Endothall Human Health Risk Assessment DP No. D422204 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 12/09/2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Endothall: Human Health Risk Assessment in Support of Registration 

Review, and the Petition to Re-evaluate Tolerances for Livestock, and 

Remove the Restriction that Prohibits Livestock from Drinking Treated 

Water. 

PC Code: 03890 I (Acid), 038904 (Dipotassium). and 

038905 (Monoalkylamine) 

DP Barcode: 0422204 and 0426245 

Decision No.: 492480 and 502452 Registration No.: 70506-174, 70506-175, 70506-176, 

70506-191 , 70506-1 90, 70506- 180, 70506-302 

Regulatory Action: Reg Review and Tolerance 

Petition 

Petition No.: 4F8293 

Risk Assessment Type: Single chemical/aggregate 

TXR No.: NA 

Case No.: 2245 

CAS No.: 145-73-3; 2 164-07-0; and 66330-88-9 

MRID No.: NA 40 CFR: 180.293 

FROM: ldeliz Negr6n-Encamaci6n, Ph.D., Che 

John Liccione, Ph.D., Tox·c I gis 

Katelynn King, Biologist 

Seyed Tadayon, Chemist.-:..-'-

Risk Assessment Branch V and Vil 

Hea lth Effects Division (7509P) if 

TH ROUGH: Michael S. Metzger, Branch Chief ~ /)) 

and ~1{1 Christina Swartz, RARC Reviewe 

Kelly Lowe, RARC Reviewer , 

Hea lth Effects Division (7509P) 

TO: Sarah Meadows, Ph.D., Risk Manager Reviewer 

Kathryn Montague, Risk Manager 

Risk Management Division (7505 P) 

and 

Garland Waleko. Risk Manager Reviewer 

Kevin Costello, Risk Manager 

Pesticide Re-evaluation Division (7508P) 

Page I of 53 
Endothall Human Health Risk Assessment DP No. D422204

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As part of Registration Review, the Pesticide Re-Evaluation Division (PRD) of the Office of 

Pesticide Programs (OPP) has requested that the Health Effects Division (HED) evaluate the 

hazard and exposure data and conduct occupational and residential exposure assessments, as 

needed, to estimate the risk to human health that will result from the currently registered uses of 

pesticides. This memorandum serves as HED’s scoping document and draft human health risk 

assessment for endothall. In addition, the Registration Division (RD) has requested the 

evaluation of United Phosphorous Inc. tolerance petition for endothall on meat, milk, poultry and 

eggs to support the removal of the restriction on consumption of water treated with endothall by 

livestock. The most recent quantitative human health risk assessment was conducted in 2013 to 

support the proposed use of the dipotassium form of endothall on apples (D403274, S. Tadayon, 

3/18/2013).
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1.0 Executive Summary ........................................................................................................... 5

2.0 HED Recommendations .................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 8

2.2 Tolerance Considerations.............................................................................................. 8

2.2.1 Enforcement Analytical Method ........................................................................... 8

2.2.2 Recommended Tolerances...................................................................................... 9

2.2.3 Revisions to Petitioned-For Tolerances .............................................................. 13

2.2.4 International Harmonization............................................................................... 13

2.3 Label Recommendations.............................................................................................. 13

2.3.1 Recommendations from Residue Reviews.......................................................... 13

2.3.2 Recommendations from Occupational Assessment........................................... 14

2.3.3 Recommendations from Residential Assessment............................................... 14

3.0 Introduction...................................................................................................................... 14

3.1 Chemical Identity ......................................................................................................... 14

3.2 Physical/Chemical Characteristics ............................................................................. 15

3.3 Pesticide Use Pattern.................................................................................................... 16

3.4 Anticipated Exposure Pathways................................................................................. 17

3.5 Consideration of Environmental Justice.................................................................... 17

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 18

4.1 Toxicology Studies Available for Analysis................................................................. 18

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 18

4.2.1 Dermal Absorption ............................................................................................... 18

4.3 Toxicology Effects ........................................................................................................ 18

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 20

4.4.1 Completeness of the Toxicology Database.......................................................... 20

4.4.2 Evidence of Neurotoxicity .................................................................................... 20

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .... 21

4.4.4 Residual Uncertainty in the Exposure Database................................................ 21

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 21

4.5.1 Recommendation for Combining Routes of Exposures for Risk Assessment. 22

4.5.2 Cancer Classification and Risk Assessment Recommendation ........................ 22

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

Assessment........................................................................................................................... 23

4.6 Endocrine Disruption................................................................................................... 25

5.0 Dietary Exposure and Risk Assessment......................................................................... 25

5.1 Residues of Concern Summary and Rationale .......................................................... 26

5.2 Food Residue Profile .................................................................................................... 27

5.3 Water Residue Profile.................................................................................................. 27

5.4 Dietary Risk Assessment.............................................................................................. 28

5.4.1 Description of Residue Data Used in Dietary Assessment ................................ 28

5.4.2 Percent Crop Treated Used in Dietary Assessment........................................... 28

5.4.3 Acute Dietary Risk Assessment ........................................................................... 29

5.4.4 Chronic Dietary Risk Assessment ....................................................................... 29

5.4.5 Cancer Dietary Risk Assessment......................................................................... 29

5.4.6 Summary Table..................................................................................................... 29

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 30

6.1 Residential Handler Exposure .................................................................................... 30
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6.2 Residential Post-application Exposure/Risk Estimates............................................ 30

6.3 Residential Risk Estimates for Use in Aggregate Assessment.................................. 32

6.4 Residential Bystander Post-application Inhalation Exposure ................................. 32

6.5 Spray Drift.................................................................................................................... 33

7.0 Aggregate Exposure/Risk Characterization.................................................................. 34

7.1 Acute Aggregate Risk................................................................................................... 34

7.2 Short-Term Aggregate Risk ........................................................................................ 34

7.3 Intermediate-Term Aggregate Risk ........................................................................... 34

7.4 Chronic Aggregate Risk .............................................................................................. 35

7.5 Cancer Aggregate Risk ................................................................................................ 35

8.0 Cumulative Exposure/Risk Characterization ............................................................... 35

9.0 Occupational Exposure/Risk Characterization ............................................................ 35

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 35

9.2 Post-Application Risk Assessment.............................................................................. 38

9.2.1 Inhalation Post-Application Risk Assessment.................................................... 38

9.2.2 Dermal Post-Application Risk Assessment......................................................... 39

10.0 Public Health and Pesticide Epidemiology Data........................................................... 39

11.0 References..................................................................................................................... 40

Appendix A. Toxicology Profile and Executive Summaries .................................................. 41

Appendix B. Physical/Chemical Properties............................................................................. 47

Appendix C. Review of Human Research................................................................................ 48

Appendix D. Use Pattern Summary Tables............................................................................. 49

Appendix E. International Residue Limits Table ................................................................... 50

Appendix F. Status of Residue Chemistry Issues Identified in the 2005 Chapter. ............... 53
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1.0 Executive Summary

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) is the active 

ingredient that forms from the breakdown of the endothall salts, and is not applied directly to use 

sites. Endothall 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. Tolerances are established in the 40 CFR § 180.293 for 

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

(aquatic) residues resulting from endothall products. An interim tolerance for negligible residues 

of endothall in sugar beets is established in 40 CFR § 180.319. In addition to exposure through 

dietary pathways, exposure may result from residential and occupational uses of endothall. This 

risk assessment is prepared in support of registration review (scoping and draft risk assessment 

actions) and the petition to remove the restriction that prohibits livestock from drinking water 

treated with endothall. 

Hazard/Toxicity

The toxicology database for endothall is complete. The Hazard and Science Policy Committee 

waived the need for acute and subchronic neurotoxicity studies (HASPOC, TXT # 0056545, 

12/19/2012) in rats and the need for an immunotoxicity study (HASPOC, TXT # 0056794, 

09/26/2013). 

Endothall is a caustic chemical with toxicity being the result of a direct degenerative effect on 

tissue. The dog is particularly sensitive to endothall toxicity. Orally, it damages the canine 

digestive tract at relatively low doses, and then the liver and kidneys at lethal doses. Dermally, it 

destroys the stratum corneum and then the underlying viable epidermis in rabbits and rats. 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. In a dermal irritation 

study, endothall was an extreme irritant. 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 and in a 21-day dermal toxicity study 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, and is a skin sensitizer. In the acute 

inhalation study, it was classified as slightly irritating, 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. 

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. 
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Appropriate endpoints were identified for the chronic dietary risk assessment based on 

proliferative lesions of the gastric epithelium in both sexes; for the short-term occupational and 

residential, and the intermediate-term occupational inhalation risk assessments based on 

indications of lung toxicity in a subchronic inhalation toxicity study in the rat; and for the shortterm incidental oral risk assessment based on decreased pup body weight in a 2-generation rat 

reproduction oral study. An acute dietary endpoint attributable to a single dose was not 

identified from any study. No dermal endpoint was selected for endothall because the dermal 

irritation observed in a repeated-dose study is considered self-limiting. 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.

Residue Chemistry

The residues of concern in plant and livestock commodities for risk assessment are endothall and 

its monomethyl ester. The residue of concern in drinking water is the free acid of endothall. 

Methods are available for enforcement of tolerances for endothall on food and feed commodities 

as a result of direct and inadvertent (aquatic) residues resulting from the use of endothall 

products. An independent laboratory validation (ILV) for a livestock enforcement method and a 

storage stability study have been submitted and evaluated in support of the removal of the label 

restriction that prohibits livestock from drinking water treated with endothall. The chemistry 

database of endothall is adequate to support the proposed updated tolerances for livestock 

commodities, the removal of the label restriction, and registration review of endothall provided 

that data needs and tolerance recommendations described in Section 2.0 are addressed. 

Dietary Exposure and Risk

A refined, chronic dietary exposure and risk assessment was conducted incorporating average 

percent crop treated data, average field trial residues for all crops, DEEM 7.81 default and crop 

specific processing factors for all commodities. The drinking water inputs were based on 

modeled surface water values from the scenario which is likely to provide the highest estimated 

environmental concentration. The estimated exposure (food and water) to the U.S. population 

from the existing uses of endothall resulted in an estimated risk equivalent to 32% of the chronic 

population adjusted dose (cPAD). The most highly exposed population subgroup is children 1-2 

years of age with an exposure equivalent to an estimated risk of 90% of the cPAD. Exposures to 

endothall for all food and water uses are below HED’s level of concern (LOC; < 100% of the 

cPAD).

Residential Exposure and Risk Estimates

Endothall products are intended for use on residential sites, but labels require certain PPE to be 

worn (long sleeve shirt, pants, gloves, and, a dust /mist respirator). Standard HED assumptions 

for residential/consumer applicator specific assessments, such as wearing shorts and a t-shirt 

without PPE like chemical-resistant gloves or respirators, would represent non-compliance with 

current endothall products; therefore, a residential handler assessment has not conducted. An 

exposure assessment for occupational handlers/applicators assuming compliance with label 

requirements for work clothing and/or PPE was conducted. If products containing endothall are 

meant to be marketed towards and performed by consumers/homeowners in on residential sites, 

HED recommends that label requirements for PPE be reevaluated or separate consumer-specific 

labels be developed and a separate residential handler assessment be conducted to evaluate such 

products.
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Based on the aquatic application scenarios, HED assessed inhalation and incidental oral (water 

ingestion) post-application exposures from the aquatic use (adult and children). Post-application 

dermal risk assessments were not conducted because no hazard was identified via the dermal 

route for the relevant exposure durations. The resulting margins of exposure (MOEs) for shortterm post-application inhalation and incidental oral exposures are not of concern to HED (i.e., 

MOEs > 30 for inhalation exposures and MOEs ≥100 for incidental oral exposures). 

Aggregate Exposure and Risk

A short-term aggregate assessment considering exposures from food and water with those from 

residential exposure (i.e., incidental ingestion of treated water (swimmers)) was conducted. 

Post-application oral exposure for adults and children were combined with the chronic dietary 

exposure from the mostly highly exposed subpopulations. The short-term risk is not of concern 

as the MOEs are above the level of concern (LOC) of 100.

Occupational Exposure and Risk Estimates

The registered labels require occupational handlers to wear the following personal protective 

equipment (PPE): long-sleeved shirts, long pants, chemical resistant gloves, protective eyewear 

and dust mist respirator (TC-21C). The occupational handler exposure and risk estimates for 

some aquatic scenarios indicate that short- and intermediate-term non-cancer inhalation MOEs 

are of concern to HED (i.e., MOEs < 30) with label recommended PPE, and even with a closed 

system (i.e., engineering control). The MOEs for aquatic scenarios range from 1 to 873. The 

occupational handler exposure and risk estimates for agricultural scenarios indicate that shortand intermediate-term non-cancer inhalation MOEs are not of concern to HED (i.e., MOEs > 30) 

with label recommended PPE (i.e., dust/mist respirator). The MOE’s for agricultural scenarios 

range from 31 to 2,900. The acute toxicity classification for primary eye irritation of endothall is 

category I which requires a 48-hour restricted entry interval (REI). The 48-hour REI listed on 

the agricultural labels is appropriate. 

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

intentionally exposed to a pesticide or other chemical. Additional information on how these 

studies are considered can be found in Appendix C.

2.0 HED Recommendations

The hazard database for endothall is complete and adequate to support registration review.

The residue chemistry database of endothall is adequate to support the removal of the restriction 

that prohibits livestock from drinking water treated with endothall; provided that data 

deficiencies, recommended tolerance levels, and tolerance expression described in Section 2.1 

and 2.2.2 are addressed.

HED concludes the following regarding the occupational and residential exposure database: 

 There are occupational inhalation risk estimates of concern associated with the currently 

registered uses of one of the two granular formulations of endothall, the dimethyl alkyl 

amine salt (Hydrothol 191 Granular; EPA Reg. No. 70506-174). The dipotassium 

granular formulation (Aquathol Super K; EPA Reg. No. 70506-191) is not likely to result 
Endothall Human Health Risk Assessment DP No. D422204

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in an inhalation risk of concern based on the following: it is coated with polymer 

minimizing formation of respirable/inhalable dust; tests performed by the registrant 

showed that granules can be ground to very small particles only by vigorous attrition 

measures, and an attrition type study with dipotassium salt of endothall demonstrated that 

small respirable particles are not formed. However, studies addressing the formation of 

respirable particles by other granular formulations, e.g. Hydrothol 191 Granular, are not 

available. As such, risks of concern are associated with these end-use products. 

2.1 Data Deficiencies

The following data deficiencies were identified in the endothall residue chemistry chapter:

 860.1340: Existing data collection methods are adequate, assuming confirmatory data are 

submitted which shows that recoveries of monomethyl ester of endothall are acceptable 

for the irrigated crops studies (D356315) and the apple blossom study (D384206). 

 860.1500: Two additional trials in Region 11 are required to support the use of endothall 

on alfalfa grown for seed (D426753 and D321179). Alternatively, enforceability of the 

label restriction to use the seed for food, feed or oil needs to be demonstrated, and that 

residues are not likely to be present in the crop grown from the harvested seed to classify 

this use as non-food, see Section 3.3.

 860.1340: The proposed enforcement method for livestock incorporating the 

recommendations of the ILV laboratory needs to be submitted to the Agency.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plants: An enforcement method (GC with microcoulometric nitrogen detection) is listed as 

Method I in the Pesticide Analytical Manual (PAM, Volume II) for the determination of 

endothall residues (total common moiety) in plant commodities. Using this method, residues in 

crop commodities are extracted using acetone acidified with HCl. Any endothall present is 

converted to the N-methoxyimide derivative by reaction with methoxyamine hydrochloride. The 

imide derivative is partitioned into chloroform, concentrated and analyzed. The method limit of 

quantitation (LOQ) is 0.1 ppm. HED modified the residue of concern definition for tolerance 

enforcement in plants to parent endothall only. Therefore, is no longer necessary that the 

recovery of the monomethyl ester is tested by the enforcement methods for plants. See section 

5.1 for further information. 

Livestock: The ILV to support Method KP-245R0 as an enforcement method for livestock 

commodities was submitted and evaluated. The method consists of extraction, followed by 

derivatization of the residues of endothall and endothall monomethyl ester via a common-moiety 

approach. The samples are analyzed by LC/MS/MS. Adequate recoveries of endothall and its 

monomethyl ester were obtained using cow and poultry commodities. The method LOQ is 0.01 

ppm for each analyte. The method is a suitable for enforcement purposes; however, some 

clarifications in the procedure as suggested by the ILV laboratory need to be incorporated, refer 

to the residue chemistry chapter (D426753).
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Confirmatory method for plants and fish: An LC/MS method (Method No. KP-218R0) is 

available for determining residues of endothall and its monomethyl ester in fish and in plant 

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

purified using a C18 solid phase extraction (SPE) column. Residues are then derivatized with 

heptafluoro-p-tolylhydrazine (HFTH) and partitioned into dichloromethane (DCM). Derivatized 

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

Residues are determined by liquid chromatography with a mass selective detector (LC/MSD) 

using the 397 amu ion for detection and quantitation. The LOQ is 0.05 ppm for fish, and range 

from 0.01-0.10 ppm for plant commodities. This method has undergone a successful 

independent laboratory validation using fish samples. 

Multiresidue Methods: Endothall is not recovered through the FDA multiresidue methods.

2.2.2 Recommended Tolerances

The residue of concern definition for endothall was reevaluated as part of registration review 

based on a proposal from the registrant to establish parent endothall only as the residue of 

concern in plants. HED understands that parent endothall is an adequate marker of misuse in 

plants as it is the only or main residue observed in metabolism studies. Although the tolerances 

established in the 40 CFR § 180.293 for plant commodities may have contribution from the 

monomethyl ester, the metabolism studies suggest that the main residue is parent endothall and 

an appropriate marker of misuse as well. The tolerances are not likely to underestimate the 

residue levels and are considered adequate for enforcement purposes as they are not likely to be 

significantly overestimated. Parent endothall and the monomethyl ester are still considered the 

residues of concern for risk assessment, refer to section 5.1. 

In support of registration review and the tolerance petition to update the current tolerances for 

milk, meat, poultry and eggs (MMPE), a new tolerance expression for inadvertent residues and 

updated/new tolerances are recommended. Table 2.2.3 summarizes the established, proposed 

and recommended tolerances for MMPE. The registrant proposes updated tolerances for all 

livestock commodities at the LOQ of the enforcement method (0.01 ppm for milk, 0.05 ppm for 

the remaining commodities) with the exception of ruminant kidney for which a tolerance of 0.06 

ppm is proposed based on residues of 0.051 ppm observed in the cow feeding study. Following 

calculations of anticipated residues, HED recommends tolerances at the LOQ level for all 

MMPE commodities. In addition, tolerances recommended for shellfish (1 ppm for crustaceans, 

and 4 ppm for mollusc) need to be included in the 40 CFR § 180.293 as previously 

recommended (D. Soderberg, D324426, 02/27/2006), and the tolerance for fish should be moved 

to section (d) Indirect or Inadvertent residues. 

Further review of the magnitude of residue study on potato shows that proportionality can be 

applied to the residue data generated at 2x and a reassessed tolerance can be established at 0.2 

ppm. Upon personal communication with RD and PRD (G. Waleko and D. Sunderland, 

02/11/2015), it was determined that uses of endothall on rice are no longer on the labels. Based 

on this, HED understands that tolerances for rice grain and rice straw can be moved from section 

(a) General (1) to section (d) Indirect or Inadvertent residues to cover residues resulting from 

irrigation with water treated with endothall. Moreover, the interim tolerance under section (a) 

General (2) to cover residues of endothall in drinking water is not needed as OPP no longer 
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establishes tolerances in drinking water. EPA’s Office of Water has established a maximum 

contaminant level (MCL) for endothall at 0.10 ppm. Finally, HED recommends the 

establishment of tolerances of 2.0 ppm for alfalfa, seed and clover, seed, 0.2 ppm for cotton, 

undelinted seed, and 8.0 ppm for cotton gin byproducts to section (a) General (1) to cover 

residues of endothall resulting from harvest aid uses on alfalfa and clover. 

An interim tolerance for negligible residues of endothall in sugar beets is established in 40 CFR 

§ 180.319. This tolerance is not needed as residues of endothall in/on sugar beets are covered 

under the tolerance for Vegetable, root and tuber, group 1 established under 40 CFR § 180.293

(d).

The tolerance expression included under the 40 CFR § 180.293 (a) General (1) and (d) needs to 

be modified in accordance with the Interim Guidance on Tolerance Expressions (S. Knizner; 

05/27/2009). A new section and tolerance expression, e.g. (e), needs to be added for tolerances in 

livestock commodities. The recommended tolerance expression is:

(a) General. 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).

(d) Indirect or inadvertent residues in plant commodities. Tolerances are established for the 

indirect or inadvertent combined residues of the herbicide endothall in potable water resulting 

from uses to control aquatic plants in canals, lakes, ponds, and other potable water sources. 

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).

(e) Indirect or inadvertent residues in livestock commodities and fish. Tolerances are established 

for the indirect or inadvertent combined residues of the herbicide endothall in potable water 

resulting from uses to control aquatic plants in canals, lakes, ponds, and other potable water 

sources. 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.

Table 2.2.2. Tolerance Summary for Endothall

Commodity

Established 

Tolerance 

(ppm)

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Comments

Correct Commodity 

Definition

40 CFR § 180.293 (a) General (1)

Alfalfa, seed1 2.0

Clover, seed1 2.0

Cotton, undelinted seed 0.1 0.2

Cotton, gin byproducts 8.0

Fish 0.1 0.1 Move to section (d)

Potato 0.1 0.2
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Table 2.2.2. Tolerance Summary for Endothall

Commodity

Established 

Tolerance 

(ppm)

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Comments

Correct Commodity 

Definition

Rice, grain 0.05 0.05 Move to section (d)

Rice, straw 0.05 0.05 Move to section (d)

40 CFR § 180.293 (a) General (2)

Water, potable 0.2 Revoke

(d) Indirect or inadvertent residues in plant commodities.

Almond, hulls 15.0

Animal feed, nongrass, group 18, 

forage

4.0

Animal feed, nongrass, group 18, 

hay

10

Apple, wet pomace 0.15

Beet, sugar, molasses 1.5

Brassica, head and stem subgroup 

5A

0.1

Brassica, leafy, subgroup 5B 2.0

Bushberry subgroup 13-07B 0.6

Caneberry subgroup 13-07A 0.6

Corn, field, grain 0.07

Corn, pop, grain 0.07

Corn, sweet, kernel plus cob with 

husks removed

0.3

Citrus, dried pulp 0.1

Feed commodities not otherwise 

listed

10.0

Food commodities not otherwise 

listed

5.0

Fruit, citrus group 10 0.05

Fruit, pome, group 11 0.05

Fruit, stone, group 12 0.3

Grain, aspirated fractions 35.0

Grain cereal, forage, fodder and 

straw, group 16

10.0

Grain, cereal, group 15, except 

corn

4.0

Grape 1.0

Grape, raisin 5.0

Grass, forage, fodder, and hay 

group 17, forage

3.5

Grass, forage, fodder, and hay 

group 17, hay

18.0

Herb and spice, group 19 5.0

Nut, tree, group 14 0.05

Okra 0.05

Pea and bean, dried shelled, 

subgroup 6C

0.2

Pea and bean, succulent shelled, 2.0
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Table 2.2.2. Tolerance Summary for Endothall

Commodity

Established 

Tolerance 

(ppm)

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Comments

Correct Commodity 

Definition

subgroup 6B

Peppermint, tops 5.0

Pistachio 0.05

Rice, hulls 8.0

Soybean, hulls 0.5

Soybean, seed 0.2

Spearmint, tops 5.0

Tomato, paste 0.1

Tomato, puree 0.1

Vegetable, bulb, group 3-07 0.5

Vegetable, cucurbit, group 9 1.5

Vegetable, foliage of legume, 

group 7

4.0

Vegetable, fruiting, group 8 0.05

Vegetable, leafy, except brassica, 

group 4

2.0

Vegetable, leaves of root and 

tuber, group 2

3.0

Vegetable, legume, edible, 

podded, subgroup 6A

2.0

Vegetable, root and tuber, group 1 1.0

Wheat, milled byproducts 5.0

40 CFR § 180.293 (e) Indirect or inadvertent residues in livestock commodities.

Cattle, meat 0.03 0.05 0.05

Cattle, kidney 0.2 0.06 0.05

Cattle, liver 0.1 0.05 0.05

Cattle, fat 0.01 0.05 0.05

Milk 0.03 0.01 0.01

Sheep, meat 0.015 0.05 0.05

Sheep, kidney 0.15 0.06 0.05

Sheep, liver 0.05 0.05 0.05

Sheep, fat 0.005 0.05 0.05

Goat, meat 0.015 0.05 0.05

Goat, kidney 0.15 0.06 0.05

Goat, liver 0.05 0.05 0.05

Goat, fat 0.005 0.05 0.05

Hog, meat 0.01 0.05 0.05

Hog, kidney 0.1 0.06 0.05

Hog, liver 0.05 0.05 0.05

Hog, fat 0.005 0.05 0.05

Poultry, meat 0.015 0.05 0.05

Poultry, liver 0.05 0.05 0.05

Poultry, fat 0.015 0.05 0.05

Poultry, meat byproducts 0.2 0.05 0.05

Egg 0.05 0.05 0.05
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Table 2.2.2. Tolerance Summary for Endothall

Commodity

Established 

Tolerance 

(ppm)

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Comments

Correct Commodity 

Definition

Fish-shellfish, crustacean2 N/A 1 1

Fish-shellfish, mollusc2 N/A 4 4

40 CFR § 180.319 (a) General

Beet, sugar 0.2 Revoke (covered 

under 180.293 

Vegetable, root and 

tuber, group 1)

1 These tolerances for direct uses are not necessary if the use in alfalfa and clover is classified as non-food. In that 

case, tolerances may be established under section (d) Indirect or inadvertent residues to support residues resulting 

from irrigation with water treated with endothall.

2 Tolerances for endothall in/on shellfish were proposed with Petition # 9F06015 at 1 ppm (crustacean) and 4 ppm 

(mollusc) based on the residue chemistry chapter D356315 (D. Soderberg, 10/22/2009).

2.2.3 Revisions to Petitioned-For Tolerances

The registrant has proposed updated tolerances for all livestock commodities at 0.05 ppm (LOQ 

of the proposed enforcement method) with the exception of milk for which the LOQ is 0.01 ppm, 

and ruminant kidney for which a tolerance of 0.06 ppm is proposed based on a residue of 0.051 

ppm observed in the ruminant feeding study. These updated tolerances are higher than the 

tolerances currently established for all commodities with the exception of ruminant kidney. 

Residue levels in livestock commodities were re-evaluated following current procedures which 

make use of highest average field trial (HAFT) and median residues instead of tolerance level 

residues in feedstuff commodities. Based on these revised residue calculations, a tolerance at the 

LOQ level of the enforcement method is adequate for all livestock commodities.

2.2.4 International Harmonization

The International Residue Limits Table is included in Appendix E. Maximum residue limits 

(MRLs) for endothall have not been established by Codex or Mexico. Canada and the US have 

the same tolerance level for residues of endothall and its monomethyl esters in/on potato at 0.1 

ppm. However, a higher tolerance for potato is recommended. It is not possible at this time to 

maintain the harmonized tolerance level of 0.1 ppm because the highest residue (0.113 ppm) 

estimated for potato is above the current tolerance level.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

HED recommends in favor of the removal of the label restriction prohibiting livestock from

drinking water treated with endothall.

The label of Desicate II (EPA Reg. No. 70506-190) includes a label restriction that states “Seed 

Crops Only - Seed from treated fields should be used for planting purposes only. Do not use seed 

for food, feed or oil purposes.” This restriction needs to be removed from the label unless its

enforceability is demonstrated, refer to Section 3.3.
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2.3.2 Recommendations from Occupational Assessment

For the agricultural uses, occupational handlers must wear the following personal protective 

equipment (PPE): long-sleeved shirts, long pants, chemical resistant gloves, protective eyewear 

and a dust mist respirator (TC-21C) for mixing/loading a liquid formulation for aerial application 

of endothall to alfalfa and clover. The 48-hour REI listed on the agricultural labels is 

appropriate. For aquatic uses, occupational handlers using a liquid formulation must wear longsleeved shirts, long pants, chemical resistant gloves, and protective eyewear for all scenarios. 

All applicators of liquid formulations for aquatic uses should use a closed system, and 

mixer/loader/applicators of liquid formulations require a respirator for certain scenarios. Risk 

estimates for use of granular formulations in aquatic scenarios result in risk estimates of concern 

even using closed systems. There is no REI listed on aquatic labels (exempt under WPS). 

2.3.3 Recommendations from Residential Assessment

None.

3.0 Introduction

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. 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. 

This memorandum serves as HED’s scoping document and draft human health risk assessment in 

support of registration review for endothall. In addition, a petition from United Phosphorous Inc. 

to update the tolerances of endothall on meat, milk, poultry and eggs, and to support the removal 

of the restriction on consumption of water treated with endothall by livestock is considered. This 

label restriction would be removed from the label of the following end-use products: Hydrothol® 

Granular Aquatic Algicide and Herbicide (EPA Reg. No. 70506-174); Hydrothol® 191 Aquatic 

Algicide and Herbicide (EPA Reg. No. 70506-175); Aquathol® K Aquatic Herbicide (EPA Reg. 

No. 70506-176); and Aquathol® Super K Granular Aquatic Herbicide (EPA Reg. No. 70506-

191). 

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

Chemical Structure

Common name Endothall acid

Molecular Formula C8H10O5

Molecular Weight 186.16

IUPAC name 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid

CAS name 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid

CAS # 145-73-3

PC Code 038901

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

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 

Chemical Structure

Common name Endothall, mono-N, N-dimethyl alkyl amine salt

Molecular Formula Not available

Molecular Weight Average: 422 

IUPAC name 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid, compound with N, Ndimethylcocoamine

CAS name Not available

CAS # 66330-88-9

PC Code 038905

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

3.2 Physical/Chemical Characteristics

OH

OH

O

O

O

O

O

O

O

O

K

+

K

+

O

OH

O

O

O N

+

CH2(n)CH3

H3C

H3C

(n = 7-17)
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The physicochemical properties of endothall are summarized in Appendix B. Endothall has a 

low vapor pressure (3.92 x 10-5 mm Hg at 24.3 ̊C); therefore, is not volatile. Endothall is a 

diacid with high solubility in water (110 to 131 g/L at 25 ̊C, depending on the pH). The 

environmental fate properties of endothall suggest that it degrades by biotic processes such as 

aerobic metabolism (N. Thurman, D356316, 09/09/2009). Laboratory studies measured firstorder degradation half-lives of 14.5 days for aerobic soil metabolism, 10 days for aerobic aquatic 

metabolism, and 9 days for anaerobic metabolism. Terrestrial dissipation studies measured 

dissipation half-lives from the soil surface of 13 to 19 days. Dissipation/disappearance half-lives 

in aquatic studies ranged from 4 to 30 days in laboratory studies, and 0.5 to 20 days in ponds and 

lakes.

3.3 Pesticide Use Pattern

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

algicide which belongs to the dicarboxylic acid chemical class. The free acid of endothall (PC 

Code 038901) is the active ingredient that forms from the breakdown of the endothall salts, and 

is not applied directly to use sites. Endothall dipotassium (PC Code 038904) and alkylamine (PC 

Code 038905) salts are registered primarily as aquatic herbicides to control a variety of plants 

including pondweed, naiad, coontail, milfoil, elodea, and algae, as well as plankton in water 

bodies. Moreover, the current labels allow for repeated broadcast applications to irrigation canals 

at rates yielding endothall concentrations of up to 5 ppm ae (acid equivalents) for the 

monoalkylamine salts and 3.5 ppm ae for the dipotassium salt. Endothall-treated water is used 

for irrigation purposes on non-food and food crops, established ornamentals, turf grass, lawns, 

and non-crop areas. There are also registered uses 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. It is also registered as an apple blossom thinner. 

A summary of the registered use directions is presented in Appendix D. The registered labels 

require occupational handlers to wear the following personal protective equipment (PPE): longsleeved shirts, long pants, chemical resistant gloves, and protective eyewear. A 48-hour 

restricted entry interval (REI) is currently listed on the agricultural labels. 

United Phosphorous Inc. submitted a petition to remove the label restriction that states “Do not 

use treated water for animal consumption within the following periods: 0.3 ppm - 7 days after 

application, 3.0 ppm - 14 days after application, and 5.0 ppm - 25 days after application.” This 

label restriction would be removed from the label of the following end-use products: Hydrothol® 

Granular Aquatic Algicide and Herbicide (EPA Reg. No. 70506-174); Hydrothol® 191 Aquatic 

Algicide and Herbicide (EPA Reg. No. 70506-175); Aquathol® K Aquatic Herbicide (EPA Reg. 

No. 70506-176); and Aquathol® Super K Granular Aquatic Herbicide (EPA Reg. No. 70506-

191). 

The label of Desicate II (EPA Reg. No. 70506-190) includes a label restriction that states “Seed 

Crops Only - Seed from treated fields should be used for planting purposes only. Do not use seed 

for food, feed or oil purposes.” This restriction needs to be removed from the label unless its

enforceability is demonstrated (ChemSAC minutes of 03/07/2001). In general, restrictions 

imposed on Section 3 registration labels to preclude the need for residue data must be practical 
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and enforceable and are subject to the following criteria: (1) the food or feedstuff must remain 

under the control of the grower; (2) preferably the crop would be grown primarily as a feedstuff; 

and (3) the label restriction should cause no economic hardship. For alfalfa grown for seed, 

enforcement of the label restrictions necessary to achieve nonfood status would require the 

involvement of States and the establishment of adequate regulatory mechanisms such as might 

be prescribed under Section 24(c) registrations. In certain situations this label restriction has 

been allowed if the harvested seed is dyed.

3.4 Anticipated Exposure Pathways

The PRD and RD have requested an assessment of human health risk to support registration 

review and the proposed elimination of the label restriction prohibiting livestock from drinking

water treated with endothall. Humans may be exposed to endothall in food and drinking water, 

since it may be applied directly or indirectly (i.e. resulting from irrigation with treated water) to 

growing crops and application may result in endothall reaching surface and ground water sources 

of drinking water. There are residential uses of endothall, so there is likely to be exposure in 

residential or non-occupational settings. In an occupational setting, applicators may be exposed 

while handling the pesticide prior to application, as well as during application. There is a 

potential for post-application exposure for workers re-entering treated fields. 

No new toxicity data have been received since the previous risk assessment (D403274, J. 

Liccione, 03/18/2013). A detailed description of the toxicity data and metabolism information 

may be found in the risk assessment dated 11/09/09 (David Soderberg, D370448). This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of endothall, but also considers the existing uses as well, particularly for the dietary and 

residential exposure assessments. 

3.5 Consideration of Environmental Justice

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

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

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

http://www.archives.gov/federal-register/executive-orders/pdf/12898.pdf). As a part of every 

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA under the 

National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) 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 post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 
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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 most recent human health risk assessment was conducted for proposed use of the 

dipotassium form of endothall on apples (D403274, 3/18/2013). No new toxicity and/or 

metabolism data have been received since the last risk assessment. This assessment includes 

summaries of these data from previous assessments (D403274, 3/18/2013). No significant 

changes have been made to the hazard characterization and toxicity endpoints for risk assessment 

since the 2013 risk assessment.

4.1 Toxicology Studies Available for Analysis

The toxicology database for endothall is complete and sufficient for hazard characterization and 

no additional studies are required at this time. HASPOC waived the requirements of the acute 

and subchronic neurotoxicity studies, and an immunotoxicity study. 

4.2 Absorption, Distribution, Metabolism, & 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

Dermal absorption in rats treated dermally for 24 hours with 0.0125 mg/cm2, 0.0625 mg/cm2, 

and 0.125 mg/cm2 was estimated at 3.9%, 2.2% and 7.3%, respectively. Urinary excretion of 

[

14C]-Endothall equivalents was 2.3% of the applied dose at 0.125 mg/cm2 dose level. Fecal 

excretion amounted to <0.1% at all dose levels. It was noted in the study report that application 

of the direct formulation of the use product (23.4 % endothall) caused severe skin irritation and 

ulceration. 

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 the lowest dose tested. Effects included erythema, edema, and fissuring and 

sloughing off of the skin. 

4.3 Toxicology Effects
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Endothall is a caustic chemical with toxicity being the result of a direct degenerative effect on 

tissue. 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 orally with endothall for 52 weeks (a no observed 

adverse effect level (NOAEL) was not determined). Proliferative lesions of the gastric 

epithelium were observed in F1 parental male and female rats treated orally with endothall in a 2-

generation reproduction study (a NOAEL was not identified). 

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 and in a 21-day dermal toxicity study 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 eye irritation study, endothall technical was extremely 

irritating to the eye, and was also lethal to 4/6 rabbits tested. 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. 

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. Decreased body weight was also 

apparent in a developmental toxicity study in the rabbit (maternal and offspring). Decreased 

body weight was noted in a 90-day dietary study in the rat. Body weight loss occurred in dogs

following a 13 week oral treatment with endothall. Body weight decrement was also 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 the lowest dose tested, 

i.e., erythema, edema, and fissuring and sloughing off of the skin at the dose site at the lowest 

tested. 

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. 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. In addition, increased lung weights and alveolar macrophages in 

both sexes were observed at scheduled necropsy. Nasal effects consisted of minimal olfactory 
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epithelial degeneration and mild goblet cell hypertrophy. At higher concentrations, subacute 

inflammation of the trachea, and degeneration of the olfactory and respiratory epithelium of the 

nasal passages. Rales and labored respiration were noted in rats that died during the study

Endothall does not cause pre-natal toxicity following in utero exposure to rats or rabbits nor preand post-natal toxicity following exposures to rats for two generations.

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.

The HASPOC (December 19, 2012) recommended a waiver for acute and subchronic neurotoxicity 

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

endothall database as well as other carboxylic acid pesticides. The HASPOC (September 26, 2013) 

also recommended waiving the immunotoxicity study. 

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

The FQPA SF was reduced to 1X 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 lowest observed adverse effect level (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 rabbits 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 database. 

4.4.1 Completeness of the Toxicology Database

The toxicological database for endothall is complete and adequate for FQPA evaluation, 

selection of points of departure (PODs) for the various routes of exposure, and for dose-response 

evaluation. HASPOC recommended waiving the requirements for immunotoxicity, acute 

neurotoxicity and subchronic neurotoxicity studies. 

4.4.2 Evidence of Neurotoxicity

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

studies are not available for endothall. However, the HASPOC (December 19, 2012) recommended 

waiving the acute and subchronic neurotoxicity studies in rats to support the proposed uses of

endothall.
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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 or rabbits in developmental toxicity studies, and pre- and post-natal exposure to 

rats in the 2-generation reproduction study. 

4.4.4 Residual Uncertainty in the Exposure Database

Non-dietary exposure. The residential post-application exposure assessments are based upon the 

2012 Residential Standard Operating Procedures (SOPs). These assessments of exposure are not 

likely to underestimate exposure to endothall.

Dietary exposure. There is no residual uncertainty in the exposure database for endothall with 

respect to dietary exposure. An adequate database with respect to both the nature and magnitude 

of residues expected in food has been provided. The chronic dietary food exposure assessment is 

conservative as field trial data along with 100% of crop treated assumptions for some 

commodities, and default processing factors for some commodities were used. Also, 

conservative modeled drinking water estimates of exposure were included in the assessments 

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

4.5 Toxicity Endpoint and Point of Departure Selections

HED selected the following toxicity endpoints (and points of departure) for chronic dietary, 

incidental oral and inhalation scenarios which are the same that were used in the previous risk 

assessment. Additional studies in the database were not updated to reflect current policies since 

these changes would not affect current PoDs and the selected endpoints are protective of all 

effects seen in the endothall database. 

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

the material with the handler’s 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 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). The current short-term incidental oral endpoint (NOAEL of 9.4 

mg/kg/day) is protective of potential gastric lesions in the offspring. The development of gastric 

lesions is dependent on the duration of exposure. For example, in the 2-generation reproductive 

toxicity study in rats, the gastric lesions were seen in the F1 parental animals but not F0 parental 

animals. In addition, the toxicity database supports the conclusion that the short-term incidental 

endpoint is protective of gastric lesions in the offspring. It was noted that the acute oral LD50 (= 

50.2 mg/kg) is greater than the offspring NOAEL. Additionally, no gastric lesions were 

observed in the subchronic oral rat and dog studies with endothall amine. Although there were 

no subchronic toxicity studies on the disodium or dipotassium endothall, at expected use 

conditions, all forms of endothall will be in the ionized state. The acute and subchronic oral 

toxicity studies in the rat, and the subchronic oral dog study, were conducted with a higher 

percentage of active ingredient compared with 2-generation reproductive toxicity rat study. 

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

4.5.1 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. 

Post-application oral and inhalation exposure was assessed for adult and child swimmers; 

however, oral and inhalation exposure should not be combined because the endpoints are 

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

4.5.2 Cancer Classification and Risk Assessment Recommendation
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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.

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

Assessment

Table 4.5.3.1. Summary of Toxicological Doses and Endpoints for Endothall for Use in Dietary, NonOccupational and Occupational 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. An 

acute RfD was not established.

Chronic Dietary

(All populations)

LOAEL= 2 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA UFL = 3X

cRfD = 

0.007 mg/kg/day

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

UFA = 10X

UFH = 10X

FQPA SF = 1X

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 handler’s body.

Long-Term Dermal NA - no exposure under use pattern

Short-Term Inhalation NOAEL = 0.001 

mg/L

Residential HEC 

= 0.00049

mg/L (HED = 

0.0143

mg/kg/day)A 

Occupational 

UFA = 3XC

UFH = 10X

FQPA SF 

= 1X

Residential 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).
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Table 4.5.3.1. Summary of Toxicological Doses and Endpoints for Endothall for Use in Dietary, NonOccupational and Occupational 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

HEC = 0.0004

mg/L ( HED = 

0.021, 0.043, 

0.074 

mg/kg/day)B

Occupational LOC 

for MOE = 30 

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 (HED = 

0.021, 0.043, 

0.074 

mg/kg/day)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). 

Long-Term Inhalation NA no exposure under this use pattern

Cancer (oral, dermal,

inhalation)

Classified as a “Not Likely” human carcinogen.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

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

(pulmonary effect) = 0.001 mg/L * (6hr/6 hr; 1.0) * (1d/1d; 1) * pulmonary RDDR (0.499) = 0. 00049 mg/L 

Residential HED = 0.00049 mg/L x ventilation rate (16.7 L/min) x relative specific activity (1.2) x human daily 

duration (2) = 0.0143 mg/kg/day.

B Refer to the table below. Occupational HEC (pulmonary effect) = rat POD * (daily duration adjustment) * weekly 

duration adjustment * RDDR = 0.001 mg/L * (6 hr /8 hr ; 0.75) * (5d/5d; 1)* pulmonary RDDR (0.499) = 0. 0004

mg/L. 

Occupational HED (pulmonary) = HEC * human specific conversion factor * daily duration * relative activity factor 

(0.6 for 8.3 L/min ventilation rate; 1.2 for 16.7 L/min ventilation rate; and 2.1 for 29 L/min ventilation rate) 

= HEC (0.0004 mg/L) * 11.8 L/hr/kg BW * 8 hrs * relative activity factor (1.2).

Ventilation rates (L/min) HED (mg/kg BW/day)

8.3 0.021

16.7 0.043

29 0.074
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4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for endothall, EPA reviewed 

these data and selected the most sensitive endpoints for relevant risk assessment scenarios from 

the existing hazard database. However, as required by FFDCA section 408(p), endothall are 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 2013 (final version 

published in June 26, 2014

1

) and includes some pesticides scheduled for Registration Review 

and chemicals found in water. For further information on the status of the EDSP, the policies 

and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening 

battery, please visit our website.2

In the interim, EPA is making no human health or environmental safety findings associated with 

the EDSP screening of endothall. Before completing this Registration Review, the Agency will 

make an EDSP FFDCA section 408(p) determination.

5.0 Dietary Exposure and Risk Assessment 

 

1 See http://www2.epa.gov/endocrine-disruption/final-second-list-chemicals-tier-1-under-endocrine-disruptorscreening-program.

2 http://www.epa.gov/endo/
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5.1 Residues of Concern Summary and Rationale

Residue Chemistry Memo: K. King, D426753 and D428908, In Progress

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

Table 5.1. The metabolism in plants and animals is qualitatively similar; parent endothall is the 

major residue while the major metabolite is the monomethyl ester with minor formation of the 

dimethyl ester. Upon further metabolism, endothall is rapidly broken down and incorporated 

into tissues as natural constituents. By combining information from soil and water metabolism,

there is sufficient information on rotated crops to conclude that the residues of concern remain 

the same in rotated crops. 

The residue of concern definition for endothall was reevaluated as part of registration review 

based on comments from the registrant indicating that the monomethyl ester is not a significant 

residue in plants and therefore it does not need to be quantitated by the data acquisition methods 

(e-mail communication from Garland Waleko, 11/18/2015). HED understands that parent 

endothall is an adequate marker of misuse in plants as it is the only or main residue observed in 

metabolism studies with sugar beets (64% TRR in tops and 37% TRR in roots), cotton (76-102% 

TRR in forage and 18% in seed) and alfalfa (99% TRR in forage, 103% TRR in seed) (S. Funk, 

10/07/96). The monomethyl ester was observed in half mature sugar beets (48 day PHI) at 12% 

of the TRR (tops) and 22% of the TRR (roots) after soil application, in alfalfa forage (9 day PHI) 

at 3.6% of the TRR, and in alfalfa seed (9 day PHI) at 4.4% of the TRR. It was not observed in 

cotton and was not measured in mature sugar beets which showed a TRR lower than 0.016 ppm. 

Based on this, parent endothall is considered the residue of concern for tolerance enforcement. 

Although the tolerances established in the 40 CFR § 180.293 for plant commodities may have 

contribution from the monomethyl ester the metabolism studies suggest that the main residue is 

parent endothall and an appropriate marker of misuse as well. The tolerances are not likely to 

underestimate the residue levels and are considered adequate for enforcement purposes as are not 

likely to be significantly overestimated. Metabolism studies reflect the direct uses of endothall 

as an herbicide in sugar beets, desiccant in alfalfa and defoliant in cotton. Currently, tolerances 

for indirect uses (i.e. irrigation with water containing residues of endothall) are established for a 

great variety of crops with tolerances ranging from 0.01 ppm to 35 ppm. Because the analytical 

methods are based on the conversion of endothall and monomethyl ester to a common moiety is 

not possible to obtain additional information about the fate of endothall in crops (specially 

irrigated crops). Therefore, based on the lack of additional information and similar toxicity 

assumed for parent endothall and the monomethyl ester, both are still considered the residues of 

concern for risk assessment. 

The monomethyl ester is a significant residue in livestock commodities, especially in poultry 

where it is at higher concentration than parent endothall. Therefore, parent endothall and its 

monomethyl ester are the residues of concern for tolerance and risk assessment in livestock 

commodities. Endothall acid is the major residue observed in the environmental fate studies so 

is included in the drinking water assessment. Endothall monomethyl ester has similar structure

as the parent compound, so is assumed to have equal toxicity. Further information on the 

metabolism may be found in the residue chemistry chapter dated 08/30/2005 (DP# D321179, D. 

Soderberg).
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Table 5.1. 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 

Rotational Crop2

Livestock

Ruminant Endothall and its monomethyl 

ester

Endothall and its monomethyl 

ester Poultry

Drinking Water Endothall Acid Endothall Acid3

1 Endothall is 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid.

2

It is expected that the residues in crops resulting from irrigation with treated water cover those from crops planted 

in rotation with endothall treated crops (i.e. rice, cotton and potatoes); therefore, field rotational studies have been 

waived (D. Soderberg, D387313, 05/03/2011).

3 A maximum contaminant level for endothall in water is established by the Office of Water.

5.2 Food Residue Profile

The nature of the residues in plants and livestock is adequately established based on acceptable 

alfalfa, cotton, sugar beet, poultry and goat metabolism studies. Tolerances are established in the 

40 CFR § 180.293 for the use of endothall on apple, cotton, hop, potato and rice. In addition, 

tolerances are established for inadvertent residues of endothall in/on all crop commodities to 

support the use of water treated with endothall for irrigation purposes. Generally, tolerances for 

food commodities range from 0.05 for tree nuts to 5.0 ppm for herbs. In addition, tolerances 

established for endothall on meat, milk, poultry, eggs and fish range from 0.005 ppm for 

hog/sheep fat to 0.2 ppm for poultry by products. 

As part of registration review, the residue chemistry database for endothall was reevaluated. 

Several deficiencies identified in the 2005 registration eligibility decision (D. Soderberg, 

D321179, 08/30/2005) have been satisfied with the submission of a livestock enforcement 

method, and irrigation, feeding, and storage stability studies. A summary of these deficiencies 

and a reference to the document in which these are resolved is included in Appendix F. 

Although recovery of the monomethyl ester of endothall by the data acquisition and enforcement

methods used for plants has not been tested, recovery has been demonstrated for the parent 

compound. Based on the conservative nature of the dietary assessment it is not likely that the 

absence of these data will result in underestimation of the dietary risk. 

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, D404321, 9/12/12). Based on personal 

communication between Brian Anderson of EFED and Michael Metzger of HED, the drinking 

water estimates from the 2012 assessment are still adequate for chronic dietary assessment. 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 
Endothall Human Health Risk Assessment DP No. D422204

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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 treat the entire reservoir. Since the label specified that the community water system 

(CWS) could not supply treated drinking water unless the residues were below 0.1 ppm (100 

μg/L), EFED assumed 100 μg/L (0.1 ppm) as the acute (peak) exposure and the constant 

exposure during the treatment period and then modeled residue decline by degradation after the 

final treatment. This resulted in a chronic (annual average) concentration of 31 μg/L (0.031 

ppm) for endothall. This represents a conservative estimate of high-end chronic exposure from 

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

Table 5.3 Summary of Estimated Surface Water and Groundwater 

Concentrations for Endothall.

Scenario Groundwater Conc., ppb

Acute 100

Chronic (non-cancer) 31

J. Lin, D404321, 9/12/12

5.4 Dietary Risk Assessment

Dietary Exposure and Risk Memo: K. King, D426752, In Progress

5.4.1 Description of Residue Data Used in Dietary Assessment

Average residue values have been used for all crops. The residue and processing data used in 

this assessment are from residue field trials and processing studies designed to produce 

maximum residues for the purpose of setting tolerances. All treatments in the field trials with 

irrigated crops were performed by overhead irrigation (i.e. are sprayed on the crops). The 

processing data available were translated to the important processed commodities of all crops. 

Where data were not available, DEEM default factors were used. 

Anticipated residues of meat, milk, poultry, and eggs have been estimated by using the 

maximum or average residues in feed stuffs as well as the maximum allowed 5 ppm 

concentration of endothall in livestock drinking water. Tolerance level residues were used for 

finfish and shellfish. Overall, the results are likely to be conservative. 

The EFED used conservative modeling to estimate the levels of the chronically available 

residues in drinking water. The estimated drinking water concentration used 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). 

5.4.2 Percent Crop Treated Used in Dietary Assessment

BEAD has provided percent crop treated (PCT) data for three crops with registered agricultural 

uses of endothall as well as another updated PCT assessment that had to be completed in order to 
Endothall Human Health Risk Assessment DP No. D422204

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provide a better estimate of the percent of crops that are irrigated. The assessment is 

conservative because it assumes that all irrigated crops will use endothall treated water. 

The following average percent crop treated estimates (LUIS Report of 12/31/2014) due to direct 

uses of endothall were used in the chronic dietary risk assessment for the following crops: 

alfalfa <1%, cotton <1%, and potatoes <2.5%. In addition, BEAD estimated PCT of irrigated 

crops. Estimated average percent crop treated for chronic dietary risk assessment was: apple 

78%, fresh market apple 84%, processing apple 49%, apple juice 22%, canned apple 55%, barley 

for grain 40%, corn for grain 21%, dry beans 35%, grape 97%, fresh market grape 99%, 

processed grape 96%, green peas 42%, oats for grain 8%, peanut for nuts 34%, rice 100%, 

sorghum for grain 19%, soybean for beans 12%, strawberry 92%, fresh market strawberry 90%, 

processed strawberry 100%, sugarbeet for sugar 37%, sugarcane for sugar 54%, watermelon 

38%, wheat for grain 13%. 

5.4.3 Acute Dietary Risk Assessment

No acute exposure and risk assessment has been performed as no acute endpoint has been 

established for endothall.

5.4.4 Chronic Dietary Risk Assessment

A refined, chronic dietary exposure and risk assessment was conducted incorporating both food 

and water residues. Typically, HED has concerns regarding dietary risk when the exposure 

estimates exceed 100% of the chronic population adjusted dose (cPAD). The Summary Table 

5.4.6 includes the exposure and risk estimates for endothall. The estimated exposure (food and 

water) to the U.S. population from the existing uses of endothall resulted in an estimated risk 

equivalent to 32% of the cPAD. The most highly exposed population subgroup is children 1-2 

years of age with an exposure equivalent to an estimated risk of 90% of the cPAD. The 

estimated exposure (food only) to the U.S. population from the existing and proposed new uses 

of endothall resulted in an estimated risk equivalent to 23% of the cPAD. The most highly 

exposed population subgroup is children 1-2 years of age with an exposure equivalent to an 

estimated risk of 77% of the cPAD. 

5.4.5 Cancer Dietary Risk Assessment

Endothall is classified as “Not likely to be carcinogenic to humans”; therefore, a quantitative 

cancer risk assessment was not performed.

5.4.6 Summary Table
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Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and 

Risk for Endothall

Population Subgroup

Chronic Dietary

Dietary Exposure

(mg/kg/day) % cPAD*

General U.S. Population 0.002247 32

All Infants (< 1 year old) 0.004492 64

Children 1-2 years old 0.006317 90

Children 3-5 years old 0.004636 66

Children 6-12 years old 0.002572 37

Youth 13-19 years old 0.001486 21

Adults 20-49 years old 0.001944 28

Adults 50+ years old 0.002008 29

Females 13-49 years old 0.001888 27

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Occupational and Residential Exposure and Risk Memo: S.Tadayon, D428969, In Progress

6.1 Residential Handler Exposure

There are no registered residential uses resulting in residential handler exposure to endothall. 

Therefore, a quantitative residential handler exposure assessment was not performed. 

6.2 Residential Post-application Exposure/Risk Estimates

Endothall is registered for use in lakes and ponds for control of nuisance aquatic weeds. As a 

result, individuals can be exposed to endothall residues in water by entering these areas if they

have been previously treated. Of the possible post-application exposures, swimming in treated 

water is considered by HED to be worse case and is used as a surrogate for all other possible 

post-application exposures, such as wading, water skiing, etc. The extent of exposure during 

recreational swimming is assumed to be short-term in duration. Risks estimates were calculated 

for inhalation and incidental oral ingestion while swimming in treated lakes or ponds. Postapplication dermal assessments are not needed since there is no short-term systemic dermal 

hazard.

The scenarios, routes of exposure and lifestages assessed include:

 Inhalation exposure during recreational swimming (both adults and children 3 < 6 years 

old).

 Ingestion of water during recreational swimming (both adults and children 3 < 6 years 
Endothall Human Health Risk Assessment DP No. D422204

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old).

The Agency considered residential post-application exposure for different segments of the 

population. The lifestages selected for each post-application scenario are based on an analysis 

provided as an Appendix in the 2012 Residential SOPs3. These lifestages are not the only 

lifestages that could be potentially exposed for these post-application scenarios; however, the 

assessment of these lifestages is health protective for the exposures and risk estimates for any 

other potentially exposed lifestages. 

The swimmer calculations have been updated from the previous assessment to reflect the revised 

body weights for adults and children. Also the water ingestion rates and the time spent in the 

water have been revised to correspond with the 2012 Residential SOPs. The average body weight 

of an adult female (i.e., 69 kilograms) is used for assessing incidental oral ingestion for adults 

since the toxicity endpoint selected is based on a reproductive study where developmental and/or 

fetal effects were observed. For children 3 to < 6 years old swimming in endothall treated water a 

body weight of 19 kg was used. The level of concern for adults and children (3 to < 6 years old) 

for short-term, inhalation exposures is MOEs < 30. The level of concern for adult females and 

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

Residential Post-application Non-Cancer Exposure and Risk Equations

The equations and inputs are generally derived from SWIMODEL 3.0, developed by EPA as a 

screening tool to conduct exposure assessments of pesticides found in swimming pools and spas. 

It uses well-accepted screening exposure assessment equations to calculate the high end exposure 

for swimmers expressed as a mass-based intake value (mg/event). The model focuses on 

potential chemical intakes only and does not take into account metabolism or excretion of the 

chemical of concern. Detailed information and the downloadable executable file are available at 

http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/swimmer-exposureassessment-model-swimodel, however, some of the inputs and parameters have been updated 

and are outlined below. The equations as provided in the SWIMODEL User's Manual (version 

3.0) were used in a spreadsheet format to estimate the exposures.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

Table 6.2.1 presents the post-application inhalation and incidental oral ingestion MOE values 

calculated for adults and children 3 to <6 years old after aquatic applications of endothall 

dipotassium. Post-application risk estimates do not exceed HED’s level of concern for any of the 

scenarios assessed. MOEs for inhalation exposures were 5 x 10 9for adults and 3 x 10 9for

children 3 to <6 years old. MOEs for oral exposures were 1,700 for adults and 250 for children 3 

to <6 years old. 

Table 6.2.1: Residential Post-application Non-cancer Exposure and Risk Estimates for Endothall (Swimmer Scenario)

Exposure Scenario Level of Concern

(LOC)

Maximum Concentration 

in Water 1(mg/L)

Dose

(mg/kg/day) 2,3

Short-term 

MOE 4

Inhalation, Adult-(Female) 30 5 2.7 x 10-

12 5 x 10 9

Inhalation, Child 3 to <6 years old 30 5 5.1 x 10-

12 3 x 10 9

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

 

3 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-proceduresresidential-pesticide
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Ingestion of water, Child 3 to <6 years 

old 100 5 0.0383 250

Notes: 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. Inhalation exposure dose (mg/kg/day) = chemical vapor concentration, vp (7.8 x 10-

11 mg/L) x inhalation rate, IR (0.64 m3 /hr 

adults and 0.42 m3/hr children 3 to < 6) x exposure time, ET (3.7 hr adults and 3 hr children 3 to < 6)

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

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

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

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

4. MOE = NOAEL or HEC/Exposure dose; short-term inhalation HEC= 0.0143 mg/kg/day; short-term incidental oral NOAEL = 

9.4 mg/kg /day. The LOC for adult females and children (3 to < 6) for short-term inhalation exposures is MOEs < 30; The LOC

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

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for endothall. 

 The recommended residential exposure for use in the adult short-term aggregate 

assessment reflects residential post-application incidental oral (water ingestion) exposure 

from swimming in treated aquatic areas. 

 The recommended residential exposure for use in the children 3 to < 6 years old shortterm aggregate assessment reflects incidental oral (water ingestion) exposure from postapplication exposure to treated aquatic areas.

Table 6.3.1. Recommendations for the Residential Exposures for the Endothall Aggregate 

Assessment.1(Aquatic Scenarios)

Lifestage

Residential Postapplication Total 

Exposure (mg/kg/day)2

Residential Post-application MOE3

LOC = 100

Adult Female 0.0056 1,700

Child (3 to <6 years old) 0.0383 250

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Residential Post-application Dose = the highest post-application dose for each applicable lifestage of all scenarios assessed from 

Table 6.2.1. Total = incidental oral only.

3 Residential Post-application MOE = the MOEs associated with the highest doses identified in Table 6.2.1. Total = incidental 

oral only. 

6.4 Residential Bystander Post-application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-

0037). The agency has evaluated the SAP report and has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 
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During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

endothall.

6.5 Spray Drift

Endothall is a systemic herbicide, meaning its herbicidal mode of action required it to be 

absorbed and translocated in the weeds. It is not a contact herbicide and thus the application 

method is not as a broadcast application meant to cover the surface area of the weeds. It is 

applied in a directed manner, usually using a hose, wand or meter, as a surface or subsurface 

application to water in order to maintain a specified herbicide concentration in the water body to 

control aquatic weeds systemically. The large/coarse droplet size and directed spray methods 

greatly reduce the spray drift potential for aquatic applications. As the application methods are 

not conducive to spray drift as described and assessed as part of the spray drift policy, a 

quantitative spray drift assessment is not required for the aquatic uses of the herbicide.

Endothall has direct uses on crops as well. Off-target movement of pesticides can occur via 

many types of pathways and it is governed by a variety of factors. Sprays that are released and 

do not deposit in the application area end up off-target and can lead to exposures to those it may 

directly contact. They can also deposit on surfaces where contact with residues can eventually 

lead to exposures (e.g., children playing on lawns where residues have deposited next to treated 

fields). The potential risk estimates from these residues can be calculated using drift modeling 

coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment includes

assessing exposures for children (1 to 2 years old) and adults who have contact with turf where 

residues are assumed to have deposited via spray drift thus resulting in an exposure scenario. 

Aside from the predicted residues available for transfer, the routes of exposure and assessment 

methodology is analogous to how exposures to turf products are considered in risk assessment. 

No dermal endpoint was selected because the dermal irritation observed in a repeated-dose study 

is considered self-limiting. Therefore, dermal risk estimates were not calculated for children 1< 2 

or adults. Incidental oral risk estimates for children 1<2 years old was calculated. The 

applicable LOC is 100 so MOEs < 100 represent risk estimates of concern. Children’s (1<2 year 

old) incidental oral risk estimates from indirect exposure to endothall related to spray drift result 

in acceptable MOEs at the field edge for aerial, airblast and groundboom applications based on 

the screening level scenarios. Results are presented in Table 6.5.1, and indicate that there is no 

risk of concern from airblast, aerial or groundboom applications. 

Table 6.5.1 Spray Drift Risk Estimate for Endothall

Crop/Rate Group Spray Type/ Nozzle 

Configuration 

Application 

Rate (lb ai/A)

Estimated TTRt 

(ug/cm2)

a

At Edge

HtM MOE

Aerial Fine to Medium

1 0.011

2,400

Groundboom High Boom Very fine to Fine 3,300

Airblast Sparse 4,300

a. TTR = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.1 and D = 0.10 per day 
Endothall Human Health Risk Assessment DP No. D422204

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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.

7.1 Acute Aggregate Risk

An appropriate acute oral endpoint attributable to a single dose was not available from any study, 

including the prenatal developmental toxicity study in rats. Based on the absence of an acute 

endpoint an acute aggregate risk assessment is not quantitatively assessed. 

7.2 Short-Term Aggregate Risk

The oral endpoint selected to assess the risk of endothall from short-term incidental oral 

exposure is based on decreased pup weight. Moreover, orally, endothall damages the digestive 

tract at relatively low doses and then the liver and kidneys at lethal doses. On the other hand, the 

inhalation endpoint is based on lung toxicity. Based on the difference between the oral and 

inhalation endpoints, an assessment aggregating these different routes of exposure is not 

appropriate. However, an aggregate assessment adding exposures from food and water with 

those from incidental ingestion of treated water (swimmers) is needed. This assessment is 

presented in Table 7.2. Adult and children’s post-application oral exposure (Table 6.3.1) were 

combined with the chronic dietary exposure from the mostly highly exposed adult (Adults 50+) 

and children’s (Children 1-2 years old) subpopulations (Table 5.4.6), 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

Population

Short- or Intermediate-Term Scenario

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

Oral

Adult 9.4 100 0.094 0.00201 0.0056 0.00761 1,200

Child 9.4 100 0.094 0.00632 0.0383 0.0446 210

1 The LOC is based on standard inter- and intra- species uncertainty factors totaling 100.

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

3 Residential Exposure = Oral exposure from incidental ingestion of treated water while swimming, refer to Table # 

6.3.1.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure

5 Aggregate MOE = NOAEL / (Avg Food & Water Exposure + Residential Exposure)

7.3 Intermediate-Term Aggregate Risk
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Intermediate-term exposure is not expected to result from the residential uses of endothall.

7.4 Chronic Aggregate Risk

The chronic aggregate assessment is represented by the chronic dietary risk assessment which 

considers exposures from food and drinking water; refer to section 5.4.4. Chronic exposure is 

not expected to result from the residential uses of endothall.

7.5 Cancer Aggregate Risk

Endothall is classified as “Not likely to be carcinogenic to humans” through the oral, dermal and 

inhalation routes of exposure. Therefore, a quantitative cancer aggregate assessment is not 

needed. 

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 tolerance action, therefore, 

EPA has not assumed that endothall has a common mechanism of toxicity with other substances. 

For information regarding EPA’s efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy 

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the registered uses

on agricultural crops and aquatic areas (S.Tadayon, D428969, In Progress).

9.1 Short- and Intermediate-Term Handler Risk

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

following scenarios which cover all the registered uses of endothall: 

 Mixing/loading liquids to support aerial applications,

 Mixing/loading granular to support aerial applications,

 Mixing/loading liquids to support airblast applications

 Mixing/loading liquids to support groundboom applications, 

 Applying sprays with groundboom equipment,

 Applying sprays with airblast application, 

 Applying sprays with aircraft,

 Mixing/loading/applying with direct metering equipment (aquatic uses),

 Mixing/loading/applying with hose end sprayer (aquatic uses),
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 Mixing/loading/applying with granular spreader (aquatic uses), 

 Flagging to support aerial spray and spreader applications.

The registered labels require occupational handlers to wear the following personal protective 

equipment (PPE): long-sleeved shirts, long pants, chemical resistant gloves, protective eyewear 

and dust mist respirator (TC-21C).

The results of the occupational handler exposure and inhalation risk assessment for the 

agricultural scenarios (i.e., harvest aid and blossom thinner products) indicate that short- and 

intermediate-term inhalation risks do not exceed HED’s LOC (i.e., an MOE > 30) at the label 

recommended PPE (i.e., dust/mist respirator). The MOEs range from 31 to 2,900. 

The results of the occupational handler exposure and inhalation risk assessment for aquatic 

products indicate that some short- and intermediate-term inhalation risks exceed HED’s LOC 

(i.e. an MOE < 30) at the label recommended PPE, and even with a closed system (i.e., 

engineering control). The MOEs range from 1 to 873. 

Dermal handler and post-application exposure and risk assessments were not conducted because 

a systemic dermal hazard was not identified for endothall.

The inhalation toxicology study was conducted with a dust aerosol formulation which by far 

results in higher respirable particles than other formulations, and therefore higher exposure. 

Since the application the dipotassium salt, one of the two granular formulations, results in no 

respirable particles, there is no inhalation risk concern for this formulation Attrition studies or 

studies addressing the formation of respirable particles for other granular end-use products, e.g. 

Hydrothol 191 Granular, are not available. As such, risks of concern are associated with some 

aquatic uses of these formulations, as shown in Table 9.1.2. 

Table: 9.1.1. Short- and Intermediate-Term Occupational Risk assessment for Agricultural uses Endothall

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

(unless 

otherwise 

noted)

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled

Dailyd

Baseline Inhalation

Unless otherwise noted

Dosee MOEf

μg/lb ai lb ai/A or

lbai/gal

Acres or 

gals mg/kg/day LOC = 30

Mixer/Loader Emulsifiable Concentrate

Mixing/Loading Liquids for 

Aerial Application

Typical Field Crops1

0.219

(0.044 PF5)

1 350 0.00096 45

High-Acreage Field 

Crops2 0.8

1200

0.00053 

(PF5) 80

High-Acreage Field 

Crops3 0.1 0.00033 130

Mixing/Loading Liquids for 

Groundboom Application

Typical Field Crops1 1 80 0.00022 200

High-Acreage Field 

Crops2 0.8

200

0.00044 98

High-Acreage Field 

Crops3 0.1 0.00005 780

Mixing/Loading Liquids for 

Airblast Application Orchard Crop4

0.4 40 0.000044 980

1 0.00011 390

Applicator
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Table: 9.1.1. Short- and Intermediate-Term Occupational Risk assessment for Agricultural uses Endothall

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

(unless 

otherwise 

noted)

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled

Dailyd

Baseline Inhalation

Unless otherwise noted

Dosee MOEf

μg/lb ai lb ai/A or

lbai/gal

Acres or 

gals mg/kg/day LOC = 30

Applying Sprays for Aerial 

Application

Typical Field Crops1

0.0049

(engineering 

controls)

1 350 0.00002 980

High-Acreage Field 

Crops2 0.8

1200

0.00006 360

High-Acreage Field 

Crops3 0.1 0.0000074 2900

Applying Sprays for 

Groundboom Application

Typical Field Crops1

0.34

1 80 0.0003 62

High-Acreage Field 

Crops2 0.8 200 0.0007 31

High-Acreage Field Crops 0.1 200 0.00009 250

Applying Sprays for Airblast 

Application Orchard Crop4 0.942(PF5) 0.4 40 0.0002 110

1 0.0005 45

Flagger

Flagging for Aerial Applications

Typical Field Crops1

0.35

1

350

0.00154 48

High-Acreage Field 

Crops2 0.8 0.00123 60

High-Acreage Field 

Crops3 0.1 0.000154 480

a Crop or Target

1Typical Field Crop, Potato at 1 lb ai/A. 

2High-Acreage Field Crops Alfalfa and Clover at 0.8 lb ai/A 

3High-Acreage Field Crop, Cotton at 0.1 lb ai/A 

4 Orchard crops, Apple blossom 0.4 lb ai/A, Hops 1.0 lb ai/A

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = Baseline, PF5 

(dust mist respirator), or engineering controls.

c

 Based on the maximum application rates on the registered labels (Reg. 70506-175, 70506-174,70506-176 and 70506-191).

See table 4.1).

d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated 

or Amount Handled Daily (A or gal/day) ÷ BW (kg).

f Short-term and intermediate-term Inhalation MOE = Inhalation HED (Human Equivalent Dose (0.021,0.043,0.074 ) mg/kg/day ÷ Inhalation 

Dose (mg/kg/day).

Table 9.1.2. Summary of Endothall Short- and Intermediate-Term Occupational Inhalation Handler Risks for Aquatic Uses

Exposure Scenario Target Application Ratea Surface Area 

or Length of 

Water Body

(acres or 

miles)b

Depth of 

Water 

Body 

(feet)b

Width of 

Water 

Body

(feet)b

Inhalation 

UE (ug/lb 

ai)c

(PPE)

Short-term

Dosed MOEe

Mixer/Loader

Mixing/loading liquid 

for groundboom and 

aerial application 

(subsurface use)

Ponds/L

akes

13.6 lb ai/A-ft 30 

Acres/day

5 NA 0.083 (EC) 0.0021 35

Mixing/loading granules 

for groundboom and 

aerial application 

(subsurface use)

30 lb ai/A-ft 30 

Acres/day

5 NA 0.083 (EC) 0.0047 16
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Table 9.1.2. Summary of Endothall Short- and Intermediate-Term Occupational Inhalation Handler Risks for Aquatic Uses

Exposure Scenario Target Application Ratea Surface Area 

or Length of 

Water Body

(acres or 

miles)b

Depth of 

Water 

Body 

(feet)b

Width of 

Water 

Body

(feet)b

Inhalation 

UE (ug/lb 

ai)c

(PPE)

Short-term

Dosed MOEe

Mixing/Loading 

Emulsifiable Concentrate 

with Direct Metering

Flowing 

Water

0.56 lb ai / minute 

at 50 cfs( cubic feet 

per second)

300

minutes/day

NA NA 0.219(NR) 0.0046 93

0.15 lb ai / minute 

at 200 cfs (cubic 

feet per second)

120

minutes/day

NA NA 0.219(NR) 0.000049 873

Applicator

Applying liquid with

Closed cab Groundboom 

(subsurface use)

Ponds/L

akes

13.6 lb ai/A-ft 30 

Acres/day

5 NA 0.043 (EC) 0.00109 67

Applying liquid with

closed cab aircraft

(subsurface use)

Ponds/L

akes

13.6 lb ai/A-ft 30 

Acres/day

5 NA 0.0049 

(EC)

0.00013 168

Applying granules with

closed cab Groundboom 

(subsurface use)

Ponds/L

akes

30 lb ai/A-ft 30 

Acres/day

5 NA 0.22 (EC) 0.012 6

Applying granules with

closed cab aircraft

(subsurface use)

Ponds/L

akes

30 lb ai/A-ft 30 

Acres/day

5 NA 1.3 (EC) 0.073 1

Mixer/Loader/Applicator

Mixing/ Loading/

Applying Emulsifiable 

Concentrates with a 

Handgun Sprayer

Ponds/ 

Lakes

13.6 lb ai/A-ft 1 Acres/ day 2 NA 3.9(NR) 0.0013 56

Canals

1.7 lb ai/canal--1 

mile X 1 ft wide x 1 

ft deep

1 miles long 2 20 0.78(PF5) 0.00066 112

1.7 lb ai/canal--1 

mile X 1 ft wide x 1 

ft deep

1 miles long 2 5 3.9 (NR) 0.00083 89

Loading/ Applying 

granules (Push type 

rotary spreader)

Ponds/ 

Lakes

30.0 lb ai/A-ft 1 Acres/ day 5 NA 2(PF5) 0.00075 30

Canals

1.6 lb ai/canal--1 

mile X 1 ft wide x 1 

ft deep

1 miles long 5 20 1(PF10) 0.00085 50

1.6 lb ai/canal--1 

mile X 1 ft wide x 1 

ft deep

1 miles long 5 5 2(PF5) 0.00021 100

a Based on the maximum application rates on the registered labels (see Table 4.1).

b Amount handled per day values are HED estimates of acres, miles, or feet treated per day based on industry sources and HED estimates.

c Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); 

d Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated 

or Amount Handled Daily (A or gal/day) ÷ BW (kg).

e Short-term and intermediate-term Inhalation MOE = Inhalation HED (Human Equivalent Dose (0.021, 0.043, 0.074 ) mg/kg/day ÷ Inhalation 

Dose (mg/kg/day). The Human Equivalent Dose (HED) was calculated with a breathing rates of 8.6, 16.7 and29 l/min

9.2 Post-Application Risk Assessment

9.2.1 Inhalation Post-Application Risk Assessment

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 
Endothall Human Health Risk Assessment DP No. D422204

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

pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 

2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037). 

The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and 

a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for endothall.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the Agency's risk assessments.

9.2.2 Dermal Post-Application Risk Assessment

A quantitative dermal post-application assessment was not conducted because a systemic dermal 

hazard for endothall has not been identified. 

Restricted-Entry Interval

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

(REIs) are included in the 40 CFR 156.208. Guidance on applying these requirements are also

included in Chapter 11 of the Office of Pesticide Programs' Label Review Manual. 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 endothalldipotassium 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. 

10.0 Public Health and Pesticide Epidemiology Data 

Adapted from: S. Recore, D423761, 12/04/2014

IDS records incidents resulting in higher severity outcomes in more detail, in a module called the 

Main IDS module. This system stores incident data for death, major and moderate incidents, and 

it includes more details about the location, date and nature of the incident. Main IDS incidents 

involving only one pesticide are considered to provide more certain information about the 

potential effects of exposure from the pesticide. The less severe human incidents (minor, 

unknown, or no effects outcomes) are reported by registrants as counts called aggregate 

summaries and are recorded in a separate module called Aggregate IDS. The SENSORPesticides database covers 11 states from 1998-2010, although reporting varies from state to 

state. Cases of pesticide-related illnesses are ascertained from a variety of sources. Although 

both occupational and non-occupational incidents are included in the database, SENSORPesticides focuses on occupational pesticide incidents, and is of particular value in providing that 

information. For this evaluation, both the IDS and SENSOR database were consulted for 

pesticide incident data on the active ingredient endothall (PC Codes: 038901, 038904, and 
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038905). In addition, we sought information from the Agricultural Health Study (AHS); 

however, endothall is not included in the AHS.

Endothall and salts were previously reviewed in 2004 (J. Blondell and M. Hawkins, 6/24/2004, 

D304467). In this earlier review, it was concluded that “Relatively few incidents of illness 

have been reported due to endothall.” For the Main IDS, from January 1, 2009 to November 13, 

2014, there were 0 incidents reported for single chemical only in the database. In Aggregate 

IDS, from January 1, 2009 to November 13, 2014, there were 31 reported incidents involving 

endothall. These incidents were classified as minor severity. Overall, there are few incidents 

involving endothall reported to IDS. SENSOR-Pesticides identifies 16 cases from 1998 to 

2010. Six cases, stemming from six separate events, involve a single active ingredient. Five 

cases were low in severity and one case was moderate in severity due to dermal burns 

following a spill of the product onto skin. The remaining five cases were low in severity. Three 

cases experienced ocular irritation and three cases experienced dermal irritation. Four cases 

were related to spills or splashes. Two cases exposed to the product as it was being applied by 

another individual. 

Conclusions: Based on the low frequency and severity of incident cases reported for endothall

in both IDS and NIOSH SENSOR-Pesticides in the current analysis, there does not appear to be 

a concern at this time that would warrant further investigation. The Agency will continue to 

monitor the incident information and if a concern is triggered, additional analysis will be 

included in the risk assessment.

11.0 References

Endothall: Residue Chemistry Chapter to Support Registration Review and the Petition to 

Remove the Label Restriction for Livestock to Drink Treated Water; K. King; D426753 and 

D428908; In Progress.

Endothall: Occupational and Residential Exposure and Risk Assessment for Registration 

Review; S. Tadayon; D428969; In Progress.

Endothall: Chronic Aggregate Dietary (Food plus Drinking Water) Exposure Assessment to 

Support permanent tolerance on Milk, Meat, Poultry, and Eggs; K. King; D428970; In Progress.
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

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

noC

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).................................... noB-

AHASPOC TXR No. 0056397. Waived. 

BHASPOC TXR No. 0056794. Waived. 

C 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
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A.2 Toxicity Profiles

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

Note: Studies in the database were not updated to reflect current policies since these 

changes would not affect current PoDs and the selected endpoints are protective of all 

effects seen in the endothall database. 

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

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.

870.3700b

Prenatal 

developmental in 

rabbit

42776301 (1993)

Acceptable/guideline

0, 0.6, 1.5, 3.75 mg/kg/day

Maternal NOAEL = 1.5 mg/kg/day

LOAEL = 3.75 mg/kg/day based on 

mortality, decreased body weights and 

food consumption.

Developmental NOAEL = 1.5 mg/kg/day
Endothall Human Health Risk Assessment DP No. D422204

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

LOAEL = decreased body weight.

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.

Developmental NOAEL = 9.4 

mg/kg/day

LOAEL = 60.0 mg/kg/day based on 

decreased pup body weights

870.4100b

Chronic toxicity dogs

40745202 (1987)

supplementary/guideline

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

1000 ppm at the 7th 

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

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

NOAEL = not determined

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

gastric epithelial hyperplasia.

870.4200b

Carcinogenicity mice

40685301 (1988)

supplementary/guideline

0, 50, 100, 300 ppm

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

21 months

NOAEL =15 mg/kg/day

LOAEL = 45 mg/kg/day based on 

decreased body weight gain and 

microscopic findings in male kidney.

no evidence of carcinogenicity

870.4200b

Carcinogenicity mice

43608301(1995)

acceptable/guideline

0, 750, 1500 ppm

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

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

79 weeks

NOAEL = not determined

LOAEL = 124 mg/kg/day based on 

decreased body weight gain in males.

No evidence of carcinogenicity.

870.4300

chronic/onco rat

41040301(1989)

acceptable 

0, 150, 300, 900, 1800ppm

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

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

NOAEL = 8 mg/kg/day

LOAEL = 16 mg/kg/day based on 

decreased body weight and body weight 

gain.

No evidence of carcinogenicity.

Gene Mutation

Guideline # OPPTS 

870.5300 [§84-2]; 

OECD 476, study type

In vitro Mammalian 

Cell Gene Mutation 

Assay

43437801 (1993)

classification Acceptable

equivalent = 11.6%) Dosed in (DMSO) at 

concentrations of 0.0116, 0.0580, 0.116, 

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

μg/mL (all concentrations expressed as active 

ingredient) without metabolic activation or at 

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

23.2 and 26.1 μg/mL with metabolic 

activation (Initial Trial). For the 

confirmatory trial, levels of 0.0116, 0.0580, 

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

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

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

29 μg/mL +S9 were processed. 

Negative

Gene Mutation

Guideline # Bacterial 

Gene Mutation Assay 

43154801 (1993).

Unacceptable

in dimethyl sulfoxide (DMSO) (equivalent 

Negative
Endothall Human Health Risk Assessment DP No. D422204

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

(Salmonella 

typhimurium)/OPPTS 

870.5100/[§84-2] 

OECD 471

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

active ingredient) with or without S9 

activation.

Cytogenetics 

In vivo Mammalian 

Cytogenetics -

Micronucleus Assay 

in Mice/OPPTS 

870.5395/[§84-2]

43157401 (1994) Acceptable

mice were administered 0.464, 0.928 and 

1.86 mg/kg Endothall Technical amine salt 

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

endothall amine 30.3%;endothall acid 

equivalent = 11.6%) via intraperitoneal 

injection (IP) in deionized water;

Negative

Cytogenetics 

In vivo Mammalian 

Cytogenetics -

Micronucleus Assay 

in Mice/OPPTS 

870.5395/[§84-2]

41700301 (1989)

Acceptable

mice were administered 2,10 or 50 mg/kg 

Endothall 

Negative

Cytogenetics 

In vitro Mammalian 

Cytogenetics OPPTS 

870.5375 [§84-2]; 

OECD 473

41700302 (1989) Acceptable

in dimethyl sulfoxide (DMSO) at 

concentrations of 2.5, 10.0, 20.0 and 40.0 

μg/mL without metabolic activation or were 

exposed for 3 hours to 15.0, 60.0, 120.0 or 

240.0 μg/mL with metabolic activation

Negative

870.7485

Metabolism and 

pharmacokinetics

42169502 (1990),

acceptable

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

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

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

Intravenous administration of 0.9 mg/kg 

resulted in excretion mainly by the urine 

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

dose, blood half-life elimination - 1.8 hrs 

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

half-life - 13.9 hours in males; the 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 
Endothall Human Health Risk Assessment DP No. D422204

Page 45 of 53

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

Guideline No./ Study 

Type

MRID No. (year)/ Classification /Doses Results

radioactivity being present in the feces 

(47.6% males, 47.5% females) At 24 

hours after dosing, less than 0.21% of the 

dose was found in the stomach (+ 

contents), small intestine (+ contents) and 

pancreas and very little detected in the 

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

of radioactivity were found in the caecum 

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

large intestine (3.2% males, 8.2% 

females).

Analysis of extracts of the urine, feces, 

caecum and large intestine of both male 

and female rats gave a single radioactive 

component corresponding to unchanged 

Endothall which accounted for >86, >96, 

>74 and >69% of total recovery from the 

respective extracts.

870.7600

Dermal penetration

42169503 (1990)

acceptable

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

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

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

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

24 hours) in each dose 

Approximately 55 to 82% of the applied 

dermal dose was washed from the 

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

Endothall equivalents was contained in 

the application site skin. Urinary 

excretion of [14C]-Endothall equivalents 

increased in a dose related manner at 10 

and 24 hours to a maximum of 2.3% of 

the applied dose at the 0.125 mg/cm2(3.0 

mg/rat)dose level. Fecal excretion 

amounted to <0.1% at all dose levels. At 

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

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

(3.0 mg/rat) dose levels, systemic 

bioavailability (absorption) of 3.9%, 2.2% 

and 7.3%, respectively, were noted at 24 

hours. A time related increase in systemic 

bioavailability occurred only at the 1.5% 

dose level. The dose related pattern of 

absorption was typical of a chemical 

which directly damages the skin. The 

percent of dose absorbed increased with 

increasing dose. The total percent 

recovery of [14C]-Endothall equivalents 

was 97.7 to 101.1% of the administered 

dose throughout the 24 hour period.

Special studies None

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 
Endothall Human Health Risk Assessment DP No. D422204

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

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

and relative lung weights, subacute 

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.

a Studies in the database were not updated to reflect current policies since these changes would not affect current 

PoDs and the selected endpoints are protective of all effects seen in the endothall database. 
Endothall Human Health Risk Assessment DP No. D422204

Page 47 of 53

Appendix B. Physical/Chemical Properties

Table C.1. Physicochemical Properties of Endothall and its Salts.

Parameter Value Reference

Endothall (acid)

Melting point 108-110 ̊C DP# 304026, D. 

pH 2.7 at 25 ̊C (1% solution) Soderberg, 6/10/2004

Density, bulk density, or specific 

gravity

0.481 g/cm3(bulk) at 25 ̊C

Water solubility at 25 ̊C 109.8 g/L

13.1 g/100 mL in water, pH 5

12.7 g/100 mL in water, pH 7

12.5 g/100 mL in water, pH 9

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

2.4 g/100 mL in n-octanol

16.0 g/100 mL in tetrahydrofuran

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

Dissociation constant, pKa 4.32 for Step 1 and 6.22 for Step 2 at 20 ̊C (0.2% solution in 20% 

basic ethanol); dissociation rate 1.8-2.3 x 103 μmho within 3-5 

minutes at ∼25 ̊C, by conductivity meter

Octanol/water partition coefficient Not applicable to endothall acid

UV/visible absorption spectrum Not available

Endothall, dipotassium salt

Melting point >360 ̊C DP# 304026, D. 

pH 9.1 at 25 ̊C (1% solution) Soderberg, 6/10/2004

Density, bulk density, or specific 

gravity

0.766 g/cm3(bulk) at 25 ̊C

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

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

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

insignificant vapor pressure.

Dissociation constant, pKa 4.16 for Step 1 and 6.14 for Step 2 at 20 ̊C in water; dissociation 

complete at 5 mins (13.6 x 103 μmho)

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

M, respectively, at 25 ̊C

UV/visible absorption spectrum Not available

Endothall, mono-N,N-dimethylalkyl amine salt

Boiling point Not available DP# 304026, D. 

pH 5.2 at 25 ̊C (1% solution) Soderberg, 6/10/2004

Density, bulk density, or specific 

gravity

1.028 g/mL at 25 ̊C

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

≥51.6 g/100 mL in water, pH 7

≥49.8 g/100 mL in water, pH 9

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

≥95.4 g/100 mL in n-octanol

≥104.3 g/100 mL in tetrahydrofuran

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

dialkylamine (C8-C20))

Dissociation constant, pKa 4.24 for Step 1 and 6.07 for Step 2 at 20 ̊C for mixed mono- and 

dialkylamine (C8-C20) in acidified ethanol/water; dissociation 

complete ∼17 minutes (1.7 x 103 μmho) at 25 ̊C

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

25 ̊C

UV/visible absorption spectrum Not available
Endothall Human Health Risk Assessment DP No. D422204

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Appendix C. 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 Aquatic use Standard Operation Procedure 

(20-Sep-2013) and 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://www2.epa.gov/pesticide-science-andassessing-pesticide-risks/occupational-pesticide-handler-exposure-data and 

http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticidepost-application-exposure. 
Endothall Human Health Risk Assessment DP No. D422204

Page 49 of 53

Appendix D. Use Pattern Summary Tables

Table D. Summary of Registered Uses for Endothall

Crop/Use Site

Application Timing 

and Type of 

Application

Registered 

Formulations

Maximum Application 

Rate

Personal Protective 

Equipment (PPE) 

and Restricted 

Entry Interval 

(REI),PHI

Registered Uses for Endothall

Quiescent, slow moving, 

and flowing water aquatic 

sites (Drainage and 

irrigation canals, ponds, 

and lakes)

Aircraft- or boatmounted spreaderGranular (G) 70506-

174

5 ppm (30 lbs ai/acre ft) PPE*

Surface or injected; 

Drip or metering; 

Aerial

Liquid (SC) 70506-175 5ppm (3.6 pints/acre ft or 

13.6 lb ai/per acre ft)

PPE*

Surface or injected; 

Drip or metering; 

Aerial

Liquid (SC)70506-176 5 ppm (13.6 lb ai /acre ft 

for broadcast and for spot 

or lake margin treatment) 

PPE*

Aircraft- or boatmounted spreaderGranular 70506-191 5ppm(13.9 lb ai/acre/ft) PPE*

Surface or injected; 

Drip or metering; 

Aerial

Liquid (SC)70506-302 1.8 ppm (4.9 lb ai/acre ft) PPE* 

Closed 

mixing/loading for 

aerial application 

Harvest Aid for Cotton Preharvest, 

Defoliation, Aerial, 

ground

Liquid (SC) 70506-180 0.1(lb ai/A) 48 hr REI, 

7 days retreatment 

interval

Harvest Aid for Alfalfa 

and Clover

Preharvest, Aerial, 

ground

Liquid (SC) 70506-190 0.8 (lb ai/A) 48 hr REI, 

7 days retreatment 

interval

Harvest Aid Potato and 

Hops

1.0 (lb ai/A) 48 hr REI, 

14 days retreatment 

interval

Apple blossoms Airblast Liquid SC 70506-296 0.4 (lb ai/A) 48 hr REI, 

24 hr retreatment 

PPE* - Label recommended PPE is long sleeve shirt, chemical resistance gloves, shoes plus socks, protective 

eyewear and PF5 dust/mist respirator
Endothall Human Health Risk Assessment DP No. D422204

Page 50 of 53

Appendix E. International Residue Limits Table

Endothall (PC Code 038901)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.293:

(a) General. (1) endothall (7-oxabicylco [2.2.1] 

heptanes-2,3-dicarboxylic acid) and its monomethyl ester.

7-oxabicyclo[2.2.1]heptane2,3-dicarboxylic acid, 

including its monomethyl 

ester

None

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

US Canada Mexico1 Codex

Apple 0.05

Apple, wet pomace 0.15

Cotton, undelinted seed 0.1

Fish 0.1

Hop, dried cones 0.1

Potato 0.1 0.1

Rice, grain 0.05

Rice, straw 0.05

Completed: M. Negussie; 09/02/15

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

(2) An interim tolerance of 0.2 parts per million is established for residues of the herbicide endothall (7 -

oxabicyclo[2.2.1] heptane-2,3-dicarboxylic acid) in water, potable from use of its potassium, sodium, diN, N-dimethylalkylamine, and mono-N-N,-dimethylalkylamine salts as algicides or herbicides to control 

aquatic plants in canals, lakes, ponds, and other potential sources of water, potable.

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.293:

(d) Indirect or inadvertent residues. Tolerances are 

established for the indirect or inadvertent combined 

residues of the herbicide, endothall (7 -

oxabicyclo[2.2.1] heptane-2,3-dicarboxylic acid) in 

potable water from use of its potassium, sodium, diN, 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 

None None

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

US Canada Mexico1 Codex

Almond, hulls 15.0

Animal feed, nongrass, group 18, 

forage

4.0

Animal feed, nongrass, group 18, 

hay

10
Endothall Human Health Risk Assessment DP No. D422204

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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Apple, wet pomace 0.15

Beet, sugar, molasses 1.5

Brassica, head and stem subgroup 

5A

0.1

Brassica, leafy, subgroup 5B 2.0

Bushberry subgroup 13-07B 0.6

Caneberry subgroup 13-07A 0.6

Cattle, fat 0.01

Cattle, kidney 0.20

Cattle, liver 0.10

Cattle, meat 0.03

Corn, field, grain 0.07

Corn, pop, grain 0.07

Corn, sweet, kernel plus cob with 

husks removed

0.3

Citrus, dried pulp 0.1

Egg 0.05

Feed commodities not otherwise 

listed

10.0

Food commodities not otherwise 

listed

5.0

Fruit, citrus group 10 0.05

Fruit, pome, group 11 0.05

Fruit, stone, group 12 0.3

Goat, fat 0.005

Goat, kidney 0.15

Goat, liver 0.05

Goat, meat 0.015

Grain, aspirated fractions 35.0

Grain cereal, forage, fodder and 

straw, group 16

10.0

Grain, cereal, group 15, except corn 4.0

Grape 1.0

Grape, raisin 5.0

Grass, forage, fodder, and hay group 

17, forage

3.5

Grass, forage, fodder, and hay group 

17, hay

18.0

Herb and spice, group 19 5.0

Hog, fat 0.005

Hog, kidney 0.10

Hog, liver 0.05

Hog, meat 0.01

Milk 0.03

Nut, tree, group 14 0.05

Okra 0.05

Pea and bean, dried shelled, 

subgroup 6C

0.2

Pea and bean, succulent shelled, 

subgroup 6B

2.0

Peppermint, tops 5.0
Endothall Human Health Risk Assessment DP No. D422204

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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

Pistachio 0.05

Poultry, fat 0.015

Poultry, liver 0.05

Poultry, meat 0.015

Poultry, meat byproducts 0.20

Rice, hulls 8.0

Sheep, fat 0.005

Sheep, kidney 0.15

Sheep, liver 0.05

Sheep, meat 0.015

Soybean, hulls 0.5

Soybean, seed 0.2

Spearmint, tops 5.0

Tomato, paste 0.1

Tomato, puree 0.1

Vegetable, bulb, group 3-07 0.5

Vegetable, cucurbit, group 9 1.5

Vegetable, foliage of legume, group 

7

4.0

Vegetable, fruiting, group 8 0.05

Vegetable, leafy, except brassica, 

group 4

2.0

Vegetable, leaves of root and tuber, 

group 2

3.0

Vegetable, legume, edible, podded, 

subgroup 6A

2.0

Vegetable, root and tuber, group 1 1.0

Wheat, milled byproducts 5.0

Completed: M. Negussie; 09/02/15
Endothall Human Health Risk Assessment DP No. D422204

Page 53 of 53

Appendix F. Status of Residue Chemistry Issues Identified in the 2005 Chapter.

Deficiency Status

Radiovalidation data to determine whether the 

current enforcement methods for plants and the 

required enforcement method(s) for animals can 

adequately extract and convert aged residues of 

the monomethyl ester to endothall. 

Not resolved for plants; however, is not required 

as parent endothall only is an adequate marker of 

misuse. 

Waived for livestock in the current residue 

chemistry chapter (D428908, In Progress).

Data collection and regulatory analytical methods 

for the determination of endothall, per se, in 

animal commodities.

Resolved in the current residue chemistry chapter

(D428908, In Progress).

Storage stability data for processed plant 

commodities, animal commodities, and fish.

Resolved for plants (D. Soderberg, D356315, 

10/22/2009), animal commodities (current 

chapter, D428908), and fish (D. Soderberg, 

D324426, 02/27/2006).

Livestock (ruminant and poultry) feeding studies. Resolved in D387313 (D. Soderberg, 05/03/2011)

A maximum seasonal rate of application to 

irrigation canal water must be proposed for the 

label. Depending upon this proposal, additional 

magnitude of the residue studies at the proposed 

seasonal rates may be required in irrigated crops. 

Additional magnitude of the residue studies are 

also required in some additional irrigated crops, 

pending discussion between HED and the 

registrant, to assure adequate coverage of all 

irrigated crops.

Resolved. Magnitude of residue studies in 

irrigated crops were reviewed in D356315 (D.

Soderberg, 10/22/2009).

Magnitude of the residue studies in potato, alfalfa 

seed, undelinted cottonseed, and cotton gin 

byproducts. Magnitude of the residue studies in 

the RACs of sugar beet and rice if the registrant 

intends to support these uses.

Alfalfa: Two additional trials are required,

tolerance recommended in this chapter.

Potato and Cotton: Resolved in the current residue 

chemistry chapter (D428908, In Progress).

Processing studies on apples, corn (field), grapes, 

orange, rice, sorghum, soybeans, sugar beet, 

tomato, and wheat, to cover irrigation uses.

Resolved in the chapter that address studies in 

irrigated crops D356315 (D. Soderberg, 

10/22/2009).

Submission of analytical reference standards for 

dipotassium and mono-N,N-dimethylalkyl amine 

salts of endothall.

Standards are available.

A confined rotational crop study identifying the 

residues of concern besides endothall is required 

or else limited rotational crop field trials may be 

performed in which the residues of concern for 

endothall (endothall and its monomethyl- and 

dimethyl- esters are tested.

The confined rotational study was waived in 

D387313 (D. Soderberg, 05/03/2011).

A radiovalidation study of the proposed 

enforcement method for determining endothall in 

fish is needed. 

The radiovalidation was waived in D324426 (D. 

Soderberg, 02/27/2006).