E nd otha ll Human H ealt h Ri s k Assess m e nt DP No

. D 422204



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C. 20460



### M E MORANDUM

D ate: 12 / 09 / 20 1 5 OFF I CE OF

C HEMICA L SAFETY AND

PO LLUT IO N PREVENTI O N



### SU BJECT: E ndothall: Human Health Ri s k Assessmen t in S upp ort of Registration

Review

, a nd t h e Petition to Re-evaluate Tolerance s for Livestock

, and

R e move the Re s triction that Prohibit s L iv estock from Drinking Treated

Water.

P C Co d e: 03890 I (Acid), 038904 (D ipotassium )

. and

038905 (Monoalkylamine) DP B arco de: 0422204 and 0426245

D ecis i o n N o.: 492480 and 502452 Regi s tration N o.: 70506-174, 70506-175, 70506-176,

70506 -191

, 70506 -1 90, 70506- 180

, 70506

- 302 Regulator y Ac ti o n : Reg R eview and Tolerance

Pe titi on P e tition No.: 4F8293

Ri s k A ss ess m e nt T y pe: S in g l e c h e mica l/agg r ega t e
TXR No. : NA C a se No.: 2245

C AS No .: 145- 73-3; 2 1 64-07-0; a nd 66330

- 88

- 9

40 C FR: 180.293 MRID No. : NA



### FROM: ld e li z Neg r6n

- Encamaci6n, Ph.D

., C h e
John Liccio n e, P h .D.

, Tox·c I gis

K ate l yn n King

, Bi o lo g i s t Seyed T adayo n
, Che mi s t .-:.. -'

- Ri s k Assess m e nt Branch V a nd V il

H ea l th Effec t s D i v i s i on (75 09P ) 

# if

TH RO UG H : Michael S

. Metzger

, Bran ch Ch i ef

# ~ /))

a nd

# ~1{1 Christina Swartz, RAR C Rev i ewe Kelly Lowe, RARC R ev i ewer**,** H ea lth Effec ts Division (7509 P )



### TO : Sara h M ea dow s, Ph .D., Ri s k Manage r Reviewer Kathryn Montag u e
, Ri sk Manage r
Ri sk Management Di vis i on (7505 P )

and

Gar l and Wa l eko

. Risk Manager R ev i ewer

Ke v in Cos t e ll o, Ri sk Manage r
P es ticid e R e-evaluation Di v i s ion (7508 P )

Pa g e I of 53

### Endothall Human Health Risk Assessment DP No. D422204

Page 2 of 5 3 

### 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 ) ev aluate 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 d ocument 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 th e restriction on consumption of water treated with endothall by

livestock. The most recent quantitative human health risk assess ment was conducted in 20 13 to support the proposed use of the dipotassium form of endothall on apples (D 403274

, S

. Tadayon

, 3 / 1 8 /20 13 ).

### Endothall Human Health Risk Assessment DP No. D422204

Page 3 of 53 

### 1.0 Executive Summary

................................ ................................ ................................ ........... 5

2.0 HED Recommendations

................................ ................................ ................................ .... 7

2.1 Da ta 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

### Endothall Human Health Risk Assessment DP No. D422204

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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

................................ . 3 2

6.5 Spray Drift

................................ ................................ ................................ .................... 33

7.0 Aggregat e 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

### Endothall Human Health Risk Assessment DP No. D422204

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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 th e 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 mono m ethyl 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 exp osure through dietary pathways, exposure may result from residential and occupational uses of endothall. This risk assessment is prepared in support of r egistration review (scoping and draft risk assessment actions) and the petition to remove the restrict ion 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, T XT # 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,

e ndothall technical was extremely irritating to the eye, and was also lethal. In a dermal irritation study, endothall was an extreme irritant. Althoug h 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 c lassified 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 post

natal toxicity following exposures to rats for two generations. In the developmental mouse study, there was severe maternal toxicity (i.e., greater than 30% mortality) at the highest dose tested; at this dose level, a slight increase in vertebral a nd rib malformations was observed in the offspring indicating that these effects were most likely secondary to severe maternal toxicity.

The hazard data for endothall indicat e no evidence of quantitative or qualitative increased susceptibility of rat fetus es exposed in utero to endothall in the developmental toxicity studies. In addition, no evidence of quantitative or qualitative increased susceptibility of rat fetuses or

neonates was observed in the 2

- generation reproduction study.

### Endothall Human Health Risk Assessment DP No. D422204

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### Appropriate endpoint s were identified f or 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 assessment s based on indications of lung toxicity in a subchronic inhalation toxicity study in the rat ; and for the short

term incidental oral risk assessment based on decreased pup body weight in a 2

- generation rat reproduction oral study. An acute dietary endpoint attributa ble 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 t o 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.

M ethods 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 ha ve been submitted and evaluated in support of the removal of the label

restriction that prohibits livestock from drink ing 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 to lerance 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 w ith an exposure equivalent t o an estimated risk of 90 % of the cPAD . E xposures to
endothall for all food and water uses are be low 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, su ch 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 occupat ional 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 recomme nds 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.

### Endothall Human Health Risk Assessment DP No. D422204

Page 7 of 53 

### 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 duration s. The resulting margins of exposure (MOEs) for short

term 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

. P ost

- application oral exposure for adults and children were comb ined with the chronic dietary exposure from the mostly highly exposed subpopulations. T he 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 oc cupational 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 fr om 1 to 873

. The occupational handler exposure and risk estimates for agricultural scenarios indicate that short

and intermediate

- term non

- cancer inhalation MOEs are not of concern to HED (i.e., MOEs > 30)

with label recommended PPE (i.e., dust/mist respi rator) . 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 )

. Th e 48

- hour REI listed on the agricult ural 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 A ppendix 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 dri nk ing 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 t he occupational and residential ex posure 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

Page 8 of 53 

### in a n inhalation risk of concern based on the following: it is coated with polymer minimizing formation of respirable/inhalable dust ; tests performe d 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 i rrigated crops studies ( D356315 ) and the apple blossom study (D384206 )

.

 860.1500: Two additional trials in Region 11 are required to support the use of endo thall on alfalfa grown for seed ( D 426753 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 : A n enforcement me thod (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 commod ities 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 met hod 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. Th e 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 com modities. 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 (D 42 6753 )

.

### Endothall Human Health Risk Assessment DP No. D422204

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### Confirmatory method for plants and fish: A n 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, acidi fied and, if necessary, purified using a C 18 

### 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 tolu ene, 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 fo r plant commodities . This method has undergone a successful independent laboratory validation using fish samples.

Multiresidue Methods: E ndothall 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 understand s that parent endothall is an adequ ate 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 sugge st that the main residue is parent endothall and an appropriate marker of misuse as well . The tolerances are not likely to under estimate the residue levels and are considered adequate for enforcement purposes as they are not likely to be significantly ove restimated

. P arent endo thall 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 co w 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

.

F urther review of the magnitude of residue study on potato shows that proportionality can be applied to the residue data generated at 2x and a reassess ed 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 wate r 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

### Endothall Human Health Risk Assessment DP No. D422204

Page 10 of 53 

### establishes tolerances in drinking water. EPA’s Office of Water has established a maxim um contaminant level ( MCL ) for endothall at 0.10 ppm. Finally, HED recommends the

e stablishment of tolerance s 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 u nder 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 esta blished 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] hept anes

- 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 fo r 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

- d icarboxylic 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 plan ts 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, seed 1 2.0
Clover, seed 1 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

### Endothall Human Health Risk Assessment DP No. D422204

Page 11 of 53 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

### Endothall Human Health Risk Assessment DP No. D422204

Page 12 of 53 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

### Endothall Human Health Risk Assessment DP No. D422204

Page 13 of 53 Table 2.2. 2 . Tolerance Summary for Endothall

Commodity Established

Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition

Fish

- shellfish, crustacean 2 N/A 1 1

Fish

- shellfish, mollusc 2 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 ir rigation 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 D 356315 (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 whic h 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 calculati ons
, 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 n ot 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 i s 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 ab ove 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

drink ing 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 treat ed 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 it s enforceability is demonstrated , refer to Section 3.3

.

### Endothall Human Health Risk Assessment DP No. D422204

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### 2.3.2 Recommendations from Occupati onal 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/loa ding 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 long

sleeved shirts, long pants, chemical resistant gloves, and protective eyewear for all scenarios.

A ll 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 f rom Residential Assessment

None.

3.0 In troduction

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 conside red . 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

### Endothall Human Health Risk Assessment DP No. D422204

Page 15 of 53 Table 3.1.1 Structure and Nomenclature of Endothall

- dipotassium

. Chemical Structure

Common name Endothall acid

Molecular Formula C 8 H 10 O 5 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 C 8 H 8 K 2 O 5 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, N

dimethylcocoamine

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

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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

aerobi c metabolism (N. Thurman, D356316, 09/09/2009). Laboratory studies measured first

order degradation half

- lives of 14.5 days for aerobic soil metabolism, 10 days for aerobic aquatic metabolism, and 9 days for anaerobic metabolism. Terrestrial dissipation st udies 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

Endotha ll is a selective contact herbicide, defoliant, desiccant, growth regulator and aquatic algicide which belong s to the dicarboxylic acid chemical class

. The free acid of endothall (PC Code 038901) is the active ingredient that forms from the breakdown of th e 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, mi lfoil, elodea, and algae , as well as plankton in water

bodies. Moreover, t he 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. The re 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): long

sleeved 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 applicat ion, 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) ; Hydr othol® 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) incl udes 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 it s enforceability is d emonstrated (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

### Endothall Human Health Risk Assessment DP No. D422204

Page 17 of 53 

### and enforceable and are subject to the following criteria: (1) the food or feedstuff mu st 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 harv ested 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 drink ing

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.

N o new toxicity data have been received since the previous risk assessment ( D403274 , J. Liccione, 03/18/2013) . A det ailed description of the toxicity data and metabolism information may be found in the risk assessment dated 11 / 09/09 ( David Soderberg , D3 70448 ). T his risk assessment considers all of the aforementioned exposure pathways based on the proposed new

uses of e ndothall, 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. Ext ensive 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 d ietary 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 applicato rs 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

### Endothall Human Health Risk Assessment DP No. D422204

Page 18 of 53 

### development of specialized software and mo dels 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 conducte d 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 the se 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, Metab olism, & Elimination (ADME)

In rats, a t 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 calculate d 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 abso rbed 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 dermall y for 24 hours with 0.0125 mg/cm 2 

### , 0.0625 mg/cm 2



### , and 0.125 mg/cm 2 

### was estimated at 3.9%, 2.2% and 7.3%, respectively. Urinary excretion of
[ 14 

### C]

- Endothall equivalents was 2.3% of the applied dose at 0.125 mg/cm 2 

### 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) , q uantification 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 hy perplasia 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 F 1 

### parental male and female rats treated orally with endoth all 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 s hown 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 or al 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

cla ssified 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 b ody weight following oral treatment. Decreased body weight was also apparent in a developmental toxicity study in the rabbit (maternal and offspring). D ecreased 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. B ody weight decrement was also identified

in a n oral carcinogenicity mouse study.

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

the 21

- day dermal toxici ty 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 inhalati on toxicity s tudies 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 schedu led necropsy. Nasal effects consisted of minimal olfactory

### Endothall Human Health Risk Assessment DP No. D422204

Page 20 of 53 

### 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

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

Endothall does not cause pre

- natal toxicity following in utero ex posure to rats or rabbits nor pre

and post

- natal toxicity following exposures to rats for two generat ions.

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 neuro tox icity

stud ies 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 pesticide s. The HASPOC (September 26, 2013) also recommended waiving the immunotoxicity study.

4.4 Safety F actor 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 3 X 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 UF L 

### is retained for chronic exposure scenarios. A 3X factor (as opposed to a 10X) was deter mined 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 increa sed 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 o f 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 n eurotoxicity

studies are not available f or endothall. However, t he HASPOC (December 19, 2012) recommended waiving the acute and subchronic neuro toxicity stud ies 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 stud ies, 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 exp osure 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 drinkin g 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 D eparture 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 woul d 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 yea rs 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 i n 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 f or 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

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

### Endothall Human Health Risk Assessment DP No. D422204

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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 b ased on clinical signs of toxicity observed ac utely 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 acut e 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 res idential 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 ar e 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

F 1 

### and F 2 

### 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). T he 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 paren tal 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 LD 50 

### (= 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

condi tions, 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 de rmal route.

Post

- application oral and i nhalation 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 an d risk were assessed.

4.5.2 Cancer Classification and Risk Assessment Recommendation

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Page 23 of 53 

### 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, Non

Occupational 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 UF A = 10X

UF H = 10X FQPA UF L = 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 UF A = 10X

UF H = 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 F 1 and F 2 generations

Short and Intermediate

Term 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

de rmal 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). Endoth all 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 UF A = 3X C

UF H = 10X FQPA S F

= 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).

### Endothall Human Health Risk Assessment DP No. D422204

Page 24 of 53 Table 4

. 5.3.1

. Summary of Toxicological Doses and Endpoints for Endothall for Use in Dietary, Non

Occupational 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 UF A = 3X C

UF H = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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) = 0.01 43 mg/kg/day

.

B Refer to the table below. Occupational HEC (pulmonary effect) = rat POD * (daily duration adjustment) * weekly duration adj ustment * 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 * relativ e activity factor (1.2).

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

8.3 0.021

16.7 0.043

29 0.074

### Endothall Human Health Risk Assessment DP No. D422204

Page 25 of 53 

### 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, sex ual 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 hum ans 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 consist s 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

in teract 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 e ffects 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 or ders/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, 201 4 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 scree ning 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

- disruptor

screening

- program

. 2 http://www.epa.gov/endo/

### Endothall Human Health Risk Assessment DP No. D422204

Page 26 of 53 

### 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 plant s and animals is qualitatively similar ; parent endothall is the major residue while the major metabolite is the monomethyl ester w ith 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 rotate d 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 do es not need to be quantitated by the data acquisition methods (e

- mail communication from Garland Waleko, 11/18/2015) . H ED 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 observe d 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 fo r 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, tolera nces 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

. The refore, 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 wate r assessment. Endothall monomethyl ester ha s 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 d ated 08/30/2005 (DP# D321179, D. Soderberg).

### Endothall Human Health Risk Assessment DP No. D422204

Page 27 of 53 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 E ndothall and its monomethyl

ester E ndothall Rotational Crop 2

Livestock Ruminant E ndothall and its monomethyl

ester E ndothall and its monomethyl

ester Poultry

Drinking Water Endothall Acid Endothall Acid 3

1 Endothall is 7

- oxabicyclo[2.2.1]heptane

- 2,3

- dicarboxylic acid

. 2 I t 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. Soderbe rg, D 387313 , 05/03/201 1 ).

3 A maximum contaminant level for endothall i n 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 inadvert ent 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

establ ished 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 re evaluated.

Several deficiencies iden tified 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 (EF ED) to support the human health risk assessment for the proposed use of endothall

treated irrigation water on a variety of crops (J . Lin, D404321 , 9/12/12 ). Based on personal

communication betwe en 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

e s timated concentra t i ons u se the simple first

- order degradation mo d e l

, assuming either static (no flow) or varying water turnover rates in the farm water body. E n d othall c o n cen t r a t io n s

### Endothall Human Health Risk Assessment DP No. D422204

Page 28 of 53 

### degraded w i th first

- o

r der kinetics star t i n g imme d i ately aft e r application. The maximum potential exposure of endothall in drinking water sources is expected to result from the di rect application of endothall to drinking wate r reservoirs to control aquatic weeds. EFED assumed

that the entire reservoir would be treated at the max imum 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 tre atment. This resulted in a chronic (annual average) concentration of 31 μ g/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 (treatm ent of a reservoir).

Table 5.3 Su mmary 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, mi lk, 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. O verall, 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

Page 29 of 53 

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

conser vative 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 be en perfo rmed 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

wa ter) to the U.S. population from the existing uses of endothall resulted in an estimated risk equivalent to 3 2 % 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 7 7 % 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 S ummary Table

### Endothall Human Health Risk Assessment DP No. D422204

Page 30 of 53 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

, D 428969

, 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 a ssumed to be short

- term in duration. Risks estimates were calculated

for inhalation and incidental oral ingestion while swimming in treated lakes or ponds. Post

application dermal assessments are not needed since there is no short

- term systemic dermal

haza rd

.

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

Page 31 of 53 

### 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 SOPs 3 

### . 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 adult s and children (3 to < 6 years old )

for short

- term, inhalation exposures is MOEs < 3 0. The level of concern fo r 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 (m g/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

- sci ence

- and

- assessing

- pesticide

- risks/swimmer

- exposure

assessment

- 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 spread sheet format to estimate the exposures.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates

Table 6 .2.1 present s 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 9 

### for adults and 3 x 10 9 

### for

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 (LO C) 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

- procedures

residential

- pesticide

### Endothall Human Health Risk Assessment DP No. D422204

Page 32 of 53 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 m aximum a pplication rate from registered labels for aquatic weed control: 0.00022 lb ai/ft 3 (EPA Reg.4581

- 388

- 82695)

. 2. Inhalation exposure dose (mg/kg/day) = chemical vapor concentration, v p (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 (adul t

- female = 69 kg; children (3 to < 6) = 19 kg) 3. Oral exposure dose (mg/kg/day) = concentration, C w ( 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= 0.01 43 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 < 3 0 ; The LOC

for adult females and children (3 to < 6) for short

- term i ncidental oral exposures is MOEs < 100.



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

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

assessm ent for endothall

.

 The recommended residential exposure for use in the adult short

- term aggregate assessment reflects residential post

- application incidental oral (water ingestion) e xposure from swimming in treated aquatic areas.

 The recommended residential exposure for use in the children 3 to < 6 years old short

term aggregate assessment reflects incidental oral (water ingestion) exposure from post

application exposure to treated a quatic areas.

Table 6 .3.1. Recommendations for the Residential Exposures for the Endothall Aggregate

Assessment. 1 (Aquatic Scenarios )

Lifestage Residential Post

application Total Exposure (mg/kg/day) 2 Residential Post

- application MOE 3

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 i dentified 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 Vo latilization Screening Analysis ( http://www.regulations.gov/#!docketDet ail;D=EPA

- HQ

- OPP

- 2014

- 0219 )

.

### Endothall Human Health Risk Assessment DP No. D422204

Page 33 of 53 

### 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 a rea 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. T he 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 quantitat ive 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 tha t 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 u sed for quantitatively incorporating spray drift into risk assessment include s 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 expos ure scenario. Aside from the predicted re sidues available for transfer, the routes of expo sure and assessment methodology is analogous to how exposures to turf products are considered in risk assessment.

N o d ermal endpoint was selected because the derma l irritation observed in a repeated

- dose study

is considered self

- limiting . Therefore

, de rmal risk estimates were not calculated for children 1< 2

or adults. I ncidental 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/cm 2 ) a At Edge

HtM MOE

Aerial Fine to Medium

1 0.011 2

, 400

Groundboom High Boom Very fine to Fine 3

, 3 00

Airblast Sparse 4

, 30 0

a. TTR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; 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

- Ter m Aggregate Risk

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

- term incidental oral

exposure is based on decrease d 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 , t he inhalation endpoint is based on lung toxicity. Based on the difference between the oral and inhalation endpoints

, an assessment aggregatin g the se 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 an d 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 (C hildren 1

- 2 years old) subpopulations (Table 5.4. 6 ), respectively, to determine

agg regate 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 LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5 Oral

Adult 9.4 100 0.094 0.00201 0.0056 0.0076 1 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 un certainty 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 E xposure)



### 7.3 Intermediate

- Term Aggregate Risk

### Endothall Human Health Risk Assessment DP No. D422204

Page 35 of 53 

### 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 hu mans ” 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 approa ch 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 cumulativ e 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

Ba sed 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

o n agricultural crops and aquatic area s ( S.Tadayon, D 428969

, In Pro gress )

.

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 wit h airblast application,

 Applying sprays with aircraft,

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

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

### Endothall Human Health Risk Assessment DP No. D422204

Page 36 of 53 

###  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 n ot exceed HED’s LOC (i.e.

, an MOE > 30) at the label

recommended PPE ( i.e., dust / mist respirator ). The MOEs range from 3 1 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 r isk 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 formulation s, results in no respirable particles, there is no inhalation risk concern for this formulation Attrition studies or

s tu dies 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 Target a Baseline

Inhalation

Unit Exposure b
(unless

otherwise noted) Maximum

Application

Rate c Area

Treated or

Amount

Handled Daily d Baseline Inhalation

Unless otherwise noted

Dose e MOE f

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 Crops 1

0.219 (0.044 PF5) 1 350 0.00096 45 High

- Acreage Field Crops 2 0.8

1200 0.00053 (PF5) 80

High

- Acreage Field Crops 3 0.1 0.00033 130

Mixing/Loading Liquids for Groundboom Application Typical Field Crops 1 1 80 0.00022 200 High

- Acreage Field Crops 2 0.8

200 0.00044 98

High

- Acreage Field Crops 3 0.1 0.00005 780

Mixing/Loading Liquids for Airblast Application Orchard Crop 4 0.4 40 0.000044 980

1 0.00011 390 Applicator

### Endothall Human Health Risk Assessment DP No. D422204

Page 37 of 53 Table: 9 .1.1. Short

- and Intermediate

- Term Occupational Risk assessment for Agricultural uses Endothall

Exposure Scenario Crop or Target a Baseline

Inhalation

Unit Exposure b
(unless

otherwise noted) Maximum

Application

Rate c Area

Treated or

Amount

Handled Daily d Baseline Inhalation

Unless otherwise noted

Dose e MOE f

μg/lb ai lb ai/A or

lbai/gal Acres or

gals mg/kg/day LOC = 30

Applying Sprays for Aerial Application Typical Field Crops 1

0.0049 (engineering controls) 1 350 0.00002 980 High

- Acreage Field Crops 2 0.8

1200 0.00006 360

High

- Acreage Field Crops 3 0.1 0.0000074 2900

Applying Sprays for Groundboom Application Typical Field Crops 1

0.34 1 80 0.0003 62 High

- Acreage Field Crops 2 0.8 200 0.0007 31

High

- Acreage Field Crops 0.1 200 0.00009 250

Applying Sprays for Airblast Application Orchard Crop 4 0.942(PF5) 0.4 40 0.0002 110

1 0.0005 45
Flagger

Flagging for Aerial Applications Typical Field Crops 1

0.35 1

350 0.00154 48 High

- Acreage Field Crops 2 0.8 0.00123 60

High

- Acreage Field Crops 3 0.1 0.000154 480

a Crop or Target

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

2 High

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

3 High

- 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 = Bas eline , PF5 (dust mist respirator), or engineering controls

.

c Based o n 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

D ose (mg/kg/day).

Table 9.1.2 . Summary of Endothall Short

- and Intermediate

- Term Occupational Inhalation Handler Risks for Aquatic Uses

Ex posure Scenario Target Application Rate a 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

Dose d MOE e

Mixer/Loader
Mixing/loading liquid

for g roundboom 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/l oading granules

for groundboom and

aerial application (subsurface use) 30 lb ai/A

- ft 30

Acres /day 5 NA 0.083 (EC) 0.0047 16

### Endothall Human Health Risk Assessment DP No. D422204

Page 38 of 53 Table 9.1.2 . Summary of Endothall Short

- and Intermediate

- Term Occupational Inhalation Handler Risks for Aquatic Uses

Ex posure Scenario Target Application Rate a 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

Dose d MOE e

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 G roundboom (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 G roundboom (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) × Applicatio n 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 rate s 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

Page 39 of 53 

### 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/#!docum entDetail;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 analysi s 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 Fo rce. 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 bec ause 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

establishe d at 48 hours. The acute toxicity classification for primary eye irritation of endothall

dipotassium is Category I. Per the Worker Protection Standard (WPS), a 48

- h ou r restricted entry interval (REI) is required for chemicals classified under Toxicity Cat egory I.

10.0 Public Health and Pesticide Epidemiology Data
Adapted from: S. Recore, D 423761 , 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 r eported by registrants as counts called aggregate summaries and are recorded in a separate module called Aggregate IDS. The SENSOR

Pesticides database covers 11 states from 1998

- 2010, although reporting varies from state to

state. Cases of pesticide

- rel ated illnesses are ascertained from a variety of sources . Although both occupational and non

- occupational incidents are included in the database, SENSOR

Pesticides focuses on occupational pesticide incidents, and is of particular value in providing that

in formation. For this evaluation, both the IDS and SENSOR database were consulted for pesticide incident data on the active ingredient endothall (PC Code s : 038901, 038904, and

### Endothall Human Health Risk Assessment DP No. D422204

Page 40 of 53 

### 038905 ). In addition, we sought information from the A gricultural Health Study (A HS); however, e ndothall 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, i t was concluded that “ Relatively few incidents of illness have been report ed 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 invo lving 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 sin gle 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 thre e 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 trigge red, additional analysis will be

included in the risk assessment.

1 1 .0 References

Endothall: Residue Chemistry Chapter to Support Registration Review and the Petition to

Remove the Label Restriction for L ivestock to Drink Treated Water ; K. King; D426753 and

D428908 ; In Progress

.

Endothall : Occupational and Residential Exposure and Risk Assessment for Registration Review; S. Tadayon; D 428969 ; In Progress

.

Endothall: Chronic Aggregate Dietary (Food plus Drinking Water) Exposure Assessment to Support permanent tolerance on Milk, Meat, Poultry, and Eggs; K. King; D 428970 ; In Progress

.

### Endothall Human Health Risk Assessment DP No. D422204

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### A ppendix 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

no A yes

yes

yes

yes

yes

870.3700a Developmental Toxicity (rat)

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

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

................................ .......................... yes

yes

yes yes

no C

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

no A

no A

CR -

-

-

-

-

870.7485 General Metabolism (rat)

................................ ............... 870.7600 Dermal Penetration (8

- hour)

, in vivo (male rat)

............. yes
CR yes

yes

870.7800 Immunotoxicity (rat).................................... no B

-

A HASPOC TXR No. 0056397 . Waived.

B HASPOC TXR No. 0056 794. 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

### Endothall Human Health Risk Assessment DP No. D422204

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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 LD 50 = 50.2/44.4[m/f] mg/kg I

870.1200 Acute dermal toxicity 42289202 LD 50 = >2000[m/f] mg/kg III

870.1300 Acute inhalation toxicity 42169501 LC 50 = 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: S tudies 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 Profil es

– Endothall a 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 NOA EL = 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

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– Endothall a 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,

2 3.2 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

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– Endothall a 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 Tec hnical 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 pharm acokinetics 42169502 (1990), acceptable a single i.v. dose at 0.9 mg/kg, a single oral dose at 0.9, 4.5 or 9.0 mg/kg and as a 15 day multiple dose at 0.9 and 9.0 mg/kg/day. Intravenous administration of 0.9 mg/kg resulted in excretion mainly by the urine (69%) and feces. At an oral 0.9 mg/kg dose, blood half

- life elimination

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

half

- life

- 13.9 hours in males; the half

life in females could not be calculated because of a double blood peak. Multiple

oral or si ngle 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 unchange d

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
[ 14 C}

- 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

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– Endothall a Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results

radioactivity being present in th e 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 radioacti vity 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 correspon ding 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/cm 2 (0.3 mg/rat), 0.0625 mg/cm 2 (1.5 mg/rat) and 0.125 mg/cm 2 (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 [ 14 C]

- Endothall equivalents was contained in the application site skin. Urinary excretion of [ 14 C]

- 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/cm 2 (3.0 mg/rat)dose level. Fecal excretion

amounted t o <0.1% at all dose levels. At the 0.0125 mg/cm 2 (0.3 mg/rat), 0.0625 mg/cm 2 (1.5 mg/rat) and 0.125 mg/cm 2 (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 increas e 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 o f [ 14 C]

- 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

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– Endothall a 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 m g/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.

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### 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. Soderberg, 6/10/2004 pH 2.7 at 25 ̊ C (1% solution) Density, bulk density, or specific gravity 0.481 g/cm 3 (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, pK a 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 10 3 μmho within 3

- 5

minutes at 

### ∼ 25 ̊

C, by conductivity meter
Octanol/water partition coefficient Not applicable to endothall acid

UV/visible absorption spectrum Not available Endothall, dipotassium salt

Melting point >360 ̊ C DP# 304026, D. Soderberg, 6/10/2004 pH 9.1 at 25 ̊ C (1% solution) Density, bulk density, or specific gravity 0.766 g/cm 3 (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, pK a 4.16 for Step 1 and 6.14 for Step 2 at 20 ̊ C in w ater; dissociation complete at 5 mins (13.6 x 10 3 μmho) Octanol/water partition coefficient K OW <0.02 and <0.3 at concentrations of 9 x 10

- 3 M and 9 x 10

- 4
M, respectively, at 25 ̊

C

UV/visible absorption spectrum Not available Endothall, mono

- N,N

- dimethylalkyl amine salt

Boiling point Not available DP# 304026, D. Soderberg, 6/10/2004 pH 5.2 at 25 ̊ C (1% solution) Density, bulk density, or specific gravity 1.028 g/mL at 25 ̊ C

Water solubility at 25 ̊

C ≥49.2 g/100mL in water, pH 5

≥51.6 g/100 mL in water, pH 7 ≥49.8 g/100 mL in water, pH 9
Solvent solubility at 25 ̊

C ≥102.5 g/100mL in acetonitrile

≥95.4 g/100 mL in n

- octanol ≥104.3 g/100 mL in tetrahydrofuran
Vapor pressure 2.09 x 10

- 5 mm Hg at 25 ̊ C (calculated; mixed mono

- and dialkylamine (C8

- C20)) Dissociation constant, pK a 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 10 3 μmho) at 25 ̊ C Octanol/water partition coefficient K OW 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

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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 tha t 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

- and

assessing

- pesticide

- risks/occupational

- pesticide

- handler

- exposure

- data and http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

post

- application

- exposure

.

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### Appe ndix 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 boat

mounted spreader Granular (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 boat

mounted spreader Granular 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

- 1 80 0.1(lb ai/A) 48 hr REI, 7 days retreatment

interval

Harvest Aid for Alfalfa

and Clover Preharvest, Aerial, ground Liquid (SC) 70506

- 1 90 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 r etreatment

PPE *

- Label recommended PPE is long sleeve shirt, chemical resistance gloves, shoes plus socks, protective eyewear and PF5 dust/mist respirator

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### Appendix E. International Residue Limits Table



## Endothall ( PC Code 038901 )

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex

40 CFR 180.293: (a) General. (1) endothall (7

- oxabicylco [2.2.1] heptanes

- 2,3

- dicarboxylic acid) and its mono

methyl ester. 7

- oxabicyclo[2.2.1]heptane

2,3

- dicarboxylic acid, including its monomethyl

ester None

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

US Canada Mexico 1 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, di

N, N

- dimethylalkylamine, and mono

- N

- N,

- dimethylalkylamine salts as algicides or her bicides 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 Mexico 1 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, di

N, N

- di methylalkylamine, 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 Mexico 1 Codex

Almond, hulls 15.0 Animal feed, nongrass, group 18, forage 4.0

Animal feed, nongrass, group 18, hay 10

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US Canada Mexico 1 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

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US Canada Mexico 1 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

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### 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 e ster 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 season al 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 resi due 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, so ybeans, sugar beet, tomato, and whea t, 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 a mine

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

endotha ll (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. Th e radiovalidation was waived in D324426 (D. Soderberg, 02/27/2006).