UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

April 9, 2009

MEMORANDUM

SUBJECT:	Penoxsulam:  Revised Human Health Risk Assessment for Proposed
Uses on Grapes and Tree Nuts.

 

PC Code:  119031	DP Barcode:  D363910

MRID Nos.:  46389701, 47444401 - 47444405	Registration No.:  62719-ANG

Petition No.:  8F7369	Regulatory Action:  Section 3

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

TXR No.:  None	CAS No.:  219714-96-2



FROM:	Christina Swartz, Branch Chief

		Risk Assessment Branch II

		Health Effects Division (7509P)

THROUGH:	Richard A. Loranger, Ph.D., Branch Senior Scientist

	Risk Assessment Branch II

	Health Effects Division (7509P)

TO:	Philip Errico/Joanne Miller (Team 23)

		Herbicide Branch	

		Registration Division (7505P)

A human health risk assessment was completed in support of the proposed
uses of the herbicide penoxsulam on grapes and tree nuts, including
pistachios (D355595; M. Doherty, 3/24/09).  During the review of the
associated draft FR notice that would announce the establishment of the
proposed tolerances, HED received comments requesting changes in the
characterization of cancer risk for penoxsulam.  Although HED continues
to conclude there is no cancer risk concern associated with the proposed
uses of penoxsulam, this revised risk assessment provides a more robust
justification for this conclusion.  In addition, HED has slightly
modified its language regarding endocrine disruption; the updated
language has been incorporated into the revised risk assessment for
penoxsulam.  No other changes have been made to the original risk
assessment. 

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc225662317 \h  4 

2.0	Ingredient Profile	  PAGEREF _Toc225662318 \h  6 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc225662319 \h  6 

2.2	Structure and Nomenclature	  PAGEREF _Toc225662320 \h  7 

2.3	Physical and Chemical Properties	  PAGEREF _Toc225662321 \h  8 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc225662322 \h  8 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc225662323 \h
 8 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc225662324 \h  10 

3.3	FQPA Considerations	  PAGEREF _Toc225662325 \h  11 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc225662326 \h  11 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc225662327 \h  12 

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc225662328 \h  12 

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc225662329 \h  12 

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc225662330 \h  12 

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc225662331 \h  12 

3.3.6.1	Determination of Susceptibility	  PAGEREF _Toc225662332 \h  12 

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility	  PAGEREF _Toc225662333 \h  12 

3.3.7	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc225662334 \h  13 

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc225662335 \h 
13 

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc225662336 \h  13 

3.5.1	Acute Reference Dose (aRfD)	  PAGEREF _Toc225662337 \h  13 

3.5.2	Chronic Reference Dose (cRfD)	  PAGEREF _Toc225662338 \h  13 

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc225662339 \h  15 

3.5.4	Dermal Absorption	  PAGEREF _Toc225662340 \h  15 

3.5.5	Dermal Exposure	  PAGEREF _Toc225662341 \h  16 

3.5.5.1	Short-Term	  PAGEREF _Toc225662342 \h  16 

3.5.5.2	Intermediate-Term	  PAGEREF _Toc225662343 \h  16 

3.5.5.3	Long-Term	  PAGEREF _Toc225662344 \h  17 

3.5.6	Inhalation Exposure	  PAGEREF _Toc225662345 \h  17 

3.5.6.1	Short- and Intermediate-Term	  PAGEREF _Toc225662346 \h  17 

3.5.6.2	Long-Term	  PAGEREF _Toc225662347 \h  18 

3.5.7	Level of Concern for Margin of Exposure	  PAGEREF _Toc225662348 \h
 18 

3.5.8	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc225662349 \h  18 

3.5.9	Classification of Carcinogenic Potential	  PAGEREF _Toc225662350
\h  19 

3.5.10	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments	  PAGEREF _Toc225662351 \h  19 

3.6	Endocrine Disruption	  PAGEREF _Toc225662352 \h  21 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc225662353 \h  22 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc225662354 \h 
22 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc225662355 \h  22 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc225662356 \h  22 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc225662357 \h  22 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc225662358 \h  22 

5.1.4	Analytical Methodology	  PAGEREF _Toc225662359 \h  23 

5.1.5	Environmental Degradation	  PAGEREF _Toc225662360 \h  23 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc225662361 \h  23 

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc225662362 \h  24 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc225662363 \h  24 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc225662364 \h  24 

5.1.10	Food Residue Profile	  PAGEREF _Toc225662365 \h  24 

5.1.11	International Residue Limits	  PAGEREF _Toc225662366 \h  25 

5.2	Dietary Exposure and Risk	  PAGEREF _Toc225662367 \h  25 

5.2.1	Acute Dietary Exposure/Risk	  PAGEREF _Toc225662368 \h  25 

5.2.2	Chronic Dietary Exposure/Risk	  PAGEREF _Toc225662369 \h  25 

5.2.3	Cancer Dietary Risk	  PAGEREF _Toc225662370 \h  25 

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc225662371 \h  26 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc225662372 \h  26 

6.1	Residential Handler Exposure	  PAGEREF _Toc225662373 \h  26 

6.2.	Residential Postapplication Exposure	  PAGEREF _Toc225662374 \h  26


6.3	Other (Spray Drift, etc.)	  PAGEREF _Toc225662375 \h  27 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc225662376 \h  28 

7.1	Acute Aggregate Risk	  PAGEREF _Toc225662377 \h  28 

7.2	Short-Term Aggregate Risk	  PAGEREF _Toc225662378 \h  28 

7.3	Intermediate-Term Aggregate Risk	  PAGEREF _Toc225662379 \h  29 

7.4	Long-Term Aggregate Risk	  PAGEREF _Toc225662380 \h  29 

7.5	Aggregate Cancer Risk	  PAGEREF _Toc225662381 \h  29 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc225662382
\h  29 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc225662383 \h  29 

9.1	Short- and Intermediate-Term Handler Risk	  PAGEREF _Toc225662384 \h
 30 

9.2	Short- and Intermediate-Term Postapplication Risk	  PAGEREF
_Toc225662385 \h  30 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc225662386 \h  31


10.1	Toxicology	  PAGEREF _Toc225662387 \h  31 

10.2	Residue Chemistry	  PAGEREF _Toc225662388 \h  31 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc225662389 \h 
31 

References	  PAGEREF _Toc225662390 \h  31 

Appendix A	Toxicology Profile	  PAGEREF _Toc225662391 \h  33 

Appendix B	Rationale for Toxicology Data Requirements	  PAGEREF
_Toc225662392 \h  39 

Appendix C	Penoxsulam and Metabolites	  PAGEREF _Toc225662393 \h  40 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

The Health Effects Division of OPP has completed an aggregate human
health risk assessment for penoxsulam.  This assessment includes all
currently registered uses as well as the requested new uses on grapes
and tree nuts.  Penoxsulam (XDE-638) is a sulfonamide herbicide used for
the selective control of grasses, broadleaf, and sedge weeds, as well as
for control of vegetation in lakes, ponds, canals, and reservoirs. 
Tolerances [40 CFR 180.605] are listed for residues of penoxsulam, per
se, in/on fish and crustacean shellfish at 0.01 ppm, rice grain and
mollusk shellfish at 0.02 ppm, and rice straw at 0.50 ppm.  The
petitioner has requested that permanent tolerances be established at
0.01 ppm for grape and tree nut commodities, including pistachio.

Technical grade penoxsulam exhibited minimal acute toxicity in the
available studies (Toxicity Category IV for all categories).  In
subchronic and chronic feeding studies in rats and dogs, the most
sensitive target organ was the urothelium of the urinary system.  In
subchronic and chronic feeding studies in mice, no effects of
toxicological significance were observed in the feeding studies.  In a
developmental toxicity study in rats and rabbits, no developmental
toxicity was observed and there was no increased quantitative or
qualitative susceptibility of fetuses, as compared to dams.  In a
2-generation reproduction study in rats, delays in preputial separation
were noted.  No other endpoints of reproductive toxicity or offspring
growth and survival were affected by treatment.  There was no increased
quantitative or qualitative susceptibility of fetuses or offspring, as
compared to adults.  No treatment-related neurotoxicity was observed in
acute or chronic neurotoxicity studies in rats, or in any of the other
available studies on penoxsulam.  No systemic or dermal toxicity was
noted in a 28-day dermal toxicity study in rats.

In a carcinogenicity study in Fisher 344 rats, mononuclear cell leukemia
(MNCL) was observed across all dose levels, and therefore HED has
classified penoxsulam as having suggestive evidence of carcinogenticity,
but recommended against quantitative assessment of cancer risk.  HED
concluded that cancer risk associated with penoxsulam is negligible
based on the following considerations.  First, it is questionable
whether the MNCL seen in the Fisher 344 rat study was treatment related,
since it was only seen in males, there was no dose-related increase in
incidence of MNCL (i.e., no dose response), and this type of tumor is
common in Fisher 344 rats, especially with aging; in the rat
chronic/carcinogenicity study, the first incidence of MNCL was observed
after 78 weeks of dosing.   Second, MNCL in Fisher 344 rats is of
questionable significance for humans, since it has not been observed in
other mammals and there is no histologically similar tumor known to
occur in humans.  Finally, there is no other evidence to indicate a
cancer concern for penoxsulam, given that the mouse carcinogenicity was
negative, penoxsulam is negative for mutagenicity, and because other
compounds in the class (triazolopyrimidines) have shown no evidence of
MNCL in Fisher 344 rats.

The toxicity database for penoxsulam is complete, except for
immunotoxicity testing.  EPA began requiring functional immunotoxicity
testing of all food and non-food use pesticides on December 26, 2007. 
This type of testing is not yet available for penoxsulam.  In the
absence of specific immunotoxicity studies, EPA has evaluated the
available penoxsulam toxicity data to determine whether an additional
database uncertainty factor is needed to account for potential
immunotoxic effects. There was no evidence of adverse effects on the
organs of the immune system at the LOAEL in any study with penoxsulam. 
In addition, penoxsulam does not belong to a class of chemicals (e.g.,
the organotins, heavy metals, or halogenated aromatic hydrocarbons) that
would be expected to be immunotoxic.  Based on these considerations, EPA
does not believe that conducting a special series 870.7800
immunotoxicity study will result in a point of departure less than the
lowest NOAEL of 14.7 mg/kg/day, used in calculating the cPAD for
penoxsulam; therefore, an additional database uncertainty factor is not
needed to account for potential immunotoxicity.

The toxicological database for penoxsulam shows no effects attributable
to a single dose and, as noted above indicates that a quantification of
cancer risk, per se, is not appropriate for this chemical.  Therefore,
doses and endpoints have been selected to assess chronic dietary
exposure as well as non-occupational short-term incidental oral and
inhalation, and intermediate-term incidental oral, dermal, and
inhalation exposures.  For occupational exposures, short- intermediate-,
and long-term doses and endpoints have been selected to assess exposure
by the dermal and inhalation routes.

The residue chemistry database for penoxsulam is essentially complete. 
The nature of the residue in plants is understood for purposes of this
petition.  The residue of concern for tolerance expression and risk
assessment is penoxsulam per se.  This conclusion is based, in part, on
the proposed use pattern and HED notes that should the use pattern for
grapes or tree nuts change (i.e., from soil to foliar applications),
additional nature of the residue data will be needed.   Acceptable field
trial, storage stability, and processing studies have been completed to
support the requested uses on grapes and tree nuts.  Analytical methods
are available for tolerance-enforcement purposes.  The current
enforcement method, Method GRM 01.25, is an LC-MS/MS method which
monitors only one ion transition.  As such, it is not acceptable on its
own, with respect to residue confirmation.  A second method, Method GRM
04.09, is similar to GRM 01.25 but monitors two ion transitions,
obviating the need for a separate confirmatory method.  Given that
Method GRM 04.09 is available and suitable for tolerance enforcement,
HED does not believe that the lack of a confirmatory method for GRM
01.25 should be an impediment to granting the requested use or for the
establishment of tolerances.

HED has estimated dietary, residential, and aggregate risks from
exposure to penoxsulam.  Dietary risk estimates are well below HED’s
level of concern for all population subgroups, with the maximum risk
estimate being 7.1% of the chronic population-adjusted dose (cPAD) for
infants.  The MOEs for residential exposure are 10,000 or more,
indicating risks below HED’s level of concern.  Likewise, MOEs for
aggregate risk range from 1,500 to 6,000 and indicate risks below
HED’s level of concern.

HED has also estimated exposures to penoxsulam associated with
occupational activities.  For workers handling and/or applying
penoxsulam, MOEs range from 340 to 64,000 and are not of concern.  Based
on the toxicological and chemical properties of penoxsulam,
postapplication exposures are not of risk concern.

There are no human health risk issues that would preclude granting
registration for the requested uses of penoxsulam on grape and tree nuts
or establishment of permanent tolerances for penoxsulam residues as
follows:  SEQ CHAPTER \h \r 1 

Almond, hulls 	0.01 ppm

Grape 	0.01 ppm

Nut, tree, group 14 	0.01 ppm

Pistachio 	0.01 ppm

Prior to registration, the petitioner should submit a revised Section F
to reflect the correct commodity definition for the tree nut crop group:
 “Nut, tree, Group 14.”  An immunotoxicity study should be submitted
to the Agency as a condition of registration.

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

2.1	Summary of Registered/Proposed Uses  TC \l2 "2.1	Summary of
Registered/Proposed Uses 

(EPA File Symbol No. 62719-ANG), a 2 lb/gal FlC formulation of
penoxsulam; the product is 100% repackaged from another 2 lb/gal FlC
formulation (Grasp™ SC; EPA Reg. No. 62719-500) which is registered
for use on rice in the U.S.  The proposed uses on grapes and tree nuts
are summarized in Table 2.1.

Table 2.1.	Summary of Directions for Use of Penoxsulam.

Applic. Timing, Type, and Equip.	Formulation

[EPA File Symbol No.]	Applic. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Grape

Winter dormant + spring;

Soil; broadcast to crop floor or banded at base of trunk;

Ground; use of a hooded/shielded sprayer is required for application
after petal fall.	2 lb/gal FlC

[62719-ANG]	0.0312 (dormant)

0.0156 (spring)	2	0.0469	60	Winter dormant application followed by an
application in the spring with an appropriate postemergence tank mix
partner in spray volumes ≥20 gal/A.  A minimum RTI of 30 days is
specified. Application to vines that are not staked or trellised unless
they are free standing, or to vines established <1 year, or to vines
established <3 years unless they are on a trellis wire 3’ above the
soil surface is prohibited.   

Tree Nuts

Winter dormant + spring;

Soil; broadcast to crop floor or banded at base of trunk;

Ground; use of a hooded/shielded sprayer is required for application
after flowering.	2 lb/gal FlC

[62719-ANG]	0.0312 (dormant)

0.0156 (spring)	2	0.0469	60	Winter dormant application followed by an
application in the spring with an appropriate postemergence tank mix
partner in spray volumes ≥20 gal/A.  A minimum RTI of 30 days is
specified. Application to tree nut crops established <9 months is
prohibited.   



Note to RD:  The proposed use pattern on the draft label differed from
the use pattern described under Section G of the petition, where the
petitioner stated that the maximum application rates for winter dormant
applications were 0.0357 lb ai/A for grape and 0.0446 lb ai/A for tree
nut, and that the maximum application rate for the second application
was 0.0179 lb ai/A for both crops for maximum seasonal rates of 0.0535
lb ai/A for grape and 0.0624 lb ai/A for tree nuts.  The rates specified
under Section G correspond more closely with the use patterns reflected
in the crop field trials.  Given that the residues in the field trials
are all < LOQ and the rates used in the occupational assessment, HED has
no concerns if the rates specified in Section G are the truly intended
rates and become listed on the final label.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

Table 2.2.1.	Penoxsulam Nomenclature.

Compound	

Common name	Penoxsulam

Company experimental name	XDE-638

IUPAC name	  SEQ CHAPTER \h \r 1
6-(2,2-difluoroethoxy)-N-(5,8-dimethoxy-s-triazolo[1,5-c]pyrimidin-2-yl)
-α,α,α-trifluoro-o-toluenesulfonamide

CAS name	  SEQ CHAPTER \h \r 1
2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4]triazolo[1,5-c]
pyrimidin-2-yl)-6-(trifluoromethyl) benzenesulfonamide

CAS registry number	  SEQ CHAPTER \h \r 1 219714-96-2

End-use product (EP)	GF-443 T&V Herbicide (EPA Reg. No. 62719-ANG) 



2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

Table 2.3.2.	Physicochemical Properties of Penoxsulam. 

Parameter	Value	Reference 1

Melting point/range	Not available

	pH	5.2	MRID 45830707

Density	1.61 g/mL at 20 °C 	MRID 45830707

Water solubility at 19 °C	Unbuffered	4.91 mg/L

pH 5	5.66 mg/L

pH 7	408 mg/L

pH 9	1460 mg/L	MRID 45830720

Solvent solubility at 19 °C	Xylene	0.017 g/L

1-Octanol	0.035 g/L

Methanol	1.48 g/L

Ethyl acetate	3.23 g/L

Acetonitrile	15.3 g/L

Acetone	20.3 g/L 

Dimethylsulfoxide	78.4 g/L	MRID 45830720

Vapor pressure	  SEQ CHAPTER \h \r 1 7.16 x 10-16 mm Hg at 25 °C	MRID
45830720

Dissociation constant, pKa	5.1 (ambient)	MRID 45830720

Octanol/water partition coefficient, Log(KOW)	Unbuffered	  SEQ CHAPTER
\h \r 1 -0.354

pH 5	  SEQ CHAPTER \h \r 1 1.137

pH 7	  SEQ CHAPTER \h \r 1 -0.602

pH 9	  SEQ CHAPTER \h \r 1 -1.418	MRID 45830720

UV/visible absorption spectrum	Not available

	1 As referenced in DP# 326985, 1/30/07, D. Soderberg.

Based on the properties of the penoxsulam molecule, there does not
appear to be significant potential for bioaccumulation (very low KOW) or
for exposure via the vapor phase.

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

Technical grade penoxsulam (XDE-638), an off-white powder of 97.5%
purity, exhibited minimal acute toxicity in the available studies.  The
acute oral LD50 in male and female rats was >5000 mg/kg (Toxicity
Category IV) and the acute dermal LD50 in male and female rabbits was
>5000 mg/kg (Toxicity Category IV).  Based on an acute inhalation
toxicity study in rats, inhalation toxicity is also Category IV.  In
primary eye and skin irritation studies in rabbits, it produced only
minimal irritation (Toxicity Category IV) and in a dermal sensitization
study in guinea pigs (maximization method), it was negative for dermal
sensitization.

In subchronic and chronic feeding studies in rats and dogs, the most
sensitive target organ was the urothelium of the urinary system.  Due to
limited solubility in urine, penoxsulam (and/or its metabolites) formed
crystals/calculi, which were regularly observed in the pelvis of the
kidney and the lumen of the urinary bladder.  These crystals/calculi
apparently irritated the urothelium in these organs and following
repeated dosing led to numerous secondary effects which resulted in
significant damage to the urinary system.  In various studies, these
secondary effects were manifested as altered clinical chemistry
parameters (increased blood urea nitrogen), altered urinalyses
parameters (increased urine volume, decreased urine specific gravity),
increased absolute and relative kidney weights, gross pathological
findings in the kidneys (calculi and roughened surface), and a variety
of histopathological findings in the kidney and urinary bladder.

In subchronic and chronic feeding studies in mice, no effects of
toxicological significance were observed in the 4-week, 13-week or
18-month feeding studies.  In these studies, the only treatment-related
effects observed at the dose levels tested were increased liver weights,
increased hepatocellular hypertrophy, and related observations
indicating stimulation of the liver microsomal enzyme system.  These
effects were considered to be an adaptive response to administration of
the test material and not toxicologically significant adverse effects.

In a developmental toxicity study in rats, decreased body weight gain,
decreased food consumption and increased kidney weights were observed in
the dams.  No developmental toxicity was observed.  There was no
increased quantitative or qualitative susceptibility of fetuses, as
compared to dams, in this study.  In a developmental toxicity study in
rabbits, decreased body weight gain, decreased food consumption and
clinical signs of toxicity (decreased/absent feces, or mucoid, soft, or
abnormally colored feces) were observed in dams at the highest dose
tested.  One high dose doe died late in the study after exhibiting signs
of clinical toxicity for several days.  No developmental toxicity was
observed.  There was no increased quantitative or qualitative
susceptibility of fetuses, as compared to dams, in this study.  In a
2-generation reproduction study in rats, microscopic lesions in the
kidney were observed in the parental females at the mid and high dose
levels.  Preputial separation, an indicator of sexual maturation, was
significantly (p≤0.05) delayed in mid and high dose F1 males.  The
delay in preputial separation at the mid and high doses was considered
to be a treatment-related effect.  No other endpoints of reproductive
toxicity or offspring growth and survival were affected by treatment. 
There was no increased quantitative or qualitative susceptibility of
fetuses or offspring, as compared to adults, in this study.

No treatment-related neurotoxicity was observed in acute or chronic
neurotoxicity studies in rats, or in any of the other available studies
on penoxsulam.  No systemic or dermal toxicity was noted in a 28-day
dermal toxicity study in rats.

In a carcinogenicity study in rats, male and female rats were given
penoxsulam in the diet for two years at dose levels of 0, 5, 50 or 250
mg/kg/day.  In this study, there was a statistically significant
increased incidence of malignant LGL leukemia (also known as mononuclear
cell leukemia or MCNL) in each of the male treatment groups.  There was
no dose response with all treated male groups having an approximately
2.5 fold increase over control animals.  The incidence in the male
treatment groups exceeded the conducting laboratory’s historical
control mean and range, but fell within the National Toxicology Program
(NTP) historical control data base of mean and range.  There was also an
increased severity (Stage 3) of LGL leukemia in all the treated male
groups compared to the control group.  There was no increase in
incidence or severity of LGL leukemia for the treated female rats in
this study. The dose levels were considered to be adequate in male rats
and marginally adequate in female rats to assess the carcinogenicity of
penoxsulam.  In a carcinogenicity study in mice, penoxsulam was
administered in the diet for 18-months at dose levels up to 375
mg/kg/day in male mice and up to 750 mg/kg/day in female mice.  No
increased incidence of treatment-related tumors of any kind was observed
in the male or female mice.  However, in males, the highest dose tested
(375 mg/kg/day) was considered to be inadequate for carcinogenicity
testing because no toxicologically significant adverse effects were
observed at this dose (or in subchronic studies at doses up to 1000
mg/kg/day).  In females, the highest dose tested (750 mg/kg/day) was
considered adequate for carcinogenicity testing, but only because it was
sufficiently close to the limit dose of 1000 mg/kg/day.  Like males, no
toxicologically significant adverse effects were observed in females at
this dose (or in subchronic studies at doses up to 1000 mg/kg/day). 
Technical grade penoxsulam did not demonstrate any mutagenic potential
in a battery of four mutagenicity studies.

Penoxsulam was classified as “Suggestive Evidence of Carcinogenicity,
but Not Sufficient to Assess Human Carcinogenic Potential” and,
furthermore, quantification of human cancer risk was not recommended. 
HED concluded that cancer risk associated with penoxsulam is negligible
based on the following considerations.  First, it is questionable
whether the MNCL seen in the Fisher 344 rat study was treatment related,
since it was only seen in males, there was no dose-related increase in
incidence of MNCL (i.e., no dose response), and this type of tumor is
common in Fisher 344 rats, especially with aging; in the rat
chronic/carcinogenicity study, the first incidence of MNCL was observed
after 78 weeks of dosing.   Second, MNCL in Fisher 344 rats is of
questionable significance for humans, since it has not been observed in
other mammals and there is no histologically similar tumor known to
occur in humans.  Finally, there is no other evidence to indicate a
cancer concern for penoxsulam, given that the mouse carcinogenicity was
negative, penoxsulam is negative for mutagenicity, and because other
compounds in the class (triazolopyrimidines) have shown no evidence of
MNCL in Fisher 344 rats.  

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

In a metabolism study in rats, 14C-penoxsulam was rapidly and nearly
completely absorbed at the low dose of 5.0 mg/kg, but at the high dose
of 250 mg/kg, there was evidence that absorption was largely incomplete
(i.e. absorption was saturated).  Both gender and dose affected the
excretion pattern.  At the low dose, the major route of excretion of
radioactivity was via the feces in males and via the urine in females. 
At the high dose, radioactivity was predominantly excreted via the feces
in both sexes.  A significant enterohepatic circulation was observed,
particularly in males.  Most (>90%) of the administered dose was
excreted within 36-48 hours. There was negligible radioactivity in
tissues at 7 days and no evidence of accumulation in any tissue/organ. 
Although numerous metabolites were revealed in the urine, feces and
bile, nearly all were <1% of the administered dose.  Parent compound and
a 2-hydroxyphenyl derivative were the major compounds in urine and
feces.

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

No evidence of neurotoxicity was observed in the acute or chronic
neurotoxicity studies in rats or in any of the subchronic or chronic
feeding studies in rats, mice or dogs.  A developmental neurotoxicity
study (DNT) is not required.  The FQPA SF has been removed (i.e. reduced
to 1x) since there are no residual uncertainties for pre- and/or
post-natal toxicity and there is no evidence of qualitative or
quantitative susceptibility in developmental and reproductive studies. 
The FQPA SF assumes that the exposure databases (dietary, food, drinking
water, and residential) are complete and that the risk assessment for
each potential exposure scenario includes all metabolites and/or
degradates of concern and does not underestimate the potential risk for
infants and children.

The FQPA SF has been removed (i.e. reduced to 1x) since there are no
residual uncertainties for pre- and/or post-natal toxicity.  The
penoxsulam risk assessment team evaluated the quality of the hazard and
exposure data; and, based on these data, recommended that the FQPA SF be
removed.  The recommendation is based on the following:

There was no toxicologically significant evidence of neurotoxicity in
either the acute or chronic neurotoxicity study.

No definitive quantitative or qualitative susceptibility was observed in
either of the developmental rat or rabbit studies.

Significant dose-related effects in the two-generation reproduction
study were limited to the delay in preputial separation.  No other
endpoints of reproductive toxicity or offspring growth and survival were
affected by treatment, and offspring effects were observed in the
presence of parental toxicity at similar doses.

The chronic dietary (food+water) and residential exposure assessments
are based on inputs and assumptions that are unlikely to underestimate
dietary exposure.

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database 

The toxicity database for penoxsulam is complete, except for
immunotoxicity testing.  EPA began requiring functional immunotoxicity
testing of all food and non-food use pesticides on December 26, 2007. 
This type of testing is not yet available for penoxsulam.  In the
absence of specific immunotoxicity studies, EPA has evaluated the
available penoxsulam toxicity data to determine whether an additional
database uncertainty factor is needed to account for potential
immunotoxic effects. There was no evidence of adverse effects on the
organs of the immune system at the LOAEL in any study with penoxsulam. 
In addition, penoxsulam does not belong to a class of chemicals (e.g.,
the organotins, heavy metals, or halogenated aromatic hydrocarbons) that
would be expected to be immunotoxic.  Based on these considerations, EPA
does not believe that conducting a special series 870.7800
immunotoxicity study will result in a point of departure less than the
lowest NOAEL of 14.7 mg/kg/day, used in calculating the cPAD for
penoxsulam; therefore, an additional database uncertainty factor is not
needed to account for potential immunotoxicity.

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity


There is not a concern for neurotoxicity resulting from exposure to
penoxsulam.

No evidence of neurotoxicity was observed in the acute or chronic
neurotoxicity studies in rats or in any of the subchronic or chronic
feeding studies in rats, mice or dogs. 

3.3.3	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental
Toxicity Studies 

In developmental toxicity studies in rats and rabbits, there was no
increased quantitative or qualitative susceptibility of fetuses or
offspring, as compared to adults.

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study 

In a 2-generation reproductive toxicity study in rates, preputial
separation, an indicator of sexual maturation, was significantly
(p≤0.05) delayed in mid- and high-dose F1 males.  The delay in
preputial separation at the mid and high doses was considered to be a
treatment-related effect.  No other endpoints of reproductive toxicity
or offspring growth and survival were affected by treatment.  There was
no increased quantitative or qualitative susceptibility of fetuses or
offspring, as compared to adults, in this study.

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources 

None

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

There is not a concern for pre- and/or postnatal toxicity resulting from
exposure to penoxsulam.

3.3.6.1	Determination of Susceptibility  TC \l4 "3.3.6.1	Determination
of Susceptibility 

There was no quantitative or qualitative evidence of susceptibility in
rats or rabbits following in utero exposures.  No developmental toxicity
was seen at the highest dose tested in either species.  Following
pre/post-natal exposure in the two-generation study, offspring toxicity
was seen at the same dose that induced parental toxicity and was not
more severe than maternal toxicity.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility  TC \l4 "3.3.6.2	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility  

There are no concerns or residual uncertainties for pre/post-natal
toxicity following exposure to penoxsulam.

  

3.3.7	Recommendation for a Developmental Neurotoxicity Study  TC \l3
"3.3.7	Recommendation for a Developmental Neurotoxicity Study 

There is not a concern for developmental neurotoxicity resulting from
exposure to penoxsulam.  A developmental toxicity study is not required.

3.4	FQPA Safety Factor for Infants and Children

Based upon the available data, the FQPA SF has been reduced to 1X since
there are no residual uncertainties for pre- and/or post-natal toxicity.
 As noted above, there is currently a data gap for the immunotoxicity
study.  HED does not believe that the lack of that study warrants an
additional uncertainty factor.

  TC \l2 "3.4	Safety Factor for Infants and Children 

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.5.1	Acute Reference Dose (aRfD)   TC \l3 "3.5.1	Acute Reference Dose
(aRfD) 

Study Selected:  None

Guideline No.:  None   

MRID No.:  None  

Executive Summary:  None

Dose and Endpoint for Establishing aPOD:  Not applicable

Uncertainty Factor (UF): Not applicable

Comments about Study/Endpoint: In the developmental toxicity study in
rabbits, one high-dose doe died on GD 27 after exhibiting clinical signs
of toxicity beginning on GD 22.  Since the test material was
administered each day from GD 7 through GD 27, this doe died only after
21 doses.  It is unlikely that this death was caused by a single dose of
the test material.  There were no other treatment-related effects
observed in any of the available toxicity studies on penoxsulam that
could be considered to have resulted from a single dose of the test
material.

3.5.2	Chronic Reference Dose (cRfD)  TC \l3 "3.5.2	Chronic Reference
Dose (cRfD) 

Study Selected: 1-Year Chronic Feeding Study in Dogs

 

Guideline No.:  § 870.4100

MRID No.: 45830914

Executive Summary:  In a chronic toxicity study (MRID 45830914), XDE-638
(penoxsulam; 97.7%; Lot No. B-765-44) was administered to four Beagle
dogs/sex/dose in the diet at concentrations of 0, 0.015, 0.045 or 0.15%
(equivalent to 0, 5.3, 14.7, or 46.2 mg/kg/day, respectively, for males
and 0, 4.4, 14.0, or 44.8 mg/kg/day, respectively, for females) for one
year.

There were no toxicologically significant compound-related effects on
mortality, clinical signs, ophthalmologic examinations, hematology,
clinical chemistry, urinalyses, organ weights, or gross pathology.  The
only effect of toxicological significance was the occurrence of very
slight, multifocal hyperplasia of the pelvic epithelium in both kidneys
of one male in the 0.15% group (46.2 mg/kg/day).  Similar lesions were
seen in male and female dogs in 4- and 13-week dietary studies. 
Exacerbation of the lesions observed in these shorter-term studies was
not observed in the one-year study.  The incidence of kidney lesions
seen in the 13-week study was actually greater (2/4 males and 2/4
females) than in the one-year study (1/4 males and 0/4 females) at the
same dietary level.  In addition, crystals were seen in the renal pelvis
and collecting ducts of both genders in the 13-week study, but not in
the one-year study.  

The LOAEL is 46.2 mg/kg/day for males based on slight multifocal
hyperplasia in the renal epithelium; a LOAEL was not established for
females (>44.8 mg/kg/day).  The NOAEL for males is 14.7 mg/kg/day; the
NOAEL for females is 44.8 mg/kg/day.

Dose and Endpoint for Establishing RfD:  NOAEL of 14.7 mg/kg/day, based
on multifocal hyperplasia of the pelvic epithelium of the kidney of
males at the LOAEL of 46.2 mg/kg/day.

Uncertainty Factor (UF): 100, based on 10X for interspecies
extrapolation and 10X for intraspecies variation.

Comments about Study/Endpoint/Uncertainty Factor: This endpoint is based
on an oral study, which is the route of interest for a dietary risk
estimate.  Although the multifocal hyperplasia of the pelvic epithelium
of the kidney observed at the LOAEL of 46.2 mg/kg/day in the selected
study was described as very slight and occurred in only one male dog,
this effect was nevertheless considered to be of sufficient concern to
be the basis for determining the chronic RfD for penoxsulam.  The reason
for this was that a higher incidence of the same histopathological
lesion in the kidneys of both male and female dogs was observed in the
13-week feeding study in dogs at almost identical dose levels.  The
LOAEL in the 13-week study was 49.4 mg/kg/day (males) and 57.1 mg/kg/day
(females) and the NOAEL was 17.8 mg/kg/day (males) and 19.9 mg/kg/day
(females).  In addition, crystals were seen in the renal pelvis and
collecting ducts of both genders in the 13-week study, but not in the
one-year study.  The available data indicate that penoxsulam (and/or its
metabolites) has a limited solubility in urine and tends to form
crystals/calculi in the kidney and urinary bladder.  These
crystals/calculi apparently irritate the tissues in these organs, and
following repeated administrations of penoxsulam, lead to hyperplasia,
inflammation and/or other secondary effects in the kidney and urinary
bladder.

Chronic RfD     =       14.7 mg/kg/day (NOAEL)      =     0.147
mg/kg/day

					100 UF

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: 13-Week Feeding Study in Dogs

Guideline No.:  § 870.3150

MRID No.: 45830909

Executive Summary:  In a 90-day oral toxicity study (MRID 45830909),
XDE-638 (penoxsulam; 97.5%; Lot No. ND05167938, TSN101773) was
administered to four Beagle dogs/sex/dose in the diet at concentrations
of 0, 0.015, 0.045 or 0.15% (equal to 0, 5.9, 17.8, and 49.4 mg/kg
bw/day, respectively, in males and 0, 5.7, 19.9 and 57.1 mg/kg bw/day,
respectively, in females) for 13 weeks.

There were no compound-related effects on mortality, clinical signs,
body weight, food consumption, ophthalmologic examinations, hematology,
clinical chemistry, urinalyses, or gross pathology.  Increased relative
liver/body weight ratios in males and females receiving 0.15% XDE-638
was considered a treatment-related effect, however, this effect did not
have correlative changes in clinical pathology or histopathology. 
Treatment-related histopathologic changes in kidneys of 0.15% males and
females consisted of very slight, multifocal pelvic epithelial
hyperplasia and crystals in the renal pelvis and collecting ducts.

The LOAEL for male dogs was 49.4 mg/kg/day and for female dogs was 57.1
mg/kg/day, based on histopathologic changes in the kidneys.  The NOAEL
was 17.8 and 19.9 mg/kg/day for males and females, respectively.

Dose and Endpoint for Risk Assessment: NOAEL of 17.8 mg/kg/day, based on
histopathologic changes in the kidneys at the LOAEL of 49.4 mg/kg/day.

Comments about Study/Endpoint: This endpoint is based on an oral study,
which is the route of interest for an oral risk estimate.  This endpoint
is also appropriate for the population of concern (infants and
children).  For this exposure scenario, a 13-week (90-day) study was
selected to establish the toxicological endpoint for short-term (1-30
days) exposures.  This selection is justified by the observation that
the kidney lesions (including histopathologicic changes) observed in the
4-week, 13-week and 1-year feeding studies in dogs did not occur at
lower dose levels or increase in severity as the duration of the study
increased.  In other words, exacerbation of the kidney lesions observed
in the shorter-term studies did not occur in the longer-term studies. 
Therefore, results in both the 4-week and 1-year studies support this
selection.  In addition, this endpoint and dose are protective of the
maternal effects observed in the developmental toxicity study in rabbits
(i.e., death, clinical signs, decreased body weight gain and decreased
food consumption at the LOAEL of 75 mg/kg/day).

3.5.4	Dermal Absorption  TC \l3 "3.5.4	Dermal Absorption 

Dermal Absorption Factor:   50% (upper bound estimate)

A dermal absorption study is not available.  The percent dermal
absorption was estimated by comparing the LOAEL for male and female rats
from a 4-week dermal study to the LOAEL for male and female rats from a
4-week feeding study.

The LOAEL for male and female rats from the 4-week dermal study was
>1000 mg/kg/day, based on the lack of any treatment-related effects at
1000 mg/kg/day (the highest dose tested, limit dose).

The LOAEL for male rats from the 4-week feeding study was 500 mg/kg/day,
based on decreased body weight, decreased body weight gain, decreased
food consumption, and decreased RBC parameters.  The NOAEL for male rats
was 100 mg/kg/day.  The LOAEL for female rats from the 4-week feeding
study was 500 mg/kg/day, based on decreased body weight, decreased body
weight gain, decreased food consumption, decreased RBC parameters,
increased kidney weights, and histopathological changes in the kidney. 
The NOAEL for female rats was 100 mg/kg/day.

LOAEL from 4-week feeding study     =         500 mg/kg/day    x   100  
=    50% (upper

LOAEL from 4-week dermal study      =    >1000 mg/kg/day                
  bound estimate)

3.5.5	Dermal Exposure  TC \l3 "3.5.5	Dermal Exposure 

3.5.5.1	Short-Term  TC \l4 "3.5.5.1	Short-Term 

Study Selected: None

Guideline No.: N/A

MRID No.: N/A

Executive Summary:  N/A

Dose and Endpoint for Risk Assessment:  Not Applicable

Comments about Study/Endpoint:  Quantification of dermal risk assessment
is not required for this exposure scenario due to the lack of dermal,
systemic, neuro, or developmental toxicity concerns.  No dermal or
systemic toxicity was seen at the limit dose in the dermal study.  In
the 4-week oral study, systemic toxicity was seen at a relatively high
dose (500 mg/kg/day; one-half of the limit dose).

3.5.5.2	Intermediate-Term  TC \l4 "3.5.5.2	Intermediate-Term 

Study Selected: 13-Week Feeding Study in Dogs

Guideline No.:  § 870.3150

MRID No.: 45830909

Executive Summary:  See 3.  Incidental Oral Exposure:  Short-Term (1-30
days)   

Dose and Endpoint for Risk Assessment:  NOAEL of 17.8 mg/kg/day, based
on histopathological changes in the kidneys at the LOAEL of 49.4
mg/kg/day.  

Comments about Study/Endpoint:  An oral dose/endpoint was selected due
to the concerns for the renal lesions seen after exposure for 90 days. 
The dermal study was determined to be not appropriate due to its shorter
duration (i.e., 28 days).  The endpoint selected for this exposure
scenario is based on an oral study and therefore a 50% dermal absorption
factor (upper bound estimate) should be used for route-to-route
extrapolation for this risk assessment. 

3.5.5.3	Long-Term  TC \l4 "3.5.5.3	Long-Term 

Study Selected: 1-Year Chronic Feeding Study in Dogs

Guideline No.:  § 870.4100

MRID No.: 45830914

Executive Summary:  See Chronic Reference Dose (RfD)

Dose and Endpoint for Risk Assessment:  NOAEL of 14.7 mg/kg/day, based
on multifocal hyperplasia of the pelvic epithelium of the kidney in
males at the LOAEL of 46.2 mg/kg/day.    

Comments about Study/Endpoint:  The endpoint selected for this exposure
scenario is based on an oral study and therefore a 50% dermal absorption
factor (upper bound estimate) should be used for route-to-route
extrapolation for this risk assessment.  This endpoint is appropriate
for the duration of exposure (> 6 months). See additional comments at
Chronic RfD.

3.5.6	Inhalation Exposure  TC \l3 "3.5.6	Inhalation Exposure 

3.5.6.1	Short- and Intermediate-Term  TC \l4 "3.5.6.1	Short- and
Intermediate-Term 

Study Selected: 13-Week Feeding Study in Dogs

Guideline No.:  § 870.3150

MRID No.: 45830909

Executive Summary: See Incidental Oral Exposure: Short-Term (1-30 days)

Dose and Endpoint for Risk Assessment: NOAEL of 17.8 mg/kg/day, based on
histopathologic changes in the kidneys at the LOAEL of 49.4 mg/kg/day.  
 

Comments about Study/Endpoint: There is no acceptable inhalation study
of any duration available on technical grade penoxsulam.  Absorption via
the inhalation route is assumed to be equivalent to oral absorption. 
The selected endpoint has been determined to be appropriate for the
duration of exposure (1-30 days). See additional comments at Incidental
Oral Exposure: Short-Term (1-30 days).  

3.5.6.2	Long-Term  TC \l4 "3.5.6.2	Long-Term 

Study Selected: 1-Year Chronic Feeding Study in Dogs   

Guideline No.:  § 870.4100

MRID No.: 45830914

Executive Summary:  See Chronic RfD

Dose and Endpoint for Risk Assessment:   NOAEL of 14.7 mg/kg/day, based
on multifocal hyperplasia of the pelvic epithelium of the kidney in
males at the LOAEL of 46.2 mg/kg/day.    

Comments about Study/Endpoint:  The endpoint selected for this long-term
inhalation risk assessment is based on an oral study.  Absorption via
the inhalation route is assumed to be equivalent to oral absorption
(i.e., 100%).  The selected endpoint is appropriate for the duration of
exposure (> 6 months). See additional comments at Chronic RfD.

3.5.7	Level of Concern for Margin of Exposure  TC \l3 "3.5.7	Level of
Concern for Margin of Exposure 

Table 3.5.7.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	N/A	100	N/A

Inhalation	100	100	N/A

Residential Exposure

Oral	100	100	N/A

Dermal	N/A	100	N/A

Inhalation	100	100	N/A

N/A = Not Applicable

For occupational and residential exposure, the MOEs are based on the
conventional uncertainty factor of 100x (10x for intraspecies
extrapolation and 10x for interspecies variation).  Although doses and
endpoints were selected for long-term dermal and inhalation risk
assessments, no long-term exposure is expected for the existing or
proposed uses.

3.5.8	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.8	Recommendation for Aggregate Exposure Risk Assessments 

Common toxicological effects were selected for assessment of short-term
exposures by oral and inhalation (oral equivalent) routes.  The
aggregate risk assessment for this exposure duration should include oral
and inhalation exposures appropriate to the populations of concern. 
Short-term dermal exposure need not be aggregated because no
toxicological endpoint was selected.  

Common toxicological effects were selected for assessment of
intermediate- and long-term oral, dermal (oral equivalent) and
inhalation (oral equivalent) routes.  The aggregate risk assessments for
these exposure durations should include oral, dermal and inhalation
exposures appropriate to the populations of concern.

3.5.9	Classification of Carcinogenic Potential  TC \l3 "3.5.9
Classification of Carcinogenic Potential 

Penoxsulam was classified as having “Suggestive Evidence of
Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic
Potential” and, furthermore, quantification of human cancer risk was
not recommended.  The classification was assigned after consultation
with experts from the Pathology Working Group (PWG), the National
Toxicology Program (NTP), and through evaluation of published literature
regarding the relevance of the mononuclear cell leukemia observed in
Fisher 344 rats.  HED concluded that cancer risk associated with
penoxsulam is negligible based on the following considerations.  First,
it is questionable whether the MNCL seen in the Fisher 344 rat study was
treatment related, since it was only seen in males, there was no
dose-related increase in incidence of MNCL (i.e., no dose response), and
this type of tumor is common in Fisher 344 rats, especially with aging;
in the rat chronic/carcinogenicity study, the first incidence of MNCL
was observed after 78 weeks of dosing.   Second, MNCL in Fisher 344 rats
is of questionable significance for humans, since it has not been
observed in other mammals and there is no histologically similar tumor
known to occur in humans.  Finally, there is no other evidence to
indicate a cancer concern for penoxsulam, given that the mouse
carcinogenicity was negative, penoxsulam is negative for mutagenicity,
and because other compounds in the class (triazolopyrimidines) have
shown no evidence of MNCL in Fisher 344 rats.

3.5.10	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments  TC \l3 "3.5.10	Summary of Toxicological Doses and
Endpoints for Use in Human Risk Assessments 

Table 3.5.10a.  Summary of Toxicological Doses and Endpoints for
Penoxsulam for Use in Dietary and Non-Occupational Human Health Risk
Assessments.

Exposure

Scenario	Point of Departure, UF	FQPA SF* and Level of Concern for Risk
Assessment	Study and Toxicological Effects

Acute Dietary

(all populations)	None

UF = N/A	Not applicable	No toxicological endpoint attributable to a
single exposure was identified in the available toxicology studies on
penoxsulam.

Chronic Dietary

(all populations)	NOAEL= 14.7 mg/kg/day

UF = 100

Chronic RfD = 0.147 mg/kg/day	FQPA SF = 1x

cPAD = 

Chronic RfD

 FQPA SF

= 0.147 mg/kg/day	1-Year Chronic Feeding Study in Dogs. LOAEL = 46.2
mg/kg/day based on multifocal hyperplasia of the pelvic epithelium of
the kidney.

Incidental Oral Short-Term

(1-30 days)	NOAEL = 17.8 mg/kg/day	Residential LOC for MOE = 100

	13-Week Feeding Study in Dogs.  LOAEL = 49.4 mg/kg/day based on
histopathologic changes in kidneys.

Incidental Oral Intermediate-Term

(1-6 months)	NOAEL = 17.8 mg/kg/day	Residential LOC for MOE = 100

	13-Week Feeding Study in Dogs.  LOAEL = 49.4 mg/kg/day based on
histopathologic changes in kidneys.

Dermal 

Short-Term

(1-30 days)	None

	Not applicable	No dermal, systemic, neuro or developmental toxicity
concerns.

Dermal 

Intermediate-Term

(1-6 months)	NOAEL= 17.8  mg/kg/day

(dermal absorption rate = 

50%)	Residential LOC for MOE = 100

 	13-Week Feeding Study in Dogs.  LOAEL = 49.4 mg/kg/day based on
histopathologic changes in kidneys.

Inhalation 

Short-Term

(1-30 days)	NOAEL= 17.8  mg/kg/day

(inhalation  absorption rate = 

100%)	Residential LOC for MOE = 100

 	13-Week Feeding Study in Dogs.  LOAEL = 49.4 mg/kg/day based on
histopathologic changes in kidneys.

Inhalation 

Intermediate-Term

(1-6 months)	NOAEL= 17.8  mg/kg/day

(inhalation  absorption rate = 

100%)	Residential LOC for MOE = 100

 	13-Week Feeding Study in Dogs.  LOAEL = 49.4 mg/kg/day based on
histopathologic changes in kidneys.

Cancer (oral, dermal, inhalation)	 “Suggestive Evidence of
Carcinogenic Potential”

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 date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  MOE = margin of exposure.  LOC = level of concern.  N/A = not
applicable.

Table 3.5.10b.  Summary of Toxicological Doses and Endpoints for
Penoxsulam for Use in Occupational Human Health Risk Assessments.

Exposure

Scenario	Point of Departure, UF	FQPA SF* and Level of Concern for Risk
Assessment	Study and Toxicological Effects

Dermal 

Short-Term

(1-30 days)	None

	Not applicable	No dermal, systemic, neuro or developmental toxicity
concerns.

Dermal 

Intermediate-Term

(1-6 months)	NOAEL= 17.8  mg/kg/day

(dermal absorption rate = 

50%)	Occupational LOC for MOE = 100 	13-Week Feeding Study in Dogs. 
LOAEL = 49.4 mg/kg/day based on histopathologic changes in kidneys.

Dermal 

Long-Term

(> 6 months)	NOAEL= 14.7 mg/kg/day

(dermal absorption rate =     50%)	Occupational LOC for MOE = 100	1-Year
Chronic Feeding Study in Dogs. LOAEL = 46.2 mg/kg/day based on
multifocal hyperplasia of the pelvic epithelium of the kidney.

Inhalation 

Short-Term

(1-30 days)	NOAEL= 17.8  mg/kg/day

(inhalation  absorption rate = 

100%)	Occupational LOC for MOE = 100 	13-Week Feeding Study in Dogs. 
LOAEL = 49.4 mg/kg/day based on histopathologic changes in kidneys.

Inhalation 

Intermediate-Term

(1-6 months)	NOAEL= 17.8  mg/kg/day

(inhalation  absorption rate = 

100%)	Occupational LOC for MOE = 100 	13-Week Feeding Study in Dogs. 
LOAEL = 49.4 mg/kg/day based on histopathologic changes in kidneys.

Inhalation 

Long-Term

(> 6 months)	NOAEL= 14.7 mg/kg/day

(inhalation absorption rate =     100%)	Occupational LOC for MOE = 100
1-Year Chronic Feeding Study in Dogs. LOAEL = 46.2 mg/kg/day based on
multifocal hyperplasia of the pelvic epithelium of the kidney.

Cancer (oral, dermal, inhalation)	 “Suggestive Evidence of
Carcinogenic Potential”

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 date (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  MOE = margin of exposure.  LOC = level of concern.  N/A = not
applicable.

3.6	Endocrine Disruption  TC \l2 "3.6	Endocrine Disruption 

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

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data 

No public health or epidemiological data were used for this risk
assessment.

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

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation 

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

The nature of the residue in plants is understood for purposes of this
petition.  The residue of concern for tolerance expression and risk
assessment is penoxsulam per se.  An acceptable rice metabolism study
reflecting foliar application was previously submitted.  Under the
current petition, an acceptable grape metabolism study reflecting soil
application has been submitted.  ChemSAC previously concluded that the
subject grape metabolism study would be adequate to determine the nature
of the residue for the proposed uses on grapes and tree nuts in
consideration of the proposed use patterns.  Both the rice and grape
metabolism studies demonstrate that penoxsulam primarily degrades to its
5-OH metabolite (5-OH XDE-638); little translocation of penoxsulam or
its metabolites into rice grain or grape vines was observed.  HED notes
that, should the use pattern for grapes or tree nuts change (i.e., from
soil to foliar applications), additional nature of the residue data will
be needed.

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

HED review of an acceptable rotational crop study concluded that no
quantifiable residues of penoxsulam or 5-OH XDE-638 are expected to be
present in the raw agricultural commodities of small grains, leafy
vegetables, and root crops planted 90 days following treatment with
penoxsulam at 0.045 or 0.090 lb ai/A (1x or 2x the rate for rice).  The
data also indicate that residues of the metabolite penoxsulam BSTCA
could be present at ≥0.01 ppm in the foliage of root crops planted 90
days following treatment at 0.090 lb ai/A (2x).  However, the MARC
determined that penoxsulam BSTCA is not a residue of concern for
penoxsulam in rotated crops.

It was noted that the submitted confined rotational crop study only
included one plantback interval, 90 days.  If in the future plantback
intervals other than 90 days are proposed, an additional confined
rotational crop study reflecting the proposed plantback interval would
be required.  Based on data from the confined rotational crop study, no
quantifiable residues of penoxsulam, its 5-OH metabolite, or BSTCA are
expected to be present in the raw agricultural commodities of small
grains, leafy vegetables, and root crops planted 90 days following
treatment with penoxsulam at 1x the maximum seasonal rate.

With regard to the current petition, grapes and tree nuts are not
rotated, no data pertaining to rotational crops and no rotational crop
restrictions are required to support the proposed uses.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock 

The nature of the residue in livestock is understood based on adequate
goat and poultry metabolism studies.  The studies indicated that
penoxsulam is primarily excreted and not significantly metabolized in
either ruminants or poultry.  The sulfonanilide bridge in penoxsulam
does not appear to be cleaved.  The residue of concern for penoxsulam in
livestock is parent only.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

No enforcement method was proposed in the subject petition; however, HED
concludes that Method GRM 04.09 is suitable for the enforcement of
tolerances in grape and tree nut commodities.  An independent laboratory
validation (ILV) of Method GRM 04.09 is not required because the method
is the same as Method GRM 05.08 for which a successful ILV was
conducted.  Based on the available information regarding method
performance and the successful ILV of Method GRM 0508, an Agency
Petition Method Validation (PMV) is not required.  

Testing results of penoxsulam analyzed according to the FDA
Multi-Residue Method Test guidelines in PAM Vol. I, Appendix II (1/94)
were previously submitted in conjunction with the rice petition (PP#
3F6542).  The multiresidue method data indicate that penoxsulam is not
adequately recovered using any of the multiresidue methods.  These data
have been forwarded to FDA for further evaluation.

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

Penoxsulam is stable to hydrolysis, and is expected to be somewhat
persistent in non-aquatic environments.  The major route of dissipation
for penoxsulam in clear and shallow surface water under favorable light
conditions is through direct aqueous photolysis (t1/2 = 1.5-14 days). 
Penoxsulam is slightly more persistent in aerobic aquatic (t1/2 = 12-38
days) and anaerobic environments (t1/2 = 5-11 days), and even more
persistent in aerobic soil environments (t1/2 = 34-118 days). 
Penoxsulam is also very mobile (Kd = 0.13-1.96), and does have the
potential to leach to ground water.  The low vapor pressure and
Henry’s Law constant, limits the potential of penoxsulam to
volatilization from soil and water.   

Eleven major degradation products have been identified for penoxsulam
(BSTCA, 2-amino-TCA, 5-OH-penoxsulam, SFA, sulfonamide,
5,8-di-OH-penoxsulam, BSA, 2-amino-TP, TPSA, BSTCA methyl, and 5-OH 2
amino TP).  Data are not available to fully characterize these
degradates and their respective degradation pathways.  Six of these
degradation products have been identified by HED as being of
toxicological concern.  These toxic residues are: BSTCA, 2-amino TCA,
5-OH-penoxsulam, SFA, sulfonamide, and 5,8-di OH.

5.1.6	Comparative Metabolic Profile TC \l3 "5.1.6	Comparative Metabolic
Profile 

Penoxsulam appears to undergo significant metabolism in rats, crops, and
the environment.  The 5-hydroxy metabolite was common to many of these. 
In the goat and hen metabolism studies, penoxsulam was excreted and not
significantly metabolized.   It is unclear at this time why penoxsulam
undergoes more metabolism in rats than in goats or hens.

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.7
Toxicity Profile of Major Metabolites and Degradates 

None of the penoxsulam metabolites or degradates have been identified as
having a higher potential toxicity then the parent compound.

5.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

Table 5.1.8  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Primary Crop	Parent only	Parent only

	Rotational Crop	Parent only	Parent only

Livestock	Ruminant	Parent only	Parent only

	Poultry	Parent only	Parent only

	Fish and Shellfish	Parent plus 5-OH penoxsulam 	Parent only

Drinking Water	Parent; BSTCA; 2-amino TCA; 5-OH-penoxsulam; SFA;
sulfonamide; 5,8-diOH*	N/A

* See Appendix C for chemical structures of these compounds.

Residues of concern were determined by the MARC in 2004.  Data submitted
since that time do not alter those determinations.

5.1.9	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water
Residue Profile 

The Environmental Fate and Effects Division (EFED) has provided HED with
Tier 1 modeled estimates of penoxsulam residues of concern in drinking
water based on the use pattern for turf grass (J. Wolf, 2 December 2008,
D355676).  Based on the turf grass use pattern (0.09 lb a.i./A),
residues of penoxsulam are not expected to be greater than 0.023 ppm
(Table 1).  Penoxsulam is registered for control of aquatic weeds.  For
that use pattern, the maximum application rate is 150 ppb (0.15 ppm) in
the water column.  For this assessment, HED has used 0.15 ppm as a
high-end estimate of penoxsulam residues in drinking water.  The
0.15-ppm value is likely to be an overestimate of actual residues in
drinking water.  Residues were incorporated in the DEEM-FCID into the
food categories “water, direct, all sources” and “water, indirect,
all sources.”

Table 5.1.9.  Summary of Residue Estimates for Penoxsulam in Drinking
Water.

Duration	Aquatic Use, ppm	Turf Use



Surface Water, ppm	Ground Water, ppm

Acute	0.15	0.0094	0.0233

Chronic	0.15	0.00092	0.0233



5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile 

Tolerances for residues of penoxsulam, per se, [40 CFR 180.605] have
been established for fish (0.01 ppm), crustaceans (0.01 ppm), mollusks
(0.02 ppm), rice grain (0.02 ppm), and rice straw (0.50 ppm).  For the
currently requested uses, adequate data from field trials and supporting
studies have been submitted for grapes, almonds, and pecans.  The data
support tolerances of 0.01 ppm in grape and tree nut (including
pistachio) commodities.  

5.1.11	International Residue Limits TC \l3 "5.1.11	International Residue
Limits 

There are no international residue limits that affect this requested
use.

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

A chronic aggregate dietary (food and drinking water) exposure and risk
assessment (M. Doherty, D360419, 29 January 2009) was conducted using
the Dietary Exposure Evaluation Model DEEM-FCID™, Version 2.03 which
use food consumption data from the U.S. Department of Agriculture’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.

Tolerance-level residues were used for all entries in the assessment and
it was assumed that 100 of crops with registered or proposed uses were
treated (i.e., 100% CT).  Although processing studies with
penoxsulam-treated grapes showed no concentration of residues upon
processing default processing factors from DEEM 7.81 were used for grape
juice and wine (1.2X), and raisins (4.3X).

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

No toxicological endpoint attributable to a single exposure was
identified in the available toxicology studies on penoxsulam.  Acute
dietary exposure is not a concern for this compound.

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

The chronic dietary exposure assessment is highly health protective.  It
is based on tolerance-level residues, assumes 100% crop treated, and
incorporates default processing factors for processed food forms.  Risk
estimates derived from these parameters are below HED’s level of
concern [i.e., < 100% of the chronic population-adjusted dose (cPAD)]
for all population subgroups.  Results are summarized in Table 5.2.

5.2.3	Cancer Dietary Risk  TC \l3 "5.2.3	Cancer Dietary Risk 

Penoxsulam has been classified as having “suggestive evidence of
carcinogenic potential” for which a dose-response assessment is not
appropriate, and therefore HED has not conducted a quantitative dietary
risk assessment for cancer.  Nonetheless, cancer risk is expected to be
negligible for penoxsulam, largely because the tumors observed in Fisher
344 rats are not expected to occur in humans.

Table 5.2.  Summary of Dietary (Food + Drinking Water) Exposure and Risk
for Penoxsulam.

Population Subgroup	Acute Dietary	Chronic Dietary	Cancer

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

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	N/A	N/A	0.003176	2.2	N/A	N/A

All Infants (< 1 year old)

	0.010391	7.1



Children 1-2 years old

	0.004745	3.2



Children 3-5 years old

	0.004430	3.0



Children 6-12 years old

	0.003049	2.1



Youth 13-19 years old

	0.002295	1.6



Adults 20-49 years old

	0.002964	2.0



Adults 50+ years old

	0.003116	2.1



Females 13-49 years old

	0.002950	2.0



The population subgroup with the highest exposure/risk estimate is
bolded.

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

The dietary exposure analysis relies on tolerance-level residues and
100% crop treated.

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

There are several end-use product (EP) formulations of penoxsulam
registered for weed control on residential and commercial turf areas
(lawns and golf courses) and aquatic sites.  Use of these formulations
in residential settings results in exposure to home owners from applying
the products on lawns and to adults and children from contacting treated
areas while playing or doing lawn maintenance.  Such exposures can be of
short- and intermediate-term durations and can be through dermal,
inhalation, or oral routes.

6.1	Residential Handler Exposure TC \l2 "6.1	Residential Handler
Exposure 

Homeowners are exposed to penoxsulam when they handle granule and liquid
products for the control of weeds on home lawns and other sites.  One
product registered for the control of aquatic weeds in residential areas
is labeled for use by professionals only; therefore, no residential
handler exposure is expected from that use.  Homeowner exposures
resulting from handling granular products were characterized previously
(Collantes, M., D339488, 5/23/2007) and are summarized in Table 6.1.

Table 6.1.  Short-term Handler Risk to Home Owners from Applying
Penoxsulam Formulations on Residential  Lawns 1. 

Exposure Scenario	Application                        rate (lb a.i./A)
Exposure (mg/kg/day)	MOE

Push-type spreader (ORETF) 	0.06	3.3 E-7	54,000,000

Low pressure hand wand or back-pack (PHED)	0.06	6.0 E-7	30,000,000

Push-type granular spreader (PHED) 	0.06	2.7 E-6	6,600,000

1. From M. Collantes (D339488, 5/23/2007), Table 4.3.2. 

6.2.	Residential Postapplication Exposure TC \l2 "6.2.	Residential
Postapplication Exposure 

Uses of penoxsulam on lawn and turf areas and in aquatic sites around
residential settings result in post-application exposures to adults and
children.  Such post-application exposures can be from dermal,
inhalation, or oral routes for short- and intermediate-term durations.
The inhalation exposures of penoxsulam to adults and children under the
post-application conditions are expected to be negligible because of its
low volatility (7.16 x 10-16 mm Hg at 25°C).  The post-application
exposures to adults and children from turf and aquatic sites were
characterized previously (Collantes, M., D339488, 5/23/2007) and are
summarized below.

Residential Post-application Turf Exposure:  Turf post-application
exposures to adults and children are considered short-term because of
the infrequent contacts to treated lawns and turf. Adults and children
may be exposed to post-application residues of penoxsulam on turf
through dermal contact.  Short-term dermal risks to adults and children
are not of concern because of the lack of an endpoint for the dermal
route.  The short-term post-application incidental oral exposures to
children from treated turf include hand-to-mouth, objects-to-mouth, and
ingestion of contaminated soil.  Risks from these exposures for children
were estimated previously and are summarized in Table 6.2.1.

Table 6.2.1:  Short-term Oral Post-application Risk to Children Exposed
to Turf Treated with Penoxsulam.1 

Children's                                           Exposure Types
Exposure                  (mg/kg/day) 	Total exposures from             
                   all routes (mg/kg/day)	Total                         
MOE 

Hand-to-Mouth 	8.9E-4	0.0011	16,000

LOC = 100

Object-to-mouth 	2.2E-4



Soil Ingestion 	3.0E-6



1. From M. Collantes (D339488, 5/23/2007), Table 4.6.2. 

Residential Post-application Aquatic Exposure:  The aquatic uses of
penoxsulam (EPA Reg. No. 67690-47, Galleon® SC) in residential settings
may result in post-application dermal and oral exposure to adults and
children while swimming in treated waters.  Such exposures can be of
short- and intermediate-term durations depending upon the frequency of
contact with treated water.  The short-term dermal exposure from
swimming is not of concern due to the lack of an endpoint appropriate
for that duration.  The exposures to adults and children from the
aquatic uses of penoxsulam have been characterized previously and are
summarized in Table 6.2.2.  The total MOEs in Table 6.2.2 are for
intermediate-term exposures and are protective for short-term exposures.
 We note that the swimmer model is based on competitive swimmers in
pools and the resulting oral and dermal exposure estimates are probably
overestimates for swimmers in treated, weed-infested waters.

Table 6.2.2:  Intermediate-term Post-application Risk to Adults and
Children From Swimming in Aquatic Sites Treated with Penoxsulam.1

Exposure                                          scenarios	Oral dose 

mg/kg/day	Dermal dose 

mg/kg/day	Total dose mg/kg/day	Total                     MOE

Children	1.7 E-3	2.5 E-7	1.7 E-3	10,000

Adult	5.4 E-4	1.8 E-7	5.4 E-4 	33,000

1. From M. Collantes (D339488, 5/23/2007), Table 4.6.1.

6.3	Other (Spray Drift, etc.) TC \l2 "6.3	Other (Spray Drift, etc.) 

Spray drift is always a potential source of exposure to residents living
in close proximity to spraying operations.  This situation is
particularly the case with aerial application.  However, to a lesser
extent, spray drift resulting from the ground application of penoxsulam
could also be a potential source of exposure.  The Agency has been
working with the Spray Drift Task Force (a membership of U.S. pesticide
registrants), EPA Regional Offices, State Lead Agencies for pesticide
regulation, and other parties to develop the best spray drift management
practices.  The Agency is now requiring interim mitigation measures for
aerial applications that must be placed on product labels/labeling.  The
Agency has completed its evaluation of the new database submitted by the
Spray Drift Task Force, and is developing a policy on how to apply
appropriately 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 risks associated with pesticide application.

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 exposure and risk from various sources,
HED considers both the route and duration of exposure.

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk 

No toxicological endpoint attributable to a single exposure was
identified in the available toxicology studies on penoxsulam.  Acute
aggregate exposure is not a concern for this compound.

7.2	Short-Term Aggregate Risk TC \l2 "7.2	Short-Term Aggregate Risk 

Short-term exposures may occur following application of penoxsulam to
turf and aquatic use sites (see Section 6.2).  HED considers the swimmer
dermal and oral margins of exposure to be over estimates of the actual
risk and therefore has not included exposure from swimming in the
aggregate MOEs; therefore, the short-term aggregate risk estimates
(Table 7.2) include dietary exposure and incidental oral exposure from
activities on turf.  The resulting short-term MOEs are greater than 100
and, therefore, reflect risk estimates that are not of concern to HED.

Table 7.2.  Aggregate Short-Term MOEs for Penoxsulam

Population Subgroup	MOE

	Dietary 1	Residential Handler 2	Incidental Oral 

(Turf) 3	Aggregate 4

General U.S. Population	5,600	6,600,000	N/A	5,500

All Infants (< 1 year old)	1,700	N/A	16,000	1,500

Children 1-2 years old	3,700	N/A	16,000	3,000

Children 3-5 years old	4,000	N/A	16,000	3,200

Children 6-12 years old	5,800	N/A	16,000	4,200

1 Dietary MOE = Short-term NOAEL (17.8 mg/kg/day) ( Chronic dietary
exposure estimate (Table 5.2)

2 Table 6.1 (worst-case value)

3 Table 6.2.1

4 Aggregate MOE = 1 ( [(1 ( Dietary MOE) + (1 ( Handler MOE) + (1 ( Turf
MOE)]

7.3	Intermediate-Term Aggregate Risk TC \l2 "7.3	Intermediate-Term
Aggregate Risk 

Intermediate-term exposures may occur following application of
penoxsulam to aquatic use sites (see Section 6.2).  As noted previously,
these exposure estimates are based on competitive swimmers in swimming
pools.  As such these estimates are considered to significantly
overestimate exposure from swimming in penoxsulam-treated, weed-infested
waters and HED does not believe it is appropriate to include these
exposure estimates in an overall aggregate assessment.  Thus there are
no intermediate-term exposure scenarios for which quantitative aggregate
risk estimates are appropriate.  In this case long-term aggregate risk
estimates (Section 7.4) are considered to be protective of
intermediate-term exposures.

7.4	Long-Term Aggregate Risk TC \l2 "7.4	Long-Term Aggregate Risk 

Based on the use patterns for penoxsulam, there are no scenarios that
result in long-term exposure other than dietary exposure.  Therefore,
the long-term aggregate risk estimates are equivalent to the chronic
dietary risk estimates presented in Table 5.2 and are below HED’s
level of concern for all population subgroups.

7.5	Aggregate Cancer Risk TC \l2 "7.5	Aggregate Cancer Risk 

Penoxsulam has been classified as having “suggestive evidence of
carcinogenic potential;” However, quantitative assessment of cancer
risk was not recommended because the tumors observed in rats in the
carcinogenicity study were not considered relevant for humans.  HED has
concluded that cancer risk for penoxsulam is negligible. 

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 mechanism of toxicity finding as to penoxsulam and any other
substances and penoxsulam 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 penoxsulam has a common mechanism of
toxicity with other substances. For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

The proposed one application of GF-443 T&V Herbicide per season on
non-bearing and bearing tree nut crops, pistachio, and grape is expected
to result in short-term exposures to mixers, loaders, and applicators. 
However, it is likely that commercial operators may use the product at
different locations for durations more than a month during the weed
growing season resulting in handler exposures of intermediate-term
duration.  Therefore both short- and intermediate-term durations of
exposures are addressed here.  The label recommended application
equipment is a ground boom sprayer; but, low pressure hand wand or
back-pack spray equipment may be used by applicators to control weeds in
small areas and around the base of trees.

9.1	Short- and Intermediate-Term Handler Risk  TC \l2 "9.1	Short- and
Intermediate-Term Handler Risk 

level of concern (MOEs ≥ 100).  Total intermediate-term risk, by
combining dermal plus inhalation exposures also are not of concern,
provided baseline clothing is worn by handlers.

Table 9.1:  Intermediate-term Risks to Handlers of Penoxsulam When Used
on Tree Nuts, Pistachio, and Grape.   

Scenario	Appl. rate,  Equip., Area treated or Volume handled	PPE &      
    (Eng. control) 1  	Dermal 2	Inhalation 3	Total MOE 4

Scenario # 1 Mixing/loading, EC (PHED)	0.031 lb ai/A, ground-boom,  80
acres/day	base line,          (open mixing)	unit exp. 2.9   dose/day
0.05187    sh. t.  MOE NA             int. t. MOE 340 	unit exp. 0.0012 
 dose/day 0.000043     sh. t.  MOE 410,000            int. t. MOE
410,000 	340

Scenario # 2 Applying EC (PHED)	0.031 lb ai/A, ground-boom,

80 acres/day	base line,         (open cab)	unit exp. 0.014   dose/day
0.00025  sh. t.  MOE NA             int. t. MOE 71,000	unit exp. 0.00074
  dose/day 0.000026         sh. t.  MOE    670,000                   
int. t. MOE    670,000	64,000

Scenario # 3 Mixing/loading/ applying EC (ORETF)	0.031 lb ai/A, low
pressure hand wand, 

2 Acres/day	base line	unit exp. 15     dose/day 0.0067

sh. t.  MOE NA             int. t. MOE 2,600  	unit exp. 0.0027  
dose/day 0.0000024       sh. t.  MOE 740,000             int. t. MOE 
740,000	2,700

Scenario # 4 Mixing/loading/ applying EC (ORETF)	0.031 lb ai/A,
back-pack,

5 Acres/day	base line	unit exp. 5.1   dose/day 0.0057

sh. t.  MOE NA             int. t. MOE 3,100	unit exp. 0.03

dose/day 0.00054

sh. t.  MOE    33,000       int. t. MOE    33,000 	3,100

1. PPE = Personal protective equipment. Base line PPE = long sleeved
shirt, long pants, and shoes with socks..  Engineering controls include
closed mixing/loading and closed cabs where applicable.

2.  Dermal dose (mg/kg/day) =  [appl. rate  * area treated (A or
gal/day) * dermal unit exp. (mg/lb ai) * dermal absorption factor (50%)]
/ body wt. (70 kg). Dermal MOE = short- or intermediate-term NOAEL
(mg/kg/day) / exposure (mg/kg/day).  NA = A short-term MOE was not
calculated because a short-term NOAEL was not selected.

3  Inhalation dose (mg/kg/day) =  [appl. rate * area treated (A or
gal/day) * inhal. unit exp. (mg/lb ai)  * inhal. absorption factor
(100%)] / body wt. (70 kg). Inhalation MOE = short- or intermediate-term
NOAEL (mg/kg/day) / exposure (mg/kg/day). 

4. Total MOE =  1/[(1/int.term dermal MOE)+(1/int.term inhalation MOE)].

9.2	Short- and Intermediate-Term Postapplication Risk  TC \l2 "9.2
Short- and Intermediate-Term Postapplication Risk 

When workers enter penoxsulam treated fields of tree nuts, pistachio,
and grape to do crop related cultivation activities, such as scouting,
hand harvesting, irrigation, etc., they may be exposed to pesticide
residues via dermal and inhalation routes.  Only short-term
post-application exposure is expected from the proposed uses on
non-bearing and bearing tree nuts, pistachio, and grape.  The
post-application short-term dermal exposure has not been quantified
because a short-term dermal NOAEL was not selected.  The
post-application short-term inhalation exposure also was not estimated
based on its use as a soil directed spray and its low vapor pressure 

(7.16 x 10-16 mm Hg at 25°C, Table 2.3.2).

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and
Label Recommendations 

10.1	Toxicology  TC \l2 "10.1	Toxicology 

870.7800 – Immunotoxicity.  An immunotoxicity study has not been
submitted for penoxsulam.  40 CFR Part 158 now specifies that an
immunotoxicity study is required for all food and non-food use pesticide
registrations and HED is recommending that submission of an acceptable,
guideline immunotoxicity study with penoxsulam be made a condition of
registration.  A review of various parameters in the submitted studies
did not reveal any definitive indications that the immune system was
compromised.  Although the lack of this study indicates a data gap in
the submission, no additional uncertainty factor (UF) is deemed
necessary at this time due to the lack of evidence showing immunological
effects.  For further information regarding the purpose of the
immunotoxicity study and how it is used by OPP, see Appendix B of this
document.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

Prior to registration, the petitioner should submit a revised Section F
to reflect the correct commodity definition for the tree nut crop group:
 “Nut, tree, Group 14.”

10.3	Occupational and Residential Exposure

None.  TC \l2 "10.3	Occupational and Residential Exposure 

References  TC \l1 "References 

CARC Report:  TXR No. 0050702, J. Kidwell, 3/24/04.

M. Collantes, D339488, 5/15/07.  “Occupational and Residential
Exposure Assessment for Use of Penoxsulam to Control Aquatic Weeds In
and Around Slow-moving and Quiescent Bodies of Water and Broadleaf Weeds
in Turfgrass, Residential Lawns, Golf Courses, Sport Fields and Sod
Farms.”

M. Doherty, D355914, DATE.  “Penoxsulam. Section 3 Registration
Application For Use of GF-443 T&V on Grape and Tree Nuts Including
Pistachio.  Summary of Analytical Chemistry and Residue Data.”

M. Doherty, D360419, DATE.  “Penoxsulam:  Chronic Aggregate Dietary
(Food and Drinking Water) Exposure and Risk Assessment to Evaluate the
Requested New Uses on Grapes and Tree Nuts”

S. Oonnithan, D355915, March 2009.  “Penoxsulam:  Occupational and
Residential Exposure Assessment of the Proposed Uses on Tree nuts,
Pistachio, and Grapes.”

J. Wolf, D355676, 2 December 2008.  “Penoxsulam (New Use) Tier 1
Drinking water exposure concentrations for the proposed new uses almond
hulls, grapes, tree nuts (crop group 14), and pistachios, and tolerance
assessments.”

Appendix A	Toxicology Profile  TC \l1 "Appendix A	Toxicology Profile 

Table A.1  Acute Toxicity Profile Penoxsulam (XDE-638) Technical

GDLN	Study Type	MRID	Results	Tox

Category

870.1100	Acute Oral

Rats	45830812	M: LD50 > 5000 mg/kg

F: LD50 > 5000 mg/kg	IV

870.1200	Acute Dermal

Rabbits	45830815	M: LD50 > 5000 mg/kg

F: LD50 > 5000 mg/kg	IV

870.1300	Acute Inhalation

Rats

	45830818	LD 50 > 2 mg/L	IV

870.2400	Primary Eye Irritation

Rabbits	45830820	Minimal irritation

	IV

870.2500	Primary Skin Irritation

Rabbits	45830823	Minimal irritation	IV

870.2600	Dermal Sensitization

Guinea Pigs

(Maximization)	45830826	Negative for dermal sensitization	N/A



Table A.2  Toxicology Study Summary

STUDY TYPE - DOSE LEVELS	NOAEL 

(mg/kg/day)	LOAEL

(mg/kg/day)

2-YR FEEDING/CARCINOGENIC, RAT (2002)

MRID 45830901, 45830913

  M: 0, 5, 50, 250 m/k/d   

  F: 0, 5, 50, 250 m/k/d

                                       Chronic
toxicity-Acceptable/Guideline

BW/BWG, RBC parameters, BUN, urine vol, urine S.G.,
kidney wt, crystals/calculi in kidney and urinary bladder,
hyperplasia of kidney pelvis epithelium and urinary bladder mucosa,
severity of chronic glomerulonephropathy.          

F: 250

In F based on BW/BWG,urine vol, crystals/calculi in urinary
bladder, hyperplasia of kidney pelvis epithelium and urinary bladder
mucosa.   

M: Possibly treatment-related  incidence of Large Granular Lymphocyte
(LGL) leukemia at 5, 50 & 250 m/k/d.  Also  severity at 250 m/k/d. 
Dosing was adequate. 

F: Negative for carcinogenicity, but dosing was only marginally
adequate.                            

18-MN CARCINOGENIC, MOUSE   (2002)

MRID 45830915

  

M: 0, 10, 100, 375 m/k/d

F: 0, 10, 100, 750 m/k/d                                    

Carcinogenicity-–UNACCEPTABLE/                          Guideline

            

	M: 375         (HDT)

F: 750

  (750)

Carcino-genicity	M: Not determined

   >375 (HDT)

F: Not determined

   >750 (HDT)

                         

M: Negative for carcinogenicity at the doses tested.   Dosing
inadequate.

F: Negative for carcinogenicity at the doses tested. Dosing adequate 
(750 mg/kg/day is sufficiently close to limit dose of 1000 mg/kg/day).

 

1-YR FEEDING, DOG           (2002)

MRID 45830914

  0, 0.015, 0.045, 0.15 % in diet

M:0, 5.3,   14.7,  46.2 m/k/d  

F:0, 4.4,   14.0,  44.8 m/k/d

Acceptable/Guideline

	M: 14.7

F: 44.8

   (HDT)

	M: 46.2            

In M based on slight multifocal hyperplasia in the kidney epithelium.

F: Not determined

   >44.8 (HDT)

2-GEN REPRODUCTION, CD RAT (Sprague-Dawley derived)      (2002)

MRID 45830920

  M: 0, 30, 100, 300 m/k/d

  F: 0, 30, 100, 300 m/k/d

Acceptable/Guideline

BW of F1 males. 

 F: 100

   Based on kidney lesions.   

Repro/offspring

100

    Based on delayed preputial separation.



DEVELOPMENTAL TOX, CD RAT (Sprague-Dawley derived)   (2000)

MRID 45830917 

F: 0, 100, 500, 1000 m/k/d

   On GD 6-20 

Acceptable/Guideline 

DER also includes results for a range-finding study in 

CD rats (MRID 45830916). 

	Mat Tox:

500  

Dev Tox:     1000 (HDT)       	Mat Tox:

1000

Based on BWG, food consumption, kidney weights   

  

Dev Tox: Not identified

         >1000 (HDT)

DEVELOPMENTAL TOX, RABBIT   (2001)

MRID 45830918

F: 0, 5, 25, 75 m/k/d

   On GD 7-27 

Acceptable/Guideline

DER also includes results for a range-finding study in 

rabbits (MRID 45830919). 

	Mat Tox: 

25

Dev Tox: 

75	Mat Tox: 

75

BWG, food consumption. 

Dev Tox: Not identified

         >75 (HDT) 

 

13-WEEK FEEDING, RAT        (2000)

MRID 45830906

M: 0, 5, 50, 250, 500 m/k/d 

F: 0, 5, 50, 250, 500 m/k/d

With a 4-week recovery phase (0 and 500 m/k/d)

Acceptable/Guideline

DER also includes results for a 4-week range-finding study in rats (MRID
45830903). 

	M:  50

F: 250	M: 250

In M based on BW/BWG, food consumption, RBC parameters.   

F: 500

In F based on mineralization and hyperplasia of the kidney pelvic
epithelium. 



13-WEEK FEEDING, DOG        (2000)

MRID 45830909

   0, 0.015, 0.045, 0.15 % in diet   

M: 0, 5.9,   17.8,  49.4 m/k/d  

F: 0, 5.7,   19.9,  57.1 m/k/d

                     

Acceptable/Guideline

DER also includes results for a 4-week range-finding study in dogs (MRID
45830908). 

	M: 17.8

F: 19.9	M: 49.4

In M based on histopathologic changes in kidney.

F: 57.1

In F based on histopathologic changes in kidney.

    

13-WEEK FEEDING, MOUSE      (2001)

MRID 45830905

  

M: 0, 10.2, 102, 511, 1027 m/k/d

F: 0, 10.4, 104, 524, 1029 m/k/d

Acceptable/Guideline

DER also includes results for a 4-week range-finding study in mice (MRID
45830904). 

	M: 1027

   (HDT) 

F: 1029

   (HDT) 	M: Not determined

   >1027 (HDT)

F: Not determined

   >1029 (HDT)

BW/BWG,food consumption, RBC parameters. 

F: 500

In F based on BW/BWG,food consumption, RBC parameters,  
Kidney weights, crystals in kidney pelvis, hyperplasia and
inflammation of kidney pelvic epithelium.

4-WEEK RANGE-FINDING, DOG (1998) 

MRID 45830908

   0, 0.09, 0.45, 0.9 % in diet

M: 0,   29,  133, 192 m/k/d 

F: 0,   32,  163, 196 m/k/d

Acceptable/Non-Guideline (as a range-finding study)

Review is in DER for 90-day dog feeding study.

	M: 29 

F: <32          (LDT) 	M: 133  

liver weights; ALT, ALK, AST; histo-pathologic changes in liver
and kidneys.    

F: 32 

In F based on histopathologic changes in kidneys.  At 163 m/k/d,
treatment-related effects very similar to those in males.

4-WEEK RANGE-FINDING, MICE (1998) 

MRID 45830904

M: 0, 10.5, 103, 530, 1018 m/k/d 

F: 0, 10.8, 110, 545, 1069 m/k/d

Acceptable/Non-Guideline (as a range-finding study)

Review is in DER for 90-day mouse feeding study.

	M: 1018

   (HDT)

F: 1069

   (HDT)

	M: Not determined

   >1018 (HDT)

F: Not determined

   >1069 (HDT)

ACUTE NEUROTOXICITY, RAT       (2000)

MRID 45830902

M: 0, 500, 1000, 2000 mg/kg

F: 0, 500, 1000, 2000 mg/kg

Acceptable/Guideline

	M: 2000

   (HDT)

F: 2000

   (HDT) 	M: Not determined

   >2000 (HDT)

F: Not determined

   >2000 (HDT)

CHRONIC NEUROTOXICITY, RAT     (2002)

MRID 45830912, 45830901

  

M: 0, 5, 50, 250  m/k/d

F: 0, 5, 50, 250  m/k/d

Acceptable/Guideline

       	M: 250

   (HDT)

F: 250

   (HDT) 	M: Not determined

   >250 (HDT)

F: Not determined

   >250 (HDT)

28-DAY DERMAL TOXICITY, RAT    (2000)

MRID 45830910

M: 0, 100, 500, 1000 m/k/d

F: 0, 100, 500, 1000 m/k/d

With a 2-week recovery phase (0 and 1000 m/k/d)

Acceptable/Guideline

	Systemic: 

M: 1000

F: 1000

Dermal: 

M: 1000

F: 1000	Systemic: 

M: Not determined

   >1000 (HDT)

F: Not determined

   >1000 (HDT)

Dermal: 

M: Not determined

   >1000 (HDT)

F: Not determined

   >1000 (HDT)

28-DAY DERMAL TOXICITY, RAT    (2002)

MRID 45830911

TEST MATERIAL: GF-443 (formulated product containing 21.9% penoxsulam)

M: 0, 100, 500, 1000 m/k/d

F: 0, 100, 500, 1000 m/k/d

Dose levels are in mg/kg/day of GF-443, and not in mg/kg/day of
penoxsulam.

Acceptable/Guideline

	Systemic: 

M: 1000

F: 1000

Dermal: 

M: 500

F: 1000	Systemic: 

M: Not determined

   >1000 (HDT)

F: Not determined

   >1000 (HDT)

Dermal: 

M: 1000 

   Based on very slight hyperplasia at test site

F: Not determined

   >1000 (HDT)

GENERAL METABOLISM, RAT   (2002)

MRID 45830927

5.0 mg/kg     (Single low oral dose)                 

250 mg/kg     (Single high oral dose)

Also 14 daily oral doses of 5.0 mg/kg/day followed by 5.0 mg/kg orally
on day 15.

Biliary elimination was examined in additional rats following a single
oral dose of 5.0 mg/kg.

Acceptable/Guideline

	At the low dose of 5.0 mg/kg, penoxsulam was rapidly and nearly
completely [81-88% of administered dose (AD)]absorbed, but at the high
dose of 250 mg/kg, there was evidence that absorption was largely
incomplete (i.e.  absorption was saturated).  Both gender and dose
affected the excretion pattern.  At the low dose, the major route of
excretion of radioactivity was via the feces in males and via the urine
in females.  At the high dose, radioactivity was predominantly excreted
via the feces in both sexes.  A significant enterohepatic circulation
was observed, particularly in males.  Most (>90%) of the AD was excreted
within 36-48 hours. There was negligible radioactivity in tissues at 7
days and no evidence of accumulation in any tissue/organ.  Although
numerous metabolites were revealed in the urine, feces and bile, nearly
all were <1% of the AD.  Parent compound and a 2-hydroxyphenyl
derivative were the major compounds in urine and feces.    

MUTA-REVERSE GENE MUTATION (1999)

     (S. typhimurium /E. coli)

MRID 45830921  

Acceptable/Guideline

	Negative without and with rat S-9 activation.

MUTA-REVERSE GENE MUTATION (2002)

     (S. typhimurium /E. coli)

MRID 45830922

TEST MATERIAL: GF-443 (formulated product containing 21.9% penoxsulam)

Acceptable/Guideline

	Negative without and with rat S-9 activation.

MUTA-FORWARD GENE MUTATION (1999)

     (CHO Cells/HGPRT locus)

MRID 45830923        

Acceptable/Guideline

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MRID 45830924 

Acceptable/Guideline    

	Negative without and with rat S-9 activation.



MUTA-in vivo MICRONUCLEUS,MICE (1999)

     (Bone marrow cells)

MRID 45830925             

Acceptable/Guideline

	Negative at oral doses (once per day on two consecutive days) of up to
2000 mg/kg.   

MUTA-in vivo MICRONUCLEUS,MICE (2002)

     (Bone marrow cells)

MRID 45830926             

TEST MATERIAL: GF-443 (formulated product containing 21.9% penoxsulam) 

Acceptable/Guideline

	Negative at oral doses (once per day on two consecutive days) of up to
2000 mg/kg.   



Appendix B	Rationale for Toxicology Data Requirements  TC "Appendix B
Rationale for Toxicology Data Requirements" \f C \l "1"  

Guideline Number:  870.7800

Study Title:  Immunotoxicity 

Rationale for Requiring the Data

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

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology in routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

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

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

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

 

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



Appendix C:	Penoxsulam and Metabolites  TC "Appendix C	Penoxsulam and
Metabolites " \f C \l "1"  

Table C.1  Penoxsulam and Metabolite Structures.

	Name	 Structure

Penoxsulam

CAS. No.: 219714-96-2

CAS Name: 2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy [1,2,4]triazolo
[1,5-c]pyrimidin-2-yl)-6-(trifluoromethyl) benzenesulfonamide

y[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-α,α,α-trifluorotoluene-2-sulfo
namide 

Synonyms: XDE-638	    

BSTCA

CAS Name:
3-[[[2-(2,2-difluoroethoxy)-6-(trifluoromethyl)phenyl]-sulfonyl]amino]-1
H-1,2,4-triazole-5-carboxylic acid

IUPAC Name:
3-[6-(2,2-Difluoroethoxy)-α,α,α-(trifluoro-o-toluenesulfonamido]-s-tr
iazole-5-carboxylic acid

Synonyms:

	      

2-amino TCA

CAS name: 2-amino-1,2,4-triazole carboxylic acid

Synonyms: Polars

	               

5-OH-XDE-638

CAS name:
2-(2,2-difluoroethoxy)-N-(5,6-dihydro-8-methoxy-5-oxo[1,2,4]triazolo[1,5
-c]pyrimidin-2-yl)-6-(trifluoromethyl)benzenesulfonamide

IUPAC name:
6-(2,2-Difluoroethoxy)-N-(5,6-dihydro-8-methoxy-5-oxo-s-triazolo[1,5-c]p
yrimidin-2-yl)-α,α,α-trifluoro-o-toluenesulfonamide

	      

SFA

摧ߕó܀-(2,2-difluoroethoxy)-N-(iminomethyl)-6-(trifluoromethyl)-benze
nesulfonamide

IUPAC name: 2-(2,2-difluoroethoxy)-N-[(E)iminomethyl-6-

	         

sulfonamide

CAS name: 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)-benzenesulfonamide

IUPAC name: 
2-(2,2-difluoroethoxy)-6-(trifluoromethyl)-benzenesulfonamide

	

5,8-diOH 

CAS
name:2-(2,2-Difluoroethoxy)-6-trifluoromethyl-N-(5,8-dihydroxy-[1,2,4]tr
iazolo[1,5-c]pyrimidin-2-yl)benzenesulfonamide

	



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