Document ID: EPA-HQ-OPP-2008-0730-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-18T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		November 9, 2009

Subject:		Endothall: Revised Human Health Risk Assessment for the
Section 3 Registration Action to Support a New Use of Endothall in
Irrigation Canals with No Required Holding Period before that Water Can
Be Used on Crops 

PC Codes:  038901, 038904 and 038905	DP Barcode:  370448

Decision No.:  399181	Registration Nos.:  70506-175 and 70506-176

Petition No.:  8E7419	Regulatory Action:  Section 3

Risk Assessment Type:  NA	Case No.:  2245

TXR No.:  NA	CAS Nos.:  145-73-3; 2164-07-0; 66330-88-9

MRID No.:  47520701 to 47520719	40 CFR:  180.293 

		              								

	From:	David Soderberg, Chemist

		Seyed Tadayon, Chemist

		John Liccione, Toxicologist 

		RABV, Health Effects Division (7509P)

	Through:	Jack Arthur, Branch Chief

		RABV, Health Effects Division (7509P)

		

	To:	Sidney Jackson, Product Manager

		Barbara Madden, Team Leader

		Registration Division (7505P)

This document has been revised to include a more thorough description of
FQPA considerations.  Endothall is currently allowed for use on
irrigation canals, but a holding period of 7 days or more is required
following use.  Interregional Research Project No. 4 (IR-4) has now
proposed amending the use directions for the 2 lb ae/gal SC/L
monoalkylamine salt and the 3 lb ae/gal dipotassium salt of endothall to
remove the holding times after water is treated with endothall.  This
change would enable use of endothall in irrigation canals and other
moving water bodies, effectively creating a zero day PHI, but would also
result in a potential for measurable residues on irrigated crops.  The
amended uses allow for retreatments with a minimum retreatment interval
(RTI) of 7 days for irrigation canals and a maximum seasonal use rate of
30 ppm ae per season (6 applications at up to 5 ppm ae/application). In
support of the proposed amendments, IR-4 has performed a set of field
trials and processing studies for representative crops and has proposed
a set of tolerances for indirect or inadvertent residues of endothall on
irrigated crops.



Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc202162117"  1.0	Executive
Summary	3 

  HYPERLINK \l "_Toc202162118"  2.0
Background……………………………………………………
…………………………10 

  HYPERLINK \l "_Toc202162122"  3.0	Summary of Proposed Uses	13 

  HYPERLINK \l "_Toc202162151"  4.0	Hazard Characterization and FQPA
Considerations	14 

  HYPERLINK \l "_Toc202162152"  5.0	Residue Chemistry and Metabolism
Update	27 

  HYPERLINK \l "_Toc202162153"  5.1	Nature of the residue - plants	28 

  HYPERLINK \l "_Toc202162165"  5.2	Nature of the residue - animals	28 

5.3     Meat, milk, poultry and eggs	29

5.4     Analytical methods	31

  HYPERLINK \l "_Toc202162165"  5.5	Storage stability update	31 

  HYPERLINK \l "_Toc202162165"  5.6	Magnitude of residue in food update
32 

  HYPERLINK \l "_Toc202162165"  5.7	Processing factors	35 

  HYPERLINK \l "_Toc202162165"  5.8	Rotational crops	36 

  HYPERLINK \l "_Toc202162165"  5.9	Proposed and recommended tolerances 
36 

  HYPERLINK \l "_Toc202162168"  6.0	Exposure Characterization/Assessment
Section Update	41 

6.1  HYPERLINK \l "_Toc202162165"   	Dietary exposure/pathway	41

	6.1.1    Acute and cancer dietary exposure and risk update	42	

	6.1.2    Chronic dietary exposure and risk update	42

  HYPERLINK \l "_Toc202162169"  7.0	Water Exposure Risk/Pathway	43 

  HYPERLINK \l "_Toc202162173"  8.0	Residential Exposure Risk
Characterization	44 

  HYPERLINK \l "_Toc202162174"  9.0	Aggregate Risk Assessment and Risk
Characterization Updates	48 

10.0	Cumulative
Risk…………………………………………………………
……………….50

  HYPERLINK \l "_Toc202162176"  11.0	Occupational Exposure/Pathway
Updates	50 

  HYPERLINK \l "_Toc202162177"  11.1	Handler exposure and risk	50 

  HYPERLINK \l "_Toc202162178"  11.2	Occupational post-application
exposure and risks	58 

  HYPERLINK \l "_Toc202162180"  12.0 	Data Needs and Label
Recommendations	59

	12.1     Toxicology	59	

	12.2     Residue chemistry	60

	12.3     Occupational and residential exposure	61

13.0     References	61

Appendix A.	Toxicology
Assessment……………………………………………………
…….63

 1.0 Executive Summary

  SEQ CHAPTER \h \r 1 Endothall is a selective contact herbicide,
defoliant, desiccant, and aquatic algaecide belonging to the
dicarboxylic acid chemical class.  The free acid of endothall and its
dipotassium and mono-N, N-dimethylalkyl-amine salts (monoalkylamine) are
registered in the United States primarily as aquatic herbicides for the
control of a variety of plants in water bodies.  This includes
irrigation canals, but only with a holding period of 7 days or more,
depending upon the concentration used.  Endothall is also registered for
desiccation/de-foliation of alfalfa/clover (grown for seed only),
cotton, and potatoes prior to harvest, and for reduction of sucker
branch growth in hops.  Permanent tolerances have been established for
these uses as the combined residues of endothall and its monomethyl
ester. [40 CFR §180.319].

There are currently three endothall end-use products registered to
United Phosphorus, Inc. (UPI) for control of algae and aquatic weeds in
drainage and irrigation canals, including two monoalkylamine salt
formulations and a dipotassium salt formulation.  The monoalkylamine
salt of endothall is formulated as either a 2 lb ae/gal SC/L formulation
(EPA Reg. No. 70506-175) or an 11% granular (G) formulation (EPA Reg.
No. 70506-174), containing 5% ae.  The dipotassium salt is formulated as
a 4.23 lb ai/gal SC/L (EPA Reg. No. 70506-176), which is equivalent to
3.0 lb ae/gal SC/L.  [In order to avoid the complications of different
molecular weights for different salts, endothall concentrations are
expressed as the free acid equivalents (ae).]  Labels for these products
allow for repeated broadcast applications to irrigation canals at rates
yielding endothall concentrations of up to 5 ppm ae for the
monoalkylamine salt and 3.5 ppm ae for the dipotassium salt.  The labels
do not currently specify a maximum number of applications per season or
a maximum seasonal use rate.  Depending on the concentration in the
treated water, current use directions specify minimum holding times of 7
days (after an application of 0.3 ppm) to 25 days (for 5 ppm) prior to
using the treated water for irrigation of crops.

 

Interregional Research Project No. 4 (IR-4) has now proposed to amend
these use directions for the 2 lb ae/gal SC/L monoalkylamine salt and
the 3 lb ae/gal dipotassium salt of endothall to remove the holding
times after water is treated with endothall before it can be used to
irrigate crops.  This change would enable use of endothall on moving
water in canals etc, and would effectively create a zero day PHI, and
consequently create the possibility that residues will be incurred in
crops produced down stream of the treatments.  The amended uses specify
minimum retreatment interval (RTI) of 7 days for irrigation canals and a
maximum seasonal use rate of 30 ppm ae per season (6 applications at up
to 5 ppm ae/application). 

To support the proposed amendments, IR-4 has submitted data from 18
field trials on representative crops, plus a number of associated
processing studies and one storage stability study.  From these data
they proposed tolerances for the major crop groups.  No studies other
than the aforementioned have been submitted to support this use, there
are no new toxicology results available, and there are no new
residential or occupational exposure scenarios expected with this use. 
This HED document provides a summary of the findings from the data
evaluation and subsequent assessment of human health risk resulting from
these submissions. 

Hazard Assessment

Toxicology and Dose-Response

Previously selected doses and endpoints for use in human health risk
assessments have been used in this current risk assessment for
endothall.  

The toxicology data base for endothall is complete except for the
neurotoxicity battery (acute and subchronic neurotoxicity studies) and
an immunotoxicity study required as a result of the revised 40 CFR Part
158 Toxicology Data requirements.  Additionally, a 28-day inhalation
toxicity study which was previously identified as a datagap has been
submitted and is under review. 

Endothall is a caustic chemical with toxicity being the result of a
direct degenerative effect on tissue. Dermally, it destroys the stratum
corneum and then the underlying viable epidermis. Orally, it attacks the
digestive tract. The dog is particularly sensitive to endothall
toxicity.  Orally, it attacks the canine digestive tract at relatively
low doses and then the liver and kidneys at lethal doses. The rabbit is
extremely sensitive to ocular instillation of endothall.  In the eye
irritation study, endothall technical was extremely irritating to the
eye, and was also lethal to 4/6 rabbits tested.  Endothall is an extreme
irritant by the dermal, oral, and ocular routes of administration
(category I), and is a skin sensitizer. By dermal application and
inhalation, it has mild toxicity (category III).

Endothall does not cause pre-natal toxicity following in utero exposure
to rats nor pre-and post- natal toxicity following exposures to rats for
two generations.  In the developmental mouse study, there was severe
maternal toxicity (i.e., greater than 30% mortality) at the highest dose
tested; at this dose level, a slight increase in vertebral and rib
malformations was observed in the offspring indicating that these
effects were most likely secondary to severe maternal toxicity.  
Endothall is classified as "not likely to be carcinogenic to humans"
based on lack of evidence of carcinogenicity in mice or rats. It has no
mutagenic potential.

In metabolism studies, endothall was excreted unchanged in the feces and
urine.  In the dermal absorption study, the dose related pattern of
absorption was typical of a chemical which directly damages the skin
destroying its barrier function.  That is, the percent of dose absorbed
increased with increasing dose.

Residue Chemistry

The qualitative nature of endothall residues in plants is adequately
understood based upon the metabolism studies on alfalfa, cotton and
sugar beets.  The qualitative nature of endothall residues in livestock
is also understood based upon the adequate goat and poultry metabolism
studies.  The Agency has concluded that endothall and its monomethyl
ester are the residues of concern in both plant and animal commodities
for purposes of the tolerance expression and risk assessment.    SEQ
CHAPTER \h \r 1 The residue of concern in water is only endothall.  

  SEQ CHAPTER \h \r 1 A GC method with microcoulometric nitrogen
detection is listed as Method I in the Pesticide Analytical Manual (PAM,
Volume II) for determining endothall residues in/on crop commodities,
and a confirmatory LC/MS method (Method No. KP218R0) is available for
determining residues of endothall and its monomethyl ester in fish and
residues of endothall in plant commodities.  For the irrigated crop
field trials and processing studies submitted with the current petition,
endothall residues in/on plant commodities were determined using an
adequate LC/MS/MS method (Method No. KP-242R1).  For this method
residues are extracted with water; derivatized with
heptafluoro-p-tolylhydrazine (HFTH) in 50% H3PO4; cleaned up by solvent
partitioning and solid phase extraction (SPE); and analyzed by LC/MS/MS.
 The derivatization step is expected to hydrolyze any methyl-ester
metabolites to parent endothall, so this procedure determines total
endothall residues.  Residues are expressed in endothall acid
equivalents, and the validated limit of quantitation (LOQ) for endothall
is 0.05 ppm.    SEQ CHAPTER \h \r 1 Adequate storage stability data are
available to support the sample storage conditions and durations used in
the irrigated crop field trials and processing studies.  

The submitted field trial data on irrigated crops were conducted
according to a previously submitted protocol.  Two to four field trials
were conducted on each of the following crops in their major growing
regions: potato, carrot, sugar beet, green and bulb onions, leaf and
head lettuce, cabbage, succulent podded peas and beans, dry beans,
soybean, tomato, cucumber, orange, apple, peach, blueberry, blackberry,
grape, pecan, almond, field and sweet corn, sorghum, wheat, rice,
alfalfa, grasses and mint.  These crops were selected to represent the
major crop groups.  In each field trial, the monoalkylamine salt of
endothall (2 lb ae/gal SC/L) was used to treat the irrigation water at a
rate of ~5 ppm ae, and the treated water was then applied via overhead
sprinklers as six broadcast foliar applications at RTIs of 5-10 days. 
[The target application volume in each trial was equivalent to ~1 acre
inch of water (27,154 gal/A).  Based on the concentration of the
endothall in the irrigation water and the amount of water applied, the
application rates for endothall were equivalent to 1.10-1.25 lb
ae/A/application, for totals of 5.64-7.17 lb ae/A/season.]   We note
that, instead of the usual 2 separate plots per trial, each field trial
comprised only a single plot that was then sampled twice to provide two
results.  With only a few exceptions, samples of the regulated raw
agricultural commodities (RACs) from each crop were harvested on the day
of the sixth application (0 days after treatment, DAT).  

Side-by-side tests were also conducted on some of these crops (sugar
beets, lettuce, cucumber, and peaches) comparing application of the
dipotassium salt of endothall (3 lb ae/gal SC/L) with the monoalkylamine
salt.  Although the dipotassium salt was applied to the irrigation water
following the label directions for that salt, the resulting
concentration of endothall in the water was 3.5 ppm ae (0.7x rate). 
[The application rates for the dipotassium salt were equivalent to
0.74-091 lb ae/A/application, for totals of 4.67-5.07 lb ae/A/season.]  

Several deficiencies were noted in the field trials (see below), but the
submitted field trial data can generally be considered adequate for
setting tolerances and for assessing the exposure due to inadvertent
residues of endothall on irrigated crops.  

Adequate processing studies were submitted for commodities from a number
of these crops.  No processing data were submitted for any crops in the
“Oilseeds Crop Group”, but an available soybean processing study can
serve that purpose and indicates that endothall residues are unlikely to
concentrate in either oilseed meal or refined oil.  Because there were
problems in the study for processing grapes into grape juice, a maximum
theoretical processing factor of 1.2x has been used in place of an
“impossible” experimental factor derived from the study data, and
grape juice can take the same tolerance as grapes.  Based on these
studies, separate tolerances are required for the following processed
commodities: apple wet pomace, raisins, dried citrus pulp, rice hulls,
soybean hulls), sugar beet molasses, tomato paste, wheat milled
byproducts, and aspirated grain fractions. 

No cattle and poultry feeding studies have been submitted for endothall.
 The exposure of livestock to endothall residues was considered as being
the sum of exposure through the consumption of feedstuffs from irrigated
crops and through the drinking of endothall treated water.  Estimated
residues in the livestock tissues, milk and eggs were based upon these
dietary burdens and the total radioactive residues (TRR) determined in
these tissues when goats and chickens were fed radiolabeled endothall at
known rates for the metabolism studies.  Approval of the proposed new
use will require confirmatory submission of the required livestock
feeding studies.  

Because the only residues of significance in rotated crops are also
endothall and its monomethyl and dimethyl esters, and because the
inadvertent exposure of crops to endothall via the use of treated
irrigation water will exceed the potential exposure of crops from being
planted in rotation with endothall treated primary crops, the
establishment of tolerances for residues of endothall on the proposed
irrigated crops can satisfy all further needs for rotational crop
tolerances.  Therefore, although limited field rotational crop trials
have previously been required, they are no longer needed for any
currently registered use.

Residential Exposure and Risk Estimates

There are no changes in residential use associated with this proposed
registration.  The proposed Section 18 rate of application is comparable
or less than the high rate of application in the 2005 RED and the
duration of exposure is less than what is estimated there.  Therefore,
the residential risk information contained in this assessment is taken
from the 2005 RED assessment. 

There is an existing residential use for treatment of ponds and garden
pools.  For residential handlers, short-term inhalation MOEs are not of
concern for the pond scenarios, because they do not exceed the
Agency’s level of concern (LOC), which is for MOEs < 100 in
nonoccupational settings.  For treating ponds, the inhalation MOEs range
from 470 to 1900.  Short-term inhalation risks to residential handlers
are not a concern for treating garden pools, the inhalation MOE is
2,700.  Because estimated risks for residential handlers all yielded
MOEs above 100, they are not of concern.

Swimming is currently prohibited in the treated irrigation canals;
however, it has been reported to have occurred on rare occasions. 
Therefore an assessment of swimmer exposure was included in the RED. 
That risk assessment was based upon rates of application comparable to
those proposed now, i.e., 1 – 5 ppm; Margins of Exposure (MOEs) were
900 for adults and 280 for children 3-5.  Since the MOEs are greater
than 100, the risk does not exceed HED’s level of concern.

 

Dietary Exposure and Risk Estimates

CID™) has been conducted for endothall.  This model uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998
to calculate dietary risk. These analyses were performed to support the
Section 3 registration of endothall for use on irrigation canals with no
holding period before the water may be used on crops.  The resulting
chronic risk assessment for food is refined, using average residues from
the field trials, and estimating residues in meat, milk, poultry and
eggs (MMPE) using average residues in the livestock feeds, and an
estimate of the highest possible chronic exposure through livestock
water.  The exposure estimate also includes an adjustment for the
percent of the harvested crop that has been irrigated.  Despite this
refinement, the results remain very conservative because the field
trials were performed under highly conservative conditions (as directed
by HED for setting tolerances).  The assessment also includes the
assumption that, while some crops are not 100% irrigated, 100% of all
irrigation canals in the US are treated at the maximum rate with
endothall and this maximally treated water is applied to the crops on
the day of harvest.  

The average residue values used in this dietary exposure assessment were
taken from the 18 sets of field trials submitted by IR-4.  Processing
factors were taken from the appropriate processing studies submitted
with these field trials.  Because this assessment needed to cover all
possible crops that might be irrigated in the USA, the appropriate crop
residues and processing studies were translated within each extant crop
group, and in addition appropriate residue values were translated to
other orphan crops outside of those crop groups as needed.  For similar
reasons appropriate processing factors were sometimes translated to
similarly processed commodities.  DEEM default concentration factors
were used for any applicable processed commodities where no applicable
processing factors could reasonably be translated, but default factors
did exist.  For certain crops no formal default values have been
established, so the processing factors for these crops were left at 1.0,
to be consistent with other contemporary assessments.  

Percents of the harvested crops that have been irrigated were determined
by BEAD (D369862, D369863, 21 Oct 2009).  These values were used in this
assessment in conjunction with the field trial residue data. 

Drinking Water Exposure and Risk Estimates

To support the proposed new/expanded irrigation uses, the potential for
chronic human exposure to endothall in drinking water was evaluated by
EFED at 0.31 ppm.  Please see memorandum D356316, N. Thurman, EFED
9/09/09, for details.  

  

Aggregate Exposure and Risk Estimates

To ensure risk characterization efforts include all sources, HED
normally aggregates the exposures/risks from food, drinking water, and
residential (oral, dermal & inhalation) sources.  This evaluation is
typically made by adding together the exposures from each source for
comparison to a quantitative estimate of hazard (NOAEL, PAD, etc.), or
just by simply aggregating the risks themselves.  When aggregating
various sources of exposures and risks, HED gives consideration to both
the route and duration of exposure.  

    

For this action, the proposed new uses of endothall will increase
potential endothall exposures through food and drinking water, but
residential exposures are not expected to change.  Thus, only the impact
on dietary exposure necessitates updating the current aggregate
short-term risk assessment for this herbicide to address this proposed
use.  To complete this evaluation, aggregate risk assessments were
revised to incorporate the new dietary exposure estimates.              
  

Since there were no acute or cancer dietary endpoints selected, and
there are no long term residential uses of endothall, no acute, cancer
or long term aggregate risk assessments were performed.  Similarly,
because of the episodic residential use of endothall, no intermediate
term aggregate risk assessment was performed.   TC \l2 "7.3
Intermediate-Term Aggregate Risk 

A long term, chronic assessment was performed for aggregated food plus
drinking water.  Based upon a chronic exposure analyses using DEEM,
neither the general U.S. population nor any of its subgroups exceeded
100% of the cPAD.  The general U.S. population is estimated to be
exposed at 32 % of the cPAD under the above assumptions.  The most
highly exposed population subgroup, children 1 – 2, was estimated at
84% of the cPAD.  

A risk assessment for aggregate exposures (food + drinking water +
residential) was conducted for the short term exposure scenario because
residential uses of endothall are expected to be only episodic.  Food
exposures are based on treated and irrigated crops, as above.  Drinking
water exposures are based on aquatic uses of endothall.  Residential
handler exposures for adults are based on granular applications of
endothall with a belly grinder to lakes or ponds.  Residential
post-application exposures for adults and children are based on
swimming.  

For adults, estimated dietary exposures via food and drinking water (for
General US Population) were combined with inhalation exposures during
application to a pond or lake and potential post-application exposures
during swimming.  The handler scenario aggregated for adults is the
exposure scenario resulting in the lowest MOE (highest risk estimate)
for residential handlers. For children, estimated dietary exposures via
food and drinking water (children 1-2 years old) were combined with
potential post-application exposures during swimming. The short term
aggregate risk estimate (MOE) for adults is 290, for children, it is
240.  These MOEs are not considered to present a risk concern, and there
are no short term aggregate (food + drinking water + residential) risk
concerns for endothall.   

Occupational Exposure Estimates

For aquatic uses data from the Pesticide Handlers Exposure Database
(PHED) and ORETF were used.  For residential handler exposure HED used
the ORETF study data and the Residential SOPs.  The short-term
inhalation handler risk assessments for endothall aquatic applications
indicate no risks concerns (MOEs (100) at baseline (i.e., no respirator)
for all scenarios.  For mixing/loading/applying liquid formulations with
direct metering, there is no risk of concern (MOEs ( 100) with closed
system engineering controls.

The intermediate-term inhalation handler risk assessments for endothall
aquatic applications indicate no risks concerns (MOEs (300) with closed
system engineering controls for mixing/loading/applying liquid
formulations through direct metering to lakes/ponds.  Thus, the results
indicate that the Agency has no risk concerns for most endothall
use-patterns involving occupational agricultural or aquatic uses. 	

Environmental Justice

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

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

Review of Human Research

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

  SEQ CHAPTER \h \r 1 Recommendations for Tolerances/Registration

The registrant must submit a revised section F proposing tolerances
through inadvertent application of endothall, to be published in 40 CFR
§180.293(d) as recommended in Table 5.9.1. 

Data Gaps

Toxicology: An immunotoxicity, an acute neurotoxicity and a subchronic
neurotoxicity are required in accordance with the revised Part 158 data
requirements.   

Residue Chemistry:  Livestock (ruminant and poultry) feeding studies
must be submitted.  

Data collection and regulatory analytical methods are needed for the
determination of 

endothall, per se, in animal commodities.  Similarly, radiovalidation
data are needed to

show that the enforcement method for endothall residues in fish can
adequately determine

the monomethyl ester.  Storage stability data are needed for animal
commodities, and

fish.  Magnitude of the residue studies in potato, alfalfa seed,
cottonseed, and cotton gin

byproducts are needed to support terrestrial use.  Similarly, magnitude
of the residue

studies in the RACs of sugar beet and rice if the registrant intends to
support intentional

direct application to these crops.

Occupational and residential: Data Gaps have been identified for (A)

mixing/loading/applying liquid formulations to aquatic areas using
handheld equipment,

(B) loading/applying liquid formulations to aquatic areas using direct
metering, and

(C) loading/applying granular formulations to aquatic areas using
centrifugal or blower-

type equipment.  

Background

  SEQ CHAPTER \h \r 1 Endothall is a dicarboxylic acid that is a
selective contact herbicide, defoliant, desiccant, and aquatic
algaecide.  The free acid of endothall (PC Code 038901) and its
dipotassium (PC Code 038904) and monoalkylamine (PC Code 038905) salts
are registered primarily as aquatic herbicides for the control of a
variety of plants in water bodies, including irrigation canals. 
However, these uses require a minimum 7 day holding period before the
water can be used on crops.  They are also registered for desiccation/
defoliation of alfalfa/clover (grown for seed only), cotton, and
potatoes prior to harvest, and for reduction of sucker branch growth in
hops.  The Reregistration Eligibility Decision (RED) for endothall was
issued September 2005. 

Permanent tolerances are established for the combined residues of
endothall and its monomethyl ester at 0.1 ppm in/on cotton seeds, dried
hops and potatoes, and at 0.05 ppm in/on rice grain and rice straw [40
CFR §180.293(a)(1)]; and an interim tolerance has also been established
for endothall on sugar beet at 0.2 ppm [40 CFR §180.319].  These
tolerances are intended to cover intended direct use of endothall on
these crops.  Permanent tolerances are also established for fish at 0.1
ppm straw [40 CFR §180.293(a)(1)].  

Residue data supporting irrigation of crops with endothall treated water
were previously submitted using cabbage, celery, grapefruit, peppers and
turnips as representative crops.  However, these studies were deemed
inadequate to support the establishment of crop group tolerances. 
Additional data were required for other representative crop group
commodities and the irrigated crop studies were conducted using
endothall in the water at 3 ppm, which is 0.6x the maximum application
rate of 5 ppm for aquatic sites.  The Endothall RED reiterated the need
for extensive crop field trials to support the use of treated irrigation
water on crops.  The application rate in these tests needed to reflect
the maximum aquatic use rate of endothall (5 ppm) and the maximum
possible number of applications per season.

In response to the above requirements, IR-4 has proposed amendments to
the use directions for endothall on irrigation canals and has submitted
extensive crop field trials to support tolerances on irrigated crops
(PP#8E7419) when endothall is used with a zero day holding period.  The
chemical structure and nomenclature of endothall and its salts are
listed in Table 2.1.  The physicochemical properties of technical grade
endothall and its salts are listed in Table 2.2. 

  SEQ CHAPTER \h \r 1 

̊C	DP# 304026, D. Soderberg, 6/10/2004

pH	2.7 at 25 ̊C (1% solution)

	Density, bulk density, or specific gravity	0.481 g/cm3 (bulk) at 25 ̊C

	Water solubility at 25 ̊C	109.8 g/L

13.1 g/100 mL in water, pH 5

12.7 g/100 mL in water, pH 7

12.5 g/100 mL in water, pH 9

	Solvent solubility at 25 ̊C	3.4 g/100 mL in acetonitrile

2.4 g/100 mL in n-octanol

16.0 g/100 mL in tetrahydrofuran

	Vapor pressure	3.92 x 10-5 mm Hg at 24.3 ̊C

	Dissociation constant, pKa	4.32 for Step 1 and 6.22 for Step 2 at 20
̊C (0.2% solution in 20% basic ethanol); dissociation rate 1.8-2.3 x
103 µmho within 3-5 minutes at ∼25 ̊C, by conductivity meter

	Octanol/water partition coefficient	Not applicable to endothall acid

	UV/visible absorption spectrum	Not available

	Endothall, dipotassium salt

Melting point	>360 ̊C	DP# 304026, D. Soderberg, 6/10/2004

pH	9.1 at 25 ̊C (1% solution)

	Density, bulk density, or specific gravity	0.766 g/cm3 (bulk) at 25 ̊C

	Water solubility	>65 g/100 mL in water, pH 5, pH 7, and pH 9

	Solvent solubility	<0.001 g/100 mL in acetonitrile, n-octanol, and
tetrahydrofuran

	Vapor pressure	Not applicable.  An organic acid K salt is anticipated
to have an insignificant vapor pressure.

	Dissociation constant, pKa	4.16 for Step 1 and 6.14 for Step 2 at 20
̊C in water; dissociation complete at 5 mins (13.6 x 103 µmho)

	Octanol/water partition coefficient	KOW <0.02 and <0.3 at
concentrations of 9 x 10-3 M and 9 x 10-4 M, respectively, at 25 ̊C

	UV/visible absorption spectrum	Not available

	Endothall, mono-N,N-dimethylalkyl amine salt

Boiling point	Not available	DP# 304026, D. Soderberg, 6/10/2004

pH	5.2 at 25 ̊C (1% solution)

	Density, bulk density, or specific gravity	1.028 g/mL at 25 ̊C

	Water solubility at 25 ̊C	≥49.2 g/100mL in water, pH 5

≥51.6 g/100 mL in water, pH 7

≥49.8 g/100 mL in water, pH 9

	Solvent solubility at 25 ̊C	≥102.5 g/100mL in acetonitrile

≥95.4 g/100 mL in n-octanol

≥104.3 g/100 mL in tetrahydrofuran

	Vapor pressure	2.09 x 10-5 mm Hg at 25 ̊C (calculated; mixed mono- and
dialkylamine (C8-C20))

	Dissociation constant, pKa	4.24 for Step 1 and 6.07 for Step 2 at 20
̊C for mixed mono- and dialkylamine (C8-C20) in acidified
ethanol/water; dissociation complete ∼17 minutes (1.7 x 103 µmho) at
25 ̊C

	Octanol/water partition coefficient	KOW 2.097 at concentrations of 8.9
x 10-3 M and 8.9 x 10-4 M, at 25 ̊C

	UV/visible absorption spectrum	Not available

	

Endothall is currently allowed for use on irrigation canals, but a
holding period of seven days is required following use.  Interregional
Research Project No. 4 (IR-4) has now proposed amending the use
directions for the 2 lb ae/gal SC/L monoalkylamine salt and the 3 lb
ae/gal dipotassium salt of endothall to remove the holding times after
water is treated with endothall.  This would enable use of endothall on
moving water in canals etc, and would effectively create a zero day PHI.
 The amended uses specify minimum retreatment interval (RTI) of 7 days
for irrigation canals and a maximum seasonal use rate of 30 ppm ae per
season (6 applications at up to 5 ppm ae/application). In support of the
proposed amendments, IR-4 has performed a set of field trials and
processing studies for representative crops and has proposed the
following tolerances for indirect or inadvertent residues of endothall
on irrigated crops:

Vegetable, root and tuber, group 1	2 ppm

Vegetable, leaves of root and tuber, group 2	3.5 ppm

Vegetable, bulb, group 3-07	2 ppm

Vegetable, leafy, except Brassica, group 4	3.5 ppm

Vegetable, Brassica, leafy, group 5	0.1 ppm

Vegetable, legume, group 6	3 ppm

Vegetable, fruiting, group 8	0.05 ppm

Vegetable, cucurbit, group 9	1.1 ppm

Fruit, citrus, group 10	0.05 ppm

Fruit, pome, group 11	0.05 ppm

Fruit, stone, group 12	0.25 ppm

Berry and small fruit, group 13-07	0.6 ppm

Nut, tree, group 14	0.05 ppm

Almond, hulls	10 ppm

Grain, cereal, group 15	2.5 ppm

Grain, cereal, forage, fodder and hay, group 16, forage	3.5 ppm

Grain, cereal, forage, fodder and hay, group 16, hay	5 ppm

Grain, cereal, forage, fodder and hay, group 16, stover	11 ppm

Grain, cereal, forage, fodder and hay, group 16, straw	6 ppm

Grain, aspirated fractions	24 ppm

Grass, forage fodder, and hay, group 17, forage	3 ppm

Grass, forage fodder, and hay, group 17, hay	19 ppm

Nongrass animal feed, group 18, forage 	3.5 ppm

Nongrass animal feed, group 18, hay	8 ppm

Grape	0.9 ppm

Peppermint tops	7 ppm

Spearmint tops	7 ppm

Rice, grain	1.7 ppm

Rice, straw	4.5 ppm

Summary of Proposed Uses

860.1200  Directions for Use

There are currently three endothall end-use products registered to UPI
for control of algae and aquatic weeds in drainage and irrigation
canals, including two monoalkylamine salt formulations and a dipotassium
salt formulation.  The monoalkylamine salt of endothall is formulated as
either a 2 lb ae/gal SC/L formulation (Hydrothol 191; EPA Reg. No.
70506-175) or an 11% G formulation (Hydrothol Granular; EPA Reg. No.
70506-174), which contains 5% acid equivalent of endothall.  The
dipotassium salt is formulated as a 4.23 lb ai/gal SC/L (Aquathol® K;
EPA Reg. No. 70506-176), which is equivalent to 3.0 lb ae/gal SC/L.  

The current labels for these products allow for repeated broadcast
applications to irrigation canals at rates yielding endothall
concentrations of up to 5 ppm ae for the monoalkylamine salts and 3.5
ppm ae for the dipotassium salt.  (HED notes that the label directions
for the dipotassium salt are expressed in lb ai rather than lb ae;
therefore the use rates for the dipotassium salt are ~0.7x the use rates
for the monoalkylamine salt.)  The labels do not currently specify a
maximum number of applications per season or a maximum seasonal use
rate.  Depending on the concentration in the treated water, the use
directions specify minimum holding times of 7 days (0.3 ppm rate) to 25
days (5 ppm rate) prior to using the treated water for irrigation of
crops.

 

IR-4 is supporting an amendment to the use directions for the 2 lb
ae/gal SC/L monoalkylamine salt and the 3 lb ae/gal SC/L dipotassium
salt of endothall to remove the holding time restriction for using
endothall-treated water from irrigation canals for the irrigation of
crops.  The amended uses continue to include re-treatments, specifying a
minimum RTI of 7 days and a maximum seasonal use rate of 30 ppm ae per
season.  Example labels containing the proposed use directions were
provided and are summarized below in Table 3.1.

Table 3.1	Summary of Proposed Use Directions for Endothall Salts on
Irrigation and Drainage Canals.

Applic. Timing, Type, and Equip.	Formulation 1

[EPA Reg. No.]	Applic. Rate 2	Maximum Seasonal Rate 2	PHI (days)	Use
Directions and Limitations

Endothall Monoalkylamine Salt (PC Code 038905)

Broadcast surface application to water; ground equipment	2.0 lb ae/gal
SC/L

[70506-175]	5.0 ppm	30 ppm	0 3	A minimum 7-day RTI is specified.

Do not use treated water for domestic purposes or animal consumption
within the following period:  0.3 ppm - 7 DAT; 3.0 ppm - 14 DAT; and
5.0 ppm - 25 DAT.

Endothall dipotassium salt  (PC Code 038904)

Broadcast surface application to water; ground equipment	3.0 lb ae/gal
SC/L

[70506-176]	3.5 ppm	21 ppm	0 3	A minimum 7-day RTI is specified.

Do not use treated water for domestic purposes or animal consumption
within the following period:  0.3 ppm - 7 DAT; 3.0 ppm - 14 DAT; and
5.0 ppm - 25 DAT.

1	The formulations are expressed in lb endothall ae/gal.

2	The maximum single and seasonal application rates are expressed in
concentration of the endothall acid.  The 30 ppm seasonal maximum rate
is equivalent to 6 applications at the maximum single use rate.

3	No holding time is required prior to use of treated water for
irrigation of crops.

NS = not specified.

Conclusions.  The submitted labels are adequate to evaluate the residue
data relative to the proposed use of endothall on irrigation canals.

4.0	HAZARD CHARACTERIZATION

The toxicology data base for endothall is complete except for the
neurotoxicity battery (acute and subchronic neurotoxicity studies) and
an immunotoxicity study required as a result of the revised 40 CFR Part
158 Toxicology Data requirements.  Additionally, a 28-day inhalation
toxicity study which was previously identified as a data gap has been
submitted and is under review. The database was previously reevaluated
and a human health risk assessment for the HED chapter of the
Reregistration Eligibility Decision Document (RED) issued (DP#: 322035,
R. P. Zendzian, 9/30/2005).  HED will conduct a revised human health
risk assessment when the required studies have been submitted and
reviewed.  

4.1	Hazard and Dose-Response Characterization

4.1.1	Database Summary

4  TC \l3 "3.1.1	Database Summary .1.1.1	Studies available and
considered (animal, human, general literature)

Studies available and considered for hazard identification and risk
assessment include acute studies (oral, dermal, inhalation, eye
irritation, dermal irritation, and skin sensitization), a 21-day dermal,
subchronic and chronic oral toxicity studies in rodents and dogs, rodent
carcinogenicity studies, rat reproductive study, and developmental
toxicity studies in the rat and mouse, and mutagenicity studies.

4.1.1.2 Pesticidal Mode of action, and Animal Metabolism and
Toxicokinetic data

Endothall acts mainly as a contact herbicide, although it is somewhat
mobile in plant tissues when applied at rates lower than those used for
contact kill and can cause plant death through foliage absorption. 
Endothall interferes with plant respiration by affecting protein and
lipid biosynthesis and disrupting plant cell membranes.  Endothall
metabolism leads either to the monomethyl ester (and some small amount
of the dimethyl ester), or to complete decomposition and uptake of the
radioactive residues into natural constituents of plant and animal
tissues.  

In metabolism studies endothall was excreted unchanged in the feces and
urine.  In the dermal absorption study the dose related pattern of
absorption was typical of a chemical which directly damages the skin. 
The percent of dose absorbed increased with increasing dosage.

4.1.1.3 Sufficiency of studies/data

At present, the available toxicity data are adequate for hazard
identification, dose-response assessment, and risk characterization. 
Revisions to the risk assessment will be conducted when the review of
the 28-day inhalation study has been completed, and the required
(immunotoxicity and neurotoxicity) studies have been submitted and
reviewed.  

4.1.2	Toxicological Effects

Endothall is a caustic chemical with toxicity being the result of a
direct degenerative effect on tissue.  Dermally, it destroys the stratum
corneum and then the underlying viable epidermis. Orally, it attacks the
digestive tract.  The dog is particularly sensitive to endothall
toxicity.  Orally, it attacks the canine digestive tract at relatively
low doses and then the liver and kidneys at lethal doses.  The rabbit is
extremely sensitive to ocular instillation of endothall.   In the eye
irritation study, endothall technical was extremely irritating to the
eye and was also lethal to 4/6 rabbits tested.

Endothall is an extreme irritant by the acute oral, and ocular routes of
administration (category I), and is a skin sensitizer. By acute dermal
application and inhalation exposure, it has mild toxicity (category
III).

Endothall does not cause pre-natal toxicity following in utero exposure
to rats nor pre-and post natal toxicity following exposures to rats for
two generations. In the developmental mouse study, there was severe
maternal toxicity (i.e., greater than 30% mortality) at the highest dose
tested; at this dose level, a slight increase in vertebral and rib
malformations was observed in the offspring indicating that these
effects were most likely secondary to severe maternal toxicity.  
Endothall is classified as "not likely to be carcinogenic to humans"
based on lack of evidence of carcinogenicity in mice or rats. It has no
mutagenic potential.

In metabolism studies, endothall was excreted unchanged in the feces and
urine.  In the dermal absorption study, the dose related pattern of
absorption was typical of a chemical which directly damages the skin
destroying its barrier function.  That is, the percent of dose absorbed
increased with increasing dose.

4.1.3	Dose-response

The most sensitive effect of endothall following oral administration is
direct irritation of the gastrointestinal system.  This effect was
evident in several species and in several studies. Proliferative lesions
of the gastric epithelium were observed in F1 parental male and female
rats treated orally with 2 mg/kg/day endothall in a 2-generation
reproduction study (a NOAEL was not identified).  Endothall caused
gastric epithelial hyperplasia in dogs treated with an oral dose of 6.5
mg/kg/day for 52 weeks (a NOAEL was not determined).  

Besides gastric irritant effects, decreased body weight was also a
sensitive effect following endothall administration.  The decreased body
weights were most likely attributable to the constant and direct
irritation of the gastric lining.  In a developmental rat study,
pregnant rats exhibited decreased body weight following oral treatment
with 25 mg/kg/day endothall; the NOAEL was 12.5 mg/kg/day.  Decreased
body weight was noted in a 90-day dietary study in the rat (LOAEL = 118
mg/kg/day; NOAEL = 39 mg/kg/day).  Body weight loss occurred in dogs
following a 13 week oral treatment with endothall (LOAEL = 27.5
mg/kg/day; NOAEL = 11.7 mg/kg/day).  A LOAEL of 45 mg/kg/day for body
weight decrement was identified in an oral carcinogenicity mouse study. 

HED selected the following toxicity endpoints (or points of departure)
for risk assessment which are the same endpoints that were used in the
previous 2005 risk assessment: 

Acute Dietary:  An acute dietary hazard value was not identified for the
general population or for females of child-bearing age (13-49 years
old). This is because there is no appropriate endpoint attributable to a
single dose in any of the studies submitted.

Chronic Dietary:  For chronic dietary exposure, the toxicology endpoint
was selected from a 2-generation reproduction toxicity study in rats in
which the LOAEL was 2 mg/kg/day based on proliferative lesions of the
gastric epithelium in both sexes.  

Dermal:  No dermal endpoint was selected because the severe dermal
irritation observed in a repeated-dose study is considered
self-limiting. Current product labels recommend protective clothing
(rubber gloves, face shields or goggles) when handling liquid
formulations. 

Inhalation:  For the short-term inhalation risk assessment, the
toxicology endpoint (NOAEL of 9.4 mg/kg/day) was selected from in a
2-generation rat reproduction (oral feeding) study in which the LOAEL
was 60 mg/kg/day based on decreased pup body weight (both sexes) on Day
0 of the F1and F2 generations.  

Incidental Oral:  The short-term incidental oral risk assessment for
endothall is based on a NOAEL of 9.4 mg/kg/day based on decreased pup
body weight (both sexes) on Day 0 of the F1and F2 generations in a
2-generation rat reproduction (oral feeding) study.  Intermediate- and
long-term incidental oral exposures are not expected.

4.2	Absorption, Distribution, Metabolism, Excretion (ADME)

In metabolism studies endothall was excreted unchanged in the feces and
urine.  In the dermal absorption study the dose related pattern of
absorption was typical of a chemical which directly damages the skin. 
The percent of dose absorbed increased with increasing dosage.

4.3	FQPA Considerations

4.3.1	Adequacy of the Toxicity Database

The toxicity data base is adequate for FQPA assessment with the
availability of pre-natal developmental studies in mice and rats and a
2-generation reproduction study in rats.  In accordance with the revised
40 CFR Part 158 data requirements, a neurotoxicity battery (i.e., acute
and subchronic neurotoxicity) and an immunotoxicity study is required
for all food and non-food use chemicals. Although the available studies
showed no evidence of neurotoxicity, these studies do not use optimal
methods to evaluate the nervous tissue structure and function.
Consequently, the neurotoxicity studies are required to detect and more
fully characterize these potential neurotoxic effects of endothall.  The
available studies do not indicate potential immunotoxicity, and
endothall does not belong to the class of compounds (e.g., the
organotins, heavy metals, or halogenated aromatic hydrocarbons) that
would be expected to be toxic to the immune system. Based on the
available data these required studies (neurotoxicity and immunotoxicity)
are not expected to provide a Point of Departure (PoD) lower than that
currently used (i.e., direct local irritation - the most sensitive
effect) for overall risk assessments.  The available studies clearly
demonstrate that local irritation (portal of entry effect) is the most
sensitive and initial effect occurring at dose levels lower than those
associated with systemic toxicity.  For instance, in dogs, gastric
irritation developed at a dose level that was one order of magnitude
lower than doses associated with clinical signs of toxicity (subdued
behavior, poor condition, thin appearance and distended abdomen).  In
the rat, gastric irritation was noted at a dose level that was 1 to 2
orders of magnitude lower than doses resulting in kidney lesions.  In
the 21-day dermal rat study, systemic toxicity (hematology and clinical
chemistry alterations) were noted at a dose level that was one order of
magnitude greater than that causing dermal irritation.  These studies
indicate that it is highly unlikely that any potential neurotoxicity and
immunotoxicity would occur at doses lower than those associated with
local irritant (portal of entry) effects.  Therefore, a database
uncertainty factor is not needed for the lack of these studies.

 Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies are not available for
endothall.  However, no clinical signs or symptoms of neurotoxicity were
detected in any of the available guideline studies.  

 Developmental Toxicity Studies

Executive Summary:  In a developmental toxicity study (MRID 42776301),
groups of pregnant Crl:CD BR rats (25/dose) were administered endothall
(19.2% a.i. Batch # CAF 21C901) via gavage at dose levels of 0, 6.25,
12.5, or 25.0 mg/kg/day during gestation Days 6-15.  Maternal toxicity
was observed at the highest dose tested as indicated by decreases in
body weight gain.  Endothall did not induce developmental toxicity at
any of the doses tested.

Based on these results, the maternal LOAEL is 25 mg/kg/day based on
decreased body weight gain.  The maternal NOAEL is 12.5 mg/kg/day.  No
developmental toxicity was observed at any dose tested.  Therefore, the
NOAEL for developmental toxicity is > 25 mg/kg/day.  A LOAEL was not
established

This developmental toxicity study in the rat is classified
Acceptable/Guideline and satisfies the requirements for a developmental
study in the rat (OPPT 870.3700a; OECD 414).

Reproductive Toxicity Study

Executive Summary:  In a 2-generation reproduction study (MRIDs 43152101
and 43629301), Endothall Turf Herbicide (disodium salt of Endothall,
19.9% ai) was administered continuously in the diet to Sprague Dawley CD
rats (26/sex/dose) at concentrations of 0, 30, 150 or 900 ppm for two
successive generations (1 litter P1 generation, 2 litters F1
generation). The dose levels were equivalent to 0, 2, 10.2, or 64
mg/kg/day for males and 0, 2.3, 11.7, or 78.7 mg/kg/day for females
during the premating period; 0, 1.8, 9.4 or 60 mg/kg/day during the
gestation period; and 0, 3.1, 17.3, or 104.7 mg/kg/day during the
lactation period. 

Males were mated after approximately 14 or 16 weeks (P1 and F1,
respectively) on the test diet.  P1 and F1 females were fed the test
diets for approximately 24 and 14-16 weeks, respectively, and mating was
initiated on study week 14 (P1) and study weeks 16 (F1 first litters)
and 27 (F1 second litters).  F1 pups were weaned on the same test diet
fed their parents.

At 900 ppm, mean body weights and body weight gains for both sexes of
the parental rats were slightly to moderately (and in most cases,
statistically significantly) depressed throughout the premating,
gestation and lactation periods (and the rest period for the F1 females
between litters).  Covariant-adjusted mean body weights of the F0/F1 pup
weights were also slightly depressed throughout lactation (statistically
significant at lactation days 0, 14, and 21).  F1-F2a and F1-F2b pup
weights were also slightly depressed during lactation (statistically
significant at day 21).  Histological alterations of minimal to moderate
(scales of 1-3 of a possible 5) proliferation of the gastric foveolar
epithelium, with increased mitotic figures of the glandular stomach,
were found in 3/3 F1 males examined.  One male also had an increased
number of mitotic figures in the glandular stomach.

At 150 ppm, covariant-adjusted mean body weights for both sexes in the
F1 first litter of pups (F2a) at Day 21 lactation were 10-11% depressed
(statistically significant) and 2/2 F1 females examined had minimal to
moderate proliferation of the gastric foveolar epithelium.

At 30 ppm, 2/3 F1 males and 1/2 F1 females examined had minimal to
moderate proliferation of the gastric foveolar epithelium.

Under conditions of this study, a NOAEL for parental systemic toxicity
has not been established; the LOAEL was estimated to be 30 ppm (2
mg/kg/day for males and 2.3 mg/kg/day for females) based on
proliferative lesions of the gastric epithelium (both sexes). The NOAEL
for offspring toxicity was 150 ppm (9.4 mg/kg/day) and the LOAEL was 900
ppm (60.0 mg/kg/day) based on decreased pup body weights (both sexes) at
Day 0 of the F1 and F2a generations.

This reproductive study in the rat is Acceptable/Guideline and satisfies
the guideline requirements for a two-generation reproduction study
(OPPTS 870.3800; OECD 416) in the rat.

4.3.5	Additional Information from Literature Sources

	

No additional information is available from open literature.

4.3.6	Pre-and/or Post-natal Toxicity

HED concluded that there is not a concern for pre- and/or postnatal
toxicity resulting from exposure to endothall in rats. In the
developmental mouse study, there was severe maternal toxicity (i.e.,
greater than 30% mortality) at the highest dose tested; at this dose
level, a slight increase in vertebral and rib malformations was observed
in the offspring indicating that these effects were likely secondary to
severe maternal toxicity.   

4.3.6.1	Determination of Susceptibility

There is no quantitative or qualitative evidence of increased
susceptibility following prenatal exposure to rats in the developmental
toxicity study and pre-/postnatal exposure to rats in the 2-generation
reproduction study. Due to high mortality observed in a range finding
study in rabbits even at low doses, a developmental toxicity study in
this species was not conducted (i.e., acute direct irritative effects of
the chemical could interfere with developmental toxicity in this
susceptible species).  Therefore, a developmental toxicity study in mice
was conducted and   there was no evidence for enhanced susceptibility in
this species.

4.3.6.2	Degree of Concern Analysis and Residual Uncertainties

There are no concerns for increased susceptibility and no residual
uncertainties for pre and/or post-natal toxicity.

4.3.7	Recommendation for a Developmental Neurotoxicity (DNT) Study

At this point, HED has concluded that a developmental neurotoxicity
study is not required for endothall.   If evaluation of newly required
neurotoxicity studies indicates neurotoxicity, this decision may be
reconsidered.  However, this is unlikely as systemic effects are less
sensitive than the irritation endpoints currently serving as points of
departure.  

Evidence that suggests requiring a DNT study:

None.

Evidence that does not support a need for a DNT study:

No clinical signs or symptoms of neurotoxicity/neuropathology were
detected in any of the available guideline studies.

FQPA Safety Factor for Infants and Children

The toxicology data base is adequate for FQPA assessment.  For the
assessment of risk following incidental oral exposure or short term
inhalation exposures, the FQPA Safety Factor for increased
susceptibility to infants and children is reduced to 3X for the
following reasons:

A LOAEL established in the two-generation reproduction study was used
for assessing chronic dietary (i.e, chronic RfD) and intermediate
inhalation exposure risks.  Since a LOAEL was used, a 3X FQPA Safety
Factor in the form of (UFL) is retained for these exposure scenarios.  A
3X factor (as opposed to a 10X) was determined to be adequate since 1)
the gastric lesions (most sensitive effect) are due to the direct
irritant properties of endothall (i.e., portal effects) and not as a
result of frank systemic toxicity; 2) the severity of the lesions were
minimal to mild; and 3) there was no apparent dose-response for this
effect.  HED is confident that the Point of Departure (i.e., 0.007
mg/kg/day) will not underestimate risks following exposure to endothall.

There is no need to retain the 10X FQPA Safety Factor for the lack of
neurotoxicity and immunotoxicity studies because a review of the entire
database indicates that irritation, the current basis for regulation,
occurs at doses 1-2 orders of magnitude below where systemic effects
occur.

There is no indication of increased susceptibility of rats or mice in
utero and/or postnatal exposure in the developmental and reproductive
toxicity studies;

There are no concerns for neurotoxicity.  Although acute and subchronic
neurotoxicity studies are not available, it is highly unlikely that
these studies will demonstrate a potential neurotoxic effect that is
more sensitive than direct local irritation (the most sensitive effect
identified in the data base); a developmental neurotoxicity study is not
required; 

The available studies do not indicate potential immunotoxicity, and
endothall does not belong to the class of compounds (e.g., the
organotins, heavy metals, or halogenated aromatic hydrocarbons) that
would be expected to be toxic to the immune system. Based on the
available data, the immunotoxicity study is not expected to provide a
Point of Departure (PoD) lower than that currently used (i.e., direct
local irritation - the most sensitive effect) for overall risk
assessments;

There are no residual uncertainties in the exposure data base.  While
the chronic dietary exposure estimates are refined (average field trial
residues and adjustment of the percent of the harvested crop that has
been irrigated) the results are very conservative because the field
trials were performed under highly conservative conditions, and it was
assumed that 100% of all irrigation canals in the US are treated at the
maximum rate for endothall, this maximally treated water is applied to
the crops on the day of harvest, and all consumers are chronically
exposed to simultaneous inadvertent residues of endothall through all
possible food and water sources.  Therefore, the estimated dietary
exposure (food and drinking water) will not underestimate the potential
risks for infants and children.  Likewise, the maximum application
rates, worst-case scenarios and central-to-high end inputs used for
estimating residential exposures should not underestimate the risks to
infants and children from the requested use.  

Hazard Identification and Toxicity Endpoint Selection

4.5.1    Acute Reference Dose (aRfD)  

  TC \l3 "3.5.1    Acute Reference Dose (aRfD) - Females age 13-49 

Study Selected:   None 

MRID No.:   None

Executive Summary:   None

Dose and Endpoint for Establishing aRfD:   Not applicable

Uncertainty Factor (UF):  Not applicable 

Comments about Study/Endpoint/Uncertainty Factor:  An acute RfD was not
established for any population subgroup because an appropriate endpoint
attributable to a single dose was not available from any study,
including the prenatal developmental toxicity study in the rat or the
mouse.

4.5.2	Chronic Reference Dose (cRfD) 

  TC \l3 "3.5.3	Chronic Reference Dose (cRfD) 

Study Selected: 2-Generation Reproduction Toxicity Study in Rats

MRID No.: 43152101 and 43629301

Executive Summary:  See Appendix A.3.3, Guideline 870.3800 

Dose and Endpoint for Risk Assessment: LOAEL = 2 mg/kg/day for males and
2.3 mg/kg/day for females) based on proliferative lesions of the gastric
epithelium in both sexes

Uncertainty Factor(s):  300.  This includes the 10x for interspecies
extrapolation and 10x for intraspecies variation, and an additional 3x
FQPA factor for the lack of a NOAEL in the study used for endpoint
selection. A 3X FQPA factor (as opposed to a 10X) was determined to be
adequate since: 1) the gastric lesions (most sensitive effect) are due
to the direct irritant properties of endothall (i.e., portal effects)
and not as a result of frank systemic toxicity; 2) the severity of the
lesions were minimal to mild; and 3) there was no apparent dose-response
for this effect.  HED is confident that the Point of Departure (i.e.,
0.007 mg/kg/day) will not underestimate risks following exposure to
endothall.   

Comments about Study/Endpoint/Uncertainty Factor:  This dose and
endpoint is appropriate with respect to the route and duration of this
exposure scenario.

Chronic RfD =      2 mg/kg/day (LOAEL)   = 0.007 mg/kg/day

			    300 (UF)

4.5.3	Incidental Oral Exposure (Short- and Intermediate-Term) 

Short-Term (1-30 days)

  TC \l3 "3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: 2-Generation Reproduction Toxicity Study in Rats

MRID Nos: 43152101 and 43629301

Executive Summary: See Appendix A.3.3, Guideline 870.3800	

	

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 9.4 mg/kg/day
based on decreased pup body weights in both sexes at Day 0 of the F1 and
F2a generations

Comments about Study/Endpoint:  This endpoint is appropriate with
respect to the duration and population of concern (i.e., hand-to-mouth
behavior in infants and children).  

Intermediate-Term (1 - 6 Months)

	

Study Selected: Rat 2-Generation Reproduction Toxicity Study

MRID Nos: 43152101 and 43629301

Executive Summary: See Appendix A.3.3, Guideline 870.3800	

	

Dose and Endpoint for Risk Assessment: The parental systemic toxicity
LOAEL was estimated to be 30 ppm (2 mg/kg/day in both sexes) based on
proliferative lesions of the gastric epithelium (both sexes).

	

Comments about Study/Endpoint: This endpoint is appropriate with respect
to the population of concern (i.e., hand-to-mouth behavior in infants
and children) and the duration of exposure (1-6 months) since stomach
lesions were seen at the end of this study which is approximately
13-weeks in duration.

4.5.4	Dermal Absorption

Dermal Absorption Factor:   7.3% at 24 hours.

Study Selected: Dermal Absorption Study in Rat

MRID No: 42169503

Executive Summary: See Appendix A.3.8, Guideline 870.7600  

This study in the rat is acceptable and satisfies the guideline
requirement for a dermal penetration study (870.7600) in rats.

4.5.5	Dermal Exposure: All Durations

The RARC recommended that dermal assessments should not be conducted,
since endothall is so toxic at the portal of entry and is therefore
self-limiting.  In the 21-day dermal toxicity study (MRID 4346520),
severe dermal effects were observed at 30 mg/kg/day (the lowest dose
tested).  The NOAEL for dermal irritation was not established due to
erythema, edema, and fissuring and sloughing off of the skin at the dose
site at the lowest tested (30 mg/kg/day).  

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

Short-Term (1-30 days)

Study Selected:  2-Generation Reproduction Toxicity Study in Rats 

MRID No.: 43152101 and 43629301

Executive Summary: See Appendix A.3.3, Guideline 870.3800

 

Dose/Endpoint for Risk Assessment: Offspring NOAEL = 9.4 mg/kg/day based
on decreased pup body weight at Day 0 of the F1 and F2 generations.

Comments about Study/Endpoint: In the absence of a repeated dose
inhalation study, an oral study was selected.  Absorption via the
inhalation route is presumed to be equivalent to oral absorption (i.e.,
100%).  A recently submitted 28-day inhalation study is under review.

	

Intermediate-Term (1- 6 Months) and Long-Term  (> 6 Months)

 

  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term) Study Selected: 2-Generation Reproduction Toxicity Study in
Rats 

MRID No.: 43152101 and 43629301

	

Executive Summary: See Appendix A.3.3, Guideline 870.3800

	

Dose/Endpoint for Risk Assessment: The parental toxicity LOAEL = 2
mg/kg/day based on proliferative lesions of the gastric epithelium in
both sexes.

	

Comments about Study/Endpoint: In the absence of a repeated dose
inhalation study, an oral study was selected.  Absorption via the
inhalation route is presumed to be equivalent to oral absorption (i.e.,
100%).

 

4.5.7	Level of Concern for Margin of Exposure

The target MOEs for risk assessments are noted below, in Table 3.5.7.

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	N/A	N/A

Inhalation	100	300	N/A

Residential (Non-Dietary) Exposure

Oral	100	300	N/A

Dermal	N/A	N/A	N/A

Inhalation	100	300	N/A

	

					

Occupational Exposure

For short-term inhalation exposure assessments, an MOE of 100 is
required based on the conventional 100x (10x for intraspecies
extrapolation and 10x for interspecies variation).

For intermediate- and long-term inhalation, an MOE of 300 is required
based on the conventional 100x (10x for intraspecies extrapolation and
10x for interspecies variation), and an additional 3x for the lack of a
NOAEL in the study used for endpoint selection. 

Residential Exposure

For short-term incidental oral and inhalation, an MOE of 100 is required
based on the conventional 100x (10x for intraspecies extrapolation and
10x for interspecies variation).

For intermediate-term incidental oral, and intermediate- and long-term
inhalation, an MOE of 300 is required based on the conventional 100x
(10x for intraspecies extrapolation and 10x for interspecies variation),
and an additional 3x for the lack of a NOAEL in the study used for
endpoint selection. 

4.5.8	Classification of Carcinogenic Potential

HED classified endothall as “not likely to be carcinogenic to
humans” according to the EPA Draft Proposed Guidelines for Carcinogen
Risk Assessment (July 2, 1999).  This classification is based on the
lack of evidence of carcinogenicity in mice and rats.

  

4.5.9	Summary of Toxicological Doses and Endpoints for Endothall for
Use in Human Risk Assessments

Table 4.5.9 Summary of Toxicological Doses and Endpoints for Endothall
Human Health Risk Assessments.

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

FQPA SF and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

(General population including infants and children)

(Females 13-50 years of age	

NA	

NA	

An appropriate endpoint attributable to a single dose was not available
from any study, including the prenatal developmental toxicity study in
rats. An acute RfD was not established.

Chronic Dietary

(All populations)	

LOAEL= 2 mg/kg/day

UF = 300

Chronic RfD = 

0.007 mg/kg/day

(MRID 43152101)	

FQPA SF = 1

cPAD = 

chronic RfD

 FQPA SF

= 0.007 mg/kg/day	

Rat 2-generation reproduction study 

LOAEL 2 mg/kg/day based on proliferative lesions of the gastric
epithelium (both sexes)

Short-Term 

Incidental Oral (1-30 days)

	

Offspring

NOAEL = 9.4 mg/kg/day

(MRID 43152101)	

Residential LOC  for MOE = 100

Occupational = NA	

Rat 2-generation reproduction study 

LOAEL 60 mg/kg/day based on decreased pup body weight (both sexes) on
Day 0 F1and F2 generations

Intermediate-Term 

Incidental Oral (1- 6 months)

	

LOAEL= 2 mg/kg/day

(MRID 43152101)	

Residential  LOC

for MOE = 300

Occupational = NA	

Rat 2-generation reproduction study 

LOAEL 2 mg/kg/day based on proliferative lesions of the gastric
epithelium (both sexes)

Short-Term Dermal 

(1 to 30 days)	

N/A	

N/A	

The RARC recommended that no dermal assessments be conducted, since
endothall is so toxic at the portals of entry. In the 21-day dermal
toxicity study (MRID43465201), severe dermal effects were observed at 30
mg/kg/day (the lowest dose tested).

Intermediate-Term

Dermal 

(1 to 6 months)	

NA	

NA	

The RARC recommended that no dermal assessments be conducted, since
endothall is so toxic at the portals of entry. In the 21-day dermal
toxicity study (MRID43465201), severe dermal effects were observed at 30
mg/kg/day (the lowest dose tested).

Long-Term Dermal

 (>6 months)

	

NA  no exposure under use pattern	

Residential NA

Occupational NA	

NA

Short-Term Inhalation

(1 to 30 days)

	

Offspring

NOAEL = 9.4 mg/kg/day

(inhalation absorption rate = 100%)

(MRID 43152101)	

Residential LOC for MOE = 100 

Occupational LOC for MOE = 100 	

Rat 2-generation reproduction study 

LOAEL 60 mg/kg/day based on decreased pup body weight (both sexes) on
Day 0 F1and F2 generations

Intermediate-Term Inhalation (1 to 6 months) and

Long-Term Inhalation (>6 months)	

LOAEL= 2 mg/kg/day

(MRID 43152101)	

Residential   LOC for MOE = 300 

Occupational LOC for MOE = 300 	

Rat 2-generation reproduction study 

LOAEL 2 mg/kg/day based on proliferative lesions of the gastric
epithelium (both sexes)

Cancer (oral, dermal, inhalation)

	

NA

(MRID 41040301)

(MRID 40685301& 43608301)	

NA	

Chronic/Onco Rat

Negative for carcinogenicity

Carcinogenicity Mice

Negative for carcinogenicity

Not likely carcinogenic to humans

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

4.6	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, endothall may be subjected to additional screening and/or
testing to better characterize effects related to endocrine disruption.

5.0	Residue Chemistry and Metabolism Update

Table 5.1. Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis)	

Commodity	

Percent TRR (PPM) 1	

Structure

Matrices - Major Residue (>10%TRR)	

Matrices - Minor Residue (<10%TRR)

	

Endothall	

Alfalfa Forage	

98% TRR	

	

	

Alfalfa Seed	

84% TRR	

Cotton	

88% TRR	

Sugarbeet Top	

64% TRR	

Sugarbeet Root	

37% TRR	

Rotational Crops	

No Data	

No Data

Goat Kidney	

51% TRR	

Goat Liver	

60% TRR	

Goat Muscle	

	

No Residue

Goat Fat	

	

No Residue

Milk	

	

No Residue

Chicken Kidney	

13% TRR	

Chicken Liver	

	

5% TRR

Chicken Muscle	

	

No Residue

Chicken Skin	

13% TRR	

Egg White	

	

No Residue

Egg Yolk	

30% TRR	

Rat	

	

Water	

100% 	

	

Endothall monomethyl ester	

Alfalfa Forage	

	

<10% TRR	

	

Alfalfa Seed	

	

<10% TRR

Cotton	

	

<10% TRR

Sugarbeet Top	

	

1.2% TRR

Sugarbeet Root	

22% TRR	

Rotational Crops	

No Data	

No Data

Goat Kidney	

26% TRR	

Goat Liver	

	

--

Goat Fat	

	

No Residue

Goat Muscle	

	

No Residue

Milk	

	

No Residue

Chicken Kidney	

74% TRR	

Chicken Liver	

54% TRR	

Chicken Skin	

54% TRR	

Chicken Muscle	

	

No Residue

Egg White	

	

No Residue

Egg Yolk	

	

9% TRR

Rat	

	

Water	

	

None

	

Endothall dimethyl ester	

Alfalfa Forage	

	

<10% TRR	

	

Alfalfa Seed	

	

<10% TRR

Cotton	

	

<10% TRR

Sugarbeet Top	

	

3.4% TRR

Sugarbeet Root	

	

0% TRR

Rotational Crops	

No Data	

No Data

Goat Kidney	

	

4% TRR

Goat Liver	

	

--

Moat Fat	

	

No Residue

Goat Muscle	

	

No Residue

Milk	

	

No Residue

Chicken Kidney	

	

0

Chicken Liver	

	

0

Chicken Skin	

	

0

Chicken Muscle	

	

No Residue

Egg White	

	

No Residue

Egg Yolk	

	

0

Rat	

	

Water	

	

None

	

The final row of the table should have a concise summary of relevant
parameters.

Alfalfa; MRID 42619201, 0.65 lbs ae/A; 3X rate, near maturity/seed pods
dying; 9 days PHI

Cotton; MRID 42619202, 0.1 lb ae/A; 1X; maturity; before and 4 and 14
days PHI.

Sugarbeet; MRID 42619203; 1.5 lbs ae/A; 2, 48 and 132 days PHI.

Goats; MRID 42792701; 13.5 and 10.4 ppm x 5 days, 4-5X

Chickens; MRID 42816601; 9.7 ppm x 14 days, 30X

Rotational Crops; MRID 43300701; D205980

Rat ; MRID 42169502; oral 0.9, 4.5 or 9.0 mg/kg single dose 0.9 or 9.0
mg/kc/day 15 day.

	

5.1	Nature of the residue – plants

The nature of endothall residues in plants is adequately understood
based on the acceptable alfalfa, cotton, and sugar beet metabolism
studies reflecting use of the dipotassium salt of [14C]endothall.  An
adequate cotton metabolism study is also available reflecting use of the
mono-N,N-dimethylalkylamine salt of [14C]endothall.  HED has concluded
that the metabolism studies using the dipotassium salt will also fulfill
metabolism data requirements for the monoalkylamine salt as the two
salts would be expected to behave similarly in plants.  The HED
Metabolism Committee (S. Funk, 11/8/96) has also concluded that the
residues of concern for both risk assessment and tolerance enforcement
in plant commodities include parent endothall and its monomethyl ester. 

5.2	Nature of the residue – animals

The qualitative nature of the endothall residues in livestock is
adequately understood based on the acceptable poultry and goat
metabolism studies.  The HED Metabolism Committee has concluded that the
residues of concern in animal commodities consist of parent endothall
and its monomethyl ester.

Meat, milk, poultry, and eggs

Livestock may be exposed to endothall through residues on feed and
through drinking water.  Therefore residues have been calculated for
these products.  

The feed only dietary burden for establishing tolerances is estimated as
in Table 5.3.1.  

Table 5.3.1.   Calculation of Dietary Burdens of Endothall Residues in
Livestock.

Feedstuff	Type1	% Dry Matter2	% Diet2	Recommended Tolerance (ppm)
Dietary Contribution (ppm)3

Beef Cattle R: 15%; CC: 80%; PC: 5%

Grass, hay	R	88	15	18	3.07

Grain, aspirated fractions	CC	85	5	35	2.06

Wheat, milled byproducts	CC	88	40	5.0	2.28

Grain, cereal, group 15	CC	88	30	4.0	1.37

Sugar, beet, molasses	CC	75	5	1.5	0.1

Soybean, meal	PC	92	5	0.24	0.01

	TOTAL BURDEN

	100

8.9

Dairy Cattle R: 45%; CC: 45%; PC: 10%

Grass, hay	R	88	20	18	4.09

Almond, hulls	R	90	5	15	0.83

Animal feed, Nongrass, group 18, forage	R	35	20	4.0	2.29

Wheat, milled byproducts	CC	88	30	5.0	1.70

Grain, cereal, group 15	CC	88	10	4.0	0.46

Sugar, beet, molasses	CC	75	5	1.5	0.1

Soybean, meal	PC	92	10	0.24	0.02

	TOTAL BURDEN

	100

9.5

Poultry  CC: 75%; PC:  25%

Grain, cereal, group 15	CC	88	75	4.0	3.0

Alfalfa , meal, (Animal feed, Nongrass, group 18, hay) 	PC	89	5	10.0	0.5

Soybean, meal	PC	92	20	0.24	0.04

	TOTAL BURDEN	--	--	100	--	3.6

Swine  CC: 85 %;  PC:  15%

Grain, cereal, group 15	CC	88	85	4.0	3.4

Alfalfa , meal, (Animal feed, Nongrass, group 18, hay) 	PC	89	5	10.0	0.5

Soybean, meal	PC	92	10	0.24	0.02

	TOTAL BURDEN	--	--	100	--	4.0

The portion of water in the dietary is calculated as follows.  For
setting a tolerance the acutely available residues in water are assumed
to be at the maximum allowed use rate of 5 ppm.  The potential
contribution of endothall residues in water to the dietary exposure of
livestock was calculated following the procedures described in
PP#1F3991/1F3935 (G. Okatie, 9/4/92), based on the concentration of
endothall in the drinking water, the daily water consumption, and the
daily feed intake.  The estimated dietary burden through foods, through
water, and in total is shown in Table 5.3.2. 

Table 5.3.2.	Calculation of Total (Feed Plus Water) Dietary Burdens of
Endothall Residues to Livestock 

Feedstuff	Feed	Water	Total

Beef cattle (feedlot cattle)	8.9	19.2	28.1

Dairy cattle (lactating cows)	9.5	45.4	54.9

Poultry (laying hens)	3.6	13.5	17.1

Swine (finishing hogs)	4.0	16.1	20.1

No feeding studies have been submitted, so TRR from the animal
metabolism studies have been used to estimate residues in meat, milk
poultry and eggs.  Maximum anticipated residues for meat, milk, poultry
and eggs tolerances are summarized in table 5.3.3.  These results are
based upon tolerance level residues in the feed stuffs and consumption
of water containing 5 ppm endothall.  

Table 5.3.3.  Calculation of estimated Residues in Livestock Tissues
Based upon the TRR in the Metabolism Studies.

Residues of Endothall in Dairy Cattle Tissues Based upon the Goat
Metabolism Study

Tissue	

Total Radioactive Residues (ppm) after Feeding at 12.0 ppm	

Anticipated Residues (ppm) after Feeding at 54.9 ppm  

Milk.	

0.006	0.028

Kidney	

0.046	0.21

Liver	

0.020	0.092

Muscle 	

0.005	0.023

Fat	

0.002	0.009

Residues of Endothall in Beef Cattle Tissues, Sheep, Goats Based upon
the Goat Metabolism Study

Tissue	

Total Radioactive Residues (ppm) after Feeding at 12.0 ppm	

Anticipated Residues (ppm) after Feeding at 28.1 

Kidney	

0.046	0.108

Liver	

0.020	0.047

Muscle 	

0.005	0.012

Fat	

0.002	0.005

Residues of Endothall in Swine Tissues Based upon the Goat Metabolism
Study

Tissue

	

Total Radioactive Residues (ppm) after Feeding at 12.0 ppm	

Anticipated Residues (ppm) after Feeding at 20.1 ppm

Kidney

	

0.046	0.077

Liver	

0.020	0.034

Muscle 

	

0.005	0.008

Fat	

0.002	0.003

Residues of Endothall in Poultry Tissues Based upon the Chicken
Metabolism Study

Tissue	

Total Radioactive Residues (ppm) after feeding at 9.7 ppm	

Anticipated Residues (ppm) after feeding at 17.1 ppm

Eggs	

0.024	0.042

    Yolk	

0.024	0.042

    White	

0.002	0.004

Kidney and Other Meat Byproducts	

0.088	0.16

Liver	

0.021	0.037

Muscle 	

0.008	0.014

Fat	

0.007	0.012

5.4	Analytical methods

Enforcement Methods

  SEQ CHAPTER \h \r 1 An enforcement method (GC with microcoulometric
nitrogen detection) is listed as Method I in the Pesticide Analytical
Manual (PAM, Volume II) for the determination of endothall residues
(total common moiety) in plant commodities, with an LOQ of 0.1 ppm.  A
second LC/MS method (Method No. KP218R0) is also available for
determining residues of endothall and its monomethyl ester in fish and
in plant commodities.  The LOQ is 0.05 ppm for fish, and range from
0.01-0.10 ppm for plant commodities.  Endothall is not recovered through
the FDA multiresidue methods.

In the irrigated crop field trials and processing studies, residues of
endothall in/on plant commodities were determined using a LC/MS/MS
method (Method No. KP-242R1) entitled “Analytical Method for
Determination of Endothall in Crops”, issued 5/4/2007.  For this
method, residues are extracted with water, cleaned-up and then
derivatized with HFTH in 50% H3PO4 at 100-120°C for 90 minutes.  The
derivatized residues are further cleaned up and analyzed by LC/MS/MS. 
The validated LOQ is 0.05 ppm for plant commodities.

Conclusions.  Adequate methods are available for enforcing the proposed
tolerances, and the residue data from the field trials and processing
studies were collected using an adequate LC/MS/MS method.  The
conditions for the derivatization step used in Method No. KP-242R1
should hydrolyze the monomethyl ester to the free acid.  However, no
data were provided as to whether or not the LC/MS/MS method can recover
residues of the methyl ester of endothall, which are also residues of
concern.  

5.5	Storage stability update

Adequate storage stability data have been submitted to support the
sample storage conditions and durations from the irrigated crop field
trials.

5.6	Magnitude of residue in food update

Irrigated Crops  

IR-4 has submitted limited field trial data covering a wide variety of
crops and crop groups that could be irrigated with endothall-treated
water, including:  carrots, potatoes and sugar beets (groups 1 and 2);
green and dry bulb onions (group 3); leaf and head lettuce (group 4);
cabbage (group 5); dried and succulent (podded) peas and beans (group
6); tomatoes (group 8), cucumbers (group 9); oranges (group 10), apples
(group 11), peaches (group 12), blueberries and blackberries (group 13);
almonds and pecans (group 14); corn, sorghum, wheat and rice (groups 15
and 16); grass (group 17); alfalfa (group 18); and mint.  Although the
field trials cover a wide variety of crops, the number of field trials
conducted on any given crops was limited, ranging from 1 to 4 tests per
crop.

In each field trial, the monoalkylamine salt of endothall (2 lb ae/gal
SC/L) was used to treat the irrigation water at a rate of ~5 ppm ae
(ae), and the treated water was then applied via overhead sprinklers as
six broadcast foliar applications at RTIs of ~7 days.  The target
application volume in each trial was equivalent to ~1 acre inch of water
(27,154 gal/A).  Based on the concentration of the endothall in the
irrigation water and the amount of water applied, the target application
rate for endothall was equivalent to 1.13 lb ae/A/application, for a
total of 6.79 lb ae/A/season.  Side-by-side tests were also conducted on
selected crop (sugar beets, lettuce, cucumber, and peaches) comparing
application of the dipotassium salt of endothall (3 lb ae/gal SC/L) with
the monoalkylamine salt.  However, although the dipotassium salt was
applied to the irrigation water according to the label directions for
that salt, the resulting concentration of endothall in the water was 3.5
ppm ae.  [Unlike the label directions for the alkylamine salt, the label
directions for the potassium salt assume that it is applied at 5 ppm as
the salt, not as the acid equivalent, that is to say, the potassium salt
labeled instructions describe application at 5 ppm ai, not 5 ppm ae.]

In each field trial, the endothall residues were determined using an
adequate LC/MS/MS method (Method No. KP-242R1).  This method has a
validated LOQ for endothall at 0.05 ppm for each commodity.  The results
of these studies are summarized in Table 5.

TABLE 5.6.1	Summary of Residue Data from Field Trials with Endothall.

Commodity	Formulation type	Total Applic. Rate 1	PHI (days)	Residue
Levels (ppm) 2

N	Min.	Max.	HAFT 3	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Root and Tuber Vegetables

Sugar beet, tops	Monoamine salt (SC/L)	5 ppm

(6.77-6.79)	0	2	1.32	1.36	1.36	1.34	1.34	0.033

	Dipotassium salt (SC/L)	3.5 ppm

(4.80-4.88)	0	2	0.527	1.114	1.114	0.820	0.820	0..415

Sugar beet, roots	Monoamine salt (SC/L)	5 ppm

(6.77-6.79)	0	2	0.165	0.493	0.493	0.330	0.330	0.230

	Dipotassium salt (SC/L)	3.5 ppm

(4.80-4.88)	0	2	0.118	0.330	0.331	0.224	0.224	0.151

Carrot	Monoamine salt (SC/L)	5 ppm

(6.77-6.79)	0	2	0.0685	0.088	0.088	0.078	0.078	0.014

Potato	Monoamine salt (SC/L)	5 ppm

(6.77-6.83)	0	2	0.0725	0.875	0.0875	0.080	0.080	0.011

Bulb Vegetables

Green Onion	5.0 ppm

(6.75)	0	1	0.259	0.259	0.259	0.259	0.259	NA

Dry Bulb onion	5.0

(6.76)	0	1	<0.05	<0.05	<0.05	<0.05	<0.05	NA

Leafy Green Vegetables – Lettuce

Leaf lettuce	Monoamine salt (SC/L)	5 ppm

(6.73-6.76)	0	2	0.436	.9915	0.9915	0.714	0.714	0.393

	Dipotassium salt (SC/L)	3.5 ppm

(4.67-4.81)	0	2	0.248	0.7975	0.7975	0.523	0.523	0.363

Head lettuce	Monoamine salt (SC/L)	5 ppm 

(6.76-7.17)	0	2	0.0865	0.5475	0.5475	0.292	0.317	0.270

	Dipotassium salt (SC/L)	3.5 ppm

(4.81-5.07)	0	2	0.066	0.509	0.509	0.2875	0.2875	0.3132

Brassica - Cabbage 

Cabbage, head with wrapper leaves	5 ppm

(5.64-7.00)	0	2	0.0615	0.0625	0.0625	0.062	0.062	0.0007

Legume Vegetables 

Succulent podded beans	5 ppm

(6.75, 9.02) 4	0	2	0.3075	0.4675	0.4675	0.3875	0.3875	0.113

Succulent podded peas	5 ppm

(6.74)	0	2	0.5295	0.939	0.939	0.734	0.734	0.290

Dried Beans	5 ppm

(6.77)	0	2	0.102	0.116	0.116	0.109	0.109	0.010

Soybean, dried seed	5 ppm

(6.75-6.77)	0-1	4	<0.050	0.07	0.07	0.034	0.034	0.025

Fruiting Vegetables – Tomatoes

Tomato	5 ppm

(6.74-6.77)	0	2	<0.05	<0.05	<0.05	0.05	0.05	N/A

Cucurbits - Cucumbers 

Fruit 	Monoamine salt (SC/L)	5 ppm

(6.75-6.77)	0	2	0.259	0.738	0.738	0.499	0.499	0.339

Fruit	Dipotassium salt (SC/L)	3.5 ppm

(4.80-4.81)	0	2	0.324	0.433	0.433	0.522	0.522	0.389

Citrus - Orange 

Orange	5 ppm

(6.63-6.78)	0	2	0.0215	0.026	0.026	0.024	0.024	0.0032

Pome Fruit – Apple

Apple	5 ppm

(6.64-6.79)	0	2	0.039	0.043	0.043	0.041	0.041	0.0028

Stone Fruits – Peach

Fruit 	Monoamine salt (SC/L)	5 ppm

(6.78-7.08)	0	2	0.044	0.152	0.152	0.098	0.098	0.076

Fruit	Dipotassium salt (SC/L)	3.5 ppm

(4.82-5.05)	0	2	0.045	0.127	0.127	0.086	0.086	0.058

Berries

Blueberry	5.0 ppm

(6.77)	0	1	0.177	0.177	0.177	0.177	0.177	N/A

Blackberry	5.0 ppm

(6.73)	0	1	0.328	0.328	0.328	0.328	0.328	N/A

Tree Nuts

Pecan, nutmeat	5 ppm

(7.01)	0	1	0.24	024	0.024	0.024	0.024	N/A

Almond, nutmeat	5 ppm

(6.80)	0	1	0.037	0.037	<0.037	0.037	0.037	N/A

Almond, hulls

0	1	7.56	7.56	7.56	7.56	7.56	N/A

Cereals, except Rice

Sweet Corn

K+CWHR	5 ppm

(6.75-6.91)

	0	2	0.05	0.17	0.17	0.11	0.11	0.085

Forage w/o ears

0	2	0.585	1.23	1.23	0.908	0.908	0.456

Forage  w/ears

0	2	0.445	0.97	0.97	0.708	0.708	0.371

Stover w/ears

0	2	0.635	4.88	4.88	2.758	2.758	3.002

Field Corn

Forage	5 ppm

(2.26-3.38) 5	0	4	0.285	0.385	0.385	0.334	0.334	0.041

Grain	5 ppm

(6.75-7.10)	0	4	0.04	0.05	0.05	0.05	0.05	0.005

Stover

0	4	1.44	3.19	3.19	2.08	2.08	0.82

Sorghum

Forage	5 ppm

(2.26-3.38) 5	0	3	0.35	2.67	2.67	1.262	1.262	1.237

Grain	5 ppm

(6.77)	0	3	0.645	1.21	1.21	1.00	1.00	0.311

Stover

0	3	0.96	4.90	4.90	2.91	2.91	1.97

Wheat

Forage	5 ppm

(2.19-3.39) 5	0	4	0.685	2.13	2.13	1.15	1.15	0.662

Hay

0	4	1.055	3.09	3.09	1.94	1.94	0.89

Grain	5 ppm

(6.58-6.77)	0-1	4	0.32	1.91	1.91	0.71	0.71	0.800

Straw

0-1	4	1.07	2.74	2.74	1.83	1.83	0.74

AGF

	1	20.3	20.3	20.3	20.3	20.3	N/A

Grasses

Forage	5 ppm

(6.64-7.02)	0-2	6	1.94	2.73	2.73	2.21	2.21	0.32

Hay

0-2	6	5.87	13.65	13.65	8.77	8.77	3.00

Alfalfa

Forage	5 ppm

(5.94-6.58)	0	2	1.77	2.12	2.12	1.95	1.95	0.25

Hay

0	2	4.93	5.20	5.20	5.07	5.07	0.19

Grapes

Grape	5.0 ppm

(6.64-6.76)	0	3	0.405	0.642	0.642	0.522	0.522	0.119

Mint

Mint	5 ppm

(6.64-6.77)	0	2	1.49	2.80	2.80	2.14	2.14	0.923

Rice

Rice grain	5 ppm

(6.75-6.77)	0-1	4	0.756	1.18	1.18	1.05	1.05	0.200

Rice Straw

0-1	4	1.02	2.6	2.6	1.90	1.90	0.66

1	The endothall concentrations are expressed in acid equivalents, and
the values in parentheses are the total application rates in terms of lb
ae/A.

m.  The LOQ was used for all values reported as ≤LOQ.

3	HAFT = Highest Average Field Trial.

4	One of the succulent podded bean field trials used 8 applications
rather than 6 applications due to slow plant growth and maturation.

5	Field corn forage, sorghum forage, and wheat forage and hay were
harvested after only two or three applications.

5.7  Processing Factors

Adequate cotton and potato processing studies are available supporting
the direct use of endothall on these two crops as a defoliate/desiccant
(DP# D321179, D. Soderberg, 8/30/2005).   Endothall residues were 1.49
ppm in/on undelinted cottonseed (RAC), which was then processed into
hulls, meal and crude and refined oils.  Endothall residues did not
concentrate in hulls (0.36x), meal (0.22x), or refined oil (0.03x). 
Mature potato tubers were processed into flakes, chips and wet peel. 
Endothall residues were 0.084 ppm in/on mature tubers, 0.088 ppm in
flakes, 0.045 ppm in chips and 0.024 ppm in wet peel.  These data
indicate that endothall residues concentrated only slightly in flakes
(1.04x) and were reduced in chips (0.54x) and wet peel (0.28x)
fractions.

In support of the current petition for use of endothall-treated water on
irrigated crops, IR-4 has submitted processing studies on apples,
grapes, field corn, mint, oranges, rice, soybeans, sorghum, sugar beets,
tomatoes and wheat.  The resulting processing factors from each study
are summarized in Table 10.

Table 5.7.1.	Summary of Processing Factors for Endothall from Crops
Irrigated with Endothall-treated water.

RAC	Processed Commodity	Application Rate 1	PHI

(days)	Processing Factor

ppm	lb ae/A

Apple 2	Juice	5.0	6.79	0	1.2x

	Wet pomace

2.8x

Field Corn	Grits	5.0	6.77	0	NC 3

	Meal

NC 3

	Flour

NC 3

	Refined oil (dry milling)

NC 3

	Starch

NC 3

	Refined oil (wet milling)

NC 3

Grape	Juice	5.0	6.73	0	1.2x5

	Raisins

4.4x

Mint	Oil	5.0	6.64	0	<0.001x

Orange 2	Dried pulp	5.0	6.63	0	2.2x

	Juice

0.7x

	Oil

<0.2x

Rice	Hulls	5.0	6.75	1	3.9x

	Bran

2.3x

	Polished rice

0.07x

Sorghum	Flour	5.0	6.77	0	0.7x

Soybean 2	Hulls	5.0	6.77	0	3.9x

	Meal

0.8x

	Refined oil

<0.005x

Sugar beet	Dried pulp	5.0	6.79	0	1.1x

	Molasses

2.4x

	Refine sugar

<0.1x

Tomato 2	Puree	5.0	6.77	0	2.1x4

	Paste

3.3x4

Wheat	Aspirated grain fractions (AGF)	5.0	6.71	0	15x

	Germ

2.6x

	Bran

2.3x

	Middlings

0.9x

	Flour

0.6x

	Shorts

1.4x

1	The rate is expressed both in terms of the concentration in the
irrigation water (ppm) and the total amount (lb ae/A) applied.

 but ≥LOD were used for calculating processing factors.

3	Residues were <LLMV and <LOD in/on field corn grain and each processed
fraction.  NC = not calculated.

4	Residues were below the LLMV (<0.05 ppm) in both fruit and puree
samples, but were well above the LOD at 0.002 ppm) 

5  1.2x is the Maximum Theoretical Processing Factor for grape juice

5.8	Rotational crops

The tolerances recommended, based upon the above studies to cover the
proposed irrigation uses on all crops, are expected to be higher than
any results from rotational crops studies, therefore  rotational crops
studies are no longer needed for any crops.

5.9	Proposed and recommended tolerances

As a result, the proposed tolerances should be revised to reflect the
recommended tolerance levels and correct commodity definitions as
specified below in Table 5.9.1.

Table 5.9.1. 	Tolerance Summary for Endothall.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

Correct Commodity Definition

40 CFR §180.293(d)

Vegetable, root and tuber, group 1	2	1.0	Based on maximum residues in
sugar beets (0.493 ppm), carrots (0.088 ppm) and potatoes (0.103 ppm)

Beet, sugar, molasses	None	1.5	Maximum expected residues are 1.18 ppm in
molasses based on HAFT residues of 0.493 ppm in sugar beet roots and a
2.4x processing factor. 

Vegetable, leaves of root and tuber, group 2	3.5	3.0	Based on maximum
residues in sugar beet tops (1.62 ppm)

Vegetable, bulb, group 3	2	0.5	Based on maximum residues in green onions
(0.26 ppm) and dry bulb onions (<0.05 ppm)

Vegetable, leafy, except brassica, group 4   	3.5	2.0	Based on maximum
independent plot residues in leaf lettuce (0.99 ppm) and head lettuce
(0.60 ppm)

Vegetable, brassica, group 5	0.1	None	Based upon Cabbage HAFT of 0.063
ppm)

Vegetable, brassica, head and stem subgroup 5A	None	0.1	Based upon
Cabbage HAFT of 0.063 ppm)

Vegetable, brassica, leafy, group 5B	None	2	Based upon maximum residues
in leaf lettuce, which better represents residues on leafy Brassica than
does cabbage.

Vegetable, legume, group 6	3	None	Separate tolerances should be
established for soybeans and the various legume subgroups based on the
maximum residues in succulent beans (0.47 ppm) and succulent peas (0.94
ppm), and those in dried beans (0.12 ppm), and on soybeans (0.07 ppm). 
Soybean seed tolerance (4 trials) is based upon tolerance spreadsheet.

Vegetable, legume, edible podded, subgroup 6A and

Pea and bean, succulent shelled, subgroup 6B

	None

	2.0

	Pea and bean, dried shelled, subgroup 6C	None	0.2

	Soybean seed	None	0.2

	Soybean, hulls 	None	0.5	Maximum expected residues are 0.27 ppm in
hulls based on HAFT residues of 0.07 ppm in soybeans and a 3.9x
processing factor. 

Vegetable, foliage of legume, group 7	None	4	Based on maximum residues
in alfalfa forage

Vegetable, fruiting, group 8	0.05	0.05	Based on maximum residues in
tomatoes (<0.05 ppm).

Okra	None	0.05

	Tomato, paste 

	None	0.1	Maximum expected residues are 0.069 ppm in paste based on HAFT
residues of 0.021 ppm in tomatoes and a 3.3x processing factor for
paste.

Tomato, puree	None	0.1	Maximum expected residues are 0.044 ppm in paste
based on HAFT residues of 0.021 ppm in tomatoes and a 2.1x processing
factor for puree.

Vegetable, cucurbit, group 9	1.1	1.5	Based on maximum residues in
cucumbers (0.74 ppm).

Fruit, citrus, group 10	0.05	0.05	Based on maximum residues in oranges
(<0.05 ppm).

Citrus, dried pulp	None	0.1	Maximum expected residues are 0.057 ppm in
dried pulp based on HAFT residues of 0.026 ppm in oranges and a 2.2x
processing factor. 

Fruit, pome, group 11	0.05	0.05	Based on maximum residues in apples
(<0.05 ppm).

Apple, wet pomace	None	0.15	Maximum expected residues are 0.109 ppm in
wet pomace based on HAFT residues of 0.039 ppm in apples and a 2.8x
processing factor. 

Fruit, stone, group 12	0.25	0.3	Based on maximum residues in peaches
(0.15 ppm).

Canebery subgroup 13-07A

and bushberry subgroup 13-07B 	0.6	0.6	Based on maximum residues in
blueberries (0.18 ppm) and blackberries (0.33 ppm).

Grape	0.9	1.0	Based upon maximum residues on grapes ( 0.64 ppm).

Grape, raisin	None	5.0	Maximum expected residues are 2.8 ppm in raisins
based on HAFT residues of 0.64 ppm in grapes and a 4.4x processing
factor. 

Nut, tree, group 14	0.05	0.05	Based on maximum residues in almond and
pecan nutmeats (<0.05 ppm).

Pistachio	None	0.05

	Almond, hulls	10	15	Based on maximum residues in hulls (8.2 ppm).

Grain, cereal, group 15, except corn	1.9	4	The available data support a
crop group tolerance, except for corn

Corn, sweet, kernel plus cob with husks removed	None	0.3	Tolerance based
on maximum residues in sweet corn K+CWHR (0.17 ppm)

Corn, field, grain	None	0.07	Tolerance based on tolerance spreadsheet
for corn grain

Corn, pop, grain	None	0.07

	Cereal, forage, fodder and straw, group 16, hay 	5.0	None	Combined into
Forage, Hay and Straw

Cereal, forage, fodder and straw, group 16, straw	6.0	None	Combined into
Forage, Hay and Straw

Cereal, forage, fodder and straw, group 16, forage	3.5	None	Combined
into Forage, Hay and Straw

Cereal, forage, fodder and straw, Group 16, except stover

 	3.5	6	Based on maximum residues on various forages (2.7) and wheat hay
and straw.  Note that field corn, sorghum and wheat forages received
only 2-3 applications prior to harvest (0.3-0.5x rate).

Cereal, forage, fodder and hay, group 16, stover	11	10	Based on adequate
data from field corn and sorghum stover (max 5.0 ppm).

Grain, aspirated fractions	24	35	Maximum expected residues in AGF are 29
ppm based on HAFT residues of 1.9 ppm for wheat grain and a
concentration factor of 15x for AGF.

Grass, forage, fodder, and hay, group 17, forage	3	3.5	Based upon
tolerance spreadsheet (6 trials)

Grass, forage, fodder, and hay, group 17, hay	19	18	Based upon tolerance
spreadsheet (6 trials)

Animal feed, Nongrass, group 18, forage	3.5	4.0	Based on maximum
residues in alfalfa forage (2.1 ppm) and hay (4.9 ppm)

Animal feed, Nongrass, group 18, hay	8	10

	Peppermint, tops	7	5	Based on maximum residues in mint tops (2.8 ppm).

Spearmint, tops	7	5

	Herb and spice, group 19	None	5

	Rice, grain	1.7	None	Separate tolerances are not required for rice
grain and straw as these commodities are covered by the tolerances on
cereal grains and cereal grain straw.

Rice, straw	4.5	None

	Rice, hulls	None	8	Based on HAFT residues of 1.0 ppm for rice grain and
a processing factor of 3.9x for hulls, the maximum expected residues in
rice hulls is 4.0 ppm.

Wheat, milled byproducts	None	5	Based on HAFT residues of 1.9 ppm for
wheat grain and processing factors of 2.6x for germ, and 2.3x for bran,
and 1.4x for shorts, the maximum expected residues in milled byproducts
is 5.0 ppm.

Food commodities	None	5	Inadvertent residues on any food crop/commodity
not included within the assigned crop groups and miscellaneous
tolerances.  Based upon Mint.

Feed commodities	None	10	Inadvertent residues on any feed crop/commodity
not included within the assigned crop groups and miscellaneous
tolerances.  Based upon Cereal Grains.

Cattle, muscle	None	0.03	Based upon calculations for Dairy Cattle using
metabolism data.

Cattle, kidney	None	0.20	Based upon calculations for Dairy Cattle using
metabolism data.

Cattle, liver	None	0.10	Based upon calculations for Dairy Cattle using
metabolism data.

Cattle, fat	None	0.01	Based upon calculations for Dairy Cattle using
metabolism data.

Milk	None	0.03	Based upon calculations for Dairy Cattle using metabolism
data.

Sheep, muscle	None	0.015	Based upon calculations for Beef Cattle using
metabolism data.

Sheep, kidney	None	0.15	Based upon calculations for Beef Cattle using
metabolism data.

Sheep, liver	None	0.05	Based upon calculations for Beef Cattle using
metabolism data.

Sheep, fat	None	0.005	Based upon calculations for Beef Cattle using
metabolism data.

Goat, muscle	None	0.015	Based upon calculations for Beef Cattle using
metabolism data.

Goat, kidney	None	0.15	Based upon calculations for Beef Cattle using
metabolism data.

Goat, liver	None	0.05	Based upon calculations for Beef Cattle using
metabolism data.

Goat, fat	None	0.005	Based upon calculations for Beef Cattle using
metabolism data.

Hog, muscle	None	0.01	Based upon calculations using metabolism data.

Hog, kidney	None	0.10	Based upon calculations using metabolism data.

Hog, liver	None	0.05	Based upon calculations using metabolism data.

Hog, fat	None	0.005	Based upon calculations using metabolism data.

Poultry, muscle	None	0.015	Based upon calculations using metabolism
data.

Poultry, liver	None	0.05	Based upon calculations using metabolism data.

Poultry, fat	None	0.015	Based upon calculations using metabolism data.

Poultry, meat byproducts	None	0.20	Based upon calculations using
metabolism data.

Egg	None	0.05	Based upon calculations using metabolism data.

International Residue Limit Status

There are no International Residue Limits for endothall, however there
is one registered product (#13894) in Canada which is used to kill
potato vines prior to harvest.6.0	Exposure Characterization/Assessment
Section Update  

6.1	Dietary exposure/pathway

Residues in plant derived foods were based upon average residues found
in the submitted field trials.  Similarly, residues in meat, milk,
poultry and eggs (MMPE) were derived from an average dietary burden,
corrected for percent of the harvest commodity that was irrigated where
this value has been determined.  The average residues in the plant crops
are shown in Table 5.6.1.  Processing factors, as shown in Table 5.7.1
were applied as possible.  Average residue values were translated within
crop groups and were also extrapolated to all other orphan crops as
appropriate.  Some processing factors were similarly translated where
appropriate.  Where empirical processing factors were not available, or
could not be translated, DEEM default factors were used.  Where no
formal default factors have been determined the processing factor was
left at 1 to assure consistency with other current assessments. 
Residues in MMPE were estimated from average residues in feed crops,
adjusted by the percent of the harvested crop that was irrigated.  Water
for the animals was taken to be incurred at 0.2 ppm, previously the
potable water tolerance and supported by BEAD for a maximum likely
chronic exposure (N. Thurman, 9/09/09 D356316).  The average residues in
MMPE are shown in Table 6.1.

Table 6.1.  Calculation of Estimated Residues in Livestock Tissues Based
upon the TRR in the Metabolism Studies and Considering Water Residues at
0.2 ppm.

Residues of Endothall in Beef Cattle Tissues Based upon the Goat
Metabolism Study

Tissue	

Total Radioactive Residues (ppm) after Feeding at 12.0 ppm	

Anticipated Residues (ppm) after Feeding at 3.6 ppm  (all assume the
higher dairy cattle diet)

Milk.	

0.006	0.002

Kidney	

0.046	0.014

Liver	

0.020	0.006

Muscle 	

0.005	0.0015

Fat	

0.002	0.0006

Residues of Endothall in Dairy Cattle Tissues Based upon the Goat
Metabolism Study

Tissue	

Total Radioactive Residues (ppm) after Feeding at 12.0 ppm	

Anticipated Residues (ppm) after Feeding at 5.9 ppm  (all assume the
higher dairy cattle diet)

Milk.	

0.006	0.003

Kidney	

0.046	0.023

Liver	

0.020	0.010

Muscle 	

0.005	0.0025

Fat	

0.002	0.001

Residues of Endothall in Swine Tissues Based upon the Goat Metabolism
Study

Tissue

	

Total Radioactive Residues (ppm) after Feeding at 12.0 ppm	

Anticipated Residues (ppm) after Feeding at 1.7 ppm

Kidney

	

0.046	0.0065

Liver	

0.020	0.0028

Muscle 

	

0.005	0.0007

Fat	

0.002	0.0003

Residues of Endothall in Poultry Tissues Based upon the Chicken
Metabolism Study

Tissue	

Total Radioactive Residues (ppm) after feeding at 9.7 ppm	

Anticipated Residues (ppm) after feeding at 1.5 ppm

Eggs	

0.024	0.0037

    Yolk	

0.024	0.0037

    White	

0.002	0.0003

Kidney and Other Meat Byproducts	

0.088	0.014

Liver	

0.021	0.003

Muscle 	

0.008	0.001

Fat	

0.007	0.001

Acute and Cancer Dietary Exposure and Risk Update

There were no acute or cancer dietary exposure endpoints so no acute or
cancer risk assessments were performed.  

Chronic Dietary Exposure and Risk Update

Chronic Aggregate Risk Assessment (Food & Drinking Water)

DEEM-FCID™ modeling.  These assessments concluded that for all
supported registered commodities and new uses, the food plus water
dietary risk estimates for acute and chronic exposure are both below the
Agency’s level of concern (<100 %  of the aPAD & cPAD).   The General
US Population was exposed at a maximum of 32% of the cPAD.  The most
highly exposed population subgroup was children 1-2 at a maximum of 84%
of the cPAD.

Table 6.1.1  Summary of Chronic Dietary (Food Only,  Food and Drinking
Water, or Drinking Water Only) Exposure and Risk for Endothall

Population Subgroup	Chronic Dietary

	Food Only	Water Only	Food Plus Water

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

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

(mg/kg/day)	% cPAD*

General U.S. Population	0.001614	23	0.000653	9	0.002268	32

All Infants (< 1 year old)	0.002320	33	0.002142	31	0.004462	64

Children 1-2 years old	0.004912	70	0.000970	14	0.005882	84

Children 3-5 years old	0.003609	52	0.000908	13	0.004517	65

Children 6-12 years old	0.001997	29	0.000627	9	0.002624	38

Youth 13-19 years old	0.001144	16	0.000472	7	0.001616	23

Adults 20-49 years old	0.001308	19	0.000610	9	0.001918	27

Adults 50+ years old	0.001367	20	0.000642	9	0.002009	28

Females 13-49 years old	0.001276	18	0.000608	9	0.001884	27

7.0	Water Exposure Risk/Pathway

A drinking water exposure assessment was conducted by the Environmental
Fate and Effects Division (EFED) to support the human health risk
assessment for the proposed use of endothall-treated irrigation water on
a variety of crops  (N. Thurman, 9/09/09, D356316).  

The maximum potential exposure of endothall in drinking water sources is
expected to result from the direct application of endothall to drinking
water reservoirs to control aquatic weeds.  EFED assumed that the entire
reservoir would be treated at the maximum rates, with no more than 10%
of the reservoir treated at one time as stated on the label, so that 10
treatments were applied 7 days apart to get the entire reservoir.  Since
the label specified that the community water system (CWS) could not
supply treated drinking water unless the residues were below 0.1 ppm
(100 µg/L), EFED assumed 100 µg/L (0.1 ppm) as the acute (peak)
exposure and the constant exposure during the treatment period and then
modeled residue decline by degradation after the final treatment.  This
resulted in a chronic (annual average) concentration of 31 µg/L (0.031
ppm) for endothall.  This represents the likely high-end chronic
exposure from endothall from the use most likely to generate the highest
exposures (treatment of a reservoir).  

8.0	Residential Exposure Risk Characterization  

8.1	Residential and Other Non-Occupational Exposures and Risks tc \l2
"6.3	Residential and Other Non-Occupational Exposures and Risks 

It has been determined that there is a potential for exposure in
residential settings during the application process for homeowners who
use endothall products to control aquatic weeds and algae in ponds and
garden pools.  There is also a potential for exposure to adults and
children from contacting water treated with endothall through swimming,
wading, water skiing, etc. As a result, risk assessments have been
completed for both residential handler and postapplication scenarios.

8.1.1	Residential Handler Exposures and Risks tc \l3 "6.3.1	Residential
Handler Exposures and Risks 

Residential handlers are addressed somewhat differently by the Agency as
homeowners are assumed to complete all elements of an application with
no use of protective equipment.

8.1.1.1	  Handler Exposure Scenarios tc \l4 "6.3.1.1	  Handler Exposure
Scenarios 

The purpose of this section is to describe how the exposure scenarios
were defined.  Much of the process for residential uses is identical to
that considered for the occupational assessment with a few notable
exceptions that include:

Residential handler exposure scenarios are only considered to be
short-term in nature due to the episodic uses associated with homeowner
products.

Homeowner handlers are expected to complete all tasks associated with
the use of a pesticide product including loading as well as the
application.

Label use rates and use information specific to residential products
serve as the basis for the risk calculations as opposed to the rates
used in the occupational assessment. 

Area treated per day in the risk assessment is based on Agency guidance
specific to residential use patterns.

It has been determined that exposure to pesticide handlers is likely
during the residential use of endothall granular products in ponds and
garden pools. The anticipated use patterns and current labeling indicate
two likely residential exposure scenarios – loading/applying granules
with a bellygrinder and applying granules by hand.  The quantitative
exposure/risk assessment developed for residential handlers is based on
these two scenarios.

(1) Granular formulation: loading/applying with bellygrinder; and

(2) Granular formulation: applying by hand.

8.1.1.2	  Data and Assumptions for Handler Exposure Scenarios tc \l4
"6.3.1.2	  Data and Assumptions For Handler Exposure Scenarios 

A series of assumptions and exposure factors served as the basis for
completing the residential handler risk assessments.  Each assumption
and factor is detailed below. In addition to these factors, unit
exposure values were used to calculate risk estimates. These unit
exposure values were taken from the Pesticide Handlers Exposure Database
(PHED).  Several of the assumptions and factors used for the assessment
are similar to those used in the occupational assessment (Section
11.1.1).  Only factors that are unique to the residential scenarios are
presented below.  

Assumptions and Factors:  The assumptions and factors used in the risk
calculations include:

The Agency always considers the maximum application rates allowed by
labels in its risk assessments to consider what is legally possible
based on the label. 

Residential risk assessments were not based on what could be applied in
a typical workday as with the occupational risk assessments presented
above.  Instead, the Agency based calculations on what would reasonably
be treated by homeowners, such as the size of a pond, or the size of a
garden pool.  This information was used by the Agency to define chemical
throughput values for handlers which in turn were coupled with unit
exposure values to calculate risks.  The daily area treated, based on
HED’s professional judgement, used in each residential scenario,
include: 

	- typical pond application: rangefinder calculation using 1 acre of
surface area and 5-feet depth and 10,000 square feet surface area and
2-feet depth.

	- typical garden pool application: 1,000 square feet of surface area
and 2 feet depth.

Residential Handler Exposure Studies:  The unit exposure values that
were used in this assessment were obtained from the Pesticide Handler
Exposure Database (PHED, Version 1.1 August 1998).

8.1.1.3	  Residential Handler Exposure and Risk Estimates tc \l4
"6.3.1.3	  Residential Handler Exposure and Risk Estimates 

The residential handler exposure and risk calculations are presented in
this section.  Risks were calculated using the Margin of Exposure (MOE)
approach, with an LOC for MOEs of <100 for short-term risk assessments. 
Residential exposures are expected to be short-term only.

Risk Summary: tc \l4 " Risk Summary:  The short-term risk calculations
for residential endothall handlers are summarized below.

Table 8.1.1.3  Endothall Short-Term  Risks to Residential Handler 

Exposure Scenario	

Crop or Target	

Application Rate

(lb ai/cubic feet)	

Surface Area Treated Daily

(square feet)	

Depth of Water 

(feet)	

Short-Term Inhalation MOE

(no respirator)

Mixer/Loader/Applicator

Loading/ Applying Granulars via Belly Grinder	

Ponds/ Lakes	

0.00022	

43,560	

2	

470

	

Ponds/ Lakes	

0.00022	

10,000	

2	

1900

Applying Granulars via Hand

	

Garden pool	

0.00022	

1,000	

2	

2700

In residential settings, the Agency does not use personal protective
equipment (PPE) to limit exposures, because PPE are viewed as
impractical and not enforceable. 

For residential handlers, short-term inhalation MOEs are not of concern
for any of the scenarios and do not exceed the Agency’s target MOE ((
100).

8.1.1.4	  Recommendations for Refining Residential Handler Risk
Assessment tc \l4 "6.3.1.5	  Recommendations For Refining Residential
Handler Risk Assessment 

In order to refine this residential risk assessment, more data on actual
use patterns including rates, timing, and areas treated would better
characterize endothall risks. 

8.1.2	Residential Postapplication Exposures and Risks tc \l3 "6.3.2
Residential Postapplication Exposures and Risks 

8.1.2.1	Residential Postapplication Exposure Scenarios tc \l4 "6.3.2.1
Residential Postapplication Exposure Scenarios 

Postapplication exposures to adults and children are expected following
applications of endothall to ponds and lakes. Of the possible
postapplication exposures, swimming in treated water is considered by
HED to be worse-case and is used as a surrogate for all other possible
postapplication exposures, such as wading, water skiing, etc. 

The Agency considered residential postapplication exposure for different
segments of the population.  Risks were calculated for swimming in
treated lakes or ponds.

8.1.2.2	Residential Postapplication Exposure and Risk Estimates tc \l4
"6.3.2.2	Residential Postapplication Exposure and Risk Estimates 

The residential postapplication exposure and risk calculations are
presented in this section. Risks were calculated using the Margin of
Exposure (MOE) approach.

The Agency has addressed residential postapplication exposures to
endothall using the SWIM model. The swimmer exposure to endothall
followed the guidance provided in the Agency’s draft SOP.  The
standard exposure factors provided in the residential SOP were used to
assess noncompetitive swimmer exposure.  The exposure to competitive
swimming was not assessed since endothall is not used in swimming pools.
Details on the Swimmer Exposure Assessment Model (SWIMODEL) used in this
assessment may be found at http://www.epa.gov/oppad001/swimodel.htm

  

The following inputs/assumptions have been used to assess
postapplication exposure to swimmers.

Body Weights					22kg for children and 70kg for adults	

Body surface area				9000 cm2 and 21000 cm2 for adults

Exposure Time 				3hrs/day

Water Intake					5 liter or 5000 ml in and out of the mouth per hour

Water ingested 				0.05 L or 50 ml per hour

Application rate				1 to 5 ppm or 1 to 5 mg/L or 1 to 5 mg/1000 cm3

Permeability coefficient Kp			8.82 x10-7 cm/hr

Octanol/water partition coefficient Kow	0.0008

Vapor pressure				3.92x10-5 mg/day

Risk Summary: tc \l4 " Risk Summary:   Table 8.1.2.2 provides the
individual exposure/risk through various routes based on the standard
factors and physical constants.  



Table 8.1.2.2. Summary of Endothall Swimmer Postapplication Risk

Exposure	

Children (6 to 10)	

Adult

	

Daily Dose mg/kg/day	

MOE	

Daily Dose mg/kg/day	

MOE

Oral	

0.0341	

280	

0.0107	

900

Dermal	

NA	

NA	

NA	

NA

Buccal	

Insignificant*	

NA	

Insignificant	

NA

Orbital/Nasal	

Insignificant	

NA	

Insignificant	

NA

Total	

	

280	

	

900

* Dosage is insignificant according to the SOP because endothall is
lipophobic (KOW = 0.0008)

For significant absorption through buccal/sublingual, orbital and nasal
exposure, the chemical must be lipophilic with a high KOW.  Since
endothall has a low Kow Value, no significant risk is expected.  Also
due to low vapor pressure, inhalation exposure is expected to be
negligible.  Finally, the expected exposure to swimmers from the dermal
route would be extremely low (the highest application rate results in a
water concentration of 5 ppm) and would not likely result in any
irritation to the skin.  The incident data contain no reports of eye or
skin irritation related to swimming in endothall-treated waters.    

Risk Summary:  

The Agency considered one residential postapplication exposure scenario
– swimming – for different segments of the population including
children, and adults.  In residential settings, the Agency does not use
restricted entry intervals (REIs) or other mitigation approaches to
limit exposures, because they are viewed as impractical and not
enforceable.  As such, risk estimates on the day of application are the
key concern.  However, several of the Special Local Needs labels do have
swimming restrictions following commercial applications of endothall.

8.1.3	Residential Risk Characterization tc \l3 "6.3.3	Residential Risk
Characterization 

8.1.3.1	Characterization of Residential Handler Risks tc \l4 "6.3.3.1
Characterization of Residential Handler Risks 

The data that were used in the endothall residential handler assessment
represent the best data

and approaches that are currently available.  For each use pattern, the
Pesticide Handlers

Exposure Database (PHED) was used to develop the unit exposure values.
All data that have

been used may not be of optimal quality, but are the best available and
are believed to be

sufficient for screening-level assessments of residential exposure.  		

The inputs for application rate and other use/usage information (e.g.,
area treated) used by the Agency were supported by the available
endothall labels.  The Agency believes that the estimates presented in
this residential assessment are supportable and protective given the
assumptions used, and the exposure, use, and toxicology data that are
available. 

8.1.3.2 Characterization of Residential Postapplication Risks

The Agency believes that the residential postapplication risk estimates
presented in this assessment are supportable and protective.  The Agency
further believes that the risks represent reasonable worse-case
estimates of exposure because maximum application rates are used to
define residue levels upon which the calculations are based.

9.0 	Aggregate Risk Assessment and Risk Characterization Updates

9.1	Acute Aggregate Risk tc \l2 "7.1	Acute Aggregate Risk 

Due to the lack of an acute RfD and acute dietary risk, an acute
aggregate risk assessment was not performed.

9.2	Short-Term Aggregate Risk tc \l2 "7.2	Short-Term Aggregate Risk 

A risk assessment for aggregate exposures (food + drinking water +
residential)                                                            
                                                                        
                                                                        
                                                                        
                                                                        
                    was conducted for the short term exposure scenario
because residential uses of endothall are expected to be only episodic. 
Food exposures are based on treated crops and irrigated crops.  Drinking
water exposures are based on aquatic uses of endothall. Although
endothall has terrestrial uses as well as aquatic uses, the aquatic uses
result in the highest estimates of potential drinking water exposures.
Residential handler exposures for adults are based on granular
applications of endothall with a belly grinder to lakes or ponds. 
Residential post-application exposures for adults and children are based
on swimming.  

For adults, estimated dietary exposures via food and drinking water were
combined with inhalation exposures during application to a pond or lake
and potential post-application exposures during swimming.  For children,
estimated dietary exposures via food and drinking water were combined
with potential post-application exposures during swimming. The short
term aggregate risk estimate (MOE) for adults is 290, for children, it
is 240.  The LOC for short-term exposures is for MOEs < 100.  Therefore,
there are no short term aggregate (food + drinking water + residential)
risk concerns for endothall.  Table 9.2 summarizes the results of the
short-term aggregate risk assessment.



Table 9.2 Short-Term Aggregate Risk 

Population	

	Short Term Scenario

	

Target

Aggregate

MOE1	

MOE

food + water2	

Residential	

Aggregate

MOE

(food + water and residential)6

	

MOE

oral3	

MOE

dermal4	

MOE

inhalation5

	

Child

 (1-2 years old)	

100	

1600	

280	

N.A.	

N.A.	

240

General US Population	

100	

4145	

900	

N.A.	

470	

290

1 Target MOE of 100 based on using uncertainty factors (UF)  of 10X for
interspecies extrapolation and 10X for intraspecies variability.

2 MOE food +water, which incorporated the dietary exposures for treated
crops, irrigated crops and aquatic uses, =  [( short-term oral
NOAEL)/(chronic dietary exposure)]. Short-term NOAEL = 9.4 mg/kg/day
from the 2-generation reproduction rat study, MRID 43152101; chronic
dietary (food+ water) exposure = 0.005882 (Children 1-2 years old), and
0.002268 (General US Population).  Note that the use of dietary
exposures (food and water) for the General US Population and Children
1-2 in an aggregate assessment is conservative when considering the
populations anticipated to be exposed from the proposed aquatic use
pattern.

3 MOE oral = [(short-term oral NOAEL)/(Oral postapplication exposure of 
Swimmers)]  Short-term NOAEL = 9.4 mg/kg/day from the 2-generation
reproduction  rat study,  MRID 43152101; Oral daily postapplication
exposure of swimmers = 0.0341 mg/kg/day , Children 6-10 years old;
0.0107 mg/kg/day, Adults  (see Table 8.1.2.2).

4 Not Applicable (N.A.)

5 MOE inhalation = [(inhalation NOAEL)/(high-end inhalation residential
handler exposure)]   Short-term inhalation NOAEL = 9.4 mg/kg/day from
the 2-generation reproduction  rat study,  MRID 43152101.

6 Aggregate MOE (food + water and residential) = 1([[(1(MOE food+ water)
+ (1(MOE oral) + (1(MOE dermal) + (1(MOE inhalation)]]

9.3	Intermediate-Term Aggregate Risk tc \l2 "7.3	Intermediate-Term
Aggregate Risk 

Due to the episodic residential use of endothall, no intermediate-term
aggregate (dietary + residential) risk assessment was performed.

9.4	Long-Term Aggregate Risk tc \l2 "7.4	Long-Term Aggregate Risk 

There are no long-term residential uses of endothall.  Aggregated
chronic exposures to endothall through food plus drinking water were
calculated in DEEMTM.  The results for directly treated crops, irrigated
crops and drinking water from aquatic uses of endothall were 32% of the
cPAD (0.002268 mg/Kg/day) for the general population.  The most highly
exposed population subgroup was CHILDREN 1-2 at 84% cPAD (0.005882
mg/Kg/day). 

9.5	Cancer Risk tc \l2 "7.5	Cancer Risk 

Endothall is considered not likely to be carcinogenic to humans.



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

11.0	Occupational Exposure/Pathway Updates

It has been determined that there is a potential for exposure to
endothall in occupational scenarios from handling endothall products
during the application process (i.e., mixer/loaders, applicators, and
mixer/loader/applicators) and a potential for postapplication worker
exposure from entering into areas previously treated with endothall.  As
a result, risk assessments have been completed for occupational handler
scenarios as well as occupational postapplication scenarios. 

11.1	Occupational Handler Exposures and Risks tc \l2 "9.1	Occupational
Handler Exposures and Risks 

Tasks associated with occupational pesticide use (i.e., for
“handlers”) can generally be categorized using one of the following
terms:

Mixers and/or Loaders:  these individuals perform tasks in preparation
for an application.  For example, prior to application, mixer/loaders
would mix the endothall and load it into the holding tank of the
groundboom sprayer. 

(	Applicators: these individuals operate application equipment during
the release of a pesticide product into the environment.  These
individuals can make applications using equipment such as groundboom.

(	Mixer/Loader/Applicators and or Loader/Applicators: these individuals
are involved in the entire pesticide application process (i.e., they do
all job functions related to a pesticide application event).  These
individuals would transfer endothall into the application equipment and
then also apply it.



HED always completes risk assessments using maximum application rates
for each scenario, because what is possible under the label must be
evaluated, for complete stewardship, in order to ensure there are no
concerns for each specific use.

  

A chemical can produce different effects based on how long a person is
exposed, how frequently exposures occur, and the level of exposure.  It
is likely that endothall exposures can occur in a variety of patterns. 
HED believes that occupational endothall exposures can occur over a
single day or up to weeks at a time for many use-patterns and
intermittent exposures over several weeks are also anticipated.  Some
applicators may apply endothall over a period of weeks, because they are
custom or commercial applicators who are completing a number of
applications for a number of different clients.  HED classifies
exposures up to 30 days as short-term and exposures greater than 30 days
up to several months as intermediate-term.  HED completes both short-
and intermediate-term assessments for occupational scenarios in
essentially all cases, because these kinds of exposures are likely and
acceptable use/usage data are not available to justify deleting
intermediate-term scenarios.  Long-term handler exposures are not
expected to occur for endothall.  Different toxicological endpoints of
concern (from an oral study) have been selected for short- and
intermediate-term inhalation exposures to endothall, therefore the risk
results for all inhalation durations of exposure are numerically
distinct.

Occupational handler exposure assessments are completed by HED using
different levels of personal protection.  HED typically evaluates all
exposures with a tiered approach.  The lowest tier is represented by the
baseline exposure scenario (i.e., long-sleeve shirt, long pants, shoes,
and socks) followed by increasing the levels of personal protective
equipment or PPE (e.g., gloves, double-layer body protection, and
respirators) and engineering controls (e.g., enclosed cabs and closed
mixing/loading systems).  This approach is always used by HED in order
to be able to define label language using a risk-based approach. In
addition, the minimal level of adequate protection for a chemical is
generally considered by HED to be the most practical option for risk
reduction (i.e., over-burdensome risk mitigation measures are not
considered a practical alternative).

11.1.1	Data and Assumptions for Handler Exposure Scenarios tc \l3 "9.1.1
Data and Assumptions For Handler Exposure Scenarios 

11.1.1.1 Assumptions for Handler Exposure Scenarios

Several tc \l4 "9.1.1.1	Assumptions for Handler Exposure Scenarios 
assumptions and exposure factors served as the basis for completing the
occupational handler risk assessments.  Each assumption and factor is
detailed below on an individual basis. The assumptions and factors used
in the risk calculations include:

Occupational handler exposure estimates were based on surrogate data
from: (1) the Pesticide Handlers Exposure Database (PHED) and (2) the
Outdoor Residential Exposure Task Force (ORETF).

The average body weight of an adult female handler (i.e., 60 kilograms)
is used for assessing inhalation dose, because the toxicity endpoint
values used for the inhalation assessments are from a reproductive study
and, therefore, are female-specific.

(	Generic protection factors (PFs) were used to calculate exposures when
data were not available.  For example, an 80 percent protection factor
was assumed for the use of a quarter-face dust/mist respirator.



(	Exposure factors used to calculate daily exposures to handlers are
based on applicable data, if available.  For lack of appropriate data,
values from a scenario deemed similar enough by the assessor might be
used.  For the endothall handler exposure assessment, the following
surrogate data was used for certain application methods, since the
nature of these application methods are believed to be similar enough to
bridge the data: 

for occupational large scale spray applications to water using
boat-mounted boom sprayers, PHED data for mixing/loading and applying
with ground boom were used; 

for occupational larger-scale spray applications to water using
boat-mounted spray tanks equipped with a handgun, ORETF data for
loading/applying with handgun equipment were used; 	

for occupational direct metering of liquid formulations to water, PHED
data for mixing/loading liquid formulations were used;

for occupational boat-mounted granular applications to water using
blower-type spreaders, PHED data for loading granulars were used; and

for residential granular applications to water, PHED data for
loading/applying granulars with bellygrinder equipment were used.

(	For occupational assessments, HED assumes the maximum application
rates allowed by labels in its risk assessments.

(	The average occupational workday is assumed to be 8 hours.  The daily
areas treated were defined for each handler scenario (in appropriate
units) by determining the amount that can be reasonably treated in a
single day (e.g. acres, square feet, cubic feet, or gallons per day).
When possible, the assumptions for daily areas treated are taken from
the Health Effects Division Science Advisory Committee on Exposure SOP
#9: Standard Values for Daily Acres Treated in Agriculture, which was
completed on July 5, 2000.  However, no standard values are available
for numerous scenarios.  Assumptions for these scenarios are based on
HED estimates and could be further refined from input from affected
sectors.

– 	Pond/Lake spray and granular applications: 30-acre surface area and
5-feet depth;

– 	Canal spray and granular applications: 10 miles in length, 5-feet
depth, and 20- or 5-feet width; and

– 	Flowing water applications: 5 hours, if water is flowing 50 cubic
feet per second and 2 hours, if water is flowing 200 cubic feet per
second.

11.1.1.2 Exposure Data for Handler Exposure Scenario

For endothall handler exposure assessments, all analyses were completed
using data that were deemed to be a source of acceptable surrogate
exposure data for the scenario.

HED uses a concept known as unit exposure as the basis for the scenarios
used to assess handler exposures to pesticides.  Unit exposures
numerically represent the exposures one would receive related to an
application.  They are generally presented as milligrams of active
ingredient exposure per pound of active ingredient handled.  HED has
developed a series of unit exposures that are unique for each scenario
typically considered in our assessments (i.e., there are different unit
exposures for different types of application equipment, job functions,
and levels of protection).  The unit exposure concept has been
established in the scientific literature and also through various
exposure monitoring guidelines published by the U.S. EPA and
international organizations such as Health Canada and OECD (Organization
For Economic Cooperation and Development). 

Pesticide Handler Exposure Database (PHED) Version 1.1 (August 1998):
PHED was designed by a task force of representatives from the U.S. EPA,
Health Canada, the California Department of Pesticide regulation, and
member companies of the American Crop Protection Association.  PHED is a
software system consisting of two parts -- a database of measured
exposure values for workers involved in the handling of pesticides under
actual field conditions and a set of computer algorithms used to subset
and statistically summarize the selected data.  Currently, the database
contains values for over 1,700 monitored individuals (i.e., replicates).

Users select criteria to subset the PHED database to reflect the
exposure scenario being evaluated.  The subsetting algorithms in PHED
are based on the central assumption that the magnitude of handler
exposures to pesticides are primarily a function of activity (e.g.,
mixing/loading, applying), formulation type (e.g., wettable powders,
granulars), application method (e.g., aerial, groundboom), and clothing
scenarios (e.g., gloves, double layer clothing).

Once the data for a given exposure scenario have been selected, the data
are normalized (i.e., divided by) by the amount of pesticide handled
resulting in standard unit exposures (milligrams of exposure per pound
of active ingredient handled).  Following normalization, the data are
statistically summarized.  The distribution of exposure values for each
body part (e.g., chest upper arm) is categorized as normal, lognormal,
or “other” (i.e., neither normal nor lognormal).  A central tendency
value is then selected from the distribution of the exposure values for
each body part.  These values are the arithmetic mean for normal
distributions, the geometric mean for lognormal distributions, and the
median for all “other” distributions.  Once selected, the central
tendency values for each body part are composited into a “best fit”
exposure value representing the entire body. 

The unit exposure values calculated by PHED generally range from the
geometric mean to the median of the selected data set.  To add
consistency and quality control to the values produced from this system,
the PHED Task Force has evaluated all data within the system and has
developed a set of grading criteria to characterize the quality of the
original study data.  The assessment of data quality is based on the
number of observations and the available quality control data. These
evaluation criteria and the caveats specific to each exposure scenario
are summarized in Appendix A , Table A7 of the Occupational and
Residential Exposure Assessment..  While data from PHED provide the best
available information on handler exposures, it should be noted that some
aspects of the included studies (e.g., duration, acres treated, pounds
of active ingredient handled) may not accurately represent labeled uses
in all cases.  HED has developed a series of tables of standard unit
exposure values for many occupational scenarios that can be utilized to
ensure consistency in exposure assessments.  Unit exposures are used
which represent different levels of personal protection as described
above.  Protection factors were used to calculate unit exposure values
for varying levels of personal protection if data were not available.

ORETF Handler Studies (MRID 449722-01):  A report was submitted by the
ORETF (Outdoor Residential Exposure Task Force) that presented data in
which the application of various products used on turf by homeowners and
lawncare operators (LCOs) was monitored.  All of the data submitted in
this report were completed in a series of studies.  The study that
monitored LCO exposure scenarios using a low pressure, high volume turf
handgun (ORETF Study OMA002) is summarized below.

LCO Handgun Sprayer:  A mixer/loader/applicator study was performed by
ORETF using Dacthal as a surrogate compound to determine “generic”
exposures to individuals applying a pesticide to turf with a
low-pressure “nozzle gun” or “handgun” sprayer.  Dermal and
inhalation exposures were estimated using whole-body passive dosimeters
and breathing-zone air samples on OVS tubes. Inhalation exposure was
calculated using an assumed respiratory rate of 17 liters per minute for
light work (NAFTA, 1999), the actual sampling time for each individual,
and the pump flow rate.  All results were normalized for pounds active
ingredient handled.  A total of 90 replicates were monitored using 17
different subjects.  Four different formulations of dacthal [75%
wettable powder (packaged in 4 and 24 pound bags), 75% wettable powder
in water soluble bags (3 pound bag), 75% water dispersible granules ( 2
pound bag) and 55% liquid flowable (2.5 gallon container)] were applied
by five different LCOs to actual residential lawns at each site in three
different locations (Ohio, Maryland, and Georgia) for a total of fifteen
replicates per formulation.  An additional ten replicates at each site
were monitored while they performed spray application only using the 75
percent wettable powder formulation.  A target application rate of 2
pounds active ingredient was used for all replicates (actual rate
achieved was about 2.2 pounds active ingredient per acre). Each
replicate treated a varying number of actual client lawns to attain a
representative target of 2.5 acres (1 hectare) of turf.  The exposure
periods averaged five hours twenty-one minutes, five hours thirty-nine
minutes, and six hours twenty-four minutes, in Ohio, Maryland and
Georgia, respectively.  Average time spent spraying at all sites was
about two hours.  All mixing, loading, application, adjusting,
calibrating, and spill clean up procedures were monitored, except for
typical end-of-day clean-up activities (e.g. rinsing of spray tank,
etc).  Dermal exposure was measured using inner and outer whole body
dosimeters, hand washes, face/neck washes, and personal air monitoring
devices.  All test subjects wore one-piece, 100 percent cotton inner
dosimeters beneath 100 percent cotton long-sleeved shirt and long pants,
rubber boots and nitrile gloves.  Gloves are typically worn by most
LCOs, and required by many pesticide labels for mixing and loading.

Overall, residues were highest on the upper and lower leg portions of
the dosimeters.  In general, concurrent lab spikes produced mean
recoveries in the range of 78-120 percent, with the exception of OVS
sorbent tube sections which produced mean recoveries as low as 65.8
percent.  Adjustment for recoveries from field fortifications were
performed on each dosimeter section or sample matrix for each study
participant, using the mean recovery for the closest field spike level
for each matrix and correcting the value to 100 percent.  The unit
exposure values are presented below. [Note the data were found to be
lognormally distributed.  As a result, all exposure values are geometric
means.]

Table 11.1.1 Unit Exposure Values Obtained From ORETF LCO Handgun
Studies (MRID 449722-01)

Application Method	

Inhalation Unit Exposure (µg/lb ai) 1

LCO Handgun Spray Mixer/Loader/Applicator Liquid Flowable3	

1.8

1Air concentration (mg/m3/lb ai) calculated using NAFTA ‘99 standard
breathing rate of 17 lpm (1 m3/hr).

2Exposure calculated using OPP/HED 50% protection factor (PF) for cotton
coveralls on torso, arms, legs.

3All commercial handlers wore long pants, long-sleeved shirt, nitrile
gloves and shoes.

11.1.2	Endothall Handler Exposure Scenarios tc \l3 "9.1.2	Endothall
Handler Exposure Scenarios 

It has been determined that exposure to pesticide handlers is likely
during the occupational application of endothall to water for aquatic
plant control.  The anticipated use patterns and current labeling
indicate several occupational exposure scenarios based on the types of
equipment and techniques that can potentially be used during endothall
applications. The quantitative exposure/risk assessment developed for
occupational handlers is based on the following scenarios. Endothall
inhalation exposure was estimated using PHED or ORETF data.]

Mixer/Loader/Applicators Applying to Water:	

(5) Liquid: Handgun Sprayer;

(6) Liquid: Direct Metering (using data for mixing/loading liquid
formulations);

(7) Granular: Blower-type Spreader (using data for loading granules).

11.1.3	 Endothall Handler Exposure and Assessment tc \l3 "9.1.3	
Endothall Handler Exposure and Assessment 

The occupational handler exposure and risk calculations are presented in
this section.

11.1.3.1 Endothall Handler Exposure and Risk Calculations tc \l4
"9.1.3.1	 Endothall Handler Exposure and Risk Calculations 

Risks were calculated using the Margin of Exposure (MOE)
[NOAEL/Exposure]. Daily dose values are calculated by first calculating
exposures by considering application parameters (i.e., rate and area
treated) along with unit exposure values.  Exposures were then
normalized by body weight and adjusted for absorption factors as
appropriate to calculate dose levels.  MOEs then were calculated.

Daily Dose:  Daily dose (inhalation) was calculated by normalizing the
daily inhalation exposure value by body weight and accounting for
inhalation absorption. For assessing an average body weight of 60
kilograms was used – representing the body weight of an average adult
female handler.  Since the inhalation toxicological endpoint of concern
is based on an oral study, an inhalation absorption rate is needed and
is assumed to be 100 percent.  Daily dose was calculated using the
following formula:

 EQ Average Daily Dose \b\lc\(\rc\)(mg /kg /day) = Daily Exposure
\b\lc\(\rc\)(\F(mg ai,day)) x \b\lc\(\rc\)(\F(Absorption Factor (%
/100),Body Weight (kg))) 

Where:

Average Daily Dose 	= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg pesticide active ingredient/kg body
weight/day);

Daily Exposure 	=	Amount  (mg ai/day) inhaled that is available for
inhalation absorption;

Absorption Factor 	= 	A measure of the amount of chemical that crosses a
biological boundary such as the skin or lungs (% of the total available
absorbed); and

Body Weight	= 	Body weight determined to represent the population of
interest in a risk assessment (kg).

Margins of Exposure:  Finally, the calculations of daily inhalation dose
received by handlers were then compared to the appropriate endpoint
(i.e., NOAEL or LOAEL) to assess the total risk to handlers for each
exposure route within the scenarios. All MOE values were calculated
inhalation exposure levels using the formula below:

 EQ MOE = \F( NOAEL \b\lc\(\rc\)(mg/kg/day),Average Daily Dose
\b\lc\(\rc\)(mg/kg/day)) 

Where:

MOE 	= 	Margin of exposure, value used by HED to represent risk or how
close a chemical exposure is to being a concern (unitless);

ADD 	= 	(Average Daily Dose) or the amount as absorbed dose received
from exposure to a pesticide in a given scenario (mg pesticide active
ingredient/kg body weight/day); and

NOAEL	= 	Dose level in a toxicity study, where no observed adverse
effects occurred (NOAEL or LOAEL) in the study

11.1.3.2	Endothall  Risk Summary tc \l4 "9.1.3.2	Endothall  Risk Summary
 (using PHED and ORETF)

Risk estimates for occupational endothall handlers are included in Table
11.1.3.2 below.



Table 11.1.3.2. Summery of  Endothall Short- and Intermediate-Term
Occupational Inhalation Handler Risks for Aquatic Uses

Exposure Scenario	

Crop or Target	

Application Rate	

Surface Area or Length of Water Body

(acres or miles)	

Depth of Water Body (feet)	

Width of Water Body

 (feet)	

Inhalation MOE

(Target Short-Term MOE = 100; Target Intermediate-Term MOE = 300)

Baseline Attire	

 PPE - 80% Respirator	

Engineering Controls

Short-term	

Intermediate-term	

Short-term	

Intermediate-term	

Short-term	

Intermediate-term

Mixer/loader

Mixing/loading liquid for groundboom application (subsurface use)	

Ponds/

Lakes	

13.5 lb ai/A-ft	

30 Acres	

5	

NA	

230	

50	

1150	

250

500 (half face respirator 90% protection)	

3150	

670

	

Ponds/

Lakes	

8 lb ai/A-ft	

30 Acres	

5	

NA	

400	

85	

2000	

425	

4700	

1000

Mixing/Loading Emulsifiable Concentrate with Direct Metering (PHED:
mixing/loading liquid  )	

Flowing Water	

0.56

lb ai / minute at 50 cfs	

300

minutes/day	

NA	

NA	

2800	

600	

14000	

3000	

40000	

8600

	

Flowing Water	

0.15

lb ai / minute at 200 cfs	

120

minutes/day	

NA	

NA	

26000	

5500	

130000	

27500	

380000	

80000

Applicator

Applying liquid with groundboom (subsurface use) 	

Ponds/

Lakes	

13.5 lb ai/A-ft	

30 Acres 	

5	

NA	

375	

80	

1900	

400	

NF	

NF

	

Ponds/

Lakes	

8 lb ai/A-ft	

30

Acres	

5	

NA	

625	

135	

3150	

675	

NF	

NF

Mixer/Loader/Applicator

Mixing/

Loading/

Applying Emulsifiable Concentrates with a Handgun Sprayer (LCO ORETF
data)	

Ponds/ Lakes	

13.5 lb ai/A-ft	

10 Acres/ day	

2	

NA	

1160	

245	

5900	

1250	

NF	

NF

	

Ponds/ Lakes	

8 lb ai/A-ft	

10 Acres/ day	

2	

NA	

1880	

400	

9800	

2100	

NF	

NF

	

Canals	

1.7 lb ai/canal--1 mile X 1 ft wide x 1 ft deep	

10 miles long	

2	

20	

470	

100	

2300	

500	

NF	

NF

	

Canals	

1.7 lb ai/canal--1 mile X 1 ft wide x 1 ft deep	

10 miles long	

2	

5	

1880	

400	

9400	

2000	

NF	

NF

	

Canals	

1lb ai/canal--1 mile X 1 ft wide x 1 ft deep	

10 miles long	

2	

20	

785	

165	

4000	

850	

NF	

NF

	

Canals	

1 lb ai/canal--1 mile X 1 ft wide x 1 ft deep	

10 miles long	

2	

5	

3135	

670	

16000	

3400	

NF	

NF

Loading/

Applying Granulars (PHED: open loading granulars) 	

Ponds/ Lakes	

9.8 lb ai/A-ft	

30 Acres/ day	

5	

NA	

230	

48	

1100	

240 

480 (half face respirator 90% protection)	

NF	

NF

	

Canals	

1.6 lb ai/canal--1 mile X 1 ft wide x 1 ft deep	

10 miles long	

5	

20	

208	

45	

1050	

220

450 (half face respirator 90% protection)	

NF	

NF

	

Canals	

1.6 lb ai/canal--1 mile X 1 ft wide x 1 ft deep	

10 miles long	

5	

5	

860	

180	

4100	

870	

NF	

NF

NA = not applicable

NF = not feasible

11.1.4 	Cancer Endothall Handler Exposure and Risk Assessment tc \l3
"9.1.4 	Cancer Endothall Handler Exposure and Risk Assessment 

No occupational handler cancer risk assessment is needed for endothall,
since no cancer endpoint of concern was identified.

11.1.5 	Summary of Risk Concerns and Data Gaps for Occupational Handlers
tc \l3 "9.1.5 	Summary of Risk Concerns and Data Gaps for Occupational
Handlers 

The occupational handler scenarios for endothall have no risks
associated with them and are above HED’s level of concern for
inhalation risk assessments (MOE > 100).  The assessment involving the
aquatic herbicide scenarios uses substitute inhalation unit exposure
values, since no data are available for assessing inhalation exposures
from the use of boat-mounted application equipment. These occupational
handler scenarios for endothall could be better refined with
equipment-specific exposure data. 

11.1.5.1	Summary of Data Gaps tc \l4 "9.1.5.1	Summary of Data Gaps 

Several data gaps were identified for endothall in many different
aquatic use areas that include:

mixing/loading/applying liquid formulations to aquatic areas using
handheld equipment;

loading/applying liquid formulations to aquatic areas using direct
metering; and

loading/applying granular formulations to aquatic areas using
centrifugal or blower-type equipment.

11.1.6	Recommendations for Refining Occupational Handler Risk Assessment
tc \l3 "9.1.6	Recommendations For Refining Occupational Handler Risk
Assessment 

In order to refine this occupational risk assessment, data on actual use
patterns including rates, timing, and areas treated would better
characterize endothall risks.  Exposure studies for many equipment types
that lack data or that are not well represented in PHED (e.g., because
of low replicate numbers or data quality) should also be considered
based on the data gaps identified above and based on a review of the
quality of the data used in this assessment.

11.2	Occupational Postapplication Exposures and Risks tc \l2 "9.2
Occupational Postapplication Exposures and Risks 

Aquatic Uses: 

The toxicity categories of the active ingredient for acute dermal, eye
irritation, and skin irritation potential are used to determine the
interim REI.  If one or more of the three acute toxicity effects are in
toxicity category I, the interim REI is established at 48 hours.  If
none of the acute toxicity effects are in category I, but one or more of
the three is classified as category II, the interim REI is established
at 24 hours.  The acute toxicity classification for primary eye
irritation of endothall is category I which requires a 48-hour REI.   

Postapplication occupational exposures following endothall application
to aquatic areas is likely limited to persons who contact the treated
water to perform tests, such as testing the levels of endothall, or
persons such as agricultural workers or irrigation water suppliers who
contact treated water in irrigation canals.  Worse-case postapplication
exposures to endothall following application in aquatic sites are likely
to be to persons who swim in the treated waters.  

12.0	DATA NEEDS AND LABEL RECOMMENDATIONS

Toxicology

The scientific quality and completeness of the available toxicology data
base are considered adequate according to the Subdivision F Guidelines
and Part 158 Data Requirements to support the registration and proposed
tolerances for endothall.   

The following studies are outstanding for endothall:

870.3700b	Developmental Toxicity/Teratology (rabbit)

28-Day Inhalation    [Note that a 28 day inhalation study has been
received just as this document is in the very last stages of being
finalized.  It is too late to review this submission for the current
action, but if review shows the study to be adequate, this submission
will be considered to have fulfilled this data gap.]

870.6200	Neurotoxicology Study

Immunotoxicity Study  

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

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

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies 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 this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

12.2	Residue Chemistry, Label Needs, Tolerance Reassessment tc \l2 "10.2
Residue Chemistry, Label Needs, Tolerance Reassessment 

Residue Chemistry Deficiencies

12.2.1.		Radiovalidation data to determine whether the current
enforcement methods for plants and the required enforcement methods for
animals and fish can adequately extract and convert aged residues of the
monomethyl ester to endothall.  

12.2.2.		Data collection and regulatory analytical methods for the
determination of endothall, per se, in animal commodities.

12.2.3.		Storage stability data for processed plant commodities, animal
commodities, and fish.

12.2.4.		Livestock (ruminant and poultry) feeding studies

12.2.5.		Magnitude of the residue studies in irrigated crops.

12.2.6.		Magnitude of the residue studies in potato, alfalfa seed,
cottonseed, and cotton gin byproducts.  Magnitude of the residue studies
in the RACs of sugar beet and rice if the registrant intends to support
these uses.

Submission of analytical reference standards for dipotassium and 
mono-N,N-dimethylalkyl amine salts of endothall

12.3	Residential and Occupational:  

	12.3.1	mixing/loading/applying liquid formulations to aquatic areas
using handheld equipment;

	

	12.3.2	loading/applying liquid formulations to aquatic areas using
direct metering; and

12.3.3	loading/applying granular formulations to aquatic areas using
centrifugal or blower-type equipment.

12.4  Label Needs	

Labeling on the Hydrothol (mono-N,N-dimethylalkyl amine salt of
endothall) formulations instructs the user how to apply the product at 5
ppm of the free acid endothall equivalents, while the Aquathol
(dipotassium salt of endothall) labels instruct the user how to apply
these formulations at 5 ppm as the dipotassium salt of endothall.  Thus,
while the application rates are nominally the same, 5 ppm, the molecular
weight difference between these two forms of endothall causes a
difference to exist between these two treatment rates.  This discrepancy
is confusing and HED recommends that the labels for the dipotassium salt
(Aquathol) should be modified to include a description of the
application rate when it is expressed as ppm in endothall, acid
equivalents.

Revised Section F

		12.5.1	     New tolerances should be proposed as recommended by EPA.

13.0  References:

MRID  47520704  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Vegetable, Brassica Leafy: Final Report. 
Project Number: Z9764, KP/2006/46, KP/242RO.  Unpublished study prepared
by Interregional Research Project No. 4, United Phosphorus, Inc. and
Agricultural Chemistry Development Services, Inc. (ACDS).  149 p.

MRID  47520717  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Mint.  Project Number: Z9758,
Z9758/07/CER13.  Unpublished study prepared by United Phosporus, Inc.,
Interregional Research Project No. 4 and University of Idaho,
Cooperative Extension.  253 p.

MRID  47520703  Arsenovic, M. (2008) Endothall (Hydrothol 191 and
Aquathol K): Magnitude of the Residue on Vegetable, Leafy, except
Brassica Group: Final Report.  Project Number: Z9757, KP/2007/1,
KP/2007/01.  Unpublished study prepared by Interregional Research
Project No. 4, United Phosphorus, Inc and Pacific Agricultural Research
Corp.  289 p.

MRID  47520710  Arsenovic, M. (2008) Endothall (Hydrothol 191 and
Aquathol K): Magnitude of the Residue on Fruit Stone Group: Final
Report.  Project Number: Z9769, Z9765/07/ALS04, 07CER13/REP. 
Unpublished study prepared by Interregional Research Project No. 4, ALS
Laboratory Group, Environmental and Ag Research Associates.  188 p.

MRID  47520711  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Berry Group: Final Report.  Project Number:
Z9770, Z9770/07/CER07, KP/2007/20.  Unpublished study prepared by
Interregional Research Project No. 4, United Phosphorus, Inc. and
Agsearch.  180 p.

MRID  47520712  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Nut Tree Group.  Project Number: Z9771,
Z9771/06/GA/22, Z9771/07/CA/40.  Unpublished study prepared by United
Phosporus, Inc., Ag Research Associates and Pacific Agricultural
Research Corp.  211 p.

MRID  13  Arsenovic, M. (2008) Endothall (Hydrothol 191): Magnitude of
the Residue on Grain Cereal Group (Except Rice).  Project Number: Z9768,
Z9768/07/CER03.  Unpublished study prepared byUnited Phosphorus, Inc.,
Interregional Research Project No. 4 and Reality Research.  590 p.

MRID  47520702  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Vegetable Bulb Group.  Project Number:
Z9763, KP/2007/29, KP242R1.  Unpublished study prepared by Interregional
Research Project No. 4, United Phosphorus, Inc. and Coastal Ag Research,
Inc.  185 p.

MRID  47520714   Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Grass, Forage, Fodder and Hay Group. 
Project Number: Z9760, Z9760/07/ALS03.  Unpublished study prepared by
United Phosphorus, Inc., Interregional Research Project No. 4 and Pest
Management Enterprises.  509 p.

MRID  47520715  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Animal Feed Nongrass Group.  Project Number:
Z9756, Z9756/07/CER06.  Unpublished study prepared by United Phosphorus,
Inc., Interregional Research Project No. 4 and Agro-Tech, Inc.  226 p.

MRID  47520719  Li, F. (2008) Stability of Endothall in Tomatoes,
Lettuce, Sugar Beet Root, Corn Grain, Soybean and Soybean Oil During
Frozen Storage Pending Analysis.  Project Number: KP/2007/11. 
Unpublished study prepared by JRF America and ALS Laboratory Group,
Environmental.  114 p.

MRID  47520705  Arsenovic, M. (2008) Endothall (Hydrothol 1910):
Magnitude of the Residue on Vegetable, Legume Group: Final Report. 
Project Number: Z9765, Z9765/07/ALS05, 07CER12/REP.  Unpublished study
prepared by Interregional Research Project No. 4, ALS Laboratory Group,
Environmental and Shoffner Farm Research.  440 p.

MRID  47520707  Arsenovic, M. (2008) Endothall (Hydrothol 191 and
Aquathol K): Magnitude of the Residue on Vegetable, Cucurbit Group:
Final Report.  Project Number: Z9755, Z9755/07/ALS01, 07CER10/REP. 
Unpublished study prepared by Interregional Research Project No. 4, ALS
Laboratory Group, Environmental and Agsearch.  215 p.

MRID  47520716  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Grapes.  Project Number: Z9754,
Z9754/07/ALS02.  Unpublished study prepared by United Phosphorus, Inc.,
ALS Laboratory Group, Environmental and ACDS Research, Inc.  272 p.

MRID  47520718  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Rice.  Project Number: Z9761,
Z9761/07/ALS06.  Unpublished study prepared by ALS Laboratory Group,
Environmental and Interregional Research Project No. 4 and GLP
Technologies.  323 p.

MRID  47520708  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Fruit Citrus Group: Final Report.  Project
Number: Z9759, Z9759/07/CER08, Z9756/06/EFP02.  Unpublished study
prepared by Interregional Research Project No. 4, United Phosphorus,
Inc. and Pacific Agricultural Research Corp.  230 p.

\

MRID  47520701  Arsenovie, M. (2008) Endothall (Hydrothol 191 and
Aquathol K): Magnitude of the Residue on Vegetable, Root and Tuber
Group: Final Report.  Project Number: Z9762/07/CER10, Z9762. 
Unpublished study prepared by Interregional Research Project No. 4,
United Phosphorus, Inc and Smith Biological Services.  389 p.

MRID  47520706  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Vegetable Fruiting Group: Final Report. 
Project Number: Z9766, Z9766/07/CER04, KP/2007/08.  Unpublished study
prepared by Interregional Research Project No. 4, United Phosphorus,
Inc. and Pacific Agricultural Research Corp.  180 p.

MRID  47520709  Arsenovic, M. (2008) Endothall (Hydrothol 191):
Magnitude of the Residue on Fruit, Pome Group: Final Report.  Project
Number: Z9767, Z9767/07/CER05, Z9767/06/ACD03.  Unpublished study
prepared by Interregional Research Project No. 4, United Phosphorus,
Inc. and Agricultural Chemistry Development Services, Inc. (ACDS).  255
p.\

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

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

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

A.1. Toxicology Data Requirements for Endothall

	

Test 

	

Technical

	

Required	

Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		

yes

yes

yes

yes

yes

yes	

yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)	

870.3150	Oral Subchronic (nonrodent)	

870.3200	21-Day Dermal	

870.3250	90-Day Dermal	

870.3465	90-Day Inhalation		

yes

yes

yes

yes

yes	

yes

yes

yes

yes

no

870.3700a	Developmental Toxicity (rodent)	

870.3700b	Developmental Toxicity (nonrodent)	

870.3800	Reproduction		

yes

yes

yes	

yes

no

yes

870.4100a	Chronic Toxicity (rodent)	

870.4100b	Chronic Toxicity (nonrodent)	

870.4200a	Oncogenicity (rat)	

870.4200b	Oncogenicity (mouse)	

870.4300	Chronic/Oncogenicity		

yes

yes

yes

yes

yes	

chronic/onco

yes

chronic/onco

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial	

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5xxx	Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx	Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)	

870.6100b	90-Day Neurotoxicity (hen)	

870.6200a	Acute Neurotox. Screening Battery (rat)	

870.6200b	90 Day Neurotox. Screening Battery (rat)	

870.6300	Developmental Neurotoxicity		

no

no

no

no

no	

-

-

-

-

-

870.7485	General Metabolism	

870.7600	Dermal Penetration		

yes

no	

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

A.2   Toxicity Profiles

A.2.a	Acute Toxicity

Table A.2.a  Acute Toxicity Profile – Endothall 

Guideline No./ Study Type	

MRID No.	

Results	

Toxicity Category

	

870.1100 Acute oral toxicity	

42289201	

LD50 = 50.2/44.4[m/f] mg/kg	

I

870.1200 Acute dermal toxicity	

42289202	

LD50 = >2000[m/f] mg/kg	

III

870.1300 Acute inhalation toxicity	

42169501	

LC50 = 1.27/2.20[m/f] mg/L	

III

870.2400 Acute eye irritation	

42289203	

Severe irritant; lethal 4/6 rabbits	

I

870.2500 Acute dermal irritation	

42289204	

Unacceptable study	

I a

870.2600 Skin sensitization	

41871901	

Sensitizer	

N/A

a Endothall has been shown to be a skin irritant in a preliminary range
finding study of the dermal absorption study (MRID 42169503) at doses of
50 ug/cm2 and higher and in the 21-day dermal toxicity study (MRID
43465201) after one application at doses of 30 mg/kg or higher. This
information is considered sufficient to classify endothall as a severe
dermal irritant.

A.2.b	Subchronic, Chronic and Other Toxicity Profiles

A.2.b	Subchronic, Chronic and Other Toxicity Profiles - Endothall

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity rodents (rat)	

43480810(1994)

Acceptable/guideline

0, 150, 600, 1800 ppm

M:0, 10, 39, 118 mg/kg/day

F: 0, 12, 51, 153 mg/kg/day	

NOAEL = 39 mg/kg/day

LOAEL = 118 mg/kg/day based on treatment related deficits in body
weight.

870.3150

13 week oral toxicity in nonrodents (dog)	

43480802 (1994)

Acceptable/guideline

0, 100, 400, 1000 ppm

M: 0, 3.2, 11.7, 27.5 mg/kg/day

F: 0, 3.2, 13.0, 28.9 mg/kg/day	

NOAEL = 11.7 mg/kg/day

LOAEL = 27.5 mg/kg/day based on decreases in body weight gain.

870.3200

21-Day dermal toxicity (rat)

range-finding	

42814101 (1992)

Acceptable/nonguide

-line

0, 80, 200, 500 mg/kg/day	

NOAEL = not determined

LOAEL = 80 mg/kg/day based systemic toxicity (death)

LOAEL = 80 mg/kg/day based on dermal irritation

870.3250

21-Day dermal toxicity (rat)	

43465201(1994)

Acceptable/guideline

0, 30, 100, 300 mg/kg/day	

NOAEL =  not determined

LOAEL = 30 mg/kg/day based on decreased body weight gains.

LOAEL = 30 mg/kg/day based on dermal irritation 

870.3700a

Prenatal developmental in rodents (rat)	

42776301 (1993)

Acceptable/guideline

0, 6.25, 12.5, 25.0 mg/kg/day	

Maternal NOAEL = 12.5 mg/kg/day

LOAEL = 25 mg/kg/day based on decreased body weight gain.

Developmental NOAEL => 25 mg/kg/day

LOAEL = not determined HDT.

870.3800

Reproduction and fertility effects	

43152101 (1993)

43629301 (1995)

Acceptable/guideline

0, 30, 150, 900 ppm

M: 0, 2, 10.2, 64 mg/kg/day

F:0, 1.8, 9.4, 60 mg/kg/day premating

0, 3.1, 17.3, 104.7 mg/kg/day lactation	

Parental/Systemic NOAEL = not established

LOAEL = 2 mg/kg/day based on proliferative lesions gastric epithelium
both sexes.

Reproductive NOAEL = 9.4 mg/kg/day

LOAEL = 60.0 mg/kg/day based on decreased pup body weights

Reproductive Offspring NOAEL = 9.4 mg/kg/day

LOAEL = 60.0 mg/kg/day based on decreased pup body weights.

870.4100b

Chronic toxicity dogs	

40745202 (1987)

supplementary/guideline

 0, 150, 450,350 ppm.  high dose lowered to 1000 ppm at the 7th 

M: 0, 5.7, 17 or 40 mg/kg/day

F: 0, 6.5, 18, 33 mg/kg/day  52 weeks. 	

NOAEL = not determined

LOAEL (LDT) = 6.5 mg/kg/day based on gastric epithelial hyperplasia.

870.4200b

Carcinogenicity mice	

40685301 (1988)

supplementary/guideline

0, 50, 100, 300 ppm

0, 7.5, 15, 45 mg/kg/day

21 months

	

NOAEL =15 mg/kg/day

LOAEL = 45 mg/kg/day based on decreased body weight gain and microscopic
findings in male kidney.

no evidence of carcinogenicity

870.4200b

Carcinogenicity mice	

43608301(1995)

acceptable/guideline

0, 750, 1500 ppm

M: 01, 124, 258 mg/kg/day

F: 0, 152, 319 mg/kg/day

79 weeks	

NOAEL = not determined

LOAEL = 124 mg/kg/day based on decreased body weight gain in males.

No evidence of carcinogenicity.

870.4300

chronic/onco rat	

41040301(1989)

acceptable 

0, 150, 300, 900, 1800ppm

M: 0, 6, 12, 37, 80 mg/kg/day 

F: 0, 8, 16, 49, 110 mg/kg/day	

NOAEL = 8 mg/kg/day

LOAEL = 16 mg/kg/day based on decreased body weight and body weight
gain.

No evidence of carcinogenicity.

Gene Mutation

Guideline #  OPPTS 870.5300 [§84-2]; OECD 476, study type

In vitro Mammalian Cell Gene Mutation Assay	

43437801 (1993)

classification Acceptable

 equivalent = 11.6%) Dosed in (DMSO) at concentrations of 0.0116,
0.0580, 0.116, 0.580, 1.16, 2.32, 2.9, 3.48, 4.06, and 4.64 µg/mL (all
concentrations expressed as active ingredient) without metabolic
activation or at 0.116, 0.58, 1.16, 5.8, 11.6, 17.4, 20.3, 21.8, 23.2
and 26.1 µg/mL with metabolic activation (Initial Trial).  For the
confirmatory trial, levels of 0.0116, 0.0580, 0.116, 0.580, 1.16, 2.32,
2.90, 3.48. 4.06. 4.64, 5.22 and 5.80 µg/mL -S9 or 0.116, 0.580, 1.16,
5.80, 11.6, 17.4, 23.2, 26.1 and 29 µg/mL +S9 were processed. 	

Negative

Gene Mutation

Guideline # Bacterial Gene Mutation Assay (Salmonella typhimurium)/OPPTS
870.5100/[§84-2] OECD 471

	

43154801 (1993).

Unacceptable

in dimethyl sulfoxide (DMSO)  (equivalent to 1.93, 5.80, 19.3, 58.0, 116
or 193 µg/plate active ingredient)  with or without S9 activation.

	

Negative

Cytogenetics 

In vivo Mammalian Cytogenetics - Micronucleus Assay in Mice/OPPTS
870.5395/[§84-2]	

43157401 (1994) Acceptable

mice were administered 0.464, 0.928 and 1.86 mg/kg Endothall Technical
amine salt (1.5:1 amine :salt ratio; Batch No. B46-44-1; endothall amine
30.3%;endothall acid equivalent = 11.6%) via intraperitoneal injection
(IP) in deionized water;	

Negative

Cytogenetics 

In vivo  Mammalian Cytogenetics - Micronucleus Assay in Mice/OPPTS
870.5395/[§84-2]

	

41700301 (1989)

Acceptable

mice were administered 2,10 or 50  mg/kg Endothall  	

Negative

Cytogenetics 

In vitro Mammalian Cytogenetics OPPTS 870.5375 [§84-2]; OECD 473	

41700302 (1989) Acceptable

in dimethyl sulfoxide (DMSO) at concentrations of 2.5, 10.0, 20.0 and
40.0 µg/mL without metabolic activation or were exposed for 3 hours to
15.0, 60.0, 120.0 or 240.0 µg/mL with metabolic activation	

Negative

870.7485

Metabolism and pharmacokinetics	

42169502 (1990),

acceptable

a single i.v. dose at 0.9 mg/kg, a single oral dose at 0.9, 4.5 or 9.0
mg/kg and as a 15 day multiple dose at 0.9 and 9.0 mg/kg/day.	

Intravenous administration of 0.9 mg/kg resulted in excretion mainly by
the urine (69%) and feces. At an oral 0.9 mg/kg dose, blood half-life
elimination - 1.8 hrs in males, 2.5 hrs females.  At 4.5 mg/kg half-life
- 13.9 hours in males; the half-life in females could not be calculated
because of a double blood peak. Multiple oral or single administration
indicated that the test material was rapidly absorbed and excreted in
the feces (89-98%) and urine (5-9%).  The compound did not
bioaccumulate.  At 24 hours tissue distribution of the compound was
extensive but low, the highest amount (<10%) being found in the
gastrointestinal tract.  By 48 hours, the compound was mostly
undetectable in the tissue.  Bile elimination was only of minor
importance. Absorbed or unabsorbed test compound in all groups was
excreted mainly as chemically unchanged Endothall in the feces and
urine.

870.7485

Metabolism and pharmacokinetics	

44263501 (1997)

acceptable

Administered to 10 Sprague Dawley rats (5/sex/dose) in distilled water
by gavage at a dose 9 mg/kg. Animals were sacrificed after 24 hours.	

Following a single oral administration of [14C}-Endothall to male and
female rats (approximately 9 mg/kg), the majority of the radioactivity
(70.8% males, 71.2% females) was excreted within the 0-24 hour time
period, with most of the radioactivity being present in the feces (47.6%
males, 47.5% females) At 24 hours after dosing, less than 0.21% of the
dose was found in the stomach (+ contents), small intestine (+ contents)
and pancreas and very little detected in the blood (below 15 ng eq/g).
Higher levels of radioactivity were found in the caecum (3.0% males, 6.
1 % females) and the large intestine (3.2% males, 8.2% females).

Analysis of extracts of the urine, feces, caecum and large intestine of
both male and female rats  gave a single radioactive component
corresponding to unchanged Endothall which accounted for >86, >96, >74
and >69% of total recovery from the respective extracts.

870.7600

Dermal penetration	

42169503 (1990)

acceptable

Dose levels were 0.0125 mg/cm2 (0.3 mg/rat), 0.0625 mg/cm2 (1.5 mg/rat)
and 0.125 mg/cm2 (3.0 mg/rat) respectively. Five (5) animals per time
period (0..5, 1, 2, 4, 10 or 24 hours) in each dose 	

Approximately 55 to 82% of the applied dermal dose was washed from the
application site.  The rest of the [14C]-Endothall equivalents was
contained in the application site skin. Urinary excretion of
[14C]-Endothall equivalents increased in a dose related manner at 10 and
24 hours to a maximum of 2.3% of the applied dose at the  0.125 mg/cm2
(3.0 mg/rat)dose level.  Fecal excretion amounted to <0.1% at all dose
levels. At the 0.0125 mg/cm2 (0.3 mg/rat), 0.0625 mg/cm2 (1.5 mg/rat)
and 0.125 mg/cm2 (3.0 mg/rat) dose levels, systemic bioavailability
(absorption) of 3.9%, 2.2% and 7.3%, respectively, were noted at 24
hours.  A time related increase in systemic bioavailability occurred
only at the 1.5% dose level. The dose related pattern of absorption was
typical of a chemical which directly damages the skin.  The percent of
dose absorbed increased with increasing dose. The total percent recovery
of [14C]-Endothall equivalents was 97.7 to 101.1% of the administered
dose throughout the 24 hour period.

Special studies	

None	

A.3  Executive Summaries TC \l2 "A.3  Executive Summaries 

A.3.1	Subchronic Toxicity

870.3100	90-Day Oral Toxicity – Rat

Study Selected: 90-Day Oral Toxicity Study in Rats

MRID No.: 43480810

Executive Summary:  See Table A.2.b.

870.3100	90-Day Oral Toxicity – Mouse; not required

870.3150 90-Day Oral Toxicity – Dog

Study Selected: 13 Weed Oral Toxicity Study in Dogs

MRID No.: 43480802

Executive Summary:  See Table A.2.b.

870.3200	21/28-Day Dermal Toxicity – Rat

Study Selected: 21-Day Dermal Toxicity Study in Rats

MRID No.: 43465201

Executive Summary:  In the subchronic dermal toxicity study (MRID
43465201), the amine salt of Endothall (30.3% active Endothall amine;
equivalent to 11.6% Endothall acid) was administered dermally to
Sprague-Dawley rats (5/sex/dose) at dose levels of 0, 30, 100, or 300
mg/kg/day for 21 days. 

Mortalities were observed in rats treated with 300 mg/kg/day (1/5 male
and 2/5 females) or 100 mg/kg/day (1/5 male and 1/5 female).
Treatment-related dermal irritations which included erythema, edema,
necrosis, fissuring of the dose site and sloughing of the skin at the
dose sites were observed in rats treated with 300, 100, or 30 mg/kg/day
of Endothall amine salt.

In the 300 mg/kg/day dose group, group mean body weights in males were
5% and 10% lower than the concurrent control on Days 7 and 14,
respectively. A significant decrease of daily mean body weight gain
(8.6% of the control) was observed in the males only through day 7. Due
to severe moribund condition, the remaining animals in the 300 mg/kg/day
dose group were sacrificed early on Day 16. Clinical chemistry data
revealed elevated BUN, ALT, and total bilirubin levels which correspond
with histopathological findings including karyorrhexis and tubular
nephrosis in the kidney and hepato-cellular degeneration and subcapsular
necrosis in the liver. Increased WBC, predominantly neutrophils, and
decreased RBC counts also were observed in both sexes.  

In the 100 mg/kg/day dose group, actual body weight losses were observed
at Day 14 for females and at Day 20 for both sexes while food
consumption was comparable to the control group. Total body weight gains
were inhibited (-57.8% for males and -65.5% for females) when compared
to controls. Significantly increased WBC and platelet counts and
decreased RBC counts were observed in females while increased platelet
counts were seen in males. Clinical chemistry data showed elevated BUN,
ALT, and total bilirubin levels (males only), and decreased A/G ratios
(both sexes). No significant histopathological findings were observed.

In the 30 mg/kg/day dose group, actual body weight losses were observed
in females at Days 14 and 20. Total body weight gains were inhibited
(-27.6% for males and -84.5% for females) when compared to controls. No
other significant systemic toxicity was observed.   

Based on the irritation data, the NOAEL for dermal irritation was not
established. The LOAEL is estimated to be 30 mg/kg/day based on
erythema, edema, fissuring of the dose site and sloughing of the skin at
the dose sites. The NOAEL for systemic toxicity also was not
established. The LOAEL is 30 mg/kg/day based on total body weight gain
inhibition.

Dose and Endpoint for Risk Assessment: LOAEL = 30 mg/kg/day based on
decreases in body weight gains in both sexes.

Comments about Study/Endpoint: This dose and endpoint is derived from a
route-specific study.  It is appropriate for use for all exposure
durations since the lowest extrapolated NOAEL of 3 mg/kg/day (30÷10 UF)
would address the concern for the stomach lesions seen after
approximately 13 weeks via the oral route at 2 mg/kg/day (LOAEL) in the
2- generation reproduction study.  The oral NOAEL of 2 mg/kg/day in
conjuction with a UF of 3X results in an extrapolated NOAEL of 0.67
mg/kg/day.  Using this value with 7.3% dermal absorption factor yields a
dermal equivalent dose of 9.5 mg/kg/day.  (2 mg/kg/day ÷3 UF = 0.67
mg/kg/day x 7.3% = 9.5 mg/kg/day).  Therefore, the dermal equivalent
dose (9.5 mg/kg/day) would be higher than the extrapolated dermal LOAEL
selected for risk assessment.

This study is classified as acceptable and satisfies the guideline
requirement for a subchronic dermal toxicity study.

870.3465	90-Day Inhalation – Rat; not satisfied

A.3.2	Pre-natal Developmental Toxicity

870.3700a Pre-natal Developmental Toxicity Study – Rat

Study Selected: Pre natal Development in Rats

MRID No.: 42776301

Executive Summary:  In a developmental toxicity study (MRID 42776301)
Groups of pregnant Crl:CD BR rats (25/dose) were administered endothall
(19.2% a.i. Batch # CAF 21C901) via gavage at dose levels of 0, 6.25,
12.5, or 25.0 mg/kg/day during gestation Days 6-15.  Maternal toxicity
was observed at the highest dose tested as indicated by decreases in
body weight gain.  Endothall did not induce developmental toxicity at
any of the doses tested. 

Based on these results, the NOAEL and LOAEL for maternal toxicity are
12.5 and 25 mg/kg/day, respectively. The LOAEL is based on decreased
body weight gain.  No developmental toxicity was observed at any dose
tested.  Therefore, the NOAEL for developmental toxicity is > 25
mg/kg/day.  A LOAEL was not established.

The developmental toxicity study in the rat is classified acceptable,
guideline and satisfies the guideline requirement for a developmental
toxicity study (OPPTS 870.3700; OECD 414) in the rat.

870.3700b Pre-natal Developmental Toxicity Study – Rabbit; not
available

A.3.3	Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

Study Selected: Generation Reproduction Toxicity Study in Rats

MRID No.: 43152101, 43629301

Executive Summary:  In a 2-generation reproduction study, Endothall Turf
Herbicide (disodium salt of Endothall, 19.9% ai) was administered
continuously in the diet to Sprague Dawley CD rats (26/sex/dose) at
concentrations of 0, 30, 150 or 900 ppm for two successive generations
(1 litter P1 generation, 2 litters F1 generation). The dose levels were
equivalent to 0, 2, 10.2, or 64 mg/kg/day for males and 0, 2.3, 11.7, or
78.7 mg/kg/day for females during the premating period; 0, 1.8, 9.4 or
60 mg/kg/day during the gestation period; and 0, 3.1, 17.3, or 104.7
mg/kg/day during the lactation period. 

Males were mated after approximately 14 or 16 weeks (P1 and F1,
respectively) on the test diet.  P1 and F1 females were fed the test
diets for approximately 24 and 14-16 weeks, respectively, and mating was
initiated on study week 14 (P1) and study weeks 16 (F1 first litters)
and 27 (F1 second litters).  F1 pups were weaned on the same test diet
fed their parents.

At 900 ppm, mean body weights and body weight gains for both sexes of
the parental rats were slightly to moderately (and in most cases,
statistically significantly) depressed throughout the premating,
gestation and lactation periods (and the rest period for the F1 females
between litters).  Covariant-adjusted mean body weights of the F0/F1 pup
weights were also slightly depressed throughout lactation (statistically
significant at lactation days 0, 14, and 21).  F1-F2a and F1-F2b pup
weights were also slightly depressed during lactation (statistically
significant at day 21).  Histological alterations of minimal to moderate
(scales of 1-3 of a possible 5) proliferation of the gastric foveolar
epithelium, with increased mitotic figures of the glandular stomach,
were found in 3/3 F1 males examined.  One male also had an increased
number of mitotic figures in the glandular stomach.

At 150 ppm, covariant-adjusted mean body weights for both sexes in the
F1 first litter of pups (F2a) at Day 21 lactation were 10-11% depressed
(statistically significant) and 2/2 F1 females examined had minimal to
moderate proliferation of the gastric foveolar epithelium.

At 30 ppm, 2/3 F1 males and 1/2 F1 females examined had minimal to
moderate proliferation of the gastric foveolar epithelium.

Under conditions of this study, a NOAEL for parental systemic toxicity
has not been established; the LOAEL was estimated to be 30 ppm (2
mg/kg/day for males and 2.3 mg/kg/day for females) based on
proliferative lesions of the gastric epithelium (both sexes). The NOAEL
for offspring toxicity was 150 ppm (9.4 mg/kg/day) and the LOAEL was 900
ppm (60.0 mg/kg/day) based on decreased pup body weights (both sexes) at
Day 0 of the F1 and F2a generations.

This study is classified Acceptable and satisfies the guideline
requirements for a 2-generation reproduction study in rats.

A.3.4	Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

Study Selected: Combined Chronic/Oncogenicity Feeding Study in Rats.

MRID No.: 41040301

Executive Summary:  See Section 870.4300, Chronic/Oncogenicity, below.

870.4100b Chronic Toxicity – Dog

Study Selected: Chronic Toxicity in Dogs

MRID No.: 40745202

Executive Summary:  See Table A.2.b

A.3.5	Carcinogenicity

870.4200a Carcinogenicity Study – Rat

Study Selected: Combined Chronic/Oncogenicity Feeding Study in Rats.

MRID No.: 41040301

Executive Summary:  See Section 870.4300, Chronic/Oncogenicity, below.

870.4200b Carcinogenicity (feeding) – Mouse

Study Selected: Carcinogenicity Study in Mice.

MRID No.: 40685301, 43608301

MRID No. 40685301

Executive Summary:  In a carcinogenicity study, disodium Endothall
(15.6% a.i.) was fed to Crl:CD®1(ICR)BR mice (64/sex/group) via diet
for 21 months at dose levels of 0, 50, 100, or 300 ppm (equivalent to 0,
7.5, 15, or 45 mg/kg/day, respectively, based on a standard conversion
factor). No treatment-related mortality, clinical signs or palpable
masses were observed throughout the study. Mean body weights of treated
animals (both sexes) were consistently lower than the respective
control; however, statistical significance only was shown in males at
100 and 300 ppm during weeks 9 and 51 and occasionally thereafter. The
final mean body weight for the 300 ppm males was 6% less than the
respective control while no effect was seen in the females. The overall
body weight gain in high dose males was 17% less than the control;
however, no apparent treatment-related trends could be established.

At necropsy, no significant treatment-related macroscopic findings were
observed. Absolute and relative organ weights at interim or terminal
sacrifices were not affected by the treatment. Leukocyte differential
analysis at interim and terminal sacrifices did not show significant
treatment-related effects.

No treatment-related microscopic lesions were observed at the interim
sacrifice. At the terminal evaluation, an increased incidence of minimal
to mild multifocal mineralization in the kidneys was reported in the 300
ppm males only. The incidence of this condition was 3/60, 9/60, 8/60, or
23/60 for 0, 50, 100, or 300 ppm groups, respectively.

Increased benign hepatocellular adenomas were observed in the treated
mice. The incidences were 2/60 (3.3%), 2/60 (3.3%), 4/60 (6.7%), and
7/59 (11.9%) for males and 0/60, 0/60, 1/60 (1.7%), and 2/60 (3.3%) for
females at 0, 50, 100, and 300 ppm, respectively. Hepatocellular
carcinomas were observed in treated males only with incidences of 0/60,
1/60 (1.7%), 2/60 (3.3%), and 1/59 (1.7%) at 0, 50, 100, and 300 ppm,
respectively. A dose-related increase of hepatocellular adenomas was
suggested. The historical control means for hepatocellular adenoma are
13% (males) and 2% (females); and for hepatocellular carcinoma are 2%
(males) and 0.5% (females).

Under conditions of this study, the NOAEL for chronic toxicity is 100
ppm (15 mg/kg/day) and the LOAEL is 300 ppm (45 mg/kg/day) based on
decreased body weight gain and microscopic findings in the kidney of
male mice. At the doses tested, there was a treatment related increase
in tumor incidence of hepatocellular adenoma (both sexes) and
hepatocellular carcinoma (males only) when compared to controls.
However, these tumor incidences were within historical control ranges. 

This study is currently classified supplementary based on the inadequacy
of the dosage.

MRID No. 43608301

Executive Summary:  In a carcinogenicity study (MRID 43608301) Disodium
Endothall Technical (19.2% active ingredient) lot # CAF 21 C901 and
851-97 was administered to 60 Crl:CD-1®(ICR)BR albino mice/sex/dose in
the diet at dose levels of 0, 750, or 1500 ppm (equivalent to 0, 124,
258 males and 0, 152, 319 females mg/kg bw/day) for 79 weeks. 

Excessive mortality was observed in males and females at the high dose
(258 and 319 mg/kg/day respectively) and decreased weight gain in males
at the low and high dose 124 and 258 mg/kg/day). Clinical signs of
toxicity consisted of dose related increases in both sexes of apparent
prolapsed rectum, paleness of the entire body and distended abdomen.
These were most apparent in animals that died or were sacrificed
moribund on study. Gross pathology revealed abnormalities indicative of
a direct (irritant) toxic effect on the digestive tract. In the
sacrificed animals treatment-related observations were dose-related
thickened wall of the glandular stomach and prolapsed rectum. In the
unscheduled death animals common findings included enlarged spleens,
liver and kidneys, pale kidneys and dark areas of the stomach.
Dose-related thickened wall of the glandular stomach and prolapsed
rectum were also observed. No dose-related increase in organ masses was
observed. Histopathology showed inflammation as the most frequent cause
of death in this study and revealed compound-related alterations in
sections of the glandular stomach. small intestine, and rectum.
Inflammation included chronic active inflammation of the heart,
abscesses and necrosis of the liver, chronic progressive nephropathy and
pyelitis of the kidneys chronic active inflammation and ulceration of
the prolapsed rectum, and chronic active inflammation and ulceration of
the skin.  No treatment-related increase in neoplasia was observed in
the study. 

The LOAEL is 124 mg/kg/day, based on decreased weight gain in the males.
 A NOAEL was not determined. The low dose (124 mg/kg/day males) can be
considered a Maximum Tolerated Dose which was exceeded in both sexes at
the high dose (258, 391 mg/kg/day, males and females respectively).

At the doses tested, there was not a treatment related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on decreased weight gain on the males at the low and high dose and
females at the high dose and increased mortality in both sexes at the
high dose.

This carcinogenicity study in the mouse is acceptable, guideline, and
(together with the previous study) satisfies the guideline requirement
for a carcinogenicity in mice.

Discussion of Tumor Data: Both studies should be reviewed as one
acceptable study. The dosing in the first study was inadequate; however,
the second study was conducted with higher doses. Adding the two studies
together will result in the following doses: 0, 7.5, 15, 45 disodium
Endothall (15.6% a.i.), and 124/152, 258/318 (M/F) disodium Endothall
Technical (19.2% a.i) mg/kg/day. In the first study (MRID 40685301), at
the doses tested, there was a treatment related increase in tumor
incidence of hepatocellular adenoma (both sexes) and hepatocellular
carcinoma (males only) when compared to controls. However, these tumor
incidences were within historical control ranges. In the second study
(MRID 43608301), at the doses tested, there was not a treatment related
increase in tumor incidence when compared to controls.

Adequacy of the Dose Levels Tested: When considering the results of the
two studies, the doses tested were adequate to assess the carcinogenic
potential of endothal in mice. 

870.4300	Chronic/Oncogenicity

Study Selected: Combined Chronic/Oncogenicity Feeding Study in Rats.

MRID No.: 41040301

Executive Summary:  In a combined chronic/oncogenicity feeding toxicity
study, disodium Endothall (12.6% a.i.) was administered in the feed to
groups of Crl:CD® (SD) BR albino rats (62/sex/group) at doses of 0,
300, 900, or 1800 ppm (0, 12, 37, or 80 mg/kg/day for males and 0, 16,
49, or 110 mg/kg/day for females, respectively; calculated by the
reviewer) for up to 2 years.  Eleven animals/sex/group were killed at 53
weeks for interim evaluation.  Because the interim study revealed
significant decreases in body weight at all doses and macroscopic and
microscopic stomach changes in the 900 and 1800 ppm rats, a
supplementary study was conducted using concentrations of 0 and 150 ppm
(0 or 6 mg/kg/day for males, and 0 or 8 mg/kg/day for females,
respectively). 

Absolute body weights in males and females exhibited treatment- and
time-related decreases; the effect was more pronounced in females. 
Statistically significant (p < 0.05) and biologically relevant decreases
in absolute body weight occurred in 900 ppm males (93-96% of control
weights) up to week 48; 1800 ppm males (84-97% of control weights) up to
week 80; 300 ppm females (91-96% of control weights) up to week 72; 900
ppm females (83-94% of control weights) up to week 92; and 1800 ppm
females (72-93% of control weights) throughout the study.  Body weight
gain was decreased in treated males up to week 52, after which
compensation for weight loss was evident in the dose-related increases
in weight gain.  By 104 weeks, no differences were observed in body
weights between any of the treated and control males.  Females in the
300, 900, and 1800 ppm groups showed a dose-related decrease in weight
gain during the treatment intervals of 0-1, 0-28, 28-52, 52-80,and
0-104.  During weeks 80-104, females began to show compensatory
increased body weight gain.  Unlike males, however, females in the high
dose group did not completely compensate for weight loss, such that by
104 weeks, 1800 ppm females still had a statistically (p < 0.05) lower
body weight compared to controls (76% of controls). 

No treatment-related changes were observed in clinical signs, survival,
or hematological or clinical chemistry parameters.  Absolute heart
weights and heart weights relative to brain weights showed dose-related
decreases in 300, 900, and 1800 ppm females at study termination (86,
81, and 77% of control weights, respectively), with the weights of the
900 and 1800 ppm females reaching statistical significance (p < 0.05). 
Although no pathological correlates were identified, this response may
be related to treatment.  

The results of gross and microscopic pathological examination for all
animals (including animals that died before the final termination) were
not reported in the summary tables, so definitive conclusions cannot be
made regarding the effect of treatment on these parameters. Macroscopic
or microscopic examination revealed that the treatment appeared to
increase (p < 0.05; 0.01) the incidence of thickening of the wall of the
nonglandular stomach in 300, 900, and 1800 ppm males (4/12, 14/22, and
14/22 vs 0/16 controls) and 900 and 1800 ppm females (16/25 and 28/39 vs
2/18 controls).  In 1800 ppm males and females, this macroscopic change
was accompanied by a statistically increased incidence (p < 0.05; 0.01)
of acanthosis with hyperkeratosis of the nonglandular stomach (males:
7/22 vs. 0/16 controls; females: 31/39 vs. 2/18 controls).  The
increased incidences of these macroscopic and microscopic lesions at
105/106 weeks were accompanied by similar findings from the animals
examined at the interim sacrifice at 53 weeks.  Males and females in the
900 and 1800 ppm interim sacrifice groups had increased incidences (p <
0.01) of thickening of the nonglandular stomach wall (males: 7/10 and
10/10 vs. 0/10 controls; females: 8/10 and 10/10 vs. 1/10 controls). 
The incidences of acanthosis with hyperkeratosis of the nonglandular
stomach were also statistically increased (p < 0.05) in 900 and 1800 ppm
interim-sacrifice males (5/10 and 5/10 vs. 0/10 controls) and in 900 ppm
interim-sacrifice females (4/10 vs. 0/10 controls).  Females in the 300,
900, and 1800 ppm main study groups had an increased incidence of
cellular alterations of the adrenal cortex (3/22, 5/25, and 19/39 vs.
2/18 controls), but these cellular alterations were not accompanied by
any other toxicological correlates. 

The chronic toxicity LOAEL is 900 ppm (37 mg/kg/day) for males and 300
ppm (16 mg/kg/day) for females based on decreased body weight and body
weight gain.  The NOAEL is 300 ppm (12 mg/kg/day) for males and 150 ppm
(8 mg/kg/day) for females. The LOAEL and NOAEL values are tentative and
are contingent upon analysis of data addressing macroscopic and
microscopic lesions in treated animals.

This study is classified as Acceptable and satisfies the requirements
for a combined chronic/oncogenicity study in rodents.

A.3.6	Mutagenicity

HED concluded that there is not a concern for mutagenicity resulting
from exposure to endothall.

Gene Mutation

Guideline #  OPPTS 870.5300 [§84-2]; OECD 476, study type  In vitro
Mammalian Cell Gene Mutation Assay

MRID 43437801

5.8 ·g/mL -S9 and  58.0 ·g/mL +S9.  Positive controls (ethyl
methanesulfonate -S9 or dimethylnitrosamine +S9) induced the appropriate
response.  There was no evidence of a reproducible mutagenic effect with
or without S9 activation at any concentration

Guideline # OPPTS 870.5100/[§84-2] OECD 471, study type Bacterial Gene
Mutation Assay (Salmonella typhimurium

MRID 43154801

classification unacceptable	In a microbial reverse gene mutation assay
(MRID 43154801), strains TA1535, TA1537, TA1538, TA98 and TA100 of
Salmonella typhimurium were exposed to concentrations of 16.7, 50.0,
500, 1670 and 5000 ·g/plate Endothall  Technical amine salt (1.5:1
amine salt ratio; Batch No. B46-44- 1; Endothall amine 30.3%; Endothall
acid equivalent = 11.6%) in dimethyl sulfoxide (DMSO)  (equivalent to
1.93, 5.80, 19.3, 58.0, 116 or 193 ·g/plate active ingredient)  with or
without S9 activation in Trial 1. For Trial 2, concentrations ranging
from 0.58 to 116 ·g/plate +/-S9 were assayed; 1.93 to 116 ·g/plate 
were processed with strains TA1537 (+S9) and 1538 (-/+S9) in Trial 3;
and a fourth test was conducted with comparable levels of the test
material with strain TA1538 without S9.  The S9 liver homogenate was
derived from Arochlor 1254 induced rat livers.

Cytotoxicity was generally seen at 58 ·g/plate -S9 or
38.7·g/plate +S9.  The positive controls induced the expected
responses in the appropriate strains.  There was no evidence of a
mutagenic response in strains TA1535, TA1537, TA98 or TA100.  However,
equivocal results were obtained with strain TA1538.  Two-fold increases
in revertant colonies were seen in TA1538 in 2/3 trials with S9 and in
all four trials without S9.  These increases were only significant
(p<0.05) and concentration- dependent in two S9-activated trials and
only one nonactivated trial.  It was, nevertheless,  noted that the
spontaneous reversion rate for this strain was very low (2-6 revertant
colonies -S9 and 8-14 revertant colonies +S9) and that the more
sensitive strain (TA98), derived from TA1538 and known to detect the
same mutagens, was negative in all trials either with or without S9
activation.

Cytogenetics	

Guideline #Mice/OPPTS 870.5395/[§84-2], study type In vivo Mammalian
Cytogenetics - Micronucleus Assay in Mice

MRID 43157401 

2.9 mg/kg) mortality occurred.  There was also a significant
(p0.05) depression in the PCE:NCE ratio (polychromatic :
normochromatic erythrocytes) for the high-dose group at 24 hours but not
at later harvests.  The positive control (triethylemelamine, 0.5 mg/kg)
induced a significant (p<0.01) increase in MPCEs. There was, however, no
evidence that Endothall technical amine salt induced a clastogenic or an
aneugenic response at any assayed level.

Guideline # OPPTS 870.5395/[§84-2], study type In vivo  Mammalian
Cytogenetics - Micronucleus Assay in Mice

MRID 41700301

classification Acceptable	In a mouse micronucleus assay (MRID 41700301)
groups of five male and five female CD-1 mice were administered 2,10 or
50  mg/kg Endothall  (89.4%; Batch No. B14-37 in 0.9% saline) once by
oral gavage.  Bone marrow cells were harvested 24, 48 and 72 hours after
treatment with the high dose or 24 hours after treatment with the low or
intermediate doses and scored for micronucleated polychromatic
erythrocytes (MPCEs).

Signs of toxicity included slight piloerection and two high-dose animals
(1 male and 1 female) were found dead 21 and 45 hours post treatment,
respectively.  There was no indication of a cytotoxic effect on the
target cells.  The positive control (chloroambucil, 30 mg/kg) induced a
significant (p<0.01) increase in MPCEs. There was, however, no evidence
that Endothall technical induced a clastogenic or an aneugenic response
at any assayed level.

Guideline # OPPTS 870.5375 [§84-2]; OECD 473, study type In vitro
Mammalian Cytogenetics

MRID 41700302

classification Acceptable	In a mammalian cell cytogenetics assay
(chromosome aberrations), MRID 41700302, human lymphocytes derived from
a single donor were exposed continuously for 24 hours to Endothall
technical (89.4%; Batch No. B14- 37) in dimethyl sulfoxide (DMSO) at
concentrations of 2.5, 10.0, 20.0 and 40.0 ·g/mL without metabolic
activation or were exposed for 3 hours to 15.0, 60.0, 120.0 or 240.0
·g/mL with metabolic activation derived from Arochlor 1254 induced male
CD rat livers. Treated cells were either harvested at the end of the
non-activated exposure or 21 hours post treatment under S9-activated
conditions and examined for structural and numerical chromosome
aberrations. 

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摧瑥ऀsted up to cytotoxic concentrations without S9 activation (40
·g/mL) or with S9 activation (240 ·g/mL).  Positive controls
(chloroambucil -S9 or cyclophosphamide +S9) induced the appropriate
response.  There was no evidence of a concentration-related clastogenic
response with or without S9 activation.  There was also no significant
increase in polyploid cells at any concentration. 

A.3.7	Neurotoxicity

870.6100 Delayed Neurotoxicity Study – Hen: Not Required

870.6200 Acute Neurotoxicity Screening Battery:  Not Required

870.6200 Subchronic Neurotoxicity Screening Battery:  Not Required

870.6300 Developmental Neurotoxicity Study:  Not Required

A.3.8	Metabolism

870.7485	Metabolism – Rat

Study Selected: Metabolism and Pharmacokinetics

MRID No: 42169502, 44263501

MRID No. 42169502 

Executive Summary: Intravenous administration of 0.9 mg/kg resulted in
excretion mainly by the urine (69%) and feces. At an oral 0.9 mg/kg
dose, blood half-life elimination - 1.8 hrs in males, 2.5 hrs females. 
At 4.5 mg/kg half-life - 13.9 hours in males; the half-life in females
could not be calculated because of a double blood peak. Multiple oral or
single administration indicated that the test material was rapidly
absorbed and excreted in the feces (89-98%) and urine (5-9%).  The
compound did not bioaccumulate.  At 24 hours tissue distribution of the
compound was extensive but low, the highest amount (<10%) being found in
the gastrointestinal tract.  By 48 hours, the compound was mostly
undetectable in the tissue.  Bile elimination was only of minor
importance. Absorbed or unabsorbed test compound in all groups was
excreted mainly as chemically unchanged Endothall in the feces and
urine.

 MRID No. 44263501

Executive Summary: Following a single oral administration of
[14C}-Endothall to male and female rats (approximately 9 mg/kg), the
majority of the radioactivity (70.8% males, 71.2% females) was excreted
within the 0-24 hour time period, with most of the radioactivity being
present in the feces (47.6% males, 47.5% females) At 24 hours after
dosing, less than 0.21% of the dose was found in the stomach (+
contents), small intestine (+ contents) and pancreas and very little
detected in the blood (below 15 ng eq/g). Higher levels of radioactivity
were found in the caecum (3.0% males, 6. 1 % females) and the large
intestine (3.2% males, 8.2% females).

Analysis of extracts of the urine, feces, caecum and large intestine of
both male and female rats  gave a single radioactive component
corresponding to unchanged Endothall which accounted for >86, >96, >74
and >69% of total recovery from the respective extracts.

870.7600	Dermal Absorption – Rat

Dermal Absorption Factor:   7.3% at 24 hours.

Study Selected: Dermal Absorption Study in Rat

MRID No: 42169503

Executive Summary: In a dermal penetration study (MRID: 42169503) [14C]-
Endothall monohydrate (>98.5-97.4%a.i., ) in dilutions of the Hydrothal
®  191 Aquatic Algicide and Herbicide formulation (23.4% w/w a.i. Lot
No Pennwalt ALC-09L8-07) was administered to ninety (90) Sprague-Dawley
CDRBR rats, consisting of 30 rats per dose group. Each rat received a
single dermal application of [14Cl-Endothall at levels of 0.15, 0.75 and
1.5% spread over 24 cm2 of skin area.  Dose levels were 0.0125 mg/cm2
(0.3 mg/rat), 0.0625 mg/cm2 (1.5 mg/rat) and 0.125 mg/cm2 (3.0 mg/rat)
respectively. Five (5) animals per time period (0, 0.5, 1, 2, 4, 10 or
24 hours) in each dose group were analyzed for [14C] -Endothall
equivalents in the urine, feces, skin site and carcass.

Approximately 55 to 82% of the applied dermal dose was washed from the
application site.  The rest of the [14C]-Endothall equivalents was
contained in the application site skin. Urinary excretion of
[14C]-Endothall equivalents increased in a dose related manner at 10 and
24 hours to a maximum of 2.3% of the applied dose at the 1.5% dose
level.  Fecal excretion amounted to <0.1% at all dose levels. At the
0.15, 0.75 and 1.5% dose levels, systemic bioavailability (absorption)
of 3.9%, 2.2% and 7.3%, respectively, were noted at 24 hours.  A time
related increase in systemic bioavailability occurred only at the 1.5%
dose level. The dose related pattern of absorption was typical of a
chemical which directly damages the skin.  The percent of dose absorbed
increased with increasing dose (see attached graph). The total percent
recovery of [14C]-Endothall equivalents was 97.7 to 101.1% of the
administered dose throughout the 24 hour period.

In a preliminary study, nominal doses of 12.5, 50, 100, 200 and 400
ug/cm2 were administered to groups of 3 male rats and evaluated for
dermal irritation at 4 and 24 hours. Erythema/Eschar was observed at 4
and 24 hours at doses of 50 ug/cm2 and higher.

This study in the rat is acceptable and satisfies the guideline
requirement for a dermal penetration study in rats.

  PAGE  56  of   NUMPAGES  80 

Endothall	Human Health Risk Assessment to Support New Uses	DP No.: 
356315

Page   PAGE  62  of   NUMPAGES  80 

Page   PAGE  76  of   NUMPAGES  80