Endothall Human Health Risk Assessment DP No. 403274 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: March 18, 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Endothall. Human Health Risk Assessment to Support Proposed Use on Apples 

PC Code:038904 DP Barcode: 0403274 

Decision No.: 416t/Zlf3 Registration No.: 70506-0EA 

Petition No.: 2F8023 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Aggregate Case No.: 2245 

TXR No.: NA CAS No.: 2164-07-0 

MRID No.: NA 40 CFR: §180.293 

FROM: Seyed 

John 

Ana Rivera

Liccione, 

Tadayon, 

-Lupiaiiez, 

Ph.D

Risk 

., 

Assesso

Toxicologist 

Chemist 

~ ~ 

Risk Assessment Branch V 

Health Effects Division (7509P) ~ } 

THROUGH: Michael Metzger, Branch Chief 'J J ' 

Danette Drew, Senior Risk assess 

Risk Assessment Branch V 

Health Effects Division (7509P) 

TO: Grant Rowland, RM Team 23 

Herbicide Branch 

Registration Division (7505P) 

Page 1 of36 
Endothall Human Health Risk Assessment DP No. 403274 

1.0 Executive Summary ..... ............................................................... .... .... ........................ ....... 4 

2.0 HED Recommendations ................... ...................................... ........................... .... ............ 6 

2.1 Data Deficiencies ........................................................................................... ................. 6 

2.2 Tolerance Considerations .................................. .... .... .................................................... 6 

2.2.1 Enforcement Analytical Method ............................................................................... 6 

2.2.2 International Harmonization ................................ .... .......................... ................. ...... 7 

2.2.3 Recommended Tolerances ........................................... ....... .... ................................... 7 

2.3 Label Recommendations ....................................... ...................... ................ ................... 8 

2.3.1 Recommendations from the Residue Chemistry Review ........................................ 8 

3.0 Introduction ................ .... ....................................................................................... .... .... ..... 8 

3.1 Chemical Identity ........................................................................................................... 8 

3.2 Pesticide Use Pattern ............................................................. ............ .............................. 9 

3.3 Anticipated Exposure Pathways .... .................. .... ....................................................... 10 

3.4 Consideration of Environmental Justice .................................... ................................ 10 

4.0 Hazard Characterization and Dose-Response Assessment .. ........................................ 11 

4.1 Toxicology Studies Available for Analysis .. .............................................................. . 11 

4.2.1 Dermal Absorption ............................... .................................................. ........ .... ...... 12 

4.3 Toxicological Effects ................................................... ................................................. 12 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ........ ....................... 14 

4.4.1 Completeness of the Toxicology Database .............................................................. 14 

4.4.2 Evidence of Neurotoxicity ......................................................... ............................... 14 

4.4.3 Evidence of Sensitivity /Susceptibility in the Developing or Young Animal ........ 15 

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 15 

4.5 Toxicity Endpoint and Point of Departure Selections .................... , .... ............ .... .... . 15 

4.5.1 Dose-Response Assessment ...................................................................................... 15 

4.5.3 Cancer Classification and Risk Assessment Recommendation ...................... ...... 17 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment .................................................................................. ....... ............ ........... ............... 1 7 

5.0 Dietary Exposure and Risk Assessment.. .................. .... ................................................. 19 

5.1 Metabolite/Degradate Residue Profile ....................................................................... 19 

5.1.1 Residues of Concern Summary and Rationale ................ .............. .... ................ .... 19 

5.2 Food Residue Profile ... ........... ...................................................................................... 20 

5.3 Water Residue Profile .................................................................................................. 20 

5.4 Dietary Risk Assessment .................. ........... ........ ... ................... ............... .................... 21 

5.4.1 Description of Residue Data Used in Dietary Assessment .................................... 21 

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 21 

5.4.3 Acute Dietary Risk Assessment ............................................................................... 21 

5.4.4 Chronic Dietary Risk Assessment .. .............. ............ .............................................. . 21 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............ ........ ........ . 22 

6.1 Residential Exposure .................................................................................................... 22 

6.2 Postapplication Exposure ......................................... ........... ....... ................................ . 23 

6.3 Combined Exposure ............................................................ ............ ... .... .... ........ .......... 23 

6.4 Residential Bystander Postapplication Inhalation Exposure .. .................. ............... 23 

6.5 Spray Drift .. ....... .............. ............................................................................................. 24 

7.0 Aggregate Exposure/Risk Characterization .................. .................. .................... .......... 24 

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Endothall Human Health Risk Assessment DP No. 403274

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7.1 Acute Aggregate Risk................................................................................................... 24

7.2 Short-Term Aggregate Risk ........................................................................................ 24

7.3 Chronic Aggregate Risk .............................................................................................. 25

8.0 Cumulative Exposure/Risk Characterization ............................................................... 25

9.0 Occupational Exposure/Risk Characterization ............................................................ 25

9.1 Short- Term Handler Risk .......................................................................................... 26

9.2 Postapplication Risk..................................................................................................... 27

9.2.2 Inhalation Postapplication Risk .............................................................................. 27

Appendix A. Toxicology Profile and Executive Summaries .................................................. 28

A.1 Toxicology Data Available for Endothall. ......................................................................... 29

Appendix B. Review of Human Research................................................................................ 35

Appendix C. International Residue Limits.............................................................................. 36
Endothall Human Health Risk Assessment DP No. 403274

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1.0 Executive Summary

HED has conducted a human health risk assessment to evaluate the petition (2F8023) requesting

Section 3 registration of the herbicide endothall (as endothall dipotassium salt) for the new use 

on apple trees as a blossom thinner. United Phosphorus Inc (UPI) has requested registration of 

the apple use and the establishment of tolerances to support that use. This assessment takes into 

account the proposed use and previously registered uses of endothall.

Endothall is a dicarboxylic acid that is a selective contact herbicide, defoliant, desiccant, growth 

regulator, 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. There are also direct uses registered for food crops. Tolerances are established 

for endothall and its monoethyl ester on food and feed items as a result of direct and inadvertent 

(aquatic) residues resulting from endothall products. The residues of concern in plant and 

livestock commodities for risk assessment are also endothall and its monoethyl ester. The residue 

of concern in drinking water is the free acid of endothall.

The proposed use directions specify that endothall dipotassium salt (5.37%) product, ThinRite, is 

to be applied by broadcast ground (air blast) application to apple trees at a maximum single 

application rate of 0.423 lb ai/A. If more than one treatment is needed, a maximum of two 

applications are permitted not to exceed a total of 0.846 lb a.i. endothall dipotassium salt per acre 

per growing season. The proposed re-entry Interval (REI) is 12 hours and the retreatment interval 

(RTI) is 24 hours. 

 

The toxicology data base for endothall is complete except for an immunotoxicity study required as a 

result of the revised 40 CFR Part 158 Toxicology Data requirements. The Hazard and Science Policy 

Committee (HASPOC, December 19, 2012) waived the need for acute and subchronic neurotoxicity

studies in rats.

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. In a dermal irritation study, endothall was an extreme irritant (category I). 

Although it was classified as a category III in an acute dermal toxicity study, endothall has been 

shown to be a severe irritant in a dermal absorption study (MRID 42169503) and in a 21-day 

dermal toxicity study (MRID 43465201) after one application. Based on all available data, 

endothall is classified as a severe dermal irritant. Endothall is also an extreme irritant by the 

acute oral and acute ocular routes of administration (category I), and is a skin sensitizer. In the 

acute inhalation study, it was classified as Category III however, there was irritation and other 

respiratory effects observed in 5-day and 28-day inhalation toxicity studies supporting the 

conclusion of the irritant effects of endothall. 
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Endothall does not cause pre-natal toxicity following in utero exposure to rats nor pre-and postnatal 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.

The hazard data for endothall indicate no evidence of quantitative or qualitative increased 

susceptibility of rat fetuses exposed in utero to endothall in the developmental toxicity studies. 

In addition, no evidence of quantitative or qualitative increased susceptibility of rat fetuses or 

neonates was observed in the 2-generation reproduction study.

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.

The residue chemistry database for endothall is complete and the nature and magnitude of the 

residue are adequately understood for the purpose of this action. An enforcement method is 

available to enforce the necessary tolerances. There are no issues with respect to the 

harmonization associated with this action. An acute dietary risk assessment was not required as 

there were no effects seen in the database which could be attributable to exposure to a single 

dose of endothall. Chronic dietary exposure and risk assessments were conducted using percent 

crop treated estimates, average field trial residues for all existing and new uses , and DEEM 7.81 

default and crop-specific processing factors from processing studies for all commodities. 

Modeled estimated drinking water concentrations (EDWCs) were incorporated into the chronic 

dietary risk assessment. No chronic dietary risks of concern were identified for the U.S. 

population or any population subgroups. The most highly exposed population subgroup is infants 

(1-2 years old) at 90% of the chronic population adjusted dose (cPAD). A quantitative dietary 

cancer risk assessment was not required since endothall is not likely carcinogenic.

There were no new residential uses requested in this petition. The existing residential use, 

aquatic applications on ponds, lakes and garden pools, has been assessed using the new 

residential SOP (01/01/2012).

Postapplication risk estimates for both adults and children exposed to treated water during 

swimming in ponds and lakes do not exceed HED’s level of concern for any of the scenarios 

assessed (MOEs > 100 for incidental oral exposures (i.e. water ingestion).

Human health aggregate risk assessments were conducted for the chronic aggregate exposure 

(food + drinking water) scenario, as well as the short-term aggregate exposure scenario which 

included food, drinking water and residential exposures. A quantitative cancer aggregate risk 

assessment was not performed since endothall is not likely carcinogenic. Chronic and short-term

aggregate risk estimates were not of concern.
Endothall Human Health Risk Assessment DP No. 403274

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Occupational handler and post application exposures and risks were evaluated for the proposed 

new use on apples. Occupational exposure scenarios assessed resulted in MOEs that do not 

exceed HED's level of concern (i.e., short-term MOEs ≥ 30) for endothall inhalation exposures, 

at some level of risk mitigation or addition of personal protective equipment (i.e., PF5R 

respirator). It should be noted that the proposed label does not require use of a respirator, which 

is needed to assure protection of endothall handlers from inhalation portal of entry effects. 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; and HED’s SOP for Residential Exposure Assessments 

(Draft; 17-Dec-1997; pages 52 -57), modified in HED’s SWIMODEL V 1.0 (W. Dang et al., 27-

Mar-1999), are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that 

review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics 

review may have included review by the Human Studies Review Board. Descriptions of data 

sources, as well as guidance on their use, can be found at the Agency website1. 

2.0 HED Recommendations

HED has no objection to the proposed registration of the new use of endothall on apples if the 

proposed label is amended to require the use of additional PPE for occupational handlers (i.e., 

PF5R respirator).

2.1 Data Deficiencies

There are no data gaps with respect to residue chemistry, occupational or residential exposure for 

endothall. An Immunotoxicity study is required in accordance with the revised Part 158 data 

requirements. The HASPOC (December 19, 2012) waived the acute and subchronic 

neurotoxicity studies in rats to support the proposed uses of endothall.

 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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 in plant 

commodities. Using this method, residues in crop commodities are extracted using acetone 

acidified with HCl. The extract is concentrated, and the oil and oil-soluble materials are 

removed by partitioning solvents. The endothall containing oil-free fraction is concentrated by 

boiling with acetic acid. Any endothall present is converted to the N-methoxyimide derivative 

by reaction with methoxyamine hydrochloride. The imide is partitioned into chloroform, 

 

1

http://www.epa.gov/pesticides/science/handler-exposure-data.html and

http://www.epa.gov/opp00001/science/residential-exposure-sop.html
Endothall Human Health Risk Assessment DP No. 403274

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concentrated and analyzed by GC using a nitrogen specific detector. The method LOQ is 0.1 

ppm. 

A confirmatory HPLC/MSD method (Method No. KP218R0) is also available for determining 

residues of endothall and its monomethyl ester in fish and residues of endothall in plant 

commodities. For this method, residues are extracted with water, acidified and, if necessary, 

purified using a C18 SPE column. Residues are then derivatized with heptafluoro-ptolylhydrazine (HFTH) and partitioned into dichloromethane (DCM). Derivatized residues are 

concentrated, redissolved in toluene, and cleaned up using a silica gel cartridge. Residues are 

determined by HPLC/MSD using the 397 amu ion for detection and quantitation. The validated 

LOQ is 0.05 ppm for fish (endothall and endothall monomethyl ester), and the LOQs for plant 

commodities range from 0.01-0.10 ppm, with the initial C18 SPE cleanup step. This method has 

undergone a successful independent laboratory validation using fish samples. 

(D384206, D. Soderberg, 09/30//2011).

2.2.2 International Harmonization

There are no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for 

any of the proposed commodities in the current registration action, therefore there are no issues 

with respect to international harmonization associated with the tolerances recommended in this 

action See Appendix C.

2.2.3 Recommended Tolerances

Tolerances are currently established for endothall in the 40 CFR §180.293; however, the residue 

definition listed in the 40CFR, does not comply with the HED Interim Guidance on Tolerance 

Expressions (S. Knizner, 5/27/09). The 40 CFR should be revised as follows:

Tolerances are established for the residues of endothall, including its metabolites and degradates, 

in or on the commodities in the table below. Compliance with the tolerance levels specified 

below is to be determined by measuring only endothall (7-oxabicylco [2.2.1] heptanes-2,3-

dicarboxylic acid) and its mono-methyl ester. 

Tolerance for residues of endothall in apples and wet apple pomace should be established under 

40 CFR §180.293(a)(1). The tolerance levels and commodity definitions are specified in Table 

2.2.3, below.

Table 2.2.3 Tolerance Summary for Endothall

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm) Commodity Definition

Apple 0.05 0.05

Apple pomace 0.15 0.15 Apple, wet pomace
Endothall Human Health Risk Assessment DP No. 403274

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2.2.4 Revisions to Petitioned-For Tolerances

The registrant-proposed and HED-recommended tolerance values for residues of endothall on 

apple and apple pomace are the same. However, the proposed commodity definition for apple

pomace is revised to “apple, wet pomace” to reflect the Agency’s correct commodity definition.

2.2.5 Reference Standards

An analytical standard for endothall is currently available in the EPA National Pesticide 

Standards Repository (personal communication with Dallas Wright, ACB, 10/23/08), but the 

refrence standard expired on 12/28/2012. Analytical reference standards must be replenished as 

requested by the Repository. Analytical standards of the endothall dipotassium salt, monomethyl 

and dimethyl esters must be submitted. 

2.3 Label Recommendations

2.3.1 Recommendations from the Residue Chemistry Review

None.

2.3.2. Recommendations from ORE Review

Occupational exposure scenarios assessed resulted in MOEs that do not exceed HED's level of 

concern (i.e., short-term MOEs ≥ 30) for endothall inhalation exposures, at some level of risk 

mitigation (i.e., addition of PF5R respirator). The proposed label-specified personal protective 

equipment (PPE) includes: gloves, eye protection, and no respirator. The proposed label should 

be amended and a PF5R respirator should be required. The acute toxicity classification for 

primary eye irritation of endothall is Category I. Per the Worker Protection Standard (WPS), a 

48 hour restricted entry interval (REI) is required for chemicals classified under Toxicity 

Category I. The proposed ThinRite Blossom Thinner label indicates an REI of 12 hour, which is 

not in compliance with the WPS.

3.0 Introduction

3.1 Chemical Identity
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Table 3.1.1 Structure and Nomenclature of Endothall-dipotassium.

Chemical Structure

Common name Endothall, di-potassium salt

Molecular Formula C8H8K2O5

Molecular Weight 262.33

IUPAC name 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxyilic acid, potassium salt

CAS name 3,6-endoxohexahydrophthallic acid, potassium salt

CAS # 2164-07-0

PC Code 038904

Current Food/Feed Site Registration Cotton, hops, potato, alfalfa grown for seed, aquatic uses 

Table 3.1.2. Physicochemical Properties of Endothall.

Parameter Value Reference

Endothall

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

3.2 Pesticide Use Pattern 

Endothall is a selective contact herbicide, defoliant, desiccant, growth regulator and aquatic 

algicide which belong to the dicarboxylic acid chemical class. Endothall (PC Code 038901) and 

its dipotassium (PC Code 038904) and alkylamine (PC Code 038905) salts are registered 

primarily as aquatic herbicides to control a variety of plants including plankton, pondweed, 

naiad, coontail, milfoil, elodea, and algae in water bodies. 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. Endothall-treated water is also used 

for irrigation purposes on non-food crops, established ornamentals, turf grass, lawns, and noncrop areas (D336685, K. M. Lowe, 06 09, 2007).

ThinRite Blossom Thinner (EPA Reg. No. 70506-EOA), an end use product formulated as a 

flowable concentrate containing the active ingredient (ai) endothall-dipotassium (5.37%), is 

proposed to be used as part of a blossom thinning program in apples. Optimum application 

O

O

O

O

O

K

+

K

+
Endothall Human Health Risk Assessment DP No. 403274

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timing is usually when approximately 60 to 80% of the blooms are open. The label specifies a 

70-day pre-harvest interval (PHI). The proposed maximum single application rate is 6 pints of 

ThinRite per acre, equivalent to 0.423 lb (ai) endothall dipotassium salt per acre using airblast 

equipment on apples.

Table 3.2 Summary of Proposed Use Pattern for Endothall-dipotassium

Formulation

[EPA Reg. No.]

Target / 

Use site

Application 

Equipment

Maximum Application Rate Re-treatment 

Interval & 

Timing

ThinRite Blossom 

Thinner

70506-OEA 

Apple Airblast Single maximum application rate:

6 pints ThinRite Blossom Thinner per acre 

[0.423 lb (ai) endothall dipotassium salt 

per acre.]

and 

A maximum of two applications are 

permitted not to exceed a total of 12 pints 

of ThinRite Blossom Thinner or 0.846 a.i. 

endothall dipotassium salt per acre per 

growing season

Retreatment 

interval (RTI) is 

24 hours

Preharvest 

Interval (PHI) is 

70 days

3.3 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new uses of the herbicide endothall dipotassium for the thinning of blossoms on apple 

trees. Humans may be exposed to endothall dipotassium in food and drinking water, since the 

chemical may be applied directly to growing crops and may reach surface and ground water 

sources of drinking water. In an occupational setting, applicators may be exposed while 

handling the pesticide prior to application (i.e., mixing/loading), as well as during application

and reentering to treated areas to perform various agricultural tasks. 

Residential uses are not being proposed with this petition. Residential risk assessments have been 

updated here to reflect assumptions in the revised 2012 residential SOP. In a residential setting, 

humans may be exposed to endothall dipotassium as a result of handling the pesticide on 

application, and also potentially after application via exposure to treated water during swimming. 

This risk assessment considers all exposure pathways based on the existing and proposed new 

uses of endothall.

3.4 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(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, 
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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.

4.0 Hazard Characterization and Dose-Response Assessment

The endothall risk assessment team has reviewed the toxicity database for endothall and has 

selected endpoints for risk assessment purposes consistent with current HED policy and which 

are appropriate for the routes and durations of exposure anticipated from the existing and newly 

proposed uses of endothall. 

5-day and subchronic inhalation toxicity studies have been received and reviewed since the last 

risk assessment, and are considered for inhalation risk assessment. Other exposure scenarios 

were based on a prior assessment (David Soderberg, 11/09/09, D370448).

4.1 Toxicology Studies Available for Analysis

The toxicological database for endothall with the exception of an immunotoxicity study is 

complete and adequate for FQPA evaluation, selection of PODs for the various routes of 

exposure, and for dose-response evaluation. The available toxicology studies for endothall are 

summarized in Table A.1 in Appendix A. 

Acute/lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, 

and dermal sensitization)

Subchronic oral toxicity studies (rat, mouse, and dog) 

Developmental (rat and rabbit) and reproductive (rat) toxicity (oral) studies

Dermal (21-day) toxicity (rabbit) study 

Chronic oral toxicity studies (rat and dog)

Carcinogenicity (oral) studies [rat (chronic combined) and mouse]

Metabolism study (rat)

Mutagenicity battery 

28- day inhalation study (rat)

The studies available for consideration of endothall risk assessment provide a comprehensive 

database, with routes of administration which are consistent with potential exposure scenarios. 
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4.2 Absorption, Distribution, Metabolism, and Elimination (ADME)

In rats, at an oral 0.9 mg/kg dose, blood half-life elimination was 1.8 hrs in males and 2.5 hrs in 

females. At 4.5 mg/kg dose, the half-life elimination was 13.9 hours in males; the half-life in 

females could not be calculated because of a double blood peak. In single oral or intravenous 

dose studies, endothall did not undergo any metabolic transformation and was excreted 

unchanged. The results of a multiple (15-day) oral administration study indicated that endothall 

was absorbed and excreted largely unchanged in the feces and urine. At 24 hours, the tissue 

distribution of the compound was extensive but low. By 48 hours, the compound was mostly 

undetectable. 

4.2.1 Dermal Absorption

Since endothall is so toxic at the portal of entry (e.g., skin), quantification of systemic toxicity 

and risk resulting from dermal exposure will not be done, and a dermal absorption factor will not 

be estimated. 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 dose tested (30 mg/kg/day). Endothall is caustic dermally because it is an acid, and 

mitigation of any potential dermal effects can be addressed with precautionary labeling 

recommending the use of gloves and other personal protection which limits contact of the 

material with the handlers body.

4.3 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. In a dermal irritation study, endothall was an extreme irritant (category I). 

Although it was classified as a category III in an acute dermal toxicity study, endothall has been 

shown to be a severe irritant in a dermal absorption study (MRID 42169503) and in a 21-day 

dermal toxicity study (MRID 43465201) after one application. Based on all available data, 

endothall is classified as a severe dermal irritant. Endothall is also an extreme irritant by the 

acute oral and acute ocular routes of administration (category I), and is a skin sensitizer. In the 

acute inhalation study, it was classified as (category III however, there was irritation and other 

respiratory effects observed in 5-day and 28-day inhalation toxicity studies supporting the 

conclusion of the irritant effects of endothall. 

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. 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. Endothall caused gastric 

epithelial hyperplasia in dogs treated with an oral dose of 6.5 mg/kg/day for 52 weeks (a 
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NOAEL was not determined). 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). 

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. 

Dermally, endothall destroys the stratum corneum and then the underlying viable epidermis. In 

the 21-day dermal toxicity study, 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). 

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.

Pulmonary toxicity was evident in 5-day and 28-day inhalation toxicity studies in the rat. 

Pulmonary effects observed in the 5-day inhalation study included rales, labored respiration, pale 

lungs (gross necropsy), increased absolute and relative lung weights, subacute inflammation, 

alveolar proteinosis, and hemorrhage. The rales and labored respiration were noted daily (0 -1 

hrs post-dosing, prior to next exposure, and during detailed examinations) in addition, decreased 

body weights and food consumption, effects on clinical chemistry parameters were noted. 

Although nasal histopathology was not performed in the 5-day inhalation study, inflammation, 

erosion, and ulceration were noted in the nasal passages of rats that died during the study. The 

LOAEL in the 5-day study was 0.025 mg/L based on pulmonary effects, clinical chemistry and 

decreased body weights. A NOAEL was not identified. In the 28-day inhalation study, acute 

effects indicative of pulmonary toxicity included rales and labored respiration, which were 

observed daily (0 -1 hrs post-dosing, prior to next exposure, and during detailed examinations) in 

rats exposed to 0.005 mg/L endothall. In addition, increased lung weights and alveolar 

macrophages in both sexes were observed at scheduled necropsy. At 0.025 mg/L, rales and 

labored respiration were noted in rats that died during the study. Subacute inflammation of the 

trachea, and degeneration of the olfactory and respiratory epithelium of the nasal passages, were 

observed in rats exposed to 0.025 mg/L. Nasal effects at 0.005 mg/L consisted of minimal 
Endothall Human Health Risk Assessment DP No. 403274

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olfactory epithelial degeneration and mild goblet cell hypertrophy. A NOAEL of 0.001 mg/L 

was identified in the 28-day inhalation study. 

The HASPOC (December 19, 2012) waived the need for acute and subchronic neurotoxicity studies

in rats to support the proposed uses of endothal based on the lack of neurotoxicity in the endothall 

database as well as other carboxylic acid pesticides.

The only toxicity database deficiency is an immunotoxicity study as required by the revised 40 

CFR Part 158 Toxicology Data requirements.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The toxicology data base is adequate for FQPA assessment. The FQPA SF was removed for all 

scenarios except the chronic dietary assessment. For the assessment of risk following chronic 

dietary exposure, the FQPA Safety Factor for increased susceptibility to infants and children is 

reduced to 3X for the following reasons:

1) A LOAEL established in the two-generation reproduction study was used for assessing 

chronic dietary risks. Since a LOAEL was used, a 3X FQPA Safety Factor in the form of 

UFL is retained for chronic exposure scenarios. A 3X factor (as opposed to a 10X) was 

determined to be adequate since the severity of the lesions were minimal to mild. HED is 

confident that the chronic Population Adjusted Dose (cPAD = 0.007 mg/kg/day) will not 

underestimate risks following exposure to endothall.

2) There is no indication of increased susceptibility of rats or mice in utero and/or postnatal 

exposure in the developmental and reproductive toxicity studies;

3) There are no concerns for neurotoxicity; 

4) There are no residual uncertainties in the exposure data base. While the chronic dietary 

exposure estimates are partially refined (average field trial residues and adjustment of the 

percent of the harvested crop that has been irrigated) the results are still very 

conservative.

5) Residential SOP uses high end conservative data and most of the exposure comes from 

children swimming in ponds and lakes treated with endothall.

4.4.1 Completeness of the Toxicology Database

The toxicology database for endothall is complete for FQPA consideration and derivation of 

endpoints, except for the immunotoxicity study. An immunotoxicity study has been identified 

as a database deficiency. UPI is in the process of submitting a waiver request for the 

immunotoxicity requirement. The requirements for ACN and SCN studies have been waived by 

HASPOC (12/19/2012) based on the lack of neurotoxicity in the endothall database as well as 

other carboxylic acid pesticides.

4.4.2 Evidence of Neurotoxicity
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There is no evidence of neurotoxicity in the endothall database. Acute and subchronic neurotoxicity 

studies are not available for endothall. The HASPOC (December 19, 2012) waived the need for 

acute and subchronic neurtoxicity studies in rats to support the proposed uses of endothall.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

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 identification of potential 

developmental toxicity in this susceptible species). Therefore, a developmental toxicity study in 

mice (MRID 0085940, 00086623) was conducted and there was no evidence for enhanced 

susceptibility in this species. Based on toxicity data from 2 different species, there is no concern 

for quantitative or qualitative susceptibility associated with endothall exposures. 

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the endothall database in regard to dietary (food and

drinking water) and residential exposures. The residue data used for dietary exposure assessment 

are described in Section 5.4.1 of this document, and will not underestimate dietary food 

exposures. Modeling using PRZM/EXAMs was done to estimate drinking water residues; this 

modeling is designed to provide drinking water residue estimates which will not underestimate 

exposures from drinking water in the diet. Residential exposure estimates are based on

conservative, health-protective assumptions that also ensure exposures are not underestimated. 

4.5 Toxicity Endpoint and Point of Departure Selections

The available hazard database is adequate to characterize any potential for prenatal or postnatal 

risk for infants and children. 

4.5.1 Dose-Response Assessment

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 
Endothall Human Health Risk Assessment DP No. 403274

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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 (and points of departure) which are the same that 

were used in the previous 2005 risk assessment with the exception of those for inhalation 

exposure. For the inhalation exposure scenarios, the recently submitted inhalation toxicity study 

was identified as the most appropriate study. 

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. The Uncertainty Factor 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 the severity of the lesions were minimal 

to mild. 

Dermal: Since endothall is so toxic at the portal of entry (e.g., skin), quantification of systemic 

toxicity and risk resulting from dermal exposure will not be done, and a dermal absorption factor

will not be estimated. 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 dose tested (30 mg/kg/day). Endothall is caustic dermally because it 

is an acid, and mitigation of any potential dermal effects can be addressed with precautionary 

labeling recommending the use of gloves and other personal protection which limits contact of 

the material with the handlers body.

 

Inhalation: 

Residential handler exposure is expected to be short-term in duration. For this short-term 

inhalation exposure scenario, a NOAEL of 0.001 mg/L was selected from a 28-day inhalation 

toxicity study in the rat based on clinical signs of toxicity observed acutely at 0.005 mg/L. These 

signs, indicative of pulmonary toxicity, included rales and labored breathing and were seen daily 

(0-1 hr postdosing, prior to next exposure, and in detailed examinations). Although the 5-day 

inhalation study also revealed acute signs of pulmonary toxicity, a NOAEL was not identified, 

but the results of the study support the findings of the 28-day inhalation study. Therefore, the 

NOAEL for acute signs noted in the subchronic inhalation study was selected for the short-term 

residential exposure scenario. Intermediate-term exposures are not likely because of the 

intermittent nature of applications by homeowners. 

For the short- and intermediate- term occupational inhalation risk assessment, a NOAEL = 

0.001 mg/L was selected from a 28-day inhalation toxicity study in the rat in which the LOAEL 
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was 0.005 mg/L based on indications of lung toxicity (rales in males and increased lung weights 

and alveolar macrophages in both sexes). Long-term inhalation exposures are not anticipated.

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. This endpoint is 

appropriate with respect to the duration and population of concern (i.e., swimmers incidental oral 

ingestion in adult and children). 

Intermediate- and long-term incidental oral exposures are not expected.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dermal exposure was not quantitatively assessed due to a lack of toxicity via the dermal route. 

Since adults were assessed for oral ingestion while swimming in endothall dipotassium treated

pond and lakes, these exposures should be combined with background levels in food and 

drinking water to determine aggregate short-term exposure. For children’s residential exposure, 

only oral postapplication exposure was assessed, and this exposure should be combined with 

background exposure from food and drinking water to determine short-term aggregate exposure. 

For occupational workers, only inhalation exposure and risk were assessed.

4.5.3 Cancer Classification and Risk Assessment Recommendation

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.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

The doses and toxicological endpoints used for occupational and residential human health risk 

assessments for currently registered products are summarized in Table 4.5.4.1.

HED’s level of concern (LOC) for short-term occupational and residential inhalation risk 

estimates is 30 (i.e., an MOE less than 30 is considered a risk of concern). The level of concern 

is based on 3X to account for interspecies extrapolation to humans from the animal test species, 

and 10X to account for intraspecies sensitivity. For the assessment of risk following chronic 

dietary exposure, the FQPA Safety Factor for increased susceptibility to infants and children is 

reduced to 3X. HED’s LOC for incidental oral exposures is 100. This level of concern is based 

on 10X to account for interspecies extrapolation to humans from the animal test species, and 10X 

to account for intraspecies sensitivity. 

Table 4.5.4.1Summary 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
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Table 4.5.4.1Summary 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 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

FQPA SF = 3

cPAD = 

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 

Offspring

NOAEL = 9.4 

mg/kg/day

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

Short and IntermediateTerm Dermal Since endothall is so toxic at the portal of entry (e.g., skin), quantification of systemic 

toxicity and risk resulting from dermal exposure will not be done, and a dermal absorption 

factor will not be estimated. 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 dose tested (30 mg/kg/day). Endothall is 

caustic dermally because it is an acid, and mitigation of any potential dermal effects can be 

addressed with precautionary labeling recommending the use of gloves and other personal 

protection which limits contact of the material with the handlers body.

Long-Term Dermal NA no exposure under use pattern

Short-Term Inhalation NOAEL = 0.001 

mg/L

Residential HEC 

= 0.00049

mg/L (0.0176

mg/kg/day)A 

Occupational 

HEC = 0.0004

mg/L ( 0.0192) 

(mg/kg/day)B

UFA = 3XC

UFH = 10X

FQPA UF 

= 1X

Residential LOC 

for MOE = 30 

Occupational LOC 

for MOE = 30 

Subchronic inhalation toxicity study (MRID 

47872201).

Residential acute scenario: LOAEL = 0.005 

mg/L based on clinical signs (rales and labored 

respiration) observed acutely (0-1 hr 

postdosing and prior to next exposure).

Occupational short-term scenario: LOAEL = 

0.005 mg/L based on indications of lung 

toxicity (rales in males and increased lung 

weights and alveolar macrophages in both 

sexes). The NOAEL is 0.001 mg/L.

Intermediate-Term 

Inhalation 

NOAEL = 0.001 

mg/L

Occupational 

HEC = 0.0004 

mg/L 

(0.0192mg/kg/da

y)B

UFA = 3XC

UFH = 10X

Occupational LOC 

for MOE = 30

Subchronic inhalation toxicity study (MRID 

47872201).

LOAEL = 0.005 mg/L based on indications of 

lung toxicity (rales in males and increased 

lung weights and alveolar macrophages in both 

sexes). The NOAEL is 0.001 mg/L.

Long-Term Inhalation NA no exposure under this use pattern

Cancer (oral, dermal,

inhalation)

Classified as a “Not Likely” human carcinogen.
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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.

A Residential Exposures are anticipated only briefly (half hour) once a month and are acute. Residential HEC 

(pulmonary effect) = 0.0001 mg/L * (6hr/6 hr; 1.0) * (1d/1d; 1) * pulmonary RDDR (0.499) = 0. 00049 mg/L 

(0.0176 mg/kg/day)

B Occupational HEC (pulmonary effect) = 0.001 mg/L * (6 hr /8 hr ; 0.75) * (5d/5d; 1)* pulmonary RDDR (0.499) = 

0. 0004 mg/L (0.0192mg/kg/day)

C

Since the RfC methodology takes into consideration the pharmacokinetic (PK) differences but not the 

pharmacodynamic (PD) differences, the UF for interspecies extrapolation may be reduced to 3X (to account for the 

PD differences) while the UF for intraspecies variation is retained at 10X.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

DP# D321179, D. Soderberg, 8/30/2005

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. 

The qualitative nature of the endothall residues in livestock is adequately understood based on 

the acceptable poultry and goat metabolism studies. The residues of concern in animal 

commodities consist of parent endothall and its monomethyl ester.

In rat 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. Endothall exists in three forms in the environment:

endothall dipotassium, endothall potassium cation, and endothall acid. These chemical

forms are highly soluble and mobile in the environment. 

Endothall degrades by biotic processes such as aerobic metabolism. Single laboratory studies 

measured first-order degradation half-lives of 14.5 days for aerobic soil metabolism, 10 days

for aerobic aquatic metabolism, and 9 days for anaerobic soil metabolism. Terrestrial

dissipation studies measured dissipation half-lives from the soil surface of 13 to 19 days. The 

percent of dose absorbed increased with increasing dosage.

5.1.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized 

in Table 5.1.1 The residues of concern for endothall for purposes of both dietary food risk 
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assessment and tolerance enforcement in plant and animal commodities include parent endothall 

and its monomethyl ester. The residue of concern in water for risk assessment is endothall and is 

expressed in terms of endothall acid equivalents. (S. Funk, 11/8/96).

Table 5.1.1 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance 

Expression

Plants Primary Crop Endothall and its Monomethyl Ester Endothall and its Monomethyl Ester

Rotational Crop

Livestock Ruminant

Poultry

Fish

Drinking Water Endothall Not Applicable

5.2 Food Residue Profile

Adequate residue chemistry data have been provided to support the use of endothall on apples. 

Field trials are of adequate number and geographic representation and were generated using 

adequate analytical methods. Storage stability data indicate that residues are stable over the 

storage durations used in the field trials. Endothall residues were shown to concentrate in apple 

juice (1.2x) and wet pomace (2.8x). The maximum expected residues in wet pomace exceeded 

the tolerance recommended for the RAC. Therefore, a separate tolerance has been set for apple 

wet pomace at 0.15 ppm. For apple juice the maximum expected residues (i.e, Highest Average 

Field Trials x 1.2) did not exceeded the tolerance (0.05 ppm) recommended for the RAC. 

Therefore, a separate tolerance has been not been recommended for apple Juice. 

 

5.3 Water Residue Profile

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 endothalltreated irrigation water on a variety of crops (J. Lin, 9/12/12, D404321). The estimated

concentrations use the simple first-order degradation model, assuming either static (no flow) or

varying water turnover rates in the farm water body. Endothall concentrations degraded with

first-order kinetics starting immediately after application. 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 
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represents a conservative estimate of high-end chronic exposure from endothall from the use 

most likely to generate the highest exposures (treatment of a reservoir). 

 Result is summarized in the table below. 

Table 5.3.Summary of Estimated Surface Water and Groundwater Concentrations for 

Endothall

Chronic (non-cancer) 31

5.4 Dietary Risk Assessment

Memo, S.Tadayon, 02/28/2013, D407814

5.4.1 Description of Residue Data Used in Dietary Assessment

For this analysis percent crop treated for endothall from BEAD, average field trial residues for 

all existing and new use of endothall dipotassium salt, DEEM 7.81 default and crop specific 

processing factors obtained from processing studies for all commodities were used (DP#s: 

407814, S. Tadayon, 02/28/2013). Drinking water was incorporated directly into the dietary 

assessment using the maximum chronic concentration for surface water generated by the 

Pesticide Root Zone Model (PRZM) - Exposure Analysis Modeling System (EXAMS) at 31 ppb. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

A screening-level usage analysis (SLUA) was provided by the Biological Economic Analysis 

Division (BEAD), 11/19/2012. The following average PCT estimates were used to calculate 

chronic dietary exposures: Apple 62%, Apple fresh market 76%, Apple processing 37%, Apple 

juice 40%,Barley for grain 36%,Com for grain 19%, Dry Beans 32 %, Grape 95%, Grape 

Fresh market 99%, Grape Processing 94%, Green Peas 43%, Oats for grain 7% , Peanut for nuts 

42%, Rice 100% , Sorghum for grain 15% , Soybean for beans 9%, Strawberry, 90% , 

Strawberry Fresh market 88%, Strawberry Processing 100 , Sugar beet for sugar 37%, 

Sugarcane for sugar 54%, Watermelon 33%, Wheat for grain 14%

5.4.3 Acute Dietary Risk Assessment

There was no appropriate endpoint identified in the toxicity data that was the result of a single 

oral exposure to endothall. Since there is no acute dietary hazard for this chemical, acute dietary 

risk was not quantified.

5.4.4 Chronic Dietary Risk Assessment

A partially refined chronic dietary exposure and risk assessment was conducted incorporating 

both food and water residues as described above. The drinking water inputs were based on 

modeled surface water values from the scenario which provides the highest estimated 

environmental concentration. The exposure to drinking water comes from the direct application

to drinking water reservoirs. In a previous drinking water assessment, EFED has concluded
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the use of endothall-treated irrigation water represents the most conservative estimates for

drinking water assessment (DP 356316, September 9, 2009). Therefore, the same drinking

water exposure estimates c ontinued to be used for the human health risk assessment. 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. 

Typically, HED has concerns regarding dietary risk when the exposure estimates exceed 100% 

of the chronic population adjusted dose (cPAD). The estimated exposure (food and water) to the 

U.S. population from the existing and proposed new uses of endothall resulted in an estimated 

risk equivalent to 32% of the cPAD. The most highly exposed population subgroup is infants (1-

2 years old) with an exposure equivalent to an estimated risk of 90% of the cPAD. This 

assessment could be significantly refined using monitoring data; however, since risks of concern 

were not identified, further refinement was not undertaken.

The results of the chronic dietary exposure analysis are reported in the Summary Table 5.4.5.

Table 5.4.5. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Endothall Dipotassium Salt.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population

N/A N/A

0.002229 32

N/A N/A

All Infants (< 1 year old) 0.004392 63

Children 1-2 years old 0.006314 90

Children 3-5 years old 0.004575 65

Children 6-12 years old 0.002554 37

Youth 13-19 years old 0.001483 21

Adults 20-49 years old 0.001932 28

Adults 50+ years old 0.001983 28

Females 13-49 years old 0.001874 27

*Population subgroups with the highest exposure are shown in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Memo, Ana Rivera-Lupiáñez, Chemist, 02/20/2013, D404325

6.1 Residential Exposure
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There are no proposed residential uses at this time; a product containing endothall is currently 

registered for aquatic applications on ponds, lakes and garden pools. Residential exposures and 

risk were previously assessed and were not of concern (DP Code: 336685, 336686, 336687, 

336688, K. M. Lowe, June 9, 2007). Howver, it is the policy of HED to use the best available 

data to assess residential exposure; therefore, residential exposures resulting from the aquatic use 

were reassessed using HED’s SOP for Residential Exposure Assessments modified in HED’s 

SWIMODEL V 1.0 (W. Dang et al., 27-Mar-1999) and using updated body weight information. 

Residential risk for residential handlers was assessed (Ana Rivera-Lupiáñez, 02/20/2013,

D404325) assessed, however the inhalation risk is not a component of the aggregate pertinent to 

this action.

6.2 Postapplication Exposure

Table 6.2 presents the postapplication incidental oral ingestion MOE values calculated for adults 

and children 3 to <6 years old swimming after aquatic applications of endothall dipotassium to 

pond and lakes. Postapplication risk estimates do not exceed HED’s level of concern for any of 

the scenarios assessed. MOEs for oral exposures were 1,700 for adults and 250 for children 3 to 

<6 years old. 

Table 6.2: Residential Postapplication Non-cancer Exposure and Risk Estimates for Endothall (Swimmer Scenario)

Exposure Scenario Level of 

Concern

Maximum Concentration 

in Water 1(mg/L)

Exposure Dose

(mg/kg/day) 2,3

Short-term 

Oral MOE 4

Ingestion of water, Adult-(Female) 100 5 0.0056 1,700

Ingestion of water, Child 3<6 years old 100 5 0.0383 250

1. Maximum concentration in water (top 1 ft.) = 5 mg/L. based on maximum application rate from registered labels for 

aquatic weed control: 0.00022 lb ai/ft3 (EPA Reg.4581-388-82695).

2. Oral exposure dose (mg/kg/day) = concentration, Cw (5 mg/L) x ingestion rate, IgR (0.021 L/hr adults and 0.049 L/hr children 

3< 6) x exposure time, ET (3.7 hr adults and 3 hr children 3< 6)

(hrs/d) x 1/BW (adult-female=69 kg; children (3< 6) = 19 kg)

4. MOE = NOAEL/Exposure dose; short-term incidental oral NOAEL = 9.4 mg/kg /day. The LOC for adult females and 

children (3< 6) for short-term incidental oral exposures is MOEs < 100. 

6.3 Combined Exposure

HED combines risk values resulting from separate exposure scenarios when it is likely they can 

occur simultaneously based on the use pattern and the behavior associated with the exposed 

population (Table 6.2). 

6.4 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

assessment was not performed for endothall at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III), low vapor pressure (9.27 x 10-7 mm Hg) and the 

proposed use rate (0.423 lb ai/A). However, volatilization of pesticides may be a potential 

source of postapplication inhalation exposure to individuals nearby to pesticide applications. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010 
Endothall Human Health Risk Assessment DP No. 403274

Page 24 of 36

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative postapplication inhalation exposure assessment 

for endothall. Although a quantitative residential postapplication inhalation exposure assessment 

was not performed, an inhalation exposure assessment was performed for residential handlers. 

This exposure scenario is representative of a worse case inhalation exposure and should be 

considered protective of most postapplication inhalation exposure scenarios.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents near spraying operations. This is 

particularly the case with aerial application, but, to a lesser extent, could also be a potential 

source of exposure from the ground application method employed for endothall. The Agency 

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead 

Agencies for pesticide regulation and other parties to develop the best spray drift management 

practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm. On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. In the case of endothall, chronic aggregate risks result from exposure 

through food and water only. For short-term risks, adult and children’s incidental oral exposures 

were combined with background exposure from food and water. 

7.1 Acute Aggregate Risk

The available toxicity data indicate that toxicity resulting from a single day oral exposure to 

endothall is unlikely. Therefore, an acute aggregate assessment was not done.

7.2 Short-Term Aggregate Risk
Endothall Human Health Risk Assessment DP No. 403274

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Adult and children’s postapplication oral exposure (Table 6.2) were combined with the chronic 

dietary exposure from the mostly highly exposed adult (General US population) and children’s 

(all children 1-2 years old) subpopulations (Table 5.4.5), respectively, to determine aggregate 

exposure and risk as shown in Table 7.2. Despite the numerous conservative assumptions in 

developing these estimates, the MOEs are above the LOC of 100, and are not of concern.

Table 7.2. Short-Term Aggregate Risk Calculations for Endothall Dipotassium

Population NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult 100 100 1 0.002229 0.0056 0.007829 1200

Child 

Postapplication 100 100 1 0.006314 0.0383 0.0446 210

1

The LOC is based on the standard inter- and intra- species uncertainty factors totaling 100. The FQPA Safety Factor has been 

reduced to 1X.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure. Residential Exposure (adult and postapplication) = incidental oral (Table 6.2).

4 Total Exposure = (Avg. Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [9.4 Total Exposure]

7.3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary (food and water) exposure and risk, which 

is not of concern. Refer to Section 5.4.4.

8.0 Cumulative Exposure/Risk Characterization

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 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/.

9.0 Occupational Exposure/Risk Characterization

ThinRite Blossom Thinner may be applied as a dilute spray with air blast orchard equipment. 

Spray should be directed to areas of the canopy where the most thinning is desired, avoiding 

excessive application on low vigor branches to reduce the potential for over thinning, fruit finish 

marking, and leaf burn. The product is not intended to be applied with handgun sprayer, aerial 

application equipment, or through any type of irrigation equipment. Handler exposure is 

expected to be short- term based on information provided on the proposed label. The personal
Endothall Human Health Risk Assessment DP No. 403274

Page 26 of 36

protective equipment (PPE) label requirements include: long-sleeved shirt, long pants, chemical 

resistance gloves, protective eyewear, and shoes plus socks. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following exposure scenarios:

Mixer/Loaders

1. Mixing/loading liquids to support airblast applications, 

Applicators

2. Applying sprays with airblast equipment

9.1 Short- Term Handler Risk

No chemical-specific handler exposure data were submitted in support of the proposed use, and 

therefore HED relied on the best available surrogate data to complete the occupational handler 

assessment. Sources of generic handler data, used as surrogate data in the absence of chemicalspecific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the 

Agricultural Handler Exposure Task Force (AHETF) database, and the Outdoor Residential 

Exposure Task Force (ORETF) database. Some of these data are proprietary (e.g., AHETF data, 

MRID No. 44339801), and subject to the data protection provisions of FIFRA. The standard 

values recommended for use in predicting handler exposure that are used in this assessment, 

known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure 

Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), 

which, along with additional information on HED policy on use of surrogate data, including 

descriptions of the various sources, can be found at 

http://www.epa.gov/pesticides/science/handler-exposure-data.html.

The proposed product label directs applicators and other handlers to wear long sleeved shirt and 

long pants, shoes plus socks, and chemical-resistant gloves. HED typically assesses handler 

exposure using “baseline” clothing assumptions, and if risks of concern are identified, the use of 

personal protective equipment (PPE) may be incorporated into the exposure assessment. In the 

case of endothall, systemic toxicity via the dermal route was not quantified; personal protective 

equipment is required to mitigate potential risks related to the caustic properties of the chemical, 

Only inhalation exposures were quantitatively assessed. Additional PPE (i.e., PFR 5 respirators) 

were needed to achieve MOEs above the LOC of 30 for airblast equipment application scenarios

Standard assumptions were used with respect to body weight for adult handlers (80 kg), the 

exposure duration (i.e., short -term), and the area treated for various types of application 

equipment and application sites. In conjunction with these standard values, HED used the 

maximum application rates from the proposed label directions. Each of the risks is presented as 

a MOE, or the ratio of the NOAEL to the calculated daily dose.

Table 9.1 presents a summary of the short-term occupational handler exposures and risk

estimates. Occupational exposure scenarios assessed resulted in MOEs that do not exceed HED's 

level of concern (i.e., short-term MOEs ≥ 30) for endothall inhalation exposures, at some level of 

risk mitigation (i.e., addition of PF5R respirator). MOEs range from 410 for mixing/loading 
Endothall Human Health Risk Assessment DP No. 403274

Page 27 of 36

flowable liquids to support airblast application at label specified PPE (i.e., no respirator), to 96

for airblast equipment applicators utilizing a PF5R respirator. It should be noted that the 

proposed label directs mixers, loaders, applicators and other handlers to wear a long-sleeved 

shirt, long pants, shoes plus socks, chemical-resistant gloves and protective eyewear, but no 

respirator is required. 

Table 9.1.Occupational Handler Short Term Risk Estimates for Endothall Applications on Apples 

(Proposed use)

Exposure Scenario Crop or 

Target

App Ratea

(lb ai/A)

Acres Treated 

Dailyb

Baseline 

Inhalation 

Unit 

Exposurec

(mg/lb ai)

Inhalationd

Dose

(mg/kg/day)

MOE

Inhalation e

Short Term- Termf

Mixer/Loader (Male)

Mixing/Loading Liquid 

Flowables for 

Airblast Applications

Apple 

Blossoms 0.423 40 0.000219 0.00004 410

Applicator (Male)

Applying Sprays via 

Airblast Equipment 

(Open Cab)

Apple 

Blossoms 0.423 40 0.00471

0.00096

0.00019

(PF5R 

respirator)

19

96

(PF5R respirator)

a Application Rates based on proposed uses on label for ThinRite Blossom Thinner (EPA Reg. No. 70506-OEA).

b Based on Exposure Science Advisory Council Policy No. 9.1.

c Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” September 2012.

d Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/acre) x acres treated / body weight (males: 80 kg).

e Short–term Inhalation MOE = NOAEL (0.0192 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 30.

f. At label specified PPE (i.e., no respirator) unless specified)

9.2 Postapplication Risk

There is a potential for short- term occupational exposure to endothall-dipotassium during 

postapplication activities. Based on the uses associated with the ThinRite Blossom Thinner

product, occupational postapplication exposure can occur via the dermal and/or inhalation route.

Dermal exposure during postapplication activities is not considered because applicable dermal 

endpoints were not identified.

9.2.2 Inhalation Postapplication Risk

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

assessment was not performed for endothall at this time primarily because it has a low vapor 

pressure (9.7 x 10-7 mm Hg), it is applied at an application rate of 0.423 lbs ai/A, and it is not 

projected to be applied via typically high inhalation exposure application equipment (e.g., aerial 

equipment). However, volatilization of pesticides may be a potential source of postapplication 

inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The 

Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation 
Endothall Human Health Risk Assessment DP No. 403274

Page 28 of 36

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative postapplication inhalation exposure assessment 

for endothall.

The Environmental Protection Agency's requirements regarding Restricted-entry Intervals

(REIs) are included in the 40 CFR 156.208. In accordance with the 40 CFR 156.208, the REI is 

based on the acute toxicity of the “technical active ingredient material”. The toxicity categories 

of the active ingredient for acute dermal, eye irritation, and skin irritation potential are used to 

determine the interim Restricted-entry Intervals. If one or more of the three acute toxicity effects 

are in toxicity category I, the interim REI is established at 48 hours. The acute toxicity 

classification for primary eye irritation of endothall-dipotassium is Category I. Per the Worker 

Protection Standard (WPS), a 48-hour restricted entry interval (REI) is required for chemicals 

classified under Toxicity Category I. The proposed ThinRite Blossom Thinner label indicates an 

REI of 12-hour, which is not in compliance with the WPS. 

10.0 References

S. Tadayon. Chronic Dietary (Food and Drinking Water) Exposure and Risk 

Assessment for the Section 3 Registration Action to Support New Use on apple.

D407814. 02/28/2013.

Ana Rivera-Lupiáñez,: Endothall-dipotassium: Occupational and Residential Risk Assessment

for Proposed uses of a new endothall-dipotassium product for thinning blossoms on apple trees. 

D404325. 02/22/2013.

David Soderberg,:Endothall; Petition for Registration of ThinRite Blossom Thinner: Summary

of Analytical Chemistry and Residue Data. D384206 09/30/2011

Appendix A. Toxicology Profile and Executive Summaries
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A.1 Toxicology Data Available for Endothall.

The toxicological data requirements (40 CFR 158.340) for food uses for endothall are in 

Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline 

protocols were used.

Table A.1 Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity .......................................................

870.1200 Acute Dermal Toxicity...................................................

870.1300 Acute Inhalation Toxicity ..............................................

870.2400 Primary Eye Irritation ....................................................

870.2500 Primary Dermal Irritation...............................................

870.2600 Dermal Sensitization ......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rat and mouse) ...................................

870.3150 Oral Subchronic (dog)....................................................

870.3200 21/28-Day Dermal (rat)..................................................

870.3250 90-Day Dermal...............................................................

870.3465 28-Day Inhalation ..........................................................

yes

yes

yes

CR

noA

yes

yes

yes

yes

yes

870.3700a Developmental Toxicity (rat).........................................

870.3700b Developmental Toxicity (rabbit)....................................

870.3800 Reproduction (rat)..........................................................

yes

yes

yes

yes

no

yes

870.4100a Chronic Toxicity (rat) ....................................................

870.4100b Chronic Toxicity (dog)...................................................

870.4200a Carcinogenicity (rat) ......................................................

870.4200b Carcinogenicity (mouse)................................................

870.4300 Chronic/Carcinogenicity (rat) ........................................

yes

yes

yes

yes

yes

chronic/onco

yes

chronic/onco

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial .....................

870.5300 Mutagenicity—Gene Mutation - mammalian ................

870.5375 Mutagenicity—Structural Chromosomal Aberrations ...

870.5395 Mutagenicity—Mammalian Erythrocyte Micronucleus.

870.5500 Mutagenicity— Bacterial DNA Damage or Repair Test

870.5550 Mutagenicity—Unscheduled DNA Synthesis.................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity. (hen) ..............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat)..................

870.6200b 90 Day Neurotoxicity Screening Battery (rat) ...............

870.6300 Developmental Neurotoxicity (rat) ................................

no

no

noA

noA

CR

-

-

-

-

-

870.7485 General Metabolism (rat)...............................................

870.7600 Dermal Penetration (8-hour), in vivo (male rat).............

yes

CR

yes

yes

870.7800 Immunotoxicity (rat)........................... yes no

AHASPOC TXR No. 0056397. Waived. 

Attachment 2. Toxicity Profile for Endothall
Endothall Human Health Risk Assessment DP No. 403274

Page 30 of 36

Table A.2.a Acute Toxicity Profile – Endothall 

Guideline No./ Study Type MRID No. Results Toxicity Category

870.1100 Acute oral toxicity 42289201 LD50 = 50.2/44.4[m/f] mg/kg I

870.1200 Acute dermal toxicity 42289202 LD50 = >2000[m/f] mg/kg III

870.1300 Acute inhalation toxicity 42169501 LC50 = 1.27/2.20[m/f] mg/L III

870.2400 Acute eye irritation 42289203 Severe irritant; lethal 4/6 rabbits I

870.2500 Acute dermal irritation 42289204 Unacceptable study I a

870.2600 Skin sensitization 41871901 Sensitizer N/A

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

870.3100

90-Day oral toxicity 

rodents (rat)

43480810(1994)

Acceptable/guideline

0, 150, 600, 1800 ppm

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

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

NOAEL = 39 mg/kg/day

LOAEL = 118 mg/kg/day based on 

treatment related deficits in body weight.

870.3150

13 week oral toxicity 

in nonrodents (dog)

43480802 (1994)

Acceptable/guideline

0, 100, 400, 1000 ppm

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

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

NOAEL = 11.7 mg/kg/day

LOAEL = 27.5 mg/kg/day based on 

decreases in body weight gain.

870.3200

21-Day dermal 

toxicity (rat)

range-finding

42814101 (1992)

Acceptable/nonguide

-line

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

NOAEL = not determined

LOAEL = 80 mg/kg/day based systemic 

toxicity (death)

LOAEL = 80 mg/kg/day based on dermal 

irritation

870.3250

21-Day dermal 

toxicity (rat)

43465201(1994)

Acceptable/guideline

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

NOAEL = not determined

LOAEL = 30 mg/kg/day based on 

decreased body weight gains.

LOAEL = 30 mg/kg/day based on dermal 

irritation 

870.3700a

Prenatal 

developmental in 

rodents (rat)

42776301 (1993)

Acceptable/guideline

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

Maternal NOAEL = 12.5 mg/kg/day

LOAEL = 25 mg/kg/day based on 

decreased body weight gain.

Developmental NOAEL => 25 

mg/kg/day

LOAEL = not determined HDT.

870.3800

Reproduction and 

fertility effects

43152101 (1993)

43629301 (1995)

Acceptable/guideline

0, 30, 150, 900 ppm

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

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

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

Parental/Systemic NOAEL = not 

established

LOAEL = 2 mg/kg/day based on 

proliferative lesions gastric epithelium 

both sexes.

Reproductive NOAEL = 9.4 mg/kg/day

LOAEL = 60.0 mg/kg/day based on 

decreased pup body 

weightsReproductive Offspring NOAEL 
Endothall Human Health Risk Assessment DP No. 403274

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

= 9.4 mg/kg/day

LOAEL = 60.0 mg/kg/day based on 

decreased pup body weights.

870.4100b

Chronic toxicity dogs

40745202 (1987)

supplementary/guideline

0, 150, 450,350 ppm. high dose lowered to 

1000 ppm at the 7th 

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

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

NOAEL = not determined

LOAEL (LDT) = 6.5 mg/kg/day based on 

gastric epithelial hyperplasia.

870.4200b

Carcinogenicity mice

40685301 (1988)

supplementary/guideline

0, 50, 100, 300 ppm

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

21 months

NOAEL =15 mg/kg/day

LOAEL = 45 mg/kg/day based on 

decreased body weight gain and 

microscopic findings in male kidney.

no evidence of carcinogenicity

870.4200b

Carcinogenicity mice

43608301(1995)

acceptable/guideline

0, 750, 1500 ppm

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

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

79 weeks

NOAEL = not determined

LOAEL = 124 mg/kg/day based on 

decreased body weight gain in males.

No evidence of carcinogenicity.

870.4300

chronic/onco rat

41040301(1989)

acceptable 

0, 150, 300, 900, 1800ppm

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

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

NOAEL = 8 mg/kg/day

LOAEL = 16 mg/kg/day based on 

decreased body weight and body weight 

gain.

No evidence of carcinogenicity.

Gene Mutation

Guideline # OPPTS 

870.5300 [§84-2]; 

OECD 476, study type

In vitro Mammalian 

Cell Gene Mutation 

Assay

43437801 (1993)

classification Acceptable

equivalent = 11.6%) Dosed in (DMSO) at 

concentrations of 0.0116, 0.0580, 0.116, 

0.580, 1.16, 2.32, 2.9, 3.48, 4.06, and 4.64 

μg/mL (all concentrations expressed as active 

ingredient) without metabolic activation or at 

0.116, 0.58, 1.16, 5.8, 11.6, 17.4, 20.3, 21.8, 

23.2 and 26.1 μg/mL with metabolic 

activation (Initial Trial). For the 

confirmatory trial, levels of 0.0116, 0.0580, 

0.116, 0.580, 1.16, 2.32, 2.90, 3.48. 4.06. 

4.64, 5.22 and 5.80 μg/mL -S9 or 0.116, 

0.580, 1.16, 5.80, 11.6, 17.4, 23.2, 26.1 and 

29 μg/mL +S9 were processed. 

Negative

Gene Mutation

Guideline # Bacterial 

Gene Mutation Assay 

(Salmonella 

typhimurium)/OPPTS 

870.5100/[§84-2] 

OECD 471

43154801 (1993).

Unacceptable

in dimethyl sulfoxide (DMSO) (equivalent 

to 1.93, 5.80, 19.3, 58.0, 116 or 193 μg/plate 

active ingredient) with or without S9 

activation.

Negative

Cytogenetics 43157401 (1994) Acceptable Negative
Endothall Human Health Risk Assessment DP No. 403274

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

In vivo Mammalian 

Cytogenetics -

Micronucleus Assay 

in Mice/OPPTS 

870.5395/[§84-2]

mice were administered 0.464, 0.928 and 

1.86 mg/kg Endothall Technical amine salt 

(1.5:1 amine :salt ratio; Batch No. B46-44-1; 

endothall amine 30.3%;endothall acid 

equivalent = 11.6%) via intraperitoneal 

injection (IP) in deionized water;

Cytogenetics 

In vivo Mammalian 

Cytogenetics -

Micronucleus Assay 

in Mice/OPPTS 

870.5395/[§84-2]

41700301 (1989)

Acceptable

mice were administered 2,10 or 50 mg/kg 

Endothall 

Negative

Cytogenetics 

In vitro Mammalian 

Cytogenetics OPPTS 

870.5375 [§84-2]; 

OECD 473

41700302 (1989) Acceptable

in dimethyl sulfoxide (DMSO) at 

concentrations of 2.5, 10.0, 20.0 and 40.0 

μg/mL without metabolic activation or were 

exposed for 3 hours to 15.0, 60.0, 120.0 or 

240.0 μg/mL with metabolic activation

Negative

870.7485

Metabolism and 

pharmacokinetics

42169502 (1990),

acceptable

a single i.v. dose at 0.9 mg/kg, a single oral 

dose at 0.9, 4.5 or 9.0 mg/kg and as a 15 day 

multiple dose at 0.9 and 9.0 mg/kg/day.

Intravenous administration of 0.9 mg/kg 

resulted in excretion mainly by the urine 

(69%) and feces. At an oral 0.9 mg/kg 

dose, blood half-life elimination - 1.8 hrs 

in males, 2.5 hrs females. At 4.5 mg/kg 

half-life - 13.9 hours in males; the halflife in females could not be calculated 

because of a double blood peak. Multiple 

oral or single administration indicated that 

the test material was rapidly absorbed and 

excreted in the feces (89-98%) and urine 

(5-9%). The compound did not 

bioaccumulate. At 24 hours tissue 

distribution of the compound was 

extensive but low, the highest amount 

(<10%) being found in the gastrointestinal 

tract. By 48 hours, the compound was 

mostly undetectable in the tissue. Bile 

elimination was only of minor 

importance. Absorbed or unabsorbed test 

compound in all groups was excreted 

mainly as chemically unchanged 

Endothall in the feces and urine.

870.7485

Metabolism and 

pharmacokinetics

44263501 (1997)

acceptable

Administered to 10 Sprague Dawley rats 

(5/sex/dose) in distilled water by gavage at a 

dose 9 mg/kg. Animals were sacrificed after 

24 hours.

Following a single oral administration of 

[

14C}-Endothall to male and female rats 

(approximately 9 mg/kg), the majority of 

the radioactivity (70.8% males, 71.2% 

females) was excreted within the 0-24 

hour time period, with most of the 

radioactivity being present in the feces 

(47.6% males, 47.5% females) At 24 

hours after dosing, less than 0.21% of the 
Endothall Human Health Risk Assessment DP No. 403274

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

dose was found in the stomach (+ 

contents), small intestine (+ contents) and 

pancreas and very little detected in the 

blood (below 15 ng eq/g). Higher levels 

of radioactivity were found in the caecum 

(3.0% males, 6. 1 % females) and the 

large intestine (3.2% males, 8.2% 

females).

Analysis of extracts of the urine, feces, 

caecum and large intestine of both male 

and female rats gave a single radioactive 

component corresponding to unchanged 

Endothall which accounted for >86, >96, 

>74 and >69% of total recovery from the 

respective extracts.

870.7600

Dermal penetration

42169503 (1990)

acceptable

Dose levels were 0.0125 mg/cm2 (0.3 mg/rat), 

0.0625 mg/cm2(1.5 mg/rat) and 0.125 

mg/cm2(3.0 mg/rat) respectively. Five (5) 

animals per time period (0..5, 1, 2, 4, 10 or 

24 hours) in each dose 

Approximately 55 to 82% of the applied 

dermal dose was washed from the 

application site. The rest of the [14C]-

Endothall equivalents was contained in 

the application site skin. Urinary 

excretion of [14C]-Endothall equivalents 

increased in a dose related manner at 10 

and 24 hours to a maximum of 2.3% of 

the applied dose at the 0.125 mg/cm2(3.0 

mg/rat)dose level. Fecal excretion 

amounted to <0.1% at all dose levels. At 

the 0.0125 mg/cm2 (0.3 mg/rat), 0.0625 

mg/cm2(1.5 mg/rat) and 0.125 mg/cm2

(3.0 mg/rat) dose levels, systemic 

bioavailability (absorption) of 3.9%, 2.2% 

and 7.3%, respectively, were noted at 24 

hours. A time related increase in systemic 

bioavailability occurred only at the 1.5% 

dose level. The dose related pattern of 

absorption was typical of a chemical 

which directly damages the skin. The 

percent of dose absorbed increased with 

increasing dose. The total percent 

recovery of [14C]-Endothall equivalents 

was 97.7 to 101.1% of the administered 

dose throughout the 24 hour period.

Special studies None

870.3465

28- day inhalation rat 

47872201/47872202 

acceptable

5 day: 0, 0.025, 0.075, and 0.152 mg/L, 

respectively) for 6 hours/day for 5 

consecutive days.

5 day: LOAEL = 0.025 mg/L, based on 

decreased body weights and food 

consumption, effects on clinical chemistry 

parameters, liver effects (subacute 

inflammation and hepatocellular necrosis) 

and pulmonary effects (increased absolute 

and relative lung weights, subacute 
Endothall Human Health Risk Assessment DP No. 403274

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

28-day: 0 (air), 0.001, 0.005, or 0.025 mg/L 

for 6 hours per day, 5 days/week for 4 weeks

inflammation, alveolar proteinosis, and 

hemorrhage). The NOAEL was not 

established.

28-day: LOAEL = 0.005 mg/L based on 

indications of lung toxicity (rales in males 

and increased lung weights and alveolar 

macrophages in both sexes). 

NOAEL is 0.001 mg/L.
Endothall Human Health Risk Assessment DP No. 403274

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Appendix B. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force 

(ORETF) database; are subject to ethics review pursuant to 40 CFR 26, have received that 

review, and are compliant with applicable ethics requirements. For certain studies that review 

may have included review by the Human Studies Review Board. Descriptions of data sources as 

well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handlerexposure-data.html and http://www.epa.gov/pesticides/science/postapp-exposure-data.html.
Endothall Human Health Risk Assessment DP No. 403274

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Appendix C. International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex

40 CFR 180.293:

Plants/Livestock: combined residues of 

endothall, 7-oxabicyclo [2, 2, 1] heptane-2, 

3-dicarboxylic acid and its monomethyl 

ester 

(d) Indirect or inadvertent residues:

endothall (7 - oxabicyclo[2.2.1] heptane2,3-dicarboxylic acid) in potable water from 

use of its potassium, sodium, di- N , N -

dimethylalkylamine, and mono- N-N , -

dimethylalkylamine salts as algicides or 

herbicides to control aquatic plants in 

canals, lakes, ponds, and other potable water 

sources that may lead to endothall residues 

7-oxabicyclo[2, 

2,1]heptane-2,3-

dicarboxylic acid, 

including its 

monomethyl ester

None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Apples 0.05

Apple, Wet 

Pomace 0.15

Completed: M. Negussie; 01/30/2013

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2Mexico adopts US tolerances and/or Codex MRLs for its export purposes.