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.

<IP_ADDRESS> 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.

<IP_ADDRESS> 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.

<IP_ADDRESS>	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.

<IP_ADDRESS>	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.

<IP_ADDRESS>	  Handler Exposure Scenarios tc \l4 "<IP_ADDRESS>	  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.

<IP_ADDRESS>	  Data and Assumptions for Handler Exposure Scenarios tc \l4 "<IP_ADDRESS>	  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).

<IP_ADDRESS>	  Residential Handler Exposure and Risk Estimates tc \l4 "<IP_ADDRESS>	  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 <IP_ADDRESS>  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).

<IP_ADDRESS>	  Recommendations for Refining Residential Handler Risk Assessment tc \l4 "<IP_ADDRESS>	  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

<IP_ADDRESS>	Residential Postapplication Exposure Scenarios tc \l4 "<IP_ADDRESS> 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.

<IP_ADDRESS>	Residential Postapplication Exposure and Risk Estimates tc \l4 "<IP_ADDRESS>	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 <IP_ADDRESS> provides the individual exposure/risk through various routes based on the standard factors and physical constants.

Table <IP_ADDRESS>. 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

<IP_ADDRESS>	Characterization of Residential Handler Risks tc \l4 "<IP_ADDRESS> 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.

<IP_ADDRESS> 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 <IP_ADDRESS>).

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

<IP_ADDRESS> Assumptions for Handler Exposure Scenarios

Several tc \l4 "<IP_ADDRESS>	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;