0.25	0.20

	

3.0	Ingredient Profile  TC \l1 "3.0	Ingredient Profile 

3.1	Summary of Proposed Uses  TC \l2 "3.1	Summary of Proposed Uses 

Tepraloxydim is a selective broad-spectrum cyclohexene oxime herbicide
intended for postemergence control of certain annual grasses and
quackgrass.  Tepraloxydim is a systemic herbicide that enters the target
weed through the foliage and translocates throughout the plant,
inhibiting acetyl-coenzyme A carboxylase (ACCase) in the plant. 
Tolerances were previously established in support of U.S. uses of
tepraloxydim on canola, cotton, and soybean, and for imported
commodities of flax, dry pea, and lentil from Canadian uses.  Under the
registered use pattern in Canada, tepraloxydim is applied to sunflower
subgroup 20B crops and Crop Group 6, subgroup 6C, Dried shelled pea and
bean (except soybean) crops.

BASF submitted a label for the 200 g/L (1.67 lb ai/gal) EQUINOX EC
Herbicide which was previously labeled in Canada under the trade name
ARAMOTM EC Herbicide (Canadian Reg. No. 27603).  The emulsifiable
concentrate formulation is identical to EQUINOX EC Herbicide, registered
in the U.S. (EPA Reg. No. 8033-12) on canola, cotton, fallow land,
non-cropland, and soybeans.  The label has been amended and approved by
PMRA in April 2010 to include its use on the additional crops in
Subgroup 6C and sunflower subgroup 20B.  BASF noted that they have no
plans to apply for U.S. registration of EQUINOX use on the additional
Subgroup 6C crops or on sunflower subgroup 20B crops at this time. 
Under the registered use pattern in Canada, tepraloxydim is applied as a
broadcast foliar spray to crop group 6, subgroup 6C crops at up to 0.045
lb ai/A (50 g ai/ha), and  to sunflower subgroup 20B crops at up to
0.036 lb ai/A (40 g ai/ha), with preharvest intervals (PHIs) of 60 days
for crops.

The summary of the proposed use directions for the intended crops is
summarized in Table 2. 



Table 2.  Summary of Directions for Use of Tepraloxydim in Canada

Applic. Timing, Type, and Equip.	Formulation

	Applic. Rate 

g ai/ha 

(lb ai/A)

	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

g ai/ha

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Crop Group 6, subgroup 6C, Dried shelled pea and bean (except soybean). 
Includes Lupinus, spp: (grain lupin, sweet, white and white sweet
lupin); Phaseolus, spp. (field bean, kidney bean, lima bean (dry), navy
bean, pinto bean, tepary bean); Vigna spp (adzuki bean, blackeyed pea,
catjang, cowpea, Chowder pea, moth bean, mung bean, rice bean, southern
pea, urd bean); Broad bean (dry), chickpea, quard, lablab bean; lentil
pea); Pisum spp. (field pea and pigeon pea). 1

Postemergence,

Broadcast, Foliar

Ground equipment	EQUINOX EC Herbicide 2

(1.67 lb ai/gal)	50

(0.045)

	NS4	50

(0.045)

	60	Add Merge® (0.5% v/v) or DASH HC (0.41% v/v) adjuvant to tank mix. 
Application may be made from emergence to the 7-trifoliate leaf stage
for dry beans and from emergence to 9 leaf for dry pea.  Do not apply
EQUINOX EC herbicide by air.

Sunflower Subgroup 20B (sunflower seed, Calendula; castor oil plant;
chinese tallow tree; euphorbia; evening primrose; jojoba; niger seed;
rose hip; safflower; stokes aster; tallowood; tea oil plant; vernonia;
cultivars, varieties, and/or hybrids of these) 3

Postemergence,

Broadcast, Foliar

Ground Equipment	EQUINOX EC Herbicide

1.67 lb/gal EC	33-40

(0.029-0.036)

	NS4	

40

(0.036)

	60	Application is made from emergence to 10 leaf stage.  Add Merge®
(0.5% v/v) or DASH HC (0.41% v/v) adjuvant to tank mix.  Application is
made at emergence to 10- leaf stage.  Do not apply EQUINOX EC herbicide
by air.

1 Dry bean variety (of the genera Phaseolus, Lupinus and Vigna) may vary
in their tolerance to herbicides, including to EQUINOX EC herbicide. 
Since not all dry bean varieties have been tested for tolerance to
EQUINOX EC herbicide, first use of EQUINOX EC herbicide should be
limited to a small area of each variety to confirm tolerance prior to
adoption as a general field practice.  Additionally, consult your seed
supplier for information on the tolerance of specific varieties of dry
beans to EQUINOX EC herbicide. 

2 For sale and use in the Prairie provinces and Peace River region of
British Columbia only.

3All types including imazethapyr and imazamox tolerant sunflower with
the CLEARFIELD trait. 

4NS= not specified on label.

3.2	Structure and Nomenclature  TC \l2 "3.2	Structure and Nomenclature 

Structure and nomenclature of tepraloxydim are reported in Table 3.



Table 3.  Tepraloxydim Structure and Nomenclature.

Chemical structure	

Molecular Formula	C17H24ClO4

Common name	Tepraloxydim 1

Company experimental name	BAS 620 H; DP

IUPAC name
(5RS)-2-{(EZ)-1-[(2E)-3-chloroallyloxyimino]propyl}-3-hydroxy-5-perhydro
pyran-4-ylcyclohex-2-en-1-one

CAS name
2-[1-[[[(2E)-3-chloro-2-propen-1-yl]oxy]imino]propyl]-3-hydroxy-5-(tetra
hydro-2H-pyran-4-yl)-2-cyclohexen-1-one

CAS registry number	149979-41-9

End-use product/EP	Aramo™ EC herbicide, Reg. No. 27603; a 1.67 lb
ai/gal EC (200 g ai/L EC)

(same as Equinox™ herbicide, EPA Reg. No. 8033-12; 1.67 lb ai/gal EC)

Chemical Class	Cyclohexene oxime herbicide

Known Impurities of Concern	None

Chemical structure:

Metabolite 	

Common name	Metabolite:  5-OH-DP; BH 620-5-OH-DP

Chemical name
2-[1-[[[(2E)-3-chloro-2-propen-1-yl]oxy]imino]propyl]-3,5-hydroxy-5-(tet
rahydro-2H-pyran-4-yl)-2-cyclohexen-1-one

Chemical structure:

Oxidation product determined by analytical method 	

Common name	GP; BH 620-GP

Chemical name	3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid

Chemical structure:

Oxidation product determined by analytical method	

Common name	OH-GP; BH 620-OH-GP

Chemical name	3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid

3.3	Physical and Chemical Properties  TC \l2 "3.3	Physical and Chemical
Properties 

The physicochemical properties of tepraloxydim are reported in Appendix
B.  

3.4	Anticipated Exposure Pathways  TC \l2 "3.4	Anticipated Exposure
Pathways 

The Registration Division has requested an assessment of human health
risk to support the proposed new uses of tepraloxydim on imported dry
bean and dry pea subgroup 6C and sunflower subgroup 20B commodities. 
For domestic uses, humans may be exposed to tepraloxydim in food and
drinking water, since tepraloxydim may be applied directly to growing
crops and application may result in tepraloxydim reaching surface and
ground water sources of drinking water.  In an occupational setting,
applicators may be exposed while handling the pesticide prior to
application, as well as during application.  There is a potential for
post-application exposure for workers re-entering treated fields.  There
are no residential uses of tepraloxydim; thus, there is no exposure in
residential or non-occupational settings.  

Several risk assessments have been previously prepared for the existing
uses of tepraloxydim.  This risk assessment considers all of the
aforementioned exposure pathways based on the proposed new uses of
tepraloxydim, but also considers the existing uses as well, particularly
for the dietary exposure assessment.  

3.5	Consideration of Environmental Justice  TC \l2 "3.5	Consideration of
Environmental Justice 

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

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, 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, nondietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
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.

4.0	Hazard Characterization/Assessment  TC \l1 "4.0	Hazard
Characterization/Assessment 

References:

TEPRALOXYDIM – Human Health Risk Assessment for Tolerances on Imported
Dry Pea, Flax and Lentil, S. Winfield, DP Number: 328441, 7/20/07

TEPRALOXYDIM – Report of the Hazard Identification Assessment Review
Committee, G. Dannan, HED Doc. No.: 014515, DP Number: 243962, 2/26/01.

TEPRALOXYDIM – Report of the FQPA Safety Factor Committee, B. Tarplee,
HED Doc. No. 014403, 12/13/00.

The most recent risk assessment was supported by the HED HIARC report
(HED Doc. No. 014515, 2/26/01).  HED has reevaluated the existing
toxicity database in accordance with the 2002 FQPA policy and has
retained the 10X FQPA Safety Factor for lack of a NOAEL in the acute
neurotoxicity study (aRfD, general population including infants and
children).  HED is no longer requiring a developmental neurotoxicity
(DNT) study.  Additionally, with the recent submission of a positive
control dataset, the 870.6200 Neurotoxicity Battery has been upgraded to
Acceptable/Guideline.

4.1	Toxicology Studies Available for Analysis  TC \l2 "4.1	Toxicology
Studies Available for Analysis 

The existing toxicity database is adequate to characterize hazard and
support the existing and requested food tolerances for tepraloxydim.

The following studies are available for consideration:

• Subchronic: Dietary 90-day toxicity (rat); dietary 90-day
toxicity (dog)

• Developmental: rat and rabbit developmental toxicity studies 

• Reproduction: 2-generation reproduction (rat) 

• Chronic: chronic oral toxicity and carcinogenicity studies (rat);
oral carcinogenicity (mouse); one-year oral toxicity (dog)

• Neurotoxicity: Acute and 90-day oral

• Mutagenicity battery

• Metabolism in rats

• Mode of action studies

• Several toxicity studies with 5-OH-tepraloxydim (5-OH-DP)

4.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "4.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

Based on pharmacokinetics/metabolism studies in the rat, tepraloxydim is
readily and almost completely absorbed after oral administration, but is
rapidly excreted mainly via the urine.  Biliary excretion was
approximately 3 times greater than fecal elimination which suggests
enterohepatic recirculation. The rat plasma half-life of radiolabeled
tepraloxydim is approximately 4.4 and 10 hours at the low and high dose,
respectively.  No accumulation of radioactivity was observed in any
tissue at 120 hours post-dosing.  Numerous metabolites were detected in
the urine, feces, and bile; the main metabolic pathway being oxidation
of the pyran ring to lactone via a hydroxy metabolite, and cleavage of
the oxime ether group with the imine and oxazol as products.  At near
plasma tmax (one hour post dosing), the plasma, liver, and kidney
contained the parent compound almost exclusively.  The results indicate
that the distribution, metabolism, and excretion of tepraloxydim are
independent of dose level, sex, route of administration (oral vs. i.v.),
and site of label (pyran vs. cyclohexanone).

4.2.1	Dermal Absorption  TC \l3 "4.2.1	Dermal Absorption 

The dermal absorption rate was estimated from the results of the 28-day
dermal toxicity study in rats (MRID 44467140) and the developmental rat
toxicity studies (MRID 44467203/44467204).  In the oral developmental
toxicity study, the maternal NOAEL/LOAELs were 120/360 mg/kg/day based
on reduced maternal body weight gain and food intake.  In the 28-day rat
dermal toxicity study, there were no treatment-related clinical signs,
or effects on body weight, food consumption, hematology, clinical
chemistry, or organ weights.  The systemic and dermal NOAEL was the
limit dose of 1000 mg/kg/day and the LOAEL was unidentified.  Assuming
the dermal LOAEL is the limit dose of 1000 mg/kg/day, an approximate
dermal absorption rate of 36% was derived by relating the ratio of the
LOAELs from the oral and dermal studies (360/1000 x 100).  This
conservative approach results in a dermal absorption rate of 36%.  

4.3	Toxicological Effects  TC \l2 "4.3	Toxicological Effects 

The main target organs for tepraloxydim toxicity are the liver, the
spleen/hematopoietic system and reproductive system.  All subchronic and
chronic toxicity/carcinogenicity feeding studies had one or more of
these liver findings: increased incidences of hepatocellular foci,
abnormal liver function parameters, increased relative liver weight,
hepatocyte hypertrophy, in addition to increased hepatocellular
neoplasms in the mouse and rat carcinogenicity studies.    SEQ CHAPTER
\h \r 1 Bile accumulation including crystalline material was also
reported within the liver cells and canaliculi at the relatively high
dose of 325 mg/kg/day in the 13-week dog study.  In a non-guideline rat
oral feeding study, tepraloxydim weakly induced
pentoxyresorufin-O-deethylase activity (cytochrome P-450 activity),
typically induced by polynuclear aromatic hydrocarbons such as
3-methylcholanthrene; however, it failed to induce peroxisomal
β-oxidation or alter the glutathione cellular levels.

The reproductive system is a major target but was affected at relatively
high doses (in excess of LOAELs established in repeat-dose mouse, rat
and dog studies).  In the mouse carcinogenicity feeding study,
tepraloxydim caused morphological microscopic changes indicative of
reduced secretory activity in the seminal vesicles and preputial glands
in male mice.  Increased uterine sclerosis, decreased corpora lutea, and
decreased follicles were observed in female mice.  The frequencies of
the changes were dose-dependent in the mid- and high-dose males (332 and
1035 mg/kg/day) and females (490 and 1456 mg/kg/day).  Additionally,
increased incidences of focal calcification of the testes were observed
in the high dose group (155 mg/kg/day) of the rat carcinogenicity
feeding study.  The male dog sex organs were also affected at high doses
(325 mg/kg/day) as evidenced in the 13-week toxicity study, by reduced
epididymal and testicular weights associated with atrophy and
azoospermia, and, in the supplementary one-year study, by diminished
epididymal and prostatic secretory activities which were accompanied by
a marked loss of acinar lumina and a moderate interacinar sclerosis at
248 mg/kg/day.

  SEQ CHAPTER \h \r 1 Tepraloxydim also affected the hematopoietic
system.  In dogs, hemolytic anemia was demonstrated by depressed
hematocrit, hemoglobin, and RBCs as early as day 40/41 among the high
dose (325 mg/kg/day) animals.  Similar effects were also reported in
dogs dosed at 248 mg/kg/day beginning on Day 88 and throughout the
one-year study period.  These changes were accompanied by compensatory
responses, including splenic hematopoiesis, femoral and sternal bone
marrow hyperplasia, increased erythroid precursors and hemosiderin-laden
macrophages, and splenic hemosiderosis.  

Prenatal developmental toxicity studies indicate that, relative to
maternal animals, the developing rat fetus had increased quantitative
and qualitative susceptibility to tepraloxydim while no increased
susceptibility was evident in the developing rabbit fetus or rat pups. 
In the rat developmental toxicity study, the developmental toxicity
LOAEL of 120 mg/kg/day, based on reduced fetal body weights, delayed
ossification and the occurrence of hydroureter, is 3-fold less than the
maternal toxicity LOAEL of 360 mg/kg/day, which is based on reduced body
weight and body weight gain.  There were additional developmental
anomalies or malformations in the observed at 360 mg/kg/day, such as
dilatation of both heart ventricles and filiform tails that were
observed externally and corresponded to absent caudal and sacral
vertebrae.  In contrast, no developmental effects were seen in the
rabbit prenatal toxicity study up to the highest tested dose of 180
mg/kg/day which was considered to be the maternal LOAEL due to reduced
maternal body weight and food consumption (maternal NOAEL = 60
mg/kg/day).  Also, in the rat multigeneration reproduction study, there
was no increase in susceptibility since the NOAEL and LOAEL (50.6 and
260.0 mg/kg/day, respectively) were equal for both the offspring
developmental systemic toxicity and the parental systemic toxicity. 
Further, there were no effects on any of the measured reproductive
parameters up to and including the highest tested dose (reproductive
NOAEL ≥260 mg/kg/day).

In both the acute and subchronic rat neurotoxicity studies, there were
mild changes in motor activity and grip strength indices.  On day 0 of
the acute oral neurotoxicity study in rats, motor activity was decreased
(by up to 40%) in all treated female groups (500, 1000 and 2000 mg/kg)
while forelimb grip strength was slightly increased (by up to 28%) in
all treated females.  In the rat subchronic neurotoxicity study, motor
activity was increased in the high dose females (428 mg/kg/day in males
and 513 mg/kg/day in females) at day 50 (37%) and in both sexes on day
85 (28-44%).  None of the studies, including both neurotoxicity studies,
reported treatment-related effects on brain weight or gross/microscopic
lesions in the tissues of the nervous system.

  SEQ CHAPTER \h \r 1 Tepraloxydim has a low acute toxicity based on its
classification in Toxicity Category III via the oral route, Toxicity
Category III by the dermal route, and Toxicity Category IV by the
inhalation route of exposure (Appendix Table A.2.1).  Tepraloxydim
produces minimal eye irritation (Toxicity Category III), is a slight
dermal irritant, and is not a dermal sensitizer.

4.4	Safety Factor for Infants and Children (FQPA Safety Factor)  TC \l2
"4.4	Safety Factor for Infants and Children (FQPA Safety Factor) 

A 10X FQPA Safety Factor is retained for assessing the acute dietary
risk (aRfD) for the general population in the form UFL since a LOAEL was
used as the point of departure (i.e., a NOAEL was not identified in the
critical study).  However the critical effect observed at the LOAEL of
500 mg/kg/day was neither severe nor irreversible; a dose-responsive
decrease in motor activity was observed in females on Day 0 in the
absence of any other treatment related clinical signs (including FOB) or
neurohistopathological effects.  The dose-response relationship of
tepraloxydim indicates that an uncertainty factor of 10X is sufficiently
protective against the critical effect and any other adverse effects at
the aRfD.

Since NOAELs are used for assessing acute dietary risk of Females 13-49
and for chronic dietary exposure scenarios, the FQPA Safety Factor is
reduced to 1X for these scenarios.

4.4.1	Completeness of the Toxicology Database  TC \l3 "4.4.1
Completeness of the Toxicity Database 

The toxicity database is complete except for immunotoxicity testing
(OPPTS Guideline 870.7800).  Recent changes to 40 CFR §158 make these
studies required for pesticide registration.  Although immunotoxicity
studies have not yet been submitted, there is no evidence of
immunotoxicity in any study in the toxicity database for tepraloxydim. 
In the absence of specific immunotoxicity studies, EPA has evaluated the
available tepraloxydim toxicity database to determine whether an
additional database uncertainty factor is needed to account for
potential immunotoxicity.  No evidence of immunotoxicity was found. 
Treatment-related effects seen in the spleen (splenic hematopoiesis) and
bone marrow (hyperplasia) are compensatory responses to
tepraloxydim-induced hemolytic anemia.  

Due to the lack of evidence of immunotoxicity for tepraloxydim, EPA does
not believe that conducting immunotoxicity study will result in a NOAEL
less than that to derive the current cRfD of 5 mg/kg bw/day. 
Consequently, the EPA believes the existing data are sufficient for
endpoint selection for exposure/risk assessment scenarios and for
evaluation of the requirements under the FQPA, and an additional
database uncertainty factor does not need to be applied.

A 28-day rat inhalation toxicity study was required in previous risk
assessments based on expected exposure patterns.  This study remains
pending.

4.4.2	Evidence of Neurotoxicity  TC \l3 "4.4.2	Evidence of
Neurotoxicity 

In the acute oral neurotoxicity study in rats, decreased motor activity
was observed on Day 0 (29-41% below control, p < 0.05 for females, NS
for males) and sustained until Day 7 in mid-dose females only (~30%,
1000 mg/kg/day; p < 0.01).  In the subchronic neurotoxicity study,
increased motor activity was observed in females on Day 50 (28-44% above
control) in both sexes on Day 85 at the highest dose tested (428
mg/kg/day, males; 513 mg/kg/day, females).  HED priorly recommended a
developmental neurotoxicity study (DNT).  However, upon reevaluation of
the data in accordance with the 2002 FQPA 10X Guidance Document, HED has
since concluded that there is no need for a DNT study.  This decision is
based on the following weight-of-evidence considerations: 1) neurotoxic
effects (changes in motor activity and grip strength) were seen at high
doses of 500 mg/kg (¼ of the limit dose), 1000 mg/kg, and 2000 mg/kg
following bolus (gavage) dosing and at 428 mg/kg/day in males and 513
mg/kg/day in females following dietary administration in the subchronic
neurotoxicity study; 2) in the two-generation reproduction study, no
clinical signs indicative of neurotoxicity were seen in the parental
animals or offspring, nor was there evidence for increased
susceptibility (the offspring LOAEL was 260 mg/kg/day based on decreased
body weight/body weight gain during lactation; and 3) because the DNT
will have to utilize testing of high doses (in order to elicit
neurotoxicity), it  will not yield a dose lower than that currently used
for acute (40 mg/kg [aPAD =0.4 mg/kg/day] and 50 mg/kg [aPAD = 0.5
mg/kg/day]) and chronic (5 mg/kg/day [cPAD = 0.05 mg/kg/day]) dietary
risk assessments (there are no residential uses).

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young
Animal  TC \l3 "4.4.3	Evidence of Sensitivity/Susceptibility in the
Developing of Young Animal 

There are qualitative and quantitative prenatal susceptibility in the
rat developmental toxicity study.  The developmental findings with a
NOAEL of 40 mg/kg/day were well characterized and included increased
developmental sensitivity in the form of reduced fetal body weights,
delayed ossification (indicative of delayed maturation) and the presence
of hydroureter at 120 mg/kg/day (developmental LOAEL).  Rare
malformations (dilatation of both heart ventricles and filiform tail)
were also detected at the high dose of 360 mg/kg/day.  The maternal
toxicity NOAEL/LOAEL of 120/360 mg/kg/day was based on reduced body
weight gain and food consumption.  There are no qualitative or
quantitative pre- or postnatal susceptibility issues in the available
developmental toxicity study in rabbits and two-generation reproduction
toxicity study in rats.

There was no evidence of increased susceptibility following prenatal
exposure to rabbits, nor was there evidence of increased susceptibility
following pre- and/or postnatal exposure to rats (in the rat
reproduction and fertility effects study).  The degree of concern is low
for the increased susceptibility seen in the developmental study in rats
(prenatal exposure) since a clear NOAEL/LOAEL was established for
developmental toxicity, and since the endpoints of concern are used for
the most sensitive population of concern (i.e., Females 13-49).  There
is no residual uncertainty for pre- and/or postnatal toxicity.

4.4.4	Residual Uncertainty in the Exposure Database  TC \l3 "4.4.4
Residual Uncertainty in the Exposure Database 

The database is adequate and there are no residual uncertainties for
pre- and/or postnatal toxicity.  Furthermore, there are no additional
residual uncertainties with respect to exposure data.  The dietary food
exposure assessment utilizes proposed tolerance level residues and 100%
CT information for all commodities.  The drinking water assessment
(screening level, Tier 1 estimates) utilizes values generated by models
and associated modeling parameters which are designed to provide
conservative, health protective, high-end estimates of water
concentrations.  By using these screening-level assessments, acute and
chronic dietary exposures/risks will not be underestimated. 
Additionally, there is no potential for residential exposure based on
proposed and registered use patterns.

4.5	Toxicity Endpoint and Point of Departure Selections  TC \l2 "4.5
Toxicity Endpoint and Point of Departure Selections 

4.5.1	Recommendation for Combining Routes of Exposures for Risk
Assessment  TC \l3 "4.5.1	Recommendation for Combing Routes of Exposures
for Risk Assessment 

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  An aggregate
exposure risk assessment was not conducted because there are no
residential uses for tepraloxydim at this time.  However, aggregate food
and drinking water exposures are considered in this assessment.

4.5.2	Cancer Classification and Risk Assessment Recommendation  TC \l3
"4.5.2	Cancer Classification and Risk Assessment Recommendation 

In accordance with the 1999 EPA’s Draft Guidelines for Carcinogen Risk
Assessment (March, 2005), tepraloxydim was classified as "Data are
inadequate for an Assessment of human carcinogenic potential because
some evidence is suggestive of carcinogenic effects, but other equally
pertinent evidence does not confirm a concern.  The Agency, however, has
determined that additional carcinogenicity studies are not required
since the doses tested in both species, mice and rats, were adequate to
assess the carcinogenic potential of tepraloxydim.  The carcinogenicity
study in mice was tested at the Limit Dose and in the rats, the highest
dose tested resulted in liver tumors.  The classification was based on
the following weak and/or conflicting evidence for carcinogenicity (TXR
No. 0014487):

In rats, there was some evidence of carcinogenicity in the females based
on an increased incidence of liver tumors only at the high dose in the
carcinogenicity phase of the study, but was not supported by the results
of the chronic phase in the same strain and sex of rats. 

In mice, liver tumors were seen in females only at an excessively toxic
dose. 

The CARC concluded that a cancer risk is not of a concern based on the
following weight of evidence considerations:

The liver tumors in female rats were seen only at the high dose (i.e.,
lack of dose response);

The incidences of these tumors were within the ranges for the historical
controls;

The liver tumors observed in one study were not seen in a parallel study
conducted at the same dose and duration (i.e, tumorogenic potential not
replicated); 

In mice, liver tumors in were seen only at excessive doses (i.e.,
greater than the Limit Dose of 1000 mg/kg/day) which may have resulted
in indirect effects that may not be present at lower doses; 

The liver tumors did not result in reduced latency in either species;  

There is no concern for mutagenicity/genotoxicity; and 

The NOAEL of 5 mg/kg/day used for deriving the chronic RfD is
approximately 55-fold lower than the lowest dose (272 mg/kg/day) that
induced liver tumors in rats.

Thus, for all these reasons, the Agency has determined that the chronic
PAD (0.05 mg/kg/day) will adequately account for all chronic effects,
including carcinogenicity, likely to result from exposure to
tepraloxydim.

4.5.3	Summary of Points of Departure and Toxicity Endpoints Used in
Human Risk Assessment  TC \l3 "4.5.3	Summary of Points of Departure and
Toxicity Endpoints Used in Human Risk Assessment 

Table 4.  Summary of Toxicological Doses and Endpoints for Tepraloxydim
for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/ Scenario	Point of Departure	Uncertainty/FQPA Safety Factors
RfD, PAD, Level of Concern for Risk Assessment	Study and Toxicological
Effects

Acute Dietary (General Population, including Infants and Children)	LOAEL
= 500 mg/kg	UFA= 10 x

UFH= 10 x

FQPA SF retained as UFL = 10 x

	Acute RfD = 0.5 mg/kg

aPAD = 0.5 mg/kg	Acute neurotoxicity screening battery 

LOAEL = 500 mg/kg based on decreased motor activity in females.  (The
NOAEL is not identified.)

Acute Dietary

(Females 13-49 years of age)	NOAEL= 40 mg/kg	UFA= 10 x

UFH= 10 x

FQPA SF = 1 x

	Acute RfD = 0.4 mg/kg

aPAD = 0.4 mg/kg	Rat developmental toxicity 

LOAEL = 120 mg/kg based on findings of   SEQ CHAPTER \h \r 1 reduced
ossification indicative of delayed maturation, and the occurrence of
hydroureter.

Chronic Dietary (All Populations)	NOAEL=5 mg/kg/day	UFA= 10 x

UFH= 10 x

FQPA SF= 1 x	Chronic RfD = 0.05 mg/kg/day

cPAD = 0.05 mg/kg/day	Rat   SEQ CHAPTER \h \r 1 carcinogenicity study 

LOAEL = 30 mg/kg/day based on   SEQ CHAPTER \h \r 1 male liver
microscopic lesions (eosinophilic foci).

Incidental Oral Short- and Intermediate-Term (1-30 days; 1-6 months)
These exposure scenarios do not apply to this risk assessment because
there are no proposed or registered residential uses of tepraloxydim.

Dermal Short- and Intermediate-Term (1-30 days; 1-6 months)	These
exposure scenarios do not apply to this risk assessment because there
are no proposed or registered residential uses of tepraloxydim.

Inhalation Short- and Intermediate-Term (1-30 days; 1-6 months)	These
exposure scenarios do not apply to this risk assessment because there
are no proposed or registered residential uses of tepraloxydim.

Cancer (oral, dermal, inhalation)	The CARC placed tepraloxydim into
category "Data are inadequate for an assessment of human carcinogenic
potential" because some evidence is suggestive of carcinogenic effects,
but other equally pertinent evidence does not confirm a concern" and
determined that the quantification of human cancer risk is not required
(CARC report dated 2/27/01, TXR 0014487).

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

4.6	Endocrine Disruption  TC \l2 "4.6	Endocrine Disruption 

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations. Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data. Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Tepraloxydim is not among the group of 58 pesticide active ingredients
on the initial list to be screened under the EDSP.  Under FFDCA Sec.
408(p), the Agency must screen all pesticide chemicals.  Accordingly,
EPA anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

Reference: Tepraloxydim on Imported Crop Subgroup 6C (Dried Shelled Pea
and Bean) and Sunflower Subgroup 20B (PP#0E7788). Summary of Analytical
Chemistry and Residue Data. DP382893, A. Acierto, 5/27/11.

5.1	Pesticide Metabolism  TC \l2 "5.1	Pesticide Metabolism 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

No new plant metabolism data were submitted with this petition. 
However, the nature of the residue in the pea and bean, dried shelled,
except soybean, subgroup 6C and the sunflower subgroup 20B is adequately
understood based on the available data for leguminous and oilseed crops
(soybean and canola).  Tepraloxydim and the metabolites containing the
2-cyclohexen-1-one moiety are the residues of concern for the pea and
bean, dried shelled, except soybean, subgroup 6C and the sunflower
subgroup 20B.  HED has determined that the tolerance expression for the
pea and bean, dried shelled, except soybean, subgroup 6C and the
sunflower subgroup 20B should include the combined residues of
tepraloxydim and its metabolites convertible to GP
(3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid) and OH-GP
(3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid).  No
additional plant metabolism data are required for new uses on legume and
oil seed plants.

5.1.2	Metabolism in Livestock  TC \l3 "5.1.2	Metabolism in Livestock 

The nature of the residues of tepraloxydim in livestock is adequately
understood based on the available metabolism data in goats and poultry. 
The residues of concern for livestock commodities are tepraloxydim and
the metabolites containing the 2-cyclohexen-1-one moiety.  HED has
determined that the tolerance expression for livestock commodities
should include the combined residues of tepraloxydim and its metabolites
convertible to GP, OH-GP, and GL
(3-(2-oxotetrahydropyran-4-yl)pentane-1,5-dioic acid).  No additional
livestock metabolism data are required to support the current petition.

5.1.3	Drinking Water Residue Profile TC \l3 "5.1.3	Drinking Water
Residue Profile 

Reference: Tier I Drinking Water Assessment for Tepraloxydim. J.
Breithaupt, DP338939, 5/1/07

No new estimated drinking water concentrations (EDWCs) were computed for
the new tolerances on imported commodities from this petition.  The
estimated environmental concentrations (EECs) previous computed for
surface water concentrations are the values provided by the
Environmental Fate and Effects Division (EFED).

The uses on soybeans, cotton, and fallow ground were chosen for modeling
since they contain the highest application rate of 0.0125 lb ai/A and
two applications 14 days apart (maximum annual rate of 0.025 lb ai/A). 
The maximum application rate and minimal application interval were used
for modeling, and result in relatively unrefined estimates.

μg/L, respectively.

to exceed 0.002 μg/L.

The models and their descriptions are available at the EPA internet
site: http://www.epa.gov/oppefed1/models/water/.  Table 5 summarizes the
modeled EECs.

Table 5.  Summary of Estimated Surface Water and Ground Water
Concentrations for Tepraloxydim.

	Parent, DP-1 and DP-2

	Surface Water Conc., ppb [μg/L] a	Ground Water Conc., ppb [μg/L] b

Acute (peak value)	1.4	0.002

Chronic (non-cancer)	0.7

	a From the Tier I FIRST - Index Reservoir model.  Input parameters are
based on the max. appl. rate of 0.0125 lb ai/A, min appl interval of 14
days, 2 applications, PCA 0.87, lowest non-sand Koc of 8.4 ml/g.

b From the SCI-GROW model assuming a max. appl. rate of 0.0125 lb ai/A,
a median Koc of 20.2 mg/g, and a half-life of 10.5 days.

5.1.4	Food Residue Profile  TC \l3 "5.1.4	Food Residue Profile 

Residues of Concern

Previously, it was determined that tepraloxydim and those metabolites
containing the 2-cylcohexen-1-one moiety are residues of concern for
canola, cotton and soybean raw agricultural commodities.  For the
imported commodities that are the subject of this assessment (sunflower
subgroup 20B, and dry bean and dry pea subgroup 6C), the residues of
concern are also tepraloxydim and those metabolites containing the
2-cyclohexen-1-one moiety, and are detected as the combined residues of
tepraloxydim and its metabolites convertible to GP and OH-GP.  For
dietary risk assessment, the combined residues of tepraloxydim and its
metabolites convertible to GP and OH-GP should be used for sunflower
subgroup 20B commodities, and the combined residues of tepraloxydim and
its metabolites convertible to GP and OH-GP plus DD should be used for
dry bean and dry pea subgroup 6C commodities.

Likewise, the residues of concern for livestock commodities are
tepraloxydim and those metabolites containing the 2-cyclohexen-1-one
moiety, but they are measured as the combined residues of tepraloxydim
and its metabolites convertible to GP, OH-GP, and GL.  Although GL by
itself is not of concern, it serves as a marker for the significant
metabolite DL due to conversion of the latter to GL by the analytical
method.

GP and OH-GP are included in the tolerance expressions not because of
their toxicity but because they are the products resulting from the
conditions employed in the enforcement analytical method.

In drinking water, levels of tepraloxydim, DP-1 and DP-2 are included in
the EECs.  Although GP and FP were present at >10% of the total residue
in some cases, these metabolites are significantly less toxic than
parent and those residues still containing the 2-cyclohexen-1-one
moiety.

HED does not require data pertaining to rotational crops to establish
tolerances on imported commodities (HED sop 98.6, “Data Requirements
for Import Tolerances,” Table 3, 12/3/98).



Table 6.  Summary of Tepraloxydim Residues to be included in the Risk
Assessment and Tolerance Expression for Imported Dry Bean and Dry Pea
Subgroup 6C and Sunflower Subgroup 20B **

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Imported Dry Bean and Dry Pea Subgroup 6C and Sunflower Subgroup 20B
Primary Crop: Flax (also Canola and Cotton), Sunflower Subgroup 20B
Parent, GP, OH-GP	Parent, GP, OH-GP

	Primary Crops: Lentil and Dry Bean and Dry Pea Subgroup 6C (also
Soybean)	Parent, GP, OH-GP, DD	Parent, GP, OH-GP 

	Rotational Crop	Parent*	Parent*

Livestock

	Ruminant	Parent and its metabolites convertible to GP, OH-GP, and GL
Parent and its metabolites convertible to GP, OH-GP, and GL

	Poultry

Drinking Water	Parent, DP-1 and DP-2***	Not applicable

*applies to domestic uses

** Nomenclature:

DD: 
2-[1-((3-chloroprop-2-(E)-en-1-yl)oximino)propyl]-5-(1,5-dihydroxypentan
-3-yl)-3-hydroxycyclohex-2-en-1-one

DP-1: 
3-hydroxy-2-(1-iminopropyl)-5-(tetrahydropyran-4-yl)cyclohex-2-en-1-one

DP-2: 
2-ethyl-6-(tetrahydropyran-4-yl)-4,5,6,7-tetrahydrobenzoxazol-4-one

GP:  3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid

OH-GP:  3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid

GL:  3-(2-oxotetrahydropyran-4-yl)pentane-1,5-dioic acid

***Although DP-8
(3-hydroxy-2-propionylamino-5-(tetrahydropyran-4-yl)cyclohex-2-en-1-one)
was included as a residue of concern for drinking water in the MARC
memo, the most recent drinking water memo points out DP-8 is not
observed in any of the fate studies, and is therefore not included in
the modeled EDWCs.

Crop Field Trials

Sunflower

The registrant submitted field trial data conducted in the U.S. and
Canada to support the proposed tolerance on the sunflower subgroup 20B. 
These data are adequate to fulfill data requirements.  The results show
that following a single broadcast foliar application of tepraloxydim at
approximately 50 g ai/ha, the combined residues of tepraloxydim ranged
from <0.10 ppm (less than combined LOQ) to 0.18 ppm in/on sunflower seed
samples harvested at a PHI of 58-61 days.  Only two of the ten treated
samples contained quantifiable residues of tepraloxydim (<0.10 and 0.18
ppm), and these samples were collected at the trials located in
Wisconsin and Saskatchewan, respectively. Combined residues were also
<0.10 ppm in/on two treated sunflower seed samples harvested 61 days
after application of tepraloxydim at the exaggerated rate of 147 g
ai/ha. The crop field study is supported by adequate storage stability
data. 

In the residue decline experiment, combined residues of tepraloxydim
were <0.10 ppm in/on duplicate treated seed samples collected at 41, 50,
61, 70 and 80 days after treatment; therefore, the results are
inconclusive with respect to decline at longer sampling intervals.

Dry Bean

The registrant submitted field trial data conducted at five locations in
the U.S. and Canada to support the proposed tolerance on subgroup 5C dry
beans and dry pea.  These data combined with previously submitted
Canadian field trial data for dry peas are adequate to fulfill data
requirements for an import tolerance for a subgroup 6C tolerance.  The
results show that following a single broadcast foliar application of 50
g a.i./ha and harvest at PHIs of 53-63 days combined residues were <LOQ
(<0.10 ppm) in all dry bean seed samples (<0.05 ppm for tepraloxydim
derived from GP and <0.05 ppm for 5-OH-DP, derived from OH-GP).  The
crop field study is supported by adequate storage stability data. 
Residues from the residue decline studies were non-quantifiable at PHIs
of 70 and 90 days.  Similar results were found in the dry pea field
trials (used previously to establish an import tolerance for dry peas).

Summary of the residue data from the crop field trials for sunflower and
bean is presented in Table 7.

TABLE 7.  Summary of Residue Data from Crop Field Trials with
Tepraloxydim.

Commodity	Total Applic. Rate

(g a.i./ha)	PHI (days)	Residue Levels (ppm)

	n	Min.	Max.	HAFT*	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Total Tepraloxydim (including metabolites convertible to GP and OH-GP)

Sunflower seed	49-52	58-60	10	<0.1	0.18	0.14	<0.1	<0.1	0.05

	147	61	2	<0.1	<0.1	<0.1	<0.1	<0.1	0

Dry bean seed	50-52	53-63	10	<0.1	<0.1	<0.1	<0.1	<0.1	0

1HAFT = Highest average field trial result

Processed Food and Feed

Sunflower

A sunflower plot was treated at an exaggerated rate of 147 g a.i./ha
(0.131 lb ai/A); this is equivalent to 3.7x the proposed seasonal
application rate.  Combined residues in the duplicate treated RAC
samples were 0.11 and 0.22 ppm (tepraloxydim, <0.05 ppm; 5-OH-DP, 0.06
and 0.17 ppm).  In duplicate treated meal samples, the combined residues
were <0.10 and 0.13 ppm (tepraloxydim, <0.05 ppm; 5-OH-DP, 0.05 and 0.08
ppm).  Residues were non-quantifiable in the refined oil.  The
processing data indicate that residues of tepraloxydim did not
concentrate in sunflower meal or refined oil.  Results are shown in
Table 8.  



TABLE 8.  Residue Data from Sunflower Processing Study with
Tepraloxydim.

RAC	Processed Commodity	Total Rate

 (g a.i./ha)	PHI

(days)	Tepraloxydim Residues (ppm)	5-OH-DP Residues (ppm)	Total Residues
(ppm)	Processing Factor

Sunflower

(Replicate A)	Whole seed	147	61	<0.05	0.17	0.22	--

	Meal

	<0.05	0.08	0.13	0.6x

	Refined oil

	<0.05	<0.05	<0.1	0.5x

Sunflower

(Replicate B)	Whole seed

	<0.05	0.06	0.11	--

	Meal

	<0.05	<0.05	<0.1	0.9x

	Refined oil

	<0.05	<0.05	<0.1	0.9x

Dry Beans

No processed commodities are associated with dry bean.

Meat, Milk, Poultry, and Eggs

The feedstuff associated with the sunflower subgroup 20B is sunflower
meal based on Table 1 Feedstuffs (June 2008).  No livestock feedstuffs
are associated with dry beans except for cowpea (seed, forage, and hay).
 These livestock feeds may be fed to livestock in Canada destined for
import into the U.S.  These items, because of the low residue levels,
will have an insignificant effect on the livestock dietary burdens.  The
maximum theoretical dietary burdens of tepraloxydim to livestock were
previously calculated in conjunction with PP#8F4945 (DP243962, L. Cheng,
10/3/00).   For this petition (PP#0E7788), a reasonably balanced diet
based on Table 1 Feedstuffs (June 2008) was determined.  The established
tolerances for livestock commodities are adequate to support the
proposed tolerances.  

Confined Accumulation in Rotational Crops

Confined accumulation in rotational crops to establish tolerances are
not required for import commodities (HED SOP 98.6, Data Requirements for
Import Tolerances, Table 3, 12/3/98).

Field Accumulation in Rotational Crops

Rotational crop data are not required to establish tolerances on
imported commodities (HED SOP 98.6, Data Requirements for Import
Tolerances, Table 3, 12/3/98).

5.2	Dietary Exposure and Risk TC \l2 "5.2	Dietary Exposure and Risk 

Reference:  Tepraloxydim:  Acute and Chronic Dietary (Food and Drinking
Water) Exposure and Risk Assessment for Residues on Imported Dry Bean
and Sunflower Subgroup 20B. D384841, A. Acierto, 6/7/11.

™, Version 2.03, which uses food consumption data from the USDA’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.

The latest acute and chronic dietary risk assessments was conducted on
dry pea, flax and lentil (D338371, N. Dodd, 7/17/07).  The only change
made to the last assessment is the addition of dry bean and sunflower
subgroup 20B.  The conservative acute and chronic dietary exposure
assessments incorporated the same input parameters used in the previous
assessment including toxicological endpoints and estimated drinking
water concentrations.  As in the previous assessment, the current
assessment used residue values at the recommended and established
tolerance levels and assumed that 100 percent of the crops were treated.
 Residues of the proposed food commodities were based on field trial
data on dry bean and sunflower.  There are no processed commodities for
dry beans.  Processing factors for the sunflower processed commodities
(meal and refined oil) were set to 1 based on the studies demonstrating
that residues did not concentrate in the sunflower processed fractions. 

5.2.1	Acute Dietary Exposure/Risk  TC \l3 "5.2.1	Acute Dietary
Exposure/Risk 

The acute dietary exposure was estimated for females 13-49 years old
separately from the general U.S. population since this population
subgroup has a different toxicological endpoint.  The surface water EEC
used for the acute dietary assessment is 1.4 ppb and was incorporated in
the DEEM-FCID model as the food categories “water, direct all
sources” and “water, indirect, all sources”.  Based on the
assumptions described above, the acute dietary exposure of females 13-49
years old as well as the general U.S. population and all population
subgroups are well below HED’s level of concern at the 95th percentile
of exposure.  Combined dietary exposure from food and drinking water for
females 13-49 years old at the 95th percentile of exposure is estimated
to be 0.001844 mg/kg/day, equivalent to <1% (0.46%) of the acute
Population Adjusted Dose (aPAD).  For the general U.S. population, the
exposure is estimated to be 0.003713 mg/kg/day, equivalent to <1%
(0.74%) of the aPAD.  For children 1-2 years old, the most highly
exposed subgroup, the exposure is estimated to be 0.010897 mg/kg/day,
equivalent to 2.2% of the aPAD.

Table 9.  Summary of Dietary (Food and Drinking Water) Exposure and Risk
for Tepraloxydim.

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary	Cancer

	aPAD	Dietary Exposure (mg/kg/day)1	% aPAD	Dietary Exposure

(mg/kg/day)1	% cPAD	Dietary Exposure

(mg/kg/day)	Risk                                                        

General U.S. Population	0.5	0.003713	<1	0.001213	2.4	N/A2	N/A2

All Infants (< 1 year old)	0.5	0.005947	1	0.001761	4	N/A	N/A

Children 1-2 years old	0.5	0.010897	2.2	0.004825	9.6

Children 3-5 years old	0.5	0.006858	 1	0.003404	7

Children 6-12 years old	0.5	0.004459	 <1	0.002092	4

Youth 13-19 years old	0.5	0.002612	<1	0.001089	2

Adults 20-49 years old	0.5	0.001902	<1	0.000817	2

Adults 50+ years old	0.5	0.001560	<1	0.000721	1

Females 13-49 years old	0.4	0.001844	 <1	0.000774	2

1The values for the highest exposed population are bolded.

2Data are inadequate for an assessment of human carcinogenic potential.

5.2.2	Chronic Dietary Exposure/Risk  TC \l3 "5.2.2	Chronic Dietary
Exposure/Risk 

The chronic dietary exposure and risk estimates are conservative since
they assume that 100% of crops are treated and that the residues are
present at tolerance levels.  The chronic surface water EEC for
tepraloxydim is 0.7 ppb.  The water residues were incorporated directly
into the DEEM-FCID into the food categories “water, direct, all
sources” and “water, indirect, all sources.”  Combined chronic
dietary exposure estimates for food and drinking water are well below
HED’s level of concern.  Using the DEEM-FCID software, dietary
exposure is estimated to be 0.001213 mg/kg/day for the general U.S.
population equivalent to 2.4% of the chronic Population Adjusted Dose
(cPAD). Dietary exposure is estimated to be 0.004825 mg/kg/day,
equivalent to 9.6% of the cPAD, for children 1-2 years old, the
population subgroup with the highest estimated chronic dietary exposure
to tepraloxydim.

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l2 "5.3	Anticipated Residue and Percent Crop Treated (%CT) Information 

The acute and chronic dietary assessments are screening-level
assessments using residues at tolerance levels and assuming that 100% of
requested crops are treated.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

This document addresses an application for tolerances of tepraloxydim on
imported dry beans and sunflower subgroup 20B commodities, and therefore
is not expected to result in residential exposure.  Additionally,
tepraloxydim is registered in the US to control grass weeds in canola,
cotton and soybean crops, as well as fallow and non-cropland in
agricultural settings (i.e., tepraloxydim is not intended for use in
public or residential settings).  Therefore, residential exposure is not
expected and no residential risk assessment was conducted.

Based on the Agency's current practices, a quantitative post-application
inhalation exposure assessment was not performed for (chemical) at this
time primarily because of the low acute inhalation toxicity (Toxicity
Category III and IV), low vapor pressure (1.1 x 10-7 hPa at 20 (C), and
the low proposed use rate (0.033 to 0.124 lb ai/A).  However,
volatilization of pesticides may be a source of post-application
inhalation exposure to individuals nearby pesticide applications.  The
Agency sought expert advice and input on issues related to
volatilization of pesticides from its Federal Insecticide, Fungicide,
and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009,
and received the SAP’s final report on March 2, 2010
(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The
Agency is in the process of evaluating the SAP report and may, as
appropriate, develop policies and procedures to identify the need for
and, subsequently, the way to incorporate post-application inhalation
exposure into the Agency's risk assessments.  If new policies or
procedures are developed, the Agency may revisit the need for a
quantitative post-application inhalation exposure assessment for
tepraloxydim.

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for [chemical]. 
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 (see
the Agency’s Spray Drift website for more information at
http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical
by chemical basis, the Agency is now requiring interim mitigation
measures for aerial applications that must be placed on product
labels/labeling.  The Agency has completed its evaluation of the new
database submitted by the Spray Drift Task Force, a membership of U.S.
pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

Although a quantitative residential post-application inhalation exposure
assessment was not performed as a result of pesticide drift from
neighboring treated agricultural fields, an inhalation exposure
assessment was previously performed for flaggers for domestic aerial
applications.  This exposure scenario is representative of a worse case
inhalation (drift) exposure and may be considered protective of most
outdoor agricultural and commercial post-application inhalation exposure
scenarios.   

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

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

There is no residential exposure expected for tepraloxydim; therefore,
the sources considered in the aggregate assessment are food and drinking
water.  Because the dietary assessment incorporates exposure from both
food and drinking water, the dietary assessment addresses concern from
aggregate exposure.  Refer to Section 5.2, which discusses dietary
exposure (food and water).

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "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 mammalian mechanism of toxicity finding as to tepraloxydim and
any other substances and tepraloxydim 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 tepraloxydim has a
common mammalian 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  TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

This document addresses risk resulting from use of tepraloxydim on
imported dry beans and sunflower subgroup 20B commodities.  Therefore,
occupational exposure and risk is not expected.

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

The requirements (40 CFR 158.500) for food uses for tepraloxydim are in
Table A.1.  Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

Table A.1.  Toxicology Data Requirements for Food Use - Tepraloxydim

Study	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    21/28-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

yes

yesa	yes

yes

yes

yes

no

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

yes

yes

yes

---	yes

yes

yes

yes

---

870.5100  Mutagenicity—Gene Mutation - bacterial

870.5300  Mutagenicity—Gene Mutation - mammalian

870.5375  Mutagenicity—Structural Chromosomal Aberrations

870.5395  Mutagenicity—Other Genotoxic Effects	

870.5550  Mutagenicity—Unscheduled DNA synthesis		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.6100a  Acute Delayed Neurotoxicity (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotoxicity Screening Battery (rat)

870.6200b  90-Day Neurotoxicity Screening Battery (rat)	

870.6300    Develop. Neurotoxicity		no

no

yes

yes

no	---

---

yes

yes

---

870.7485  General Metabolism	

870.7600  Dermal Penetration	

870.7800  Immunotoxicity		yes

nob

yes	yes

nob

no

a A 28-day inhalation study is required.

b The available dermal absorption study (MRID 44467211) is classified
Unacceptable/Non-guideline.

A.2  Toxicity Profiles TC \l2 "A.2  Toxicity Profiles 

Table A.2.1	Acute Toxicity Profile - Tepraloxydim 

Guideline No.	Study Type	MRID	Results	Toxicity Category

870.1100	Acute oral (rat)	44467131	LD50 = 5000 mg/kg	III

870.1200	Acute dermal (rabbit)	44496403	LD50 > 2000 mg/kg	III

870.1300	Acute inhalation (rat)	44467132	LC50 > 5.1 mg/L	IV

870.2400	Acute eye irritation (rabbit)	44467133	minimal eye irritation
III

870.2500	Acute dermal irritation (rabbit)	44467134	slight dermal
irritation	IV

870.2600	Skin sensitization (guinea pig)	44467135	not a dermal
sensitizer	N/A

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

Guideline No. 	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3100

	90-Day oral toxicity (rat)	  SEQ CHAPTER \h \r 1 44467137 (1996)

Acceptable/guideline

0, 300, 3000, or 5000 ppm 

M: .0, 22, 223, and 383 mg/kg/day 

F: 0, 26, 257, and 440 mg/kg/day	NOAEL = 22 mg/kg/day

LOAEL = 223 mg/kg/day based on decreased body weight, body weight gain,
and proximal kidney tubule changes in males in addition to clinical
chemistry findings indicative of kidney and liver toxicity in both
sexes.

870.3150

	90-Day oral toxicity (dog)	  SEQ CHAPTER \h \r 1 44467139 (1997)
Acceptable/guideline

  SEQ CHAPTER \h \r 1 0, 400, 2000, or 10,000 ppm 

Males: 0, 12.9, 63.3, and 325.0 mg/kg/day 

Females: 0, 14.3, 68.0, and 357.7 mg/kg/day	  SEQ CHAPTER \h \r 1 NOAEL
= 12.9 mg/kg/day

LOAEL = 63.3 mg/kg/day based on increased liver and thyroid weights in
addition to spleen histopathology findings and other changes indicative
of hemolytic compensatory anemia in females.

870.3200

	28-Day dermal toxicity (rat)	44467140 (1997)

Acceptable/guideline

  SEQ CHAPTER \h \r 1 0, 50, 200, or 1000 mg/kg/day	NOAEL (Dermal or
Systemic) = 1000 mg/kg/day

LOAEL (Dermal or Systemic) > 1000 mg/kg/day.

870.3700a

	Prenatal developmental in (rat)	  SEQ CHAPTER \h \r 1 44467203 (1995)
Acceptable/guideline

0,   SEQ CHAPTER \h \r 1 40, 120, and 360 mg/kg/day	Maternal NOAEL = 120
mg/kg/day

LOAEL = 360 mg/kg/day based on findings of decreased body weight gain
and a marginal decrease in food intake (at days 6-8 only).

Developmental NOAEL = 40 mg/kg/day

LOAEL = 120 mg/kg/day based on   SEQ CHAPTER \h \r 1 reduced fetal body
weights, retarded ossification indicative of delayed maturation and the
occurrence of hydroureter.

870.3700b

	Prenatal developmental in (rabbit)	  SEQ CHAPTER \h \r 1 44496404
(1995)

Acceptable/guideline

  SEQ CHAPTER \h \r 1 0, 20, 60, or 180 mg/kg/day 	  SEQ CHAPTER \h \r 1
Maternal NOAEL = 60 mg/kg/day

≥ 180 mg/kg/day 

LOAEL >180 mg/kg/day.

870.3800

	Reproduction and fertility effects

(rat)	44467205 (1997)

Acceptable/guideline

  SEQ CHAPTER \h \r 1 0, 100, 500, or 2500 ppm

Premating doses 

F0 Males: 0, 10.2, 50.9, and 253.1 mg/kg/day 

F0 females: 0, 11.2, 54.7, and 273.8 mg/kg/day 

F1 males: 0, 10.0, 50.3, and 266.9 mg/kg/day 

F1 females: 0, 11.0, 55.3, and 278.0 mg/kg/day.	  SEQ CHAPTER \h \r 1
Parental/Systemic NOAEL (M/F) = 50.6/55 mg/kg/day

LOAEL (M/F) = 260/276 mg/kg/day based on decreased body weight/weight
gain and food consumption.

 ≥ 260 mg/kg/day

LOAEL  > 260 mg/kg/day .

Offspring NOAEL (M/F) = 50.6/55 mg/kg/day

LOAEL M/F = 260/276 mg/kg/day based on reduced pup body weight gain and
lower pup body weight during lactation.

870.4100a

	Chronic toxicity

(rat)	44467145 (1997) Acceptable/guideline

  SEQ CHAPTER \h \r 1 0, 100, 600, or 3000 (male) or 4000 ppm (females)

Males:   SEQ CHAPTER \h \r 1 0, 5, 29, and 154 mg/kg/day

Females:   SEQ CHAPTER \h \r 1 0, 6, 38, and 273  mg/kg/day	  SEQ
CHAPTER \h \r 1 NOAEL (M/F) = 29/38 mg/kg/day

LOAEL (M/F) =154/273 mg/kg/day based on reduced body weight, weight
gain, and food efficiency in addition to microscopic liver lesions
(eosinophilic foci in both sexes and cellular polymorphism in females).

870.4100b

	Chronic toxicity (dog)	44467146 (1997) Acceptable/guideline

0, 100, 400, or 2000 ppm

Males: 0, 3.0, 11.5, and 56.0 mg/kg/day 

Females: 0, 3.1, 12.5, and 60.6 mg/kg/day	  SEQ CHAPTER \h \r 1 NOAEL
=11.5mg/kg/day

LOAEL = 56.0 mg/kg/day based on reduced epididymal and prostate
activities, transitional epithelial hyperplasia of the urinary bladder,
abnormal liver function, and liver foci.

870.4100b

	Chronic toxicity - Supplementary (dog)	44467147 (1997)
Acceptable/Non-guideline

0, or 8000 ppm

Males: 0, or 248 mg/kg/day 

Females: 0, or 265 mg/kg/day	  SEQ CHAPTER \h \r 1 NOAEL < 248 mg/kg/day

LOAEL = 248 mg/kg/day based on anemia and hepatobiliary toxicity in both
sexes; focal hemorrhage of bladder’s transitional epithelia and
testicular toxicity (males only).

870.4200

	Carcinogenicity

(rat)	44467201 (1997)

Acceptable/guideline

  SEQ CHAPTER \h \r 1 0, 100, 600, or 3000 (male) or 4000 ppm (females)

Males:   SEQ CHAPTER \h \r 1 0, 5, 30, and 155 mg/kg/day

Females:   SEQ CHAPTER \h \r 1 0, 6, 38, and 272  mg/kg/day	  SEQ
CHAPTER \h \r 1 NOAEL (M/F) = 5/38 mg/kg/day

LOAEL (M/F) = 30/272 mg/kg/day based on eosinophilic foci in males and
eosinophilic foci and cellular polymorphism in females in addition to
other findings in females including decreased body weight, weight gain,
food intake, and food efficiency. 

Some evidence of carcinogenicity

870.4300

	Carcinogenicity

(mouse)	44467202 (1997)

Acceptable/guideline

  SEQ CHAPTER \h \r 1 0, 200, 1800, or 5000 ppm

Males: 0, 37, 332, and 1035 mg/kg/day

Females: 0, 52, 490, and 1456 mg/kg/day	  SEQ CHAPTER \h \r 1 NOAEL
(M/F) = 37/52 mg/kg/day

LOAEL (M/F) = 332/490 mg/kg/day based on decreased body weight/weight
gain in both sexes, increased relative liver weight and altered foci
(eosinophilic and basophilic) in males, and uterine sclerosis.

Female mice developed liver tumors at an excessively toxic dose.

Some evidence of carcinogenicity

870.5100 	Gene Mutation

Bacterial reverse mutation assay	44467206 (1993)

Acceptable/guideline	  SEQ CHAPTER \h \r 1 Negative ± S9 up to 5000
µg/ml with cytotoxicity at this concentration or at 2500 µg/ml.

870.5300	Gene Mutation

Mammalian (CHO/ HPRT) forward mutation assay	44467207 (1995)

Acceptable/guideline	Negative ± S9 up to cytotoxic and precipitating
concentrations (3000 µg/ml).

870.5300	Cytogenetics

Chromosomal aberrations (CHO cells)	44467209 (1993)

Acceptable/guideline	Negative ± S9 up to its limit of solubility at
1000 µg/ml.

870.5395

	Micronucleus Assay (mouse)	44467208 (1995)

Acceptable/guideline	Negative for clastogenic/aneugenic activity in
male/female mouse bone marrow up to 500 mg/kg (animals died at 600
mg/kg).

870.5550	UDS in primary male rat hepatocytes	44467210 (1996)

Acceptable/guideline	Negative up to 500 µg/ml; cytotoxic at ( 100
µg/ml.

870.6200a

	Acute neurotoxicity screening battery	44467136 (1997)

Acceptable/guideline

0, 500, 1000, or 2000 mg/kg	  SEQ CHAPTER \h \r 1 NOAEL = < 500 mg/kg

LOAEL = 500 mg/kg based on decreased motor activity in females

870.6200b

	Subchronic neurotoxicity screening battery	44467141 (1997)

Acceptable/guideline

0, 400, 1,500, or 6,000 ppm

Males: 0, 28, 103, or 428 mg/kg/day

Females: 0, 33, 124, or 513 mg/kg/day	NOAEL (M/F) = 103/124 mg/kg/day

LOAEL (M/F) = 428/513 mg/kg/day based on increased motor activity as
well as decreased body weights, food consumption, and food efficiency.

870.7485

	Metabolism and pharmacokinetics

(species)	[44496405 (1993), 5101301 (1996), 45101302 (1996), 45101303
(1997)

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oral administration (single dose of 30 or 300 mg/kg), but was rapidly
excreted mainly via the urine (65-80%).  Excretion was nearly 2-3 fold
higher in the bile than the feces, which suggests enterohepatic
recirculation. The rat plasma half-life of radiolabeled tepraloxydim is
nearly 4.4 and 10 hours at the low and high dose, respectively.  No
accumulation of radiolabel was observed in any tissue at 120 hours
post-dosing.  A large number of metabolites were detected in the urine,
feces, and bile; the main metabolic pathway being oxidation at the pyran
ring to the lactone via a hydroxy metabolite, and cleavage of the oxime
ether group with the imine and oxazol as products.  At near plasma tmax
(one hour post dosing), the plasma, liver, and kidney almost exclusively
contained the parent compound.  The results indicate that the
distribution, metabolism, and excretion of tepraloxydim is independent
from dose levels, sex, route of administration (oral vs. i.v.), or site
of label (pyran vs. cyclohexanone).

870.7600	Dermal penetration (species)	44467211 (1997)

Unacceptable/non-guideline	The available rat dermal absorption study is
considered unacceptable.  A dermal absorption rate of 36% was derived
based on the results of a 28-day dermal toxicity study in rats and
developmental toxicity study in rats.

Appendix B:  Physical and Chemical Properties TC \l1 " Appendix B: 
Physical and Chemical Properties 

Table B.	Physicochemical Properties of Tepraloxydim.

Parameter	Value	Reference

Molecular Weight	341.8	PMRA Proposed Regulatory Decision Document
PRDD2004-01  

Melting point/range	72.5-74.4 (C

	pH	3.9

	Density	1.284 g/mL at 20 (C

	Water solubility	0.43 g/L at 20 (C (pH 6.5)

7.25 g/L at 20 (C (pH 9)

	Solvent solubility	Solvent

Acetone

Methanol

2-Propanol

Ethyl acetate

Acetonitrile

Dichloromethane

Toluene

n-Heptane

1-Octanol

Olive oil	g/100 mL at 20 (C

70

33

16

69

77

119

82

1.0

15

8.0

	Vapor pressure	1.1 x 10-7 hPa at 20 (C

2.7 x 10-7 hPa at 25 (C

	Dissociation constant, pKa	pKa = 4.58 at 20 ºC

	Octanol/water partition coefficient, Log(KOW)	pH

pure water

4

7

9	Log Kow

1.5

2.44

0.20

-1.15

	UV/visible absorption spectrum	 Λ

204

225

258

290

300	ε (1 x Mol-1 x cm-1)

9.5 x 103

4.6 x 103

1.1 x 104

6.8 x 103

3.1 x 103

	

Appendix C:  International Residue Limit Status  TC \l1 "Appendix C: 
International Residue Limit Status 

TEPRALOXYDIM (PC Code 121005; 04/14/2011)

Table C. Summary of US and International Tolerances and Maximum Residue
Limits

Residue Definition:

US	Canada	Mexico2	Codex3

40 CFR 180.573:

Plants: tepraloxydim
(2-[1-[[[(2E)-3-chloro-2-propenyl]oxy]imino]propyl]-3-hydroxy-5-(tetrahy
dro-2H-pyran-4-yl)-cyclohexene-1-one) and its metabolites convertible to
GP (3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid) and OH-GP
(3-hydroxy-3-(tetrahydropyran-4-yl)pentane-1,5-dioic acid), calculated
as tepraloxydim 

Livestock: combined residues of tepraloxydim and its metabolites
convertible to GP, OH-GP, and GL
(3-(2-oxotetrahydropyran-4-yl)-1,5-dioic acid), calculated as
tepraloxydim 
Plants:(EZ)-(RS)-2-{1-[(2E)-3-chloroallyloxyimino]propyl}-3-

hydroxy-5-perhydropyran-4-ylcyclohex-2-en-1-one,

including metabolites convertible to 3-perhydropyran-

4-ylglutaric acid and 3-hydroxy-3-perhydropyran-4-

ylglutaric acid, as parent equivalent

Livestock:(EZ)-(RS)-2-{1-[(2E)-3-chloroallyloxyimino]propyl}-3-

hydroxy-5-perhydropyran-4-ylcyclohex-2-en-1-one,

including metabolites convertible to dimethyl 3-

(perhydropyran-4-yl)glutarate, dimethyl 3-hydroxy-3-

(perhydropyran-4-yl)glutarate and dimethyl 3-(pentan-

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昀Ĵ瑹䭿 ฀of stored grains.  PoP = processed postharvest treated
commodity, such as processing of treated stored wheat. (fat) = to be
measured on the fat portion of the sample. MRLs indicated as proposed
have not been finalized by the CCPR and the CAC.

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