Endothall Human Health Risk Assessment D P 

### No. 403274

UN ITED ST ATES ENVIRONMENTAL PROTECTION AGENCY

WASHING T ON, D.C. 20460



### MEMORANDUM

Date: March 18, 2013 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PRE VEN T I ON



### SUBJECT: Endothall. Human Health Risk Assessment to Support Proposed Use o n App l es

PC Code : 038904 DP Barcode : 0403274

Decision No. : 

### 416t/Zlf3 Registration N o.: 70506

- 0EA

Pet i tion No.: 2F8023 Regu l at o ry Act i on: Section 3 R egistration

R i sk Assessment Type: Single Chemical Aggregate Case No

. : 2245

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

MRID No.: NA 40 CFR: §180

. 293



### FROM: Seyed Tadayon, Ri sk

# Assesso**~** Ana Rivera

- Lupiaiiez, Chemist

## ~ John Liccione, Ph.D

. , Toxicologist

Ris k Assessment Branch V

Heal t h Effects Division (7509P)**~** }



### THROUGH: Michael Metzger, Branch Chief 

# 'J 

# J '

Danette Drew, Senio r Risk assess Risk Assessment Branch V

Health Effects D i vision (7509P)



### TO: Grant Rowland, RM Team 

### 23

Herbicide B ranch Registrat i on D i vision (7505P)

Page 1 of36Endothall Human Health R isk Assessment DP No. 403274

1.0 Executive Summary

... .. .................. ... ...... .. .. .. .. . ...................... . . ... . ... . ... . .... ................ ... .. .. .. . 4

2.0 HED Recommendatio ns

............... .. .. ................................ .. .. .. .................. . . ... . ... .. .. .. .. ........ 6

2.1 Data Deficiencies

.......... . .. ... ................................ . ...... .. .. . ........................ .. .. ... .. .. .. .. ......... 6

2

. 2 Tolerance Considerations

. ....................... ....... . .. .. .. .. .. ............................ .. ...................... 6

2

. 2.1 Enforcement Analytical Method

................................................... . ........................... 6

2 .2.2 International Harmonization

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

2

. 2.3 Recommended Tolerances

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

2.3 Label Recommendations

.............. . ............. .. .. .. .. ... ................... ... ..... .. ....... .. . .. ................ 8

2

. 3 .1 Recommendations from the Residue Chemistry Review

..................................... .. . 8

3

. 0 Introduction

.............. .. .. .. .. .. ............................ . ... . . ... . ... . ... . . ..................... . .......... .. .. .. .. .. .. .. .. . 8

3 .1 Chemical Id entity

............................................................................... . ............. .. .. .......... 8

3.2 Pe sticide Use Pattern

...... .. ...................... . ............................ .. . .. .. .. .. ... .. ............................ 9

3.3 Anticipated Exp osure Pathways

.. .. ........ .. .. .. .. .. .. .. .. ...... ..................................... .. .. .. .... 10

3.4 Consideration of Environmental Justice

................................ .. .. .. .............................. 10

4.0 Hazard Characterization and Dose-Response Assessment

.. .. .. ................................ .... 11

4.1 Tox icology Studies Available for Analysis

.. .. .. .. .................................................... .. .. . 11

4.2.1 Dermal Absorption

...... ........ ....... . .. .. .. . .. ........................................ ... ..... .. .. .. .. .. .. .. ...... 12

4.3 Toxicological Effects

............................................ . .. .. .. .. .. ............................................. 12

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

...... .. ...... .. .. .. ........... 14

4.4.1 Completeness of the Toxicology Database

.............................................................. 14

4.4.2 Evidence of Neurotoxicity

.................................................. . .. .. .. ............................... 14

4.4

. 3 Evidence of Sensitivity /Susceptibility in the D eveloping or Young Animal

. .. ..... 15

4.4.4 Residual Uncertainty in the Exposur e Database

........................................ .. ...... ... 15

4

. 5 Toxicity Endpoin t and Point of Departure Selections

.................... , .. .. .......... .. .. .. .. .. . 1 5

4.5.1 Dose-Response Assessment

.............................................. . .. ..................................... 15

4

. 5

. 3 Cancer Classification and Risk Assessment Recommendation

............ .... .. .. .. .. .. .. 17

4.5.4 Summary of Points of Departure and Toxic ity Endpoints Used in Human Risk

Assessment

....................... . .............................................. . ........ ... ..... .. ...... .. .. .. .. .. .. . .. .. ... . .. .. .. .. ... 1 7

5.0 Dietary Exp osure and Risk Assessment..

............ .. .. .. .. .. .. ...... ........ ...... .. .. ...... .. .. ............. 19

5.1 Metabolite/Degradate Residue Profile

....................................................................... 19

5

. 1.1 Residues of Concern Summary and Rationale

.. .. ...... .. .. .. ............ .. .. .. .. .. .. .. .. .. .. .. .... 19

5.2 F ood Residue Profile

. .. .. .. . .. . ... . .. .............. . ............................................ . ........ . ...... . ....... 20
5

. 3 Water Residue Profile

................................................................................ .. . . ............. . 20

5.4 D ietary Risk Assessm ent

. ....... ....... ... ......... .. ...... .. . .. .. ...... . .. .. .. .. .. . .. .. .. ...... .. ...... .. .. ..... .. ... 21
5.4

. 1 Description o f Residue Data Used in Dietary Assessment

.................................... 21

5

. 4.2 Percent Crop Treated Used in Dietary Assessment

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

............................................................................... 21

5.4.4 Chronic Dietary Risk Assessment

.. ............ .. .......... .. ................ .. .. .. ...................... .. . 21

6

. 0 Residential (Non

- Occupational) Exposure/Risk Characterization

.. .. ...... .. ...... .. .. .. .. .. . 22

6

. 1 Residential Exposure

.......... ..... .................... .. ............................................................... 22

6.2 Postapplication Exposure

...... . ...... .... .. .. .. .......... .. .. .. .. . .. .. .. .. .. . .. .. .. .. .............. ..... ....... . ... . 23

6.3 Combined Exposure

............................. . ............................ .. .......... .. . .. .. .. .. .. ...... .. .. .. .. .. .. 23

6.4 Residential Bystander Postapplication Inhalation Exposure

.. .. ........ ...... .. .. ............. 23

6.5 Spray Drift

.. .. .. . .. ...... . . .. .. .. ...... ..... ................................. . ................................................ 24

7.0 Aggregate Exposure/Risk Characterization

................ .. ........ .. ...... .. .................. .. .......... 24

Page 2 of36Endothall Human Health Risk Assessment DP No. 403274

Page 3 of 36 7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 24

7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 24

7.3 Chronic Aggregate Risk

................................ ................................ .............................. 25

8.0 Cu mulative Exposure/Risk Characterization

................................ ............................... 25

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 25

9.1 Short

- Term Handler Risk

................................ ................................ .......................... 26

9.2 Postapplication Risk

................................ ................................ ................................ ..... 27

9.2.2 In halation Postapplication Risk

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

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

................................ ................................ ......... 29 Appendix B. Review of Human Research

................................ ................................ ................ 35 Appendix C. International Residue Limits

................................ ................................ .............. 36Endothall Human Health Risk Assessment DP No. 403274

Page 4 of 36 1.0 Executive Summary

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

Section 3 regist ration of the herbicide endothall (as endothall dipotassium salt) for the new use on apple trees as a blossom thinner. United Phosphorus Inc (UPI) has requested registration of the apple use and the establishment of tolerances to support that use. This assessment takes into

account the proposed use and previously registered uses of endothall

.

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

, and aquatic algaecide. The free acid of endothall (PC Code 038901) and its dipotassium (PC Code 038904) and monoalkylamine (PC Code 038905) salts are registered primarily as aquatic herbicides for the control of a variety of plants in water bodies, including irrigation canals. There are also direct uses registered for food crops. Tolerances are established for endothall and its monoethyl ester on food and feed items as a result of direct and inadvertent (aquatic) residues resulting from endothall products. The residues of concer n in plant and livestock commodities for risk assessment are also endothall and its monoethyl ester. The residue of concern in drinking water is the free acid of endothall.

The proposed use directions specify that endothall dipotassium salt (5.37%) produc t, ThinRite, is to be applied by broadcast ground (air blast) application to apple trees at a maximum single application rate of 0.423 lb ai/A

. If more than one treatment is needed, a maximum of two applications are permitted not to exceed a total of 0. 846 lb a.i. endothall dipotassium salt per acre per growing season. The proposed re

- entry Interval (REI) is 12 hours and the retreatment interval (RTI) is 24 hours.

The toxicology data base for endothall is complete except for an immunotoxicity study required as a result of the revised 40 CFR Part 158 Toxicology Data requirements. The Hazard and Science Policy

Committee ( HASPOC

, December 19, 2012) waived the need for acute and subchronic neur otoxicity

stud ies in rats.

Endothall is a caustic chemical with toxicity being the result of a direct degenerative effect on tissue. Dermally, it destroys the stratum corneum and then the underlying viable epidermis. Orally, it attacks the digestive tract. The dog is particularly sensitive to endothall toxicity. Orally, it attacks the canine digestive tract at relatively low doses and then the liver and kidneys

at lethal doses. The rabbit is extremely sensitive to ocular instillation of endothall. In the eye irritation study, e ndothall technical was extremely irr itating to the eye, and was also lethal to 4/6

rabbits tested. In a dermal irritation study, endothall was an extreme irritant (category I). Although it was classified as a category III in an acute dermal toxicity study, endothall has been

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

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

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

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

acute inhalation study , it was classified as C ategory 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.Endothall Human Health Risk Assessment DP No. 403274

Page 5 of 36 Endothall does not cause pre

- natal toxicity following in utero exposure t o 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 incre ase in vertebral and rib malformations was observed in the offspring indicating that these effects were most likely secondary to severe maternal toxicity.

The hazard data for endothall indicate no evidence of quantitative or qualitative increased susceptib ility of rat fetuses exposed in utero to endothall in the developmental toxicity studies. In addition, n o evidence of quantitative or qualitative increased susceptibility of rat fetuses or

neonates was observed in the 2

- generation reproduction study.

En dothall is classified as "not likely to be carcinogenic to humans" based on lack of evidence of carcinogenicity in mice or rats. It has no mutagenic potential.

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

The residue chemistry database for endothall is complete and the nature and magnitude of the residue are adequately understood for the purpose of this action. An enforcement method is available to enforce the necessary tolerances. There are no issues wit h respect to the

harmonization associated with this action. An acute dietary risk assessment was not required as there were no effects seen in the database which could be attributable to exposure to a single

dose of e ndothall . Chronic dietary exposure an d risk assessments were conducted using percent crop treated estimates

, average field trial residues for all existing and new use s
, and DEEM 7.81

default and crop

- specific processing factors from processing studies for all commodities.

Modeled estimated drinking water concentrations (EDWCs) were incorporated into the chronic dietary risk assessment. No chronic dietary risks of concern were identified for the U.S. population or any population subgroup s

. The most highly exposed population subgroup is infan ts (1

- 2 years old) at 90% of the chronic population adjusted dose ( cPAD )

. A quantitative dietary cancer risk assessment was not required since e ndothall is not likely carcinogenic.

There were no new residential uses requested in this petition. The existi ng residential use

, aquatic applications on ponds

, lakes and garden pools

, ha s been assessed using the new residential SOP ( 01 /01/2012)

.

Postapplication risk estimates for both adults and children exposed to treated water during swimming in ponds and lakes do not exceed HED’s level of concern for any of the scenarios

assessed ( MOEs > 10 0 for incidental oral exposures (i.e. water ingestion )

.

Human health aggregate risk assessments were conducted for the chronic aggregate exposure (food + drinking water) scenario, as well as the short

- term aggregate exposure scenario which included food, drinking water and residential exposures . A quantitative cancer aggregate risk assessment was not performed since endothall is not likely carcinogenic. Chronic and s hort

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

Page 6 of 36 Occupational handler and post application exposures and risks were evaluated for the proposed

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

exceed HED's level of concern (i.e., short

- term MOEs ≥ 30) for endothall inhalation exposures, at some level of risk mitigation or addition of personal protective equipment (i.e., PF5R respirator). It should be noted that the proposed label does not requir e use of a respirator , which is needed to assure protection of endothall handlers from inhalation portal of entry effects

.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database ; and HED’s SOP for Residential Exposure Assessments (Draft; 17

- Dec

- 1997; p ages 52

- 57), modified in HED’s SWIMODEL V 1.0 (W. Dang et al. , 27

- Mar

- 1999)

, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethic s review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1

.

2.0 HED Recommendations

HED has no objection to the proposed registration of the new use of endothall on apples if the proposed label is amended to require the use of additional PPE for occupational handlers (i.e., PF5R respirator).

2.1 Data Deficiencies

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

endothall

. A n Immunotoxicity study is required in accordance with the revised Part 158 data requirements. The HASPOC (December 19, 2012) waived the acute and subchronic

neuro toxicity stud ies in rats to support the proposed uses of endoth all

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A n enforcement method (GC with microcoulometric nitrogen detection) is listed as Method I in the Pesticide Analytical Manual (PAM, Volume II) for the determination of endothall in plant commodities. Using this method, residues in crop commodities are extra cted using acetone acidified with HCl. The extract is concentrated, and the oil and oil

- soluble materials are removed by partitioning solvents. The endothall containing oil

- free fraction is concentrated by boiling with acetic acid. Any endothall present is converted to the N

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

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/opp00001/science/residential

- exposure

- sop.htmlEndothall Human Health Risk Assessment DP No. 403274

Page 7 of 36 concentrated and analyzed by GC using a nitrogen specific detector. The method LOQ is 0.1

ppm.

A confirmatory HPLC/MSD method (Method No. KP218R0) is also available for determining residues of endothall and its monomethyl ester in fish and residues of endothall in plant commodities. For this method, residues are extracted with water, acidified and, if necessary, purified using a C 18 SPE column. Residues are then derivatized with heptafluoro

- p

tolylhydrazine (HFTH) and partitioned into dichloromethane (DCM). Derivatized residue s are concentrated, redissolved in toluene, and cleaned up using a silica gel cartridge. Resid ues are determined by HPLC/MSD using the 397 amu ion for detection and quantitation. The validated LOQ is 0.05 ppm for fish (endothall and endothall monomethyl ester), and the LOQs for plant commodities range from 0.01

- 0.10 ppm, with the initial C 18 SPE c leanup step. This method has undergone a successful independent laboratory validation using fish samples. ( D3 84206 , D. Soderberg, 09/30/ /2011 )

.

2.2.2 International Harmonization

There are no Maximum Residue Limits (MRLs) established by Codex, Canada, or Mexico for any of the proposed commodities in the current registration action , therefore there are no issues with respect to international harmonization associated with the tolerances recommended in this

action See Appendix C

.

2.2.3 Recommended Toler ances

Tolerances are currently established for endothall in the 40 CFR §180.293; however, the residue definition listed in the 40CFR, does not comply with the HED Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09). The 40 CFR should be revised as follow s :

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 specifi ed below is to be determined by measuring only endothall ( 7

- oxabicylco [2.2.1] heptanes

- 2,3

- dicarboxylic acid ) and its mono

- methyl ester.

T olerance for residues of endothall in apples and wet apple pomace should be established under 40 CFR §180.293(a)(1) . The tolerance levels and commodity definition s are specified in Table

2.2

. 3, below.

Table 2.2.3 Tolerance Summary for Endothall

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Commodity Definition Apple 0.05 0.05 Apple pomace 0.15 0.15 Apple

, wet pomaceEndothall Human Health Risk Assessment DP No. 403274

Page 8 of 36 2.2.4 Revisions to Petitioned

- For Tolerances

The registrant

- proposed and HED

- recommended tolerance values for residues of endothall on apple and apple pomace are the same. However, the proposed commodity definition for apple pomace is revised to “apple, wet pomace” to reflect the Agency’s correct commodity definition.

2.2.5 Reference Standards

An a nalytical standard for endothall is currently available in the EPA National Pesticide Standards Repository ( personal communication with Dallas Wright, ACB, 10/23/08 ) , but the refrence standard expired on 12/28/2012 . Analytical reference standard s must be replenished as requested by the Repository. Analytical standards of the endothall dipotassium salt, monometh yl and dimethyl esters must be submitted.

2.3 Label Recommendations

2.3.1 Recommendations from the Residue Chemistry Review

None

.

2.3.2. Recommendations from ORE Review

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

concern ( i.e., short

- term MOEs ≥ 30) for endothall inhalation exposures, at some l evel of risk mitigation (i.e., addition of PF5R respirator). The proposed label

- specified p ersonal p rotective

e quipment ( PPE ) includes: gloves, eye protection, and no respirator. The proposed label should be amended and a PF5R respirator should be required. T he acute toxicity classification for primary eye irritation of endothall is Category I. Per the Worker Protection Standard (WPS), a

48 hour restricted entry interval (REI) is required for chemicals classified under Toxicity Category I. The proposed ThinRite Blossom Thinner label indicates an REI of 12 hour , which is

not in compliance with the WPS.

3.0 Introduction

3.1 Chemical IdentityEndothall Human Health Risk Assessment DP No. 403274

Page 9 of 36 Table 3.1. 1 Structure and Nomenclature of Endothall

- dipotassium

. 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

Table 3. 1.2 . Physicochemical Properties of Endothall.

Parameter Value Reference

Endothall Melting point >360 C DP# 304026, D. Soderberg, 6/10/2004
pH 9.1 at 25 C (1% solution) Density, bulk density, or specific gravity 0.766 g/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

3. 2 Pesticide Use Pattern

Endothall is a selective contact herbicide, defoliant, desiccant, growth regulator and aquatic algicide which b elong to the dicarboxylic acid chemical class. Endothall (PC Code 038901) and

its dipotassium (PC Code 038904) and alkylamine (PC Code 038905) salts are registered primarily as aquatic herbicides to control a variety of plants including plankton, pondweed, naiad, coontail, milfoil, elodea, and algae in water bodies. They are also regist ered for desiccation/defoliation of alfalfa/clover (grown for seed only), cotton, and potatoes prior to harvest, and for reduction of sucker branch growth in hops. Endothall

- treated water is also used for irrigation purposes on non

- food crops, established ornamentals, turf grass, lawns, and non

crop areas (D336685, K. M. Lowe, 06 0 9, 2007).

ThinRite Blossom Thinner (EPA Reg. No. 70506

- EOA), an end use product formulated as a flowable concentrate containing the active ingredient (ai) endothall

- dipotassium ( 5.37%), is proposed to be used as part of a blossom thinning program in apples

. Optimum applicationEndothall Human Health Risk Assessment DP No. 403274

Page 10 of 36 timing is usually when approximately 60 to 80% of the blooms are open

. T he label specifies a

70

- day pre

- harvest interval ( PHI ) . The proposed maximum single application rate is 6 pints of ThinRite per acre, equivalent to 0.423 lb (ai) endothall dipotassium salt per acre using airblast equipment on apples.

Table 3. 2 Summary of Proposed Use Pattern for Endothall

- dipotassium

Formulation [EPA Reg. No.] Target /

Use site Application

Equipment Maximum Application Rate Re

- treatment
Interval & Timing

ThinRite Blossom

Thinner

70506

- OEA Apple Airblast Single maximum application rate: 6 pints ThinRite Blossom Thinner per acre [0.423 lb (ai) endothall dipotassium salt

per acre

. ]

and
A maximum of two applications are permitted not to exceed a total of 12 pints

of ThinRite Blossom Thinner or 0.846 a.i. endothall dipotassium salt per acre per growing season Retreatment interval (RTI) is

24 hours

Preharvest

Interval (PHI) is 70 days

3. 3 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use s of the herbicide endothal l dipotassium for the thinning of blossoms on apple

trees. H umans may be exposed to endothall dipotassium in food and drinking water, since the chemical may be applied directly to growing crops and may reach surface and ground water sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior to application (i.e., mixing/loading), as well as during application and reentering to treated areas to perform various agricultural tasks.

Residential uses are not being proposed with this petition. Residential r isk assessments have been updated here to reflect assumptions in the revised 2012 residential SOP. In a residential setting, humans may be exposed to endothall dipotassium as a result of handling the pesticide on application, and also potentially after application via exposure to treated water during swimming.

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

use s of endothal l

.

3. 4 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in acco rdance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justic e/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption,Endothall Human Health Risk Assessment DP No. 403274

Page 11 of 36 and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing

Surve y of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products a nd associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the deve lopment of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The endothal l r isk a ssessment t eam has reviewed the toxicity database for endothall and has

selected endpoints for risk assessment purposes consistent with current HED policy and which are appropriate for the routes and durations of exposure anticipated from the existing and newly proposed uses of endothall

.

5

- day and subchronic inhalation toxicity studies have been received and reviewed since the last risk assessment, and are considered for inhalation risk assessment. Other exposure scenarios were based on a prior assessm ent ( David Soderberg

, 11/09/09, D370448).

4.1 Toxicology Studies Available for Analysis

The toxicological database for endothal l with the exception of an immunotoxicity study is complete and adequate for FQPA evaluation, selection of PODs for the various routes of exposure, and for dose

- response evaluation. The available toxicology studies for endothal l are summarized in Table A.1 in Appendix A.

Acute/lethality studies (oral , dermal, inhalation, primary eye and dermal irritation, and dermal sensitization) Subchronic oral toxicity studies (rat, mouse, and dog) Developmental (rat and rabbit) and reproductive (rat) toxicity (oral) studies Dermal (21

- day) toxicity (rabbit) study Chronic oral toxicity studies (rat and dog) Carcinogenicity (oral) studies [rat (chronic combined) and mouse] Metabolism study (rat) Mutagenicity battery

28

- day inhalation study (rat)

The studies available for c onsideration of endotha l l risk assessment provide a comprehensive database, with routes of administration which are consistent with potential exposure scenarios.Endothall Human Health Risk Assessment DP No. 403274

Page 12 of 36 4. 2 Absorption, Distribution, Metabolism, and 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 calculated because of a double blood peak. In si ngle oral or intravenous dose studies, endothall did not undergo any metabolic transformation and was excreted unchanged. The results of a multiple (15

- day) oral administration study indicated that endothall was absorbed and excreted largely unchanged in the feces and urine. At 24 hours, the tissue distribution of the compound was extensive but low. By 48 hours, the compound was mostly

undetectable.

4.2.1 Dermal Absorption

Since endothall is so toxic at the portal of entry (e.g., skin) , quantificat ion 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 do se tested). The NOAEL for dermal irritation was not established due to erythema, edema, and fissuring and sloughing off of the skin at the dose site at

the lowest dose tested (30 mg/kg/day). Endothall is caustic dermally because it is an acid, and mitiga tion of any potential dermal effects can be addressed with precautionary labeling recommending the use of gloves and other personal protection which limits contact of the material with the handlers body.

4.3 Toxicological Effects

Endothall is a caustic c hemical with toxicity being the result of a direct degenerative effect on tissue. Dermally, it destroys the stratum corneum and then the underlying viable epidermis. Orally, it attacks the digestive tract. The dog is particularly sensitive to endothall tox icity. Orally, it attacks the canine digestive tract at relatively low doses and then the liver and kidneys

at lethal doses. The rabbit is extremely sensitive to ocular instillation of endothall. In the eye irritation study, e ndothall technical was extre mely irritating to the eye, and was also lethal to 4/6

rabbits tested. In a dermal irritation study, endothall was an extreme irritant (category I). Although it was classified as a category III in an acute dermal toxicity study, endothall has been

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

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

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

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

acute inhalation study , it was classified as (category III however, there was irritation and other respiratory effects observed in 5

- day and 28

- day inhalation toxicity studies supporting the

conclusion of the irritant effects of endothall.

The most sensitive effect of endothall following oral administration is d irect 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 th e liver and kidneys at lethal doses. Endothall caused gastric epithelial hyperplasia in dogs treated with an oral dose of 6.5 mg/kg/day for 52 weeks (aEndothall Human Health Risk Assessment DP No. 403274

Page 13 of 36 NOAEL was not determined). Proliferative lesions of the gastric epithelium were observed in F 1 parenta l male and female rats treated orally with 2 mg/kg/day endothall in a 2

- generation reproduction study (a NOAEL was not identified).

Besides gastric irritant effects, decreased body weight was also a sensitive effect following

endothall administration. The decreased body weights were most likely attributable to the constant and direct irritation of the gastric lining. In a developmental rat study, pregnant rats exhibited decreased body weight follo wing oral treatment with 25 mg/kg/day endothall; the NOAEL was 12.5 mg/kg/day. D ecreased body weight was noted in a 90

- day dietary study in the rat (LOAEL = 118 mg/kg/day; NOAEL = 39 mg/kg/day). Body weight loss occurred in dogs following a 13 week oral treatment with endothall (LOAEL = 27.5 mg/kg/day; NOAEL = 11.7 mg/kg/day). A LOAEL of 45 mg/kg/day for body weight decrement was identified in a n oral carcinogenicity mouse study.

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

the 21

- day dermal toxicity study

, severe dermal effects were observed at 30 mg/kg/day (the lowest dose tested). The NOAEL for dermal irritation was not established due to erythema, edema, and fissuring and sloughing off of the skin a t the dose site at the lowest tested ( 30 mg/kg/d ay)

.

Endothall does not cause pre

- natal toxicity following in utero exposure to rats nor pre

- and post natal toxicity following exposures to rats for two generations. In the developmental mouse study,

there was severe maternal toxicity (i.e., greater than 30% mortality) at the highest dose tested; at this dose level, a slight increase in vertebral and rib malformations was observed in the offspring indicating that these effects were most likely secondary to severe maternal toxicity. Endothall is classified as "not likely to be carcinogenic to humans" based on lack of evidence of carcinogenicity in mice or rats. It has no mutagenic potential.

Pulmonary toxicity was evident in 5

- day and 28

- day inhalation tox icity studies in the rat. Pulmonary effects observed in the 5

- day inhalation study included rales, labored respiration, pale lungs (gross necropsy), increased absolute and relative lung weights, subacute inflammation, alveolar proteinosis, and hemorrhag e

. The rales and labored respiration were noted daily (0

- 1 hrs post

- dosing, prior to next exposure, and during detailed examinations) i n addition, decreased body weights and food consumption, effects on clinical chemistry parameters were noted. Although nasal histopathology was not performed in the 5

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

LOAEL in the 5

- day study was 0.025 mg/L based on pulmonary effects, clini cal chemistry and decreased body weights. A NOAEL was not identified. In the 28

- day inhalation study, acute
effects indicative of pulmonary toxicity included rales and labored respiration, which were observed daily (0

- 1 hrs post

- dosing

, prior to next ex posure , and during detailed examinations ) in rats exposed to 0.005 mg/L endothall . In addition, increased lung weights and alveolar macrophages in both sexes were observed at scheduled necropsy

. At 0.025 mg/L, rales and labored respiration were noted in rats that died during the study. Subacute inflammation of the trachea, and degeneration of the olfactory and respiratory epithelium of the nasal passages, were observed in rats exposed to 0.025 mg/L. Nasal effects at 0.005 mg/L consisted of minimalEndothall Human Health Risk Assessment DP No. 403274

Page 14 of 36 olfa ctory epithelial degeneration and mild goblet cell hypertrophy. A NOAEL of 0.001 mg/L

was identified in the 28

- day inhalation study.

The HASPOC (December 19, 2012) waived the need for acute and subchronic neur o toxicity stud ies in rats to support the proposed uses of endothal based on the lack of neurotoxicity in the endothall

database as well as other carboxylic acid pesticide s.

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

CFR Part 158 Toxicology Data requirements.

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

The toxicology data base is adequate for FQPA assessment. The FQPA SF was removed for all scenarios except the chronic dietary assessment. For the a ssessment 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 LOAEL established in the two

- generation reproduction study was used for assessi ng 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 determined to be adequate since the severity of the lesions were minimal to mild

. HED is

confident that the chronic Population Adjusted Dose ( cPAD = 0.007 mg/kg/day) will not underestimate risks following exposure to endothall. 2) There is no indication of increased susceptibility of rats or mice in utero and/or postnatal

exposure in the developmental and reproductive toxicity studies; 3) There are no concerns for neurotoxicity; 4) There are no residual uncertainties in the exposure data base. While the chronic dietary exposure estimates are partially refined (average field trial residues and adjustment of the percent of the harvested crop that has been irrigated) the results are st ill very conservative

. 5) Residential SOP uses high end conservative data and most of the exposure comes from children swimming in ponds and lakes treated with endothall.

4.4.1 Completeness of the Toxicology D a t abase

The toxicology database for endothall i s complete for FQPA consideration and derivation of endpoints , except for the immunotoxicity study . An i mmunotoxicity study has been identified as a database deficiency. UPI is in the process of submitting a waiver request for the immunotoxicity requirem ent. The requirements for ACN and SCN studies have been waived by HASPOC (12/19/2012) based on the lack of neurotoxicity in the endothall database as well as

other carboxylic acid pesticide s.

4.4.2 Evidence of N eurotoxicityEndothall Human Health Risk Assessment DP No. 403274

Page 15 of 36 There is no evidence of neurotoxicity in the endothall database. Acute and subchronic n eurotoxicity

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

acute and subchronic neur toxicity stud ies in rats to support t he proposed uses of endothal l

.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There is no quantitative or qualitative evidence of increased susceptibility following prenatal exposure to rats in the developmental toxicity study and pre

- /postnatal exposure to rats in the 2

- generation reproduction study. Due to high mortality observed in a range finding study in rabbits

even at low doses

, a developmental toxicity study in this species was not conducted (i.e., acute

direct ir ritative effects of the chemical could interfere with identification of potential developmental toxicity in this susceptible species). Therefore, a developmental toxicity study in

mice (MRID 0085940, 00086623) was conducted and there was no evidence for enhanced susceptibility in this species. Based on toxicity data from 2 different species, there is no concern for quantitative or qualitative susceptibility associated with endothall exposures

.

4.4.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertaint ies in the endothal l database in re gard to dietary (food and drinking water) and residential exposures. The residue data used for dietary exposure assessment

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

exposures

. Modeling using PRZM/EXAMs was done to estimate drinking water residues; this modeling is designed to provide drinking water residue estimates which will not underestimate exposures from drinking water in the diet. R esidential exposure estimates are based on conservative, health

- protective assumptions that also ensure exposures are not underestimated.

4.5 Toxicity Endpoint and Point of D eparture Selections

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

risk for infants and children.

4.5.1 Dose

- Response Assessment

The most sensitive effect of endothall following oral administration is direct irritation of the gastrointestinal system. This effect was evident in several species and in several studies. Proliferative lesions of the gastric epithelium were observed in F 1 parental male and female rats treated orally with 2 mg/kg/day endothall in a 2

- generation reproduction study (a NOAEL was not identified). Endothall caused gastric epithelial hyperplasia in dogs treated with an oral dose of 6.5 mg/kg/day for 52 weeks (a NOAEL was not determined).

Besides gastric irritant effects, decreased body weight was a lso a sensitive effect following

endothall administration. The decreased body weights were most likely attributable to the constant and direct irritation of the gastric lining. In a developmental rat study, pregnant rats exhibited decreased body weight f ollowing oral treatment with 25 mg/kg/day endothall; the NOAEL was 12.5 mg/kg/day. D ecreased body weight was noted in a 90

- day dietary study in the rat (LOAEL = 118 mg/kg/day; NOAEL = 39 mg/kg/day). Body weight loss occurred in dogsEndothall Human Health Risk Assessment DP No. 403274

Page 16 of 36 following a 13 week o ral treatment with endothall (LOAEL = 27.5 mg/kg/day; NOAEL = 11.7 mg/kg/day). A LOAEL of 45 mg/kg/day for body weight decrement was identified in a n oral carcinogenicity mouse study.

HED selected the following toxicity endpoints ( and points of departu re) which are the same that

were u sed in the previous 2005 risk assessment with the exception of th ose for inhalation exposure. For the inhalation exposure scenario s , the recently submitted inhalation toxicity study was identified as the most appropriate study.

Acute Dietary: An acute dietary hazard value was not identified for the general population or for

females of child

- bearing age (13

- 49 years old). This is because there is no appropriate endpoint attributable to a single dose in any of the studies submitted.

Chronic Dietary: For chronic dietary exp osure, the toxicology endpoint was selected from a 2

- generation reproduction toxicity study in rats in which the LOAEL was 2 mg/kg/day based on proliferative lesions of the gastric epithelium in both sexes. The Uncertainty Factor includes the

10x for inte rspecies extrapolation and 10x for intraspecies variation, and an additional 3x FQPA factor for the lack of a NOAEL in the study used for endpoint selection. A 3X FQPA factor (as opposed to a 10X) was determined to be adequate since the severity of the les ions 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 t he 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 do se site at the lowest dose tested (30 mg/kg/day). Endothall is caustic dermally because it is an acid, and mitigation of any potential dermal effects can be addressed with precautionary labeling recommending the use of gloves and other personal protection which limits contact of the material with the handlers body.

Inhalation:

Residential handler exposure is expected to be short

- term in duration. For this short

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

- day inhalation toxicity study in the rat b ased on clinical signs of toxicity observed acutely at 0.005 mg/L. These signs, indicative of pulmonary toxicity, included rales and labored breathing and were seen daily (0

- 1 hr postdosing, prior to next exposure, an d in detailed examinations). Although the 5

- day inhalation study also revealed acute signs of pulmonary toxicity, a NOAEL was not identified, but the results of the study support the findings of the 28

- day inhalation study. Therefore, the

NOAEL for acut e signs noted in the subchronic inhalation study was selected for the short

- term residential exposure scenario. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners.

For the short

- and intermediate

- term occupational inhalation risk assessment, a NOAEL = 0.001 mg/L was selected from a 28

- day inhalation toxicity study in the rat in which the LOAELEndothall Human Health Risk Assessment DP No. 403274

Page 17 of 36 was 0.005 mg/L based on indications of lung toxicity (rales in males and increased lun g weights and alveolar macrophages in both sexes). Long

- term inhalation exposures are not anticipated.

Incidental Oral: The short

- term incidental oral risk assessment for endothall is based on a NOAEL of 9.4 mg/kg/day based on decreased pup body weight (both sexes) on Day 0 of the

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).

Intermediate

- and long

- term incidental oral exposures are not expected

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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

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

, these exposures should be combined with backgroun d levels in food and drinking water to determine aggregate short

- term exposure. For children’s residential exposure, only oral post application exposure was assessed, and this exposure should be combined with background exposure from food and drinking wate r to determine short

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

4.5. 3 Cancer Classification and Risk Assessment Recommendation

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

.

4.5. 4 Summary of Points of Departure and Toxicity Endpoints Used in H uman Risk

Assessment

The doses and toxicological endp oints used for occupational and residential human health risk assessments for currently registered products are summarized in Table 4.5.4.1

. HED’s level of concern (LOC) for short

- term occupational and residential inhalation risk estimates is 30 (i.e., an MOE less than 30 is considered a risk of concern). The level of concern is based on 3X to account for interspecies extrapolation to humans from the animal test species, and 10X to account for intraspe cies sensitivity. 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

. HED’s LOC for incidental oral exposures is 100. This level of concern is based on 10X to account for interspecies extrapolation to humans from the animal test species, and 10X to account for intraspecies sensitivity.

Table 4.5. 4 .1Summary of Toxicological Doses and Endpoints for Endothal l Human Health Risk Assessments. Exposure

Scenario Dose Used in

Risk Assessment, UF FQPA SF and

Level of Concern

for Risk

Assessment Study and Toxicological EffectsEndothall Human Health Risk Assessment DP No. 403274

Page 18 of 36 Table 4.5. 4 .1Summary of Toxicological Doses and Endpoints for Endothal l Human Health Risk Assessments. Exposure

Scenario Dose Used in

Risk Assessment, UF FQPA SF and

Level of Concern

for Risk

Assessment Study and Toxicological Effects

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

established.

Chronic Dietary (All populations) LOAEL= 2 mg/kg/day

UF = 300

Chronic RfD =

0.007 mg/kg/day FQPA SF = 3

cPAD = 0.007 mg/kg/day Rat 2

- generation reproduction study

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

Short

- Term

Incidental Oral Offspring

NOAEL = 9.4 mg/kg/day Residential LOC

for MOE = 100 Occupational = NA Rat 2

- generation reproduction study

LOAEL 60 mg/kg/day based on decreased pup body weight (both sexes) on Day 0 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
dermal effects were observed at 30 mg/kg/day (the lowest dose tested). The NOAEL for dermal irritation was not established due to erythema, edema, and fissuring and sloughing off of the skin at the dose site at the lowest dose tested (30 mg/kg/day). Endothall is caustic dermally because it is an acid, and mitigation of any potential dermal effects can be addressed with precautionary labeling recommending the use of gloves and other personal protection which limits contact of the material with the handlers body.

Long

- Term Dermal NA no exposure under use pattern

Short

- Term Inhalation NOAEL = 0.001 mg/L

Residential HEC

= 0. 00049 mg/L ( 0.0176 mg/kg/day) A

Occupational

HEC = 0.0004 mg/L ( 0.0192 ) ( mg/kg/day) B UF A = 3X C

UF H = 10X FQPA UF

= 1X

Residential LOC

for MOE = 3 0

Occupational LOC

for MOE = 3 0 Subchronic inhalation toxicity study ( MRID

47872201 )

.

Residential acute scenario: LOAEL = 0.005 mg/L based on clinical signs (rales and labored respiration) observed acutely (0

- 1 hr postdosing and prior to next exposure ). Occupational short

- term scenario: LOAEL = 0.005 mg/L based on indications of lung toxicity (rales in males and increased lung weights and alve olar macrophages in both sexes). The NOAEL is 0.001 mg/L.

Intermediate

- Term

Inhalation NOAEL = 0.001 mg/L

Occupational

HEC = 0.0004 mg/L ( 0.0192 mg/kg/da y) 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). The NOAEL is 0.001 mg/L.

Long

- Term Inhalation NA no exposure under this use pattern

Cancer (oral, dermal, inhalation) Classified as a “Not Likely” human carcinogen.Endothall Human Health Risk Assessment DP No. 403274

Page 19 of 36 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable.

A Residential E xposures are anticipated only briefly (half hour) once a month and are acute. R esidential HEC (pulmonary effect) = 0.0 001 mg/L * (6 hr / 6 hr ; 1.0 ) * ( 1d / 1 d ; 1 ) * pulmonary RDDR (0.49 9 ) = 0. 00049 mg/L ( 0.0176 mg/kg/day)

B Occupational HEC (pulmonary effect) = 0.0 01 mg/L * (6 hr /8 hr ; 0.75) * (5 d /5 d ; 1)* pulmonary RDDR (0.49 9 ) =

0. 00 04 mg/L ( 0.0192 mg/kg/day)

C Since the RfC methodology takes into consideration the pharmacokinetic (PK) differences but not the pharmacodynamic (PD) differences, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained a t 10X.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

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

The nature of endothall r esidues in plants is adequately understood based on the acceptable alfalfa, cotton, and sugar beet metabolism studies re flecting use of the dipotassium salt of [ 14 C]

endothall . An adequate cotton metabolism study is also available reflecting use of the mono

- N,

N

- dimethylalkylamine salt of [ 14 C] endothall

. HED has concluded that the metabolism studies

u sing the dipotassium salt will also fulfill metabolism data requirements for the monoalkylamine

salt as the two salts would be expected to behave similarly in plants. The HED Metabolism Committee (S. Funk, 11/8/96) has also concluded that the residues o f concern for both risk assessment and tolerance enforcement in plant commodities include parent endothall and its monomethyl ester.

The qualitative nature of the endothall residue s in livestock is adequately understood based on the acceptable poultry and goat metabolism studies. The residue s of concern in animal

commodities consist of parent endothall and its monomethyl ester

.

In rat metabolism studies endothall was excreted unchanged in the feces and urine. In the dermal absorption study the dose related pattern of absorption was typical of a chemical which directly damages the skin. Endothall exists in three forms in the environment:

endothall dipotassium, endothall potassium cation, and endothall acid. These c h emic a l

forms are highly so l uble and mobile in t h e environment.

Endoth a ll degrades b y biot i c processes such as a e robic metabolism. Single laboratory studies

measured first

- order degrad a t ion half

- liv e s of 14.5 days for aerobic so i l meta b o l i s m
, 10 da y s for aerob i c aquatic metabolism, and 9 days for a n ae robic soil metabolism. Terrest r ial

d i s s ip a tion st u di e s measured dissipation half

- lives from t h e so i l surface of 13 to 19 day s

. The percent of dose absorbed increased with increasing dosage.

5.1. 1 Residues of Concern Summary and Rationale

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

in Table 5.1. 1 The residues of concern for endothall for purposes of both dietary food riskEndothall Human Health Risk Assessment DP No. 403274

Page 20 of 36 assessment and tolerance enforcement in plant and animal commodities include parent endothall and its monomethyl ester. The residue of concern in water for risk assessment is endothall and is expressed in terms of en d otha l l acid e qu i vale nts. ( S . Funk, 11/8/96 )

.

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

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

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

Rotational Crop

Livestock Ruminant

Poultry

Fish

Drinking Water Endothall Not Applicable

5.2 Food Residue Profile

Adequate residue chemistry data have been provided to support the use of endothall on apples. Field trials are of adequate number and geographic representation and were generated using adequate analytical methods. Storage stability data indicate that residues are stable over the storage durations used in the field trials. Endothall residues were shown to concentrate in apple j uice (1.2x) and wet pomace (2.8x) . The maximum expected residues in wet pomace exceeded

the tolerance recommended for the RAC. Therefore, a separate tolerance has been set for apple wet pomace at 0.15 ppm. For apple juice the maximum expected residues (i.e, Highest Average Field Trials x 1.2) did not exceeded the tolerance (0.05 ppm) recommended for the RAC. Therefore, a separate tolerance has been not been recommended for apple Juice.

5.3 Water Res idue Profile

A drinking water exposure assessment was conducted by the Environmental Fate and Effects Division (EFED) to support the human health risk assessment for the proposed use of endothall

treated irrigation water on a variety of crops (J

. Lin , 9/ 12 / 12 , D 404321 )

. 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 wate r body. E n d othall c o n cen t r a t io n s degraded w i th

first

- o r der kinetics star t i n g imm e d i ately aft e r application. The maximum potential exposure of endothall in drinking water sources is expected to result from the direct application of endothall to drinking water reservoirs to control aquatic weeds. EFED assumed that the entire reservoir

would be treated at the maxi mum rates, with no more than 10% of the reservoir treated at one time as stated on the label, so that 10 treatments were applied 7 days apart to get the entire reservoir. Since the label specified that the community water system (CWS) could not supply

tre ated drinking water unless the residues were below 0.1 ppm (100 μ g/L), EFED assumed 100

μ g/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 treatm ent. This resulted in a chronic (annual average) concentration of 31 μ g/L (0.031 ppm) for endothall. ThisEndothall Human Health Risk Assessment DP No. 403274

Page 21 of 36 represents a conservative estimate of high

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

Result is summarized in the table below.

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

Endothall

Chronic (non

- cancer) 31

5.4 Dietary Risk Assessment

Memo, S.Tadayon

, 02 / 28 / 201 3

, D 4 07814

5.4.1 Description of Residue Data Used in Dietary Assessment

For this analysis percent crop treated for endothal l from BEAD

, average field trial residues for all existing and new use of endothall d i potassium salt, DEEM 7.81 default and crop specific processing factors obtained from processing studies for all commodities were used ( DP#s:

407814

, S

. Tadayon, 02 / 28 / 2013 ). Drinking water was incorporated directly into the dietary assessment using the maximum chronic concentration for surface water generated by the Pesticide Root Zone Model (PRZM)

- Exposure Analysis Modeling System (EXAMS) at 31 ppb.

5.4.2 Percent Crop Treated Used in Dietary Assessment

A screening

- level usage analysis (SLUA) was provided by the Biological Economic Analysis Division (BEAD), 11/19/2012. The following average PCT estimates were used to calculate chronic dietary exposures: A pple 62%, Apple fresh market 76%, Apple processing 37%, Apple juice 40%,Barley for grain 36 %, Com for gr ain 19%, Dry Beans 32 %, Grape 95%, Grape Fresh market 99%, Grape Processing 94%, Green Peas 43%, Oats for grain 7% , Peanut for nuts 42%, Rice 100% , Sorghum for grain 15% , Soybean for beans 9%, Strawberry, 90% , Strawberry Fresh market 88%, St rawberry Processing 100 , Sugar beet for sugar 37%, Sugarcane for sugar 54%, Watermelon 33%, Wheat for grain 14%

5.4.3 Acute Dietary Risk Assessment

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

oral exp o sure to endothall. Since there is no acute dietary hazard for this chemical, acute dietary

risk was not quantified

.

5.4.4 Chronic Dietary Risk Assessment

A partially refined chronic dietary exposure and risk assessment was conducted incorporati ng both food and water residues as described above

. The drinking water inputs were based on modeled surface water values from the scenario which provide s the highest estimated

environmental concentration. The exposure to drinking water come s from the direct app l ication

to drinking water reserv o ir s

. In a previous drinking water assessment, EFED has concludedEndothall Human Health Risk Assessment DP No. 403274

Page 22 of 36 the use of endothall

- treated irrigation water represents t h e most co n servative estimates for drinking water assessment (DP 356316, September 9, 200 9 ). Therefor e
, the same drinking

water exposure estimates c ontinue d to be used for the human health risk assessment. EFED

assumed 100 μ g/L (0.1 ppm) as the acute (peak) exposure and the constant exposure during the treatment period and then modeled residue decline by degradation after the final treatment.

Typically, HED has concerns regarding dietary risk when the exposure estimates exceed 100% of the chronic population adjust ed dose (cPAD). The estimated exposure (food and water) to the U.S. population from the existing and proposed new uses of endothall resulted in an estimated risk equivalent to 32% of the cPAD

. The most highly exposed population subgroup is infants (1

- 2 ye ars old) with an exposure equivalent to an estimated risk of 90% of the cPAD. This assessment could be significantly refined using monitoring data; however, since risks of concern were not identified, further refinement was not undertaken.

The results of the chronic dietary exposure analys i s are reported in the Summary Table 5.4.5

.

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

.

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary Cancer

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

General U.S. Population

N/A N/A 0.002229 32

N/A N/A All Infants (< 1 year old) 0.004392 63

Children 1

- 2 years old 0.006314 90

Children 3

- 5 years old 0.004575 65

Children 6

- 12 years old 0.002554 37

Youth 13

- 19 years old 0.001483 21

Adults 20

- 49 years old 0.001932 28

Adults 50+ years old 0.001983 28

Females 13

- 49 years old 0.001874 27

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Memo, Ana Rivera

- Lupiáñez, Chemist

, 02 / 20 /201 3

, D 404325

6.1 Residential ExposureEndothall Human Health Risk Assessment DP No. 403274

Page 23 of 36 There are no proposed residential uses at this time; a product containing endothall is currently registered for aquatic applications on ponds

, lakes and garden pools

. Residential exposures and risk were previously assessed and were not of concern (DP Code : 336685, 336686, 336687, 336688, K. M. Lowe, June 9, 2007). Howver, i t is the policy of HED to use the best available data to assess residential exposure; therefore, residential exposures resulting from the aquatic use were reassessed using HED’s SOP for Residential Exposure Assessments m odified in HED’s SWIMODEL V 1.0 (W. Dang et al. , 27

- Mar

- 1999) and using updated body weight information. Residential risk for residential handlers was assessed ( Ana Rivera

- Lupiáñez, 02/20/2013, D404325) assessed, however the inhalation risk is not a component of the aggregate pertinent to

this action.

6.2 Postapplication Exposure

Table 6 .2 presents the post application incidental oral ingestion MOE values calculated for adults and children 3 to <6 years old swimming after aquatic applications of endothall dipotassium to pond and lakes

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

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

Table 6.2 : Residential Post application Non

- cancer Exposure and Risk Estimates for Endothall (Swimmer Scenario)

Exposure Scenario Level of

Concern Maximum Concentration

in Water 1 (mg/L) Exposure Dose (mg/kg/day) 2 ,3 Short

- term

Oral MOE 4

Ingestion of water, Adult

- (Female) 100 5 0.00 56 1,700 Ingestion of water, Child 3<6 years old 100 5 0.0383 250
1. Maximum concentration in water (top 1 ft.) = 5 mg/L. based on maximum application rate from registered labels for aquatic weed control: 0.00022 lb ai/ft3 (EPA Reg.4581

- 388

- 82695).

2. Oral exposure dose (mg/kg/day) = concentration, Cw ( 5 mg/L) x ingestion rate, IgR (0.021 L/hr adults and 0.049 L/hr children 3< 6) x exposure time, ET (3.7 hr adults and 3 hr children 3< 6) (hrs/d) x 1/BW (adult

- female=69 kg; children (3< 6) = 19 kg) 4. MOE = NOAEL/Exposure dose; short

- term incidental oral NOAEL = 9.4 mg/kg /day. The LOC for adult females and children (3< 6) for short

- term incidental oral exposures is MOEs < 100.

6.3 Combined Exposure

HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population (Table 6.2)

.

6.4 Residential Bystander Postapp lication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for endothall at this time primarily because of the low acute inhalation toxicity (Toxicity Category I II )

, low vapor pressure (9.27 x 10 - 7 mm Hg) and the

p roposed use rate ( 0.423 lb ai/A) . However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010Endothall Human Health Risk Assessment DP No. 403274

Page 24 of 36 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post app lication inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative pos t application inhalation exposure assessment

for endothall. Although a quantitative residen tial postapplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for residential handlers. This exposure scenario is representative of a worse case inhalation exposure and should be considered protecti ve of most postapplication inhalation exposure scenarios.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents near spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could a lso be a potential source of exposure from the ground application method employed for endothall . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develo p the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm . On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for a erial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to approp riately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift

management p ractices to reduce off

- target drift with specific products with significant risks

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

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

risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregat ed. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. In the case of endothall , chronic aggregate risks result from exposure through food and water only. For short

- term risks, adult and chi ldren’s incidental oral exposures were combined with background exposure from food and water.

7.1 Acute Aggregate Risk

The available toxicity data indicate that toxicity resulting from a single day oral exposure to endothall is unlikely. Therefore, an acute aggregate assessment was not done.

7.2 Short

- Term Aggregate RiskEndothall Human Health Risk Assessment DP No. 403274

Page 25 of 36 Adult and children’s post application oral exposure (Table 6. 2 ) were combined with the chronic dietary exposure from the mostly highly exposed adult (General US population) and children’s (all children 1

- 2 years old) subpopulations (Table 5.4.5), respectively, to determine aggregate exposure and risk as shown in Tabl e 7.2. Despite the numerous conservative assumptions in developing these estimates, the MOEs are above the LOC of 100, and are not of concern.

Table 7.2. Short

- Term Aggregate Risk Calculations for Endothall Dipotassium

Population NOAEL

mg/kg/day LOC 1 M ax

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

Adult 100 100 1 0.002229 0.0056 0.007829 1200

Child Postapplication 100 100 1 0.006314 0.038 3 0.0446 210

1 The LOC is based on the standard inter

- and intra

- species uncertainty factors totaling 100. The FQPA Safety Factor has been

reduced to 1X.

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

3 Residential E xposure. Residential Exposure ( adult and p ostapplication) = incidental oral (Table 6.2).

4 Total Exposure = (Avg

. Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [ 9.4 Total Exposure]

7.3 Chronic Aggregate Risk

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

is not of concern. Refer to Section 5.4.4.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to endothall and any other substances and endothall does not appear to produc e a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not

assumed that endothall has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from su bstances found to have a common mechanism on

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

.

9.0 Occupational Exposure/Risk Characterization

ThinRite Blossom Thinner may be applied as a dilu te spray with air blast orchard equipment. Spray should be directed to areas of the canopy where the most thinning is desired, avoiding excessive application on low vigor branches to reduce the potential for over thinning, fruit finish marking, and leaf bu rn. The product is not intended to be applied with handgun sprayer, aerial application equipment, or through any type of irrigation equipment. Handler exposure is expected to be short

- term based on information provided on the proposed label. The personalEndothall Human Health Risk Assessment DP No. 403274

Page 26 of 36 protective equipment (PPE) label requirements include: long

- sleeved shirt, long pants, chemical resistance gloves , protective eyewear, and shoes plus socks.

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

fo llowing exposure scenarios:

Mixer/Loaders

1. Mixing/loading liquids to support airblast applications, Applicators

2. Applying sprays with airblast e quipment

9.1 Short

- T erm Handler Risk

No chemical

- specific handler exposure data were submitted in support of th e proposed use, and therefore HED relied on the best available surrogate data to complete the occupational handler

assessment

. Sources of generic handler data, used as surrogate data in the absence of chemical

specific data, include the Pesticide Handl ers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and the Outdoor Residential Exposure Task Force (ORETF) database. Some of these data are proprietary (e.g., AHETF data, MRID No. 44339801), and su bject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surroga te Reference Table” ( http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf ), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pestici des/science/handler

- exposure

- data.html.

The proposed product label directs applicators and other handlers to wear long sleeved shirt and long pants, shoes plus socks, and chemical

- resistant gloves. HED typically assesses handler exposure using “baseline” clothing assumptions, and if risks of concern are identified, the use of personal protective equipment (PPE) may be incorporated into the exposure assessment. In the

case of endothall

, systemic toxicity via the dermal route was not quantified; personal p rotective equipment is required to mitigate potential risks related to the caustic properties of the chemical

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

were needed to achieve MOEs above the LOC of 3 0 for airblast equipment application scenarios

Standard assumptions were used with respect to body weight for adult handlers (80 kg), the exposure duration (i.e., short

- term), and the area treated for various types of application equipment and application sites. In conjunction with these standard values, HED used the maximum application rates from the proposed label directions. Each of the risks is presented as a MOE, or the ratio of the NOAEL to the calculated daily dose.

Table 9 .1 presents a summary of the short

- term occupational handler exposures and risk

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

level of concern ( i.e., short

- term MOEs ≥ 30) for endothall inhalation exposures, at some l eve l of risk mitigation (i.e., addition of PF5R respirator). MOE s range from 410 for mixing/loadingEndothall Human Health Risk Assessment DP No. 403274

Page 27 of 36 flowable liquids to support airblast application at label specified PPE (i.e., no respirator), to 96 for airblast equipment applicators utilizing a PF5R respir ator

. It should be noted that the proposed label direct s mixers, loaders, applicators and other handlers to wear a long

- sleeved shirt, long pants, shoes plus socks

, chemical

- resistant gloves and protective eyewear, but no respirator is required

.

Table 9

. 1. Occupational Handler Short Term Risk Estimates for Endothall Applications on Apples (Proposed use )

Exposure Scenario Crop or Target App Rate a

(lb ai/A) Acres Treated

Daily b Baseline

Inhalation

Unit Exposure c (mg/lb ai) Inhalation d

Dose (mg/kg/day) MOE

Inhalation e

Short Term

- Term f

Mixer/Loader (Male)

Mixing/Loading Liquid

Flowables for Airblast Applications Apple

Blossoms 0.423 40 0.000219 0.00004 410

Applicator (Male)

Applying Sprays via Airblast Equipment (Open Cab) Apple

Blossoms 0.423 40 0.00471 0.00096

0.00019 (PF5R respirator) 19

96 (PF5R respirator)

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

- OEA).

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

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

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

e Short

– term Inhalation MOE = NOAEL (0.0192 mg/kg/day) / inhalation daily dose (mg/ kg/ day). LOC = 30. f. At label specified PPE (i.e., no respirator) unless specified)

9.2 P ostapplication Risk

There is a potential for short

- term occupational exposure to endothall

- dipotassi um during postapplication activities. Based on the uses associated with the ThinRite Blossom Thinner product, occupational post application exposure can occur via the dermal and/or inhalation route. Dermal exposure during post application activities is not considered because applicable dermal endpoints were not identified.

9.2.2 Inhalation Postapplication Risk

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for endothall at this time primarily because it has a low vapor pressure ( 9.7 x 10 - 7 mm Hg ), it is applied at an application rate of 0. 423 lbs ai/A, and it is not projected to be applied via typically high inhalation exposure application equipment (e.g., aerial equipme nt ). However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalationEndothall Human Health Risk Assessment DP No. 403274

Page 28 of 36 exposure into the Agency's risk assessments. If new policies or pro cedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment

for endothall

.

The Environmental Protection Agency's requirements regarding Restricted

- entry Intervals (REIs) are included in the 40 CFR 156.208. In accordance with the 40 CFR 156.208, the REI is based on the acute toxicity of the “technical active ingredient material”. The toxicity categories of the active ingredient for acute dermal, eye irritation, and skin irritation potential a re used to

determine the interim Restricted

- entry Intervals. If one or more of the three acute toxicity effects are in toxicity category I, the interim REI is established at 48 hours. The acute toxicity classification for primary eye irritation of endothal l

- 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 Category I. The proposed ThinRite Blossom Thinner label indicates an

REI of 12

- h our , which is not in compliance with the WPS.

10.0 References

S. Tadayon. Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action to Support New Use on apple

. D40 7814

. 0 2 / 28 /201 3

.

Ana Rivera

- Lupiáñe z, : Endothall

- dipotassium : Occupational and Residential Risk Assessment for Proposed uses of a new endothall

- dipotassium product for thinning blossoms on apple trees.

D 404325

. 0 2 / 22 /201 3

.

David Soderberg,:Endothall; Petition for Registration of ThinRite Blossom Thinner: Summary of Analytical Chemistry and Residue Data. D384206 09/30/2011

A ppendix A . Toxicology Profile and Executive SummariesEndothall Human Health Risk Assessment DP No. 403274

Page 29 of 36 A.1 Toxicology Data Available for Endothall

.

The toxicological data requirements (40 CFR 158.340) for food uses for endothall are in Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 Test Technica l

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

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)........................... y es no

A HASPOC TXR No. 0056397 . Waived.

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

Page 30 of 36 Table A.2.a Acute Toxicity Profile

– Endothall

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

870.1100 Acute oral toxicity 42289201 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

A.2.b Subchronic, Chronic and Other Toxicity Profil es

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

870.3100

90

- Day oral toxicity rodents (rat) 43480810(1994) Acceptable/guideline 0, 150, 600, 1800 ppm M:0, 10, 39, 118 mg/kg/day F: 0, 12, 51, 153 mg/kg/day NOAEL = 39 mg/kg/day LOAEL = 118 mg/kg/day based on treatment related deficits in body weight.

870.3150 13 week oral toxicity in nonrodents (dog) 43480802 (1994) Acceptable/guideline 0, 100, 400, 1000 ppm M: 0, 3.2, 11.7, 27.5 mg/kg/day F: 0, 3.2, 13.0, 28.9 mg/kg/day NOAEL = 11.7 mg/kg/day LOAEL = 27.5 mg/kg/day based on decreases in body weight gain.

870.3200

21

- Day dermal toxicity (rat)

range

- finding 42814101 (1992) Acceptable/nonguide

- line 0, 80, 200, 500 mg/kg/day NOAEL = not determined LOAEL = 80 mg/kg/day based systemic toxicity (death) LOAEL = 80 mg/kg/day based on dermal

irritation

870.3250

21

- Day dermal toxicity (rat) 43465201(1994) Acceptable/guideline 0, 30, 100, 300 mg/kg/day NOAEL = not determined LOAEL = 30 mg/kg/day based on decreased body weight gains. LOAEL = 30 mg/kg/day based on dermal

irritation

870.3700a

Prenatal developmental in rodents (rat) 42776301 (1993) Acceptable/guideline 0, 6.25, 12.5, 25.0 mg/kg/day Mater nal NOAEL = 12.5 mg/kg/day LOAEL = 25 mg/kg/day based on decreased body weight gain. Developmental NOAEL = > 25 mg/kg/day

LOAEL = not determined HDT.

870.3800 Reproduction and fertility effects 43152101 (1993) 43629301 (1995) Acceptable/guideline 0, 30, 150, 900 ppm M: 0, 2, 10.2, 64 mg/kg/day F:0, 1.8, 9.4, 60 mg/kg/day premating 0, 3.1, 17.3, 104.7 mg/kg/day lactation Parental/Systemic NOAEL = not

established LOAEL = 2 mg/kg/day based on proliferative lesions gastric epithelium

both sexes. Reproductive NOAEL = 9.4 mg/kg/day LOAEL = 60.0 mg/kg/day based on decreased pup body weights Reproductive Offspring NOAELEndothall Human Health Risk Assessment DP No. 403274

Page 31 of 36 A.2.b Subchronic, Chronic and Other Toxicity Profil es

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

= 9.4 mg/kg/day LOAEL = 60.0 mg/kg/day based on decreased pup body weights.

870.4100b Chronic toxicity dogs 40745202 (1987) supplementary/guideli ne 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 carcin ogenicity.

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 ( Salmonella typhimurium )/OPPTS 870.5100/[§84

- 2]

OECD 471 43154801 (1993). Unacceptable in dimethyl sulfoxide (DMSO) (equivalent to 1.93, 5.80, 19.3, 58.0, 116 or 193 μg/plate active ingredient) with or without S9

activation. Negative

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

Page 32 of 36 A.2.b Subchronic, Chronic and Other Toxicity Profil es

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

In vivo Mammalian Cytogenetics

- Micronucleus Assay

in Mice/OPPTS 870.5395/[§84

- 2] mice were administered 0.464, 0.928 and 1.86 mg/kg Endothall Technical amine salt (1.5:1 amine :salt ratio; Batch No. B46

- 44

- 1; endothall amine 30.3%;endothall acid equivalent = 11.6%) via intraperitoneal injection (IP) in deionized water;

Cytogenetics

In vivo Mammalian Cytogenetics

- Micronucleus Assay

in Mice/OPPTS 870.5395/[§84

- 2] 41700301 (1989) Acceptable mice were administered 2,10 or 50 mg/kg

Endothall Negative

Cytogenetics

In vitro Mammalian Cytogenetics OPPTS 870.5375 [§84

- 2];

OECD 473 41700302 (1989) Acceptable in dimethyl sulfoxide (DMSO) at concentrations of 2.5, 10.0, 20.0 and 40.0 μg/mL without metabolic activation or were exposed for 3 hours to 15.0, 60.0, 120.0 or 240.0 μg/mL with metabolic activation Negative

870.7485

Metabolism and pharmacokinetics 42169502 (1990), acceptable a sing le 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, blo od half

- life elimination

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

half

- life

- 13.9 hours in males; the half

life in females could not be calculated because of a double blood peak. Multiple oral or single administration indicated that

the test mat erial was rapidly absorbed and excreted in the feces (89

- 98%) and urine (5

- 9%). The compound did not

bioaccumulate. At 24 hours tissue distribution of the compound was extensive but low, the highest amount (<10%) being found in the gastrointestinal

tract . By 48 hours, the compound was mostly undetectable in the tissue. Bile elimination was only of minor importance. Absorbed or unabsorbed test compound in all groups was excreted mainly as chemically unchanged

Endothall in the feces and urine.

870.7485

M etabolism 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 radioactivity being present in the feces (47.6% males, 47.5% female s) At 24 hours after dosing, less than 0.21% of theEndothall Human Health Risk Assessment DP No. 403274

Page 33 of 36 A.2.b Subchronic, Chronic and Other Toxicity Profil es

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

dose was found in the stomach (+ contents), small intestine (+ contents) and pancreas and very little detected in the blood (below 15 ng eq/g). Higher levels of radioactivity were found in the caecum (3.0 % males, 6. 1 % females) and the large intestine (3.2% males, 8.2% females).

Analysis of extracts of the urine, feces, caecum and large intestine of both male and female rats gave a single radioactive component corresponding to unchanged

Endothall which accounted for >86, >96, >74 and >69% of total recovery from the respective extracts.

870.7600 Dermal penetration 42169503 (1990) acceptable Dose levels were 0.0125 mg/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 to <0.1% at all dose levels. At

the 0.0 125 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 increase in systemic bioavailability occurred only at the 1.5% dose level. The dose related pattern of absorption was typical of a chemical which directly damages the skin. The percent of dose absorbed increased with increasing dose. The total percent recovery of [ 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 and relative lung weights, subacuteEndothall Human Health Risk Assessment DP No. 403274

Page 34 of 36 A.2.b Subchronic, Chronic and Other Toxicity Profil es

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

28

- day: 0 (air), 0.001, 0.005, or 0.025 mg/L for 6 hours per day, 5 days/week for 4 weeks inflammation, alveolar proteinosis, and hemorrhage). The NOAEL was not

established.

28

- day: LOAEL = 0.005 mg/L based on indications of lung toxic ity (rales in males and increased lung weights and alveolar macrophages in both sexes). NOAEL is 0.001 mg/L.Endothall Human Health Risk Assessment DP No. 403274

Page 35 of 36 Appendix B. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and the Outdoor Residential Expo sure Task Force (ORETF) database; are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Bo ard. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler

exposure

- data.html and http://www.epa.gov/pesticides/science/ post app

- exposure

- data.html.Endothall Human Health Risk Assessment DP No. 403274

Page 36 of 36 Appendix C. International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex

40 CFR 180.293:

Plants/Livestock: combined residues of endothall, 7

- oxabicyclo [2, 2, 1] heptane

- 2,

3

- dicarboxylic acid and its monomethyl

ester

(d) Indirect or inadvertent residues : endothall (7

- oxabicyclo[2.2.1] heptane

2,3

- dicarboxylic acid) in potable water from use of its potassium, sodium, di

- N

, N

- dimethylalkylamine, and mono

- N

- N

, - dimethylalkylamine salts as algicides or herbicides to control aquatic plants in canals, lak es, ponds, and other potable water sources that may lead to endothall residues 7

- oxabicyclo[2, 2,1]heptane

- 2,3

- dicarboxylic acid, including its monomethyl ester None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex
Apples 0.05
Apple , Wet

Pomace 0.15

Completed: M. Negussie; 01/30/2013

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

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