UN I TED STATES E NV I RONMENTA L PROTECT I ON AGENCY



### WASHINGTON, D.C. 20460

D A T E : September 15

, 2015 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SU B JEC T : E thopr o p: Draft Human H ea lth Risk Assessment for Regi s tratio n R eview.



### P C Co d e : 041101



### Deci s ion N o .: 476334



### P e titi o n No .: NA

Ri s k As s e s s ment 

### T y pe: Single Chemical / Aggregate

T XR N o.: NA

MRID 

### N o

. : 4562 1 5-01 

### DP Barcod e : D4 1 0028



### R e gi s t r a tion No

. : NA



### R e gu lat ory Action: R egi s tratio n R ev iew

C a s e 

### N o.: NA

C A S 

### No. : 1 3194-48-4

40 CF R: 

### § 180. 262

Matthew Llo y d

, C T H

, Risk Assesso r 

# w i (**~** Kate l ynn King

, Chem i st

. 

## F ROM:

John Li cc ion e, T ox ico 1 ogist '**c____,,~?'":::""Z:_'-:::..__-..:::..._-R..__** 

### R i sk Assessmen t Branch 

### V I V I

Health Effec t s Division (HE

&



### Michael Barr e tt, Chem i st

Environmenta l Fa t e and Effect

THRO UG H : M i chael Metzger, C hief '. 

# I**~ ~**  

# ()

RAB V & 

### V Jl /HED

# (75~)"{_ ;\,

*hurston Morton

, RA R C Reviewer 

# IJJ l.

# ~ Charles Smith, RA R C R eviewer 

# }-QR- 

# ?

,

T O : Eric M i ederhoff

Chemical Re v iew Manager

Ri s k M anageme n t a n d Im p l ementation Branch Il I

Pesticide Re- Eva luation Di v i s ion ( PRD ) (7508 P )

Thi s document provid es th e HED 's human health risk assessment for the Reg i strat i o n Review of Ethoprop [S ,S -dipropyl 0

- et h yl phosphorodithioate]. The occupational and r esidential exposure
assessment/r i sk assessment we r e provided by Matt h ew Ll oyd (RA B 57); th e r es idu e c h em i stry

assessment and dietary exposure assessments were pro v ided by Katel y nn King (RAB57) ; and the

ha z ard characterization and e n dpoi n t se l ec t ion was p r ov i ded by Jo hn Licc i one (RAB57).

Page I of93Page 2 of 94



### Table of Contents

1.0 Executive Summary

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

2.0 HED Recommendations

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

2.1 Da ta Deficiencies

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Revisions to Established Tolerances

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

2.3 Label Recommendations

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

3.0 Introduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

3.4 Anticipated Exposure Pathways

................................ ................................ ................. 13

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Toxicology Studies Available for Analysis

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

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

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

4.2.1 Dermal Absorption

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

4.3 Toxicological Effects

................................ ................................ ................................ .... 16

4.3.1 Critical Durations of Exposure

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

4.4 Literature Review on Neurodevelopment Effects

................................ ..................... 18 4.5 Safety Factor for Infants and Children (FQPA SF)

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

4.5.1 Completeness of the Toxicology Database

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

4.5.2 Evidence of Neurotoxicity

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

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

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

4.5.4 Residual Uncertainty in the Exposure Database

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

4.6 Toxicity Endpoint and Point of Departure Selections

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

4.6.1 Do se

- Response Assessment

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

4.6.2 Recommendation for Combining Routes of Exposures for Risk Assessment

........ 29

4.6.3 Cancer Classification and Risk Assessment Recommendation

................................ 30

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

Assessment

................................ ................................ ................................ ............................... 30

4.7 Endocrine Disruption

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

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 34

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ....... 34

5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ................. 34

5.1.2 Summary of Environmental Degradation

................................ ................................ .. 34

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ........... 35

5.1.4 Residues of Concern Summary and Rationale

................................ .......................... 35

5.2 Food Residue Profile

................................ ................................ ................................ .... 35

5.3 Water Residue Profile

................................ ................................ ................................ .. 36

5. 4 Dietary Risk Assessment

................................ ................................ .............................. 36

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ........ 37

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................. 37

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................... 37Page 3 of 94



### 5.4.4 Steady

- State Dietary Risk Assessment

................................ ................................ .......... 38

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ................ 39

5.4.6 Characterization of Uncertainties in the Dietary Risk Assessment

................................ 39

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 40

6.1 Non

- Occupation al Bystander Post

- Application Inhalation Exposure

.................... 40

6.2 Residential Bystander Post

- Application Inhalation Risk Characterization

.................... 44

6.3 Non

- Occupational Spray Drift Exposures and Risk Estimates

............................... 45

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 52

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 53

9.1.1 Occupational Handler Exposure/Risk Estimates (Surrogate Unit Exposure Scenarios) 53 9.1.3.1 Occupational Handler Cancer Risk Estimates (Standard LADD Approach)

............... 64 9.1.3.2 Occupational Handler Cancer Risk Estimates (Based on Biomonitoring Data)

........... 71

9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

............................. 72

9.2.2 Occupational Post

- Application Dermal Exposure/Risk Estimates

................................ 72

10.0 Incident Re port

................................ ................................ ................................ ................. 73 Appendix A. Toxicology Profile

................................ ................................ ................................ . 77 Appendix B. Summary of OPP’s Cholinesterase Policy & Use of BMD Modeling

................... 88 Appendix C. Summary Tables of Benchmark Dose (BMD) Analyses

................................ ....... 89 Appendix D. Physica l/Chemical Properties

................................ ................................ ................. 93 Appendix E. International Residue Limits

................................ ................................ .................. 94Page 4 of 94



### 1.0 Executive Summary

Background Ethoprop [ S,S

- dipropyl O

- ethyl phosphorodithioate] is an organophosphate (OP) insecticide/nematicide currently registered as an emulsifiable concentrate (EC) and two granular formulations (15% and 20% ai) for use on various agricultural crops

. T he end use products are applied in the field using ground and soil incorporated equipment once early in the season (typically pre

- plant). All the avail able products are classified as Restricted Use and may be purchased and used only by certified applicators or persons under their direct supervision. The currently registered application rates for ethoprop generally range from 3 lbs ai/A to 12 lbs ai /A

via ground application. The applications are specified to be conducted with closed systems , with the exception of backpack granular application for bananas

.

Based on the registered use sites

, humans may be exposed to ethoprop in food and drinking

water si nce ethoprop may be applied directly to growing crops and application may result in ethoprop reaching surface and ground water sources of drinking water. D ermal and inhalation exposures are anticipated for occupational handlers. There are currently no re gistered residential

uses of ethoprop . T here is the potential for non

- occupational exposure as a result of spray drift and ambient bystander exposure

.

Hazard Assessment Ethoprop is a member of the OP class of pesticides. Like other OPs, the initiating event in the

adverse outcome pathway (AOP)/mode of action (MOA) for ethoprop involves inhibition of the enzyme acetylcholinesterase (AChE) via phosphorylation of the serine residue at the active site of the enzyme. This inhibition leads to accumulation of acetylcholine and ultimately to neurotoxicity in the central and/or peripheral nervous system . For ethoprop , AChE inhibition is the most sensitive endpoint in the toxicology data base in multiple species, durations, lifestages,

and routes. Ethoprop, unlike some other OPs, does not require metabolic activation to the oxo n metabolite to inhibit AChE (i.e., the parent compound is the active form inhibiting AChE). OPs

also exhibit a phenomenon known as steady

- state AChE inhibition. After repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the production of new, uninhibited enzyme

. In the case of ethoprop, the results show a clear pattern of s teady state reached within two weeks of exposure. As such, endpoint selection is identified for the acute, single day effects and steady state effects. For the purposes of the occupational risk assessment, only the steady

- state duration is relevant to th e exposure scenarios. For the purposes of the non

occupational risk assessments, the acute and steady

- state durations are relevant to the exposure scenarios.

The toxicology database for ethoprop is considered adequate for risk assessment. There are

acce ptable studies available for toxicity endpoint selection

. Ethoprop has dose

- response data across multiple lifestages, durations, and routes for both red blood cell (RBC) and brain AChE

inhibition. Dermal , oral, and inhalation studies allow for route

- spec ific evaluation

. There are two separate steady

- state dermal POD s selected for the liquid and granular formulations of ethoprop , although both are based on red blood cell (RBC) cholinesterase inhibition

. Clinical signs of neurotoxicity related to inhibition of AChE by ethoprop have been noted at higher doses

in a number of studies. The CCA acute and repeated dose studies suggest quantitative sensitivity to ethoprop with respect to RBC AChE inhibition . Ad ditionally, t he Food Quality Protection ActPage 5 of 94



### (FQPA) Safety Factor (SF) has been retained for infants, children, youth, and women of childbearing age for all exposure scenarios due to uncertainty in the human dose

- response relationship for neurodevelopmental effects (See section 4.4)

. For all exposure scenarios, interspecies (10X) and intraspecies (10X) uncertainty factors were applied . As a result, a total uncertainty factor of 1

, 000X was applied for all non

- cancer exposure scenarios , except dietary

exposu res for the adult population subgroup 50

- 99 years old where the FQPA SF does not apply (total uncertainty factor = 100X) and inhalation exposures where the interspecies uncertainty factor has been reduced to 3X (total uncertainty factor = 300X)

.
Ethoprop is classified "likely to be carcinogenic to humans" based on malignant adrenal pheochromocytomas in male rats and is regulated with a Q 1 

### *. A quantitative cancer risk assessment is required (dietary and occupational handler ) ; the Q 1 

### * for ethoprop is 2.81x 10

- 2


### mg/kg/day

- 1



### .
Dietary (Food and Water) Exposure and Risk The existing residue chemistry database for ethoprop is adequate for risk assessment purposes. An unrefined acute dietary exposure assessment was conducted to estimate the dietary exposure and risk associated with Registration

Review. Because food and water dietary risk assessments exceed 100% of their respective population adjusted doses (aPAD & s sPAD), a combined dietary assessment was not completed.

The acute dietary exposure assessment incorporated tolerance level residues, DEEM default processing factors, and 100% crop treated (PCT). The most conservative exposure model was

used to assess the contributions from drinking water and the Estimated Drinking Water Concentrations (EDWCs) used PRZM

- GW

. The acute aggregate dietary (food only + drinking water only) exposure estimates are above HED’s level of concern [>100% the acute population adjusted dose (aPAD)] for the U.S. population and all population subgroups 1 

### . Dietary exposure from food only at the 95 th 

### percentile of exposure is 260% of the aPAD for the U.S. population and 630% of the aPAD for all infants (<1 year old), the highest exposed popu lation subgroup. Dietary exposure from drinking water only at the 95 th 

### percentile of exposure is 3,200% of the aPAD for the U.S. population and >10,000% of the aPAD for all infants (<1 year old), the highest exposed population subgroup.

The DEEM acute module was used to conduct refined steady

- state assessments using the steady

state endpoint, two

- day average dietary exposure, and 21

- day rolling water averages. EFED provided daily time

- series outputs that simulate 29 years of residues of ethoprop in the drinking water application scenario. This distribution was used as a residue distribution file (RDF) in

DEEM for direct

, all sources and indirect

, all sources. For the steady

- state aggregate assessment,
the un refined food alone and water alone exposure estimates are well above HED’s level of concern for the U.S. population and all population subgroups at the 95 th 

### percentile of exposure 1



### . At the 9 5 th 

### percentile of exposure, all infants (<1 year old) are the highest exposed subpopulation

at >10,000 % of the steady

- state population adjusted dose (ssPAD) for the drinking water only dietary assessments

.
In the case of ethoprop, a dietary cancer risk for food and drinking water together (i.e., the aggregate cancer dietary assessment) was not c ompleted because even though the food only cancer risk estimate could be refined, the water only cancer risk estimate drives the dietary

cancer risk estimat ion . Refinements of the water only cancer risk estimates are not available at

1 Except adults 50

- 99 years old (acute & steady

- state, food only )Page 6 of 94



### this time. Applying th e ethoprop Q1* of 0.0281 (mg/kg/day)

- 1 

### , the cancer risk estimate for the U.S. general population is 7 x 10

- 6 

### for food alone (based on incorporated tolerance level residues, DEEM default processing factors, and 100% crop treated (PCT) ) and 5 x 10

- 5 

### for water only.

Residential (Non

- Occupational) Exposure and Risk There are currently no registered residential uses of ethoprop ; therefore, a quantitative residential

assessment was not conducted.

Bystander Inhalation The Agency has developed a preliminary b ystander volatilization inhalation exposure assessment for ethoprop utilizing the currently available inhalation toxicity and air monitoring data. No risk estimates of concern were identified for either the single day or steady state analysis.

Spray Drift A quantitative non

- occupational spray drift assessment was conducted for the registered uses of ethoprop based on the emulsifiable concentrate formulation 2



### . HED believes a quantitative spray drift assessment is applicable only for pre

- plant ground bo om soil

- directed spray applications. Risk estimates related to spray drift are of concern at various distances from the edge of the field for adults and children (1 to <2 years) depending on the spray drift scenario. For adults, the screening level scena rio of a high boom and f ine to medium/coarse spray requires a distance of

over 300 feet to reach a dermal margin of exposure ( MOE ) ≥ 1000. For children, the screening level scenario also requires a distance of over 300 feet to reach a combined (dermal and incidental oral) MOE ≥1000. Drift reduction technologies, such as using coarser sprays can reduce risk concerns; however, there are still risk estimates of concern at the field edge regardless of the drift scenario assessed

.
Occupational Exposure and Risk Occupational handler non

- cancer dermal and inhalation exposure and risk estimates were calculated for the registered uses of ethoprop

. Occupational handler risk estimates were evaluated for ethoprop based on both unit exposure data (chemical

- specific and surrogate data) and available biomonitoring data. For the unit exposure data approach, r isk estimates for the emulsifiable concentrate (EC) and granular (G) formulations are calculated separately because

different dermal POD s were selected according to formulation type

. In both cases, mixer/loader scenarios drive the occupational non

- cancer risk and the level of concern (LOC) for the combined risk estimates are MOEs < 1,000. All combined (dermal + inhalation) risk estimates

are of concern using labe l

- defined engineering controls for occupational handler mixer/loaders, loaders, and applicators. For mixer/loaders using the label

- defined engineering controls, t otal

MOEs (dermal + inhalation) range from <1

- 1 1 for the liquid formulation and 19

- 190 for th e granular formulation.

HED also evaluated the potential exposure to ethoprop using urinary concentrations of M1 ( O

ethyl

- S

- propylphosphorothioate), as an exposure biomarker in an available observational biomonitoring study. While the individual result s varied widely, non

- cancer risk estimates derived from the biomonitoring study result in risk estimates of concern (i.e, MOEs below the LOC of 1,000) for mixer/loaders, applicators, and worker s who conducted all three tasks. Results from the biomonitoring study are most applicable to crops/conditions in the Pacific Northwest

2 [EPA Reg. No. 5481

- 9041]Page 7 of 94



### because of the additional personal protective equipment ( PPE ) that study participants wore

. As the original biomonitoring study occurred in a large portion of the occupational handler group for ethoprop occupational handlers in a discrete geographic location, there is uncertainty bridging the use of the data to other occupational handler groups w ith different agricultural practices and geographic variations.

HED also conducted a quantitative occupational handler cancer risk assessment using surrogate unit exposure data and a screening assessment based on the available biomonitoring data. Usin g the surrogate unit exposure approach, the cancer risk estimates representing label

- defined engineering controls range from 10

- 4 

### to 10

- 6 

### depending on the formulation (granular versus emulsifiable concentrate) and application parameters regarding “private” versus “commercial”

handlers (differ in terms of days/year of exposure)

. Quantitative cancer risk estimates were also calculated based on the available biomonitoring data. Those cancer risk estimates reflect engineering controls plus the use of extensive dermal PPE common in the Pacific Northwest. For those scenarios, the cancer risk estimates range from 10

- 4 

### to 10

- 6 

### depending on the application parameters around “private” versus “commercial” handlers.

A quantitative post

- application non

- cancer dermal exposure assessment has not been conducted for ethoprop because ethoprop is typically applied pre

- plant/pre

- emergent in the growing season.

T he REI on the currently registered labels (48 hours [and 72 hours in areas that receive less than

25 inches of rain per year]) meets the minimum requirements of the Worker Protection Standard

based on active ingredients that are classified as Toxicity Category I for acute dermal, eye irritation, or primary skin irritation.

Based on the Agency's current practic es, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for ethoprop at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational

post

- application inhalation exposure assessment for ethoprop

.

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

- Income Populations 3 

### ".

Human Studies Re view : 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 Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultur al Handler Exposure Task Force (AHETF) database; the Residential SOPs (Turf/Incidental Oral SOP), other registrant

submitted exposure monitoring studies (MRID 45621501 ), are : (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review , and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency web site 4



### .

3 http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf

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

- exposure

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

- app

- exposure

- data.htmlPage 8 of 94



### 2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies for the Registration Review eligibility of ethoprop

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The FDA PESTDATA database indicates that ethoprop is completely recovered using FDA Multiresidue Protocol D (PAM I Section 232.4) and partially recovered using FDA Multiresidue

Protocol E for non

- oily matrices (PAM I Section 211.1). Recovery of ethoprop u sing Protocol E for oily matrices (PAM I Section 212.1) is small. The registrant has submitted data pertaining to the recovery of Metabolite IV through FDA Multiresidue Protocols, and these data have been forwarded to the FDA for review (03/27/1998, J. Ab botts, D239294).

2.2.2 International Harmonization

U.S. permanent tolerances are summarized in Appendix E along with International Maximum Residue Limits (MRLs) established by Codex Alimentarius Commission. Mexico adopts the U.S. tolerances and/or Codex MRLs for its export purposes. At this time the following Canada tolerances (0.09 ppm) have been used in place of the US tolerances for harmonization purposes : bean, lima and bean

, snap
, succulent . The following Codex tolerances (0.05 ppm) have been used in place of the US tolerances for harmonization purposes; potato and sweet potato root. Cucumber tolerances for the US and Canada are both equal at 0.02 ppm however, the Codex

tolerances is at 0.01 ppm. Even though new tolerances are being recommended for harmonization, the established tolerances (as identified in Table 2.2.3.1) were used in the dietary

assessment as residues

.

2.2.3 Revisions to Established Tolerances

No revisions to established tolerances are required at this time. A tolerance summary for ethoprop is provided in Table 2.2.3.1.

Table 2.2.3.1. Tolerance Summary for Ethoprop

Commodity Established Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments

( correct commodity definition )

Banana 0.02 0.02 N/A

Bean, lima 0.02 0.09 HED recommends a tolerance change

for harmonization with the Canadian

tolerance.Page 9 of 94

Bean, snap, succulent 0.02 0.09 HED recommends a tolerance change

for harmonization with the Canadian

tolerance. Cabbage 0.02 0.02 N/A Corn, field, forage 0.02 0.02 N/A Corn, field, grain 0.02 0.02 N/A
Corn, field, stover 0.02 0.02 N/A Corn, sweet, forage 0.02 0.02 N/A
Corn, sweet, kernel plus

cob with husks removed 0.02 0.02 N/A

Corn, sweet, stover 0.02 0.02 N/A

Cucumber 0.02 0.02 N/A Hop, dried cones 0.02 0.02 N/A Peppermint, tops 0.02 0.02 N/A Pineapple 5 0.02 0.02 N/A

Potato 0.02 0.05 HED recommends a tolerance change

for harmonization with the Codex

tolerance. Spearmint, tops 0.02 0.02 N/A Sugarcane, cane 0.02 0.02 N/A

Sweet potato, roots 0.02 0.05 HED recommends a tolerance change

for harmonization with the Codex

tolerance.



### 2.3 Label Recommendations

No label recommendations have been identified. A summary of the risk estimates has been provided, and shows that there are risk estimates of concern for registered uses of ethoprop based

on the use information and label

- required engineering controls

.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Nomenclature of Ethoprop and its Metabolites of Concern.

Ethoprop or Ethoprophos

O

- ethyl

- S,S

- dipropyl phosphorodithioate

CAS: 13194

- 48

- 4

5 There are no U.S. registrations as of July 23, 2009, except for existing stocks bearing old labeling whose sale, distribution, and use is allowed, provided it is consistent with the terms of the cancellation order of July 9, 2009; i.e. , the EPA will allow the technical registrant to continue to sell and distribute existing stocks of the amended registered produ ct bearing old labeling for use on pineapple for 18 months (until January 9, 2011) and persons other than the registrant may continue to sell and/or use existing stocks of product bearing the old labeling unt il such stocks are exhausted, provided that such use is consistent with the terms of the previously approved labeling on, or that accompanied, the modified product.Page 10 of 94

Table 3.1. Nomenclature of Ethoprop and its Metabolites of Concern.

Metabolite II (S

- Me)

O

- ethyl

- S

- methyl

- S

- propyl phosphorodithioate

Metabolite III (O

- Me)

O

- ethyl

- O

- methyl

- S

- propyl phosphorodithioate

Metabolite IV (M

- 1)

O

- ethyl

- S

- propyl phosphorodithioate

SSDP (S,S

- dipropyl degradate)
S,S

- dipropylphosphorodithioate



### S

- Me, O

- Me, and M

- 1 are all plant and animal metabolites and are also environmental degradates detectable in water. SSDP is an environmental degradate but is not a plant or animal

metabolite.

S

- Me and O

- Me are AChE inhibitors and are therefore of concern for non

- cancer risk

assessments. M

- 1 and SSDP are not AChE inhibitors and are not of concern for non

- cancer risk assessments. All four metabolite/degradates should be included in cancer risk assessments.

3.2 Phys ical/Chemical Characteristics

Ethoprop (O

- ethyl S,S

- dipropyl phosphorodithioate) is a colorless to yellow tinted liquid with a strong mercaptan odor and a boiling point of 86

- 91 o 

### C at 0. 2 mm Hg . Ethoprop is only slightly

soluble in water ( 843 ppm at 21 C ), but is soluble in most organic solvents ( hexane, xylene,

acetone, and ethanol ). Ethoprop has a low vapor pressure (4.6 x 10

- 2 

### Pa). A summary of physical/chemical properties for ethoprop can be found in Appendix D.

3.3 Pesticide Us e Pattern

Ethoprop is an organophosphate insecticide/nematicide currently registered as an emulsifiable concentrate (EC) and two granular formulations (15% and 20% ai) for use on various agricultural

crops

. Ethoprop products are classified as Restricted Use Pesticide (RUP) and may be purchasedPage 11 of 94



### and used only by certified applicators ( or persons under their direct supervision )

. T he end use products are applied in the field using ground and soil incorporated equipment early in the season (typically pre

- plant). This application procedure is independent of the formulation

. For some crops, only banded (not broadcast) applications are permitted. This restriction applies to

the EC formulation for cabbage

, and the EC and granular formulations for sweet potatoes. The EC formulation of ethoprop may also be applied by chemigation. Airblast

, aerial , and h and held application s are prohibited o n the existing registered labels (with the exception of a backpack

gr anular application for bananas)

. There are no registered residential products that could be used by homeowners. With the exception of the granular application to bananas, all use patterns require engineering controls on the registered product labels. The loader/applicator scenario for bananas involves backpack application of the 15G product and requires coveralls over long

sleeve shirt and long pants

, chemical

- resistant gloves, chemical

- resistant footwear plus socks,

and a non

- powered air

- purifying respir ator equipped with an N, R, or P

- series filter.

The label requires a REI of 48 hours (72 hours in areas where rainfall is less than 25 inches per year).

Table 3. 3.1. Summary of Directions for Use of Ethoprop

.
Applic. Timing, Type, and Equip. Formula tion

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Field Grown Ornamental

Pre

- plant 5481

- 09041

[EC] 3 1 Same as single app.

rate Not

listed CA, OR, WA only;

Preplant broadcast only; Immediately incorporate to a depth of 2

- 4 inches
Hops

Pre

- plant During season (after pruning,

before stringing) 5481

- 09041

[EC] 3 1 Same as single app.

rate 90 Apply via chemigation,

banded or broadcast application; soil incorporate 2

- 4 inches or

water in

Tobacco

At plant Up to 1 week 5481

- 09040

[15G] 6 1 Same as single app.

Rate Not

listed Apply via banded or

broadcast application; Mix in top 2

- 4 inches of

soil
Beans, succulent (snap & lima)
At plant Up to 3 days

pre

- plant 5481

- 09040

[15G] 8.1 1 Same as single app.

Rate Not

listed Apply via banded or

broadcast application

Cabbage
At plant Up to 1 week

pre

- plant 5481

- 09040

[15G] 5.1 1 Same as single app.

Rate Not

listed Apply via banded or

broadcast application

At plant 5481

- 09041

[EC] 5.1 1 Same as single app.

Rate Not

listed Apply via banded

application; CA only

CucumberPage 12 of 94

Table 3. 3.1. Summary of Directions for Use of Ethoprop

.
Applic. Timing, Type, and Equip. Formula tion

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

At plant 5481

- 09040

[15G] 1.95 1 Same as single app.

Rate Not

listed Apply via banded

application; do not allow granules to contact seed

Corn, Field & Corn, Sweet

At plant

Pre

- plant 5481

- 09040

[15G] 1

- 3

rootwor
ms/wire

worms 1.5

- 6 1 Same as single app.

Rate Not

listed Apply as broadcast or

banded application; soil incorporate

Mint

pre

- plant or

post

- season 5481

- 09040

[15G] 3

- 6 lbs

ai/A 1 Same as single app.

Rate Not

listed Broadcast & soil

incorporate/irrigate

Pre

- plant

After last

harvest 5481

- 09041

[EC] 3

- 6 lbs

ai/A 1 Same as single app.

Rate 225 Broadcast; soil incorporate

2

- 4 inches or water

- in via irrigation

Potato (East)

Prior to plant/At plant/pre

emergence 5481

- 09040

[15G]

5481

- 09041 [EC] 4

- 6

(symphyl

ans/wire worms)

6

- 9 (nematod es) 1 Same as single app.

rate Not

listed Apply via broadcast or

banded application; Soil incorporate after either app. Method

– 2

- 4 inches

Potatoes (West)

Prior to plant/At plant/pre

emergence 5481

- 09040

[15G] 4

- 6

(symphyl

ans/wire worms)

6

- 12 (nematod es) 1 Same as single app.

rate Not

listed Apply via broadcast or

banded application; Soil incorporate after either app. Method

– 2

- 4 inches

Prior to plant/At plant/pre

emergence 5481

- 09041

[EC] 4

- 6

(symphyl

ans/wire worms)

6

- 12 (nematod es) 1 Same as single app.

rate Not

listed Apply via broadcast or

banded application; Soil incorporate after either app. Method

– 2

- 4 inches

Sugarcane

At planting 5481

- 09040

[15G] 5.88 1 5.88 Not

listed Apply via banded

application; Workers doing hand planting apps or other

direct contact activitiesPage 13 of 94

Table 3. 3.1. Summary of Directions for Use of Ethoprop

.
Applic. Timing, Type, and Equip. Formula tion

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per

Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

cannot be present with 100 ft. of application equipment

At planting 5481

- 09042

[20G] 5.88 1 5.88 Not

listed Apply via banded application; mix in top 2

- 4

inches of soil Workers doing hand planting apps or other

direct contact activities cannot be present with 100 ft. of application equipment

Sweet Potato

2

- 3 weeks before plant 5481

- 09040

[15G] 3

- 3.9 1 3.9 Not

listed Apply via broadcast or soil

band treatment; Soil incorporate w/ mechanical equipment

2

- 3 weeks before plant 5481

- 09041

[EC] 3

- 3.9 1 3.9 Not

listed Apply via soil band

treatment; Soil incorporate w/ mechanical equipment

Banana

Granule backpack application 5481

- 09040

[15G] 40 grams

15G product per 3⁄4

meter
radius

around

base of

tree 2 (121 lbs ai/A

based on typical area

treated for backpack spreaders ) Not

listed Evenly apply granules; soil incorporate by hand raking

1

– Ethoprop rate information expressed in this document as lbs ai/A; many crop application rates are also expressed in a

rate/linear foot.

2

– EC = Emulsifiable Concentrate; G = Granular



### 3.4 Anticipated Exposure Pathways

Humans may be exposed to ethoprop in food and drinking water since ethoprop may be applied directly to growing crops and application may result in ethoprop reaching surface and ground water sources of drinking water. There are no residential uses of ethoprop . T here is the potential

for non

- occupational exposure as a result of spray drift (via the dermal and incidental oral routes of exposure) and ambient inhalation exposure as a result of agricultural applications

. Based on the registered use pattern for ethoprop

, steady

- state dermal an d inhalation exposures are anticipated for occupational handlers.Page 14 of 94



### 3.5 Consideration of Environmental Justice

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

- Income Populations 6



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

- es tablished procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting

. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstance s warrant

. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated

. Further con siderations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among sp ecific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Ethoprop is a member of the OP class of pesticides. Like other OPs , the initiating event in the adverse outcome pathway (AOP)/ mode of action (MOA), for ethoprop involves inhibition of the

enzyme AChE via phosphorylation of the serine residue at the active site of the enzyme. This

inhibition leads to accumulation of ace tylcholine and ultimately to neurotoxicity in the central and/or peripheral nervous system (see Figure 1). For ethoprop , AChE inhibition is the most sensitive endpoint in the toxicology database across multiple species, durations, lifestages, and

routes

. AChE inhibition is the focus of this hazard characterization ; t he availability of reliable AChE inhibition dose response data is one of the key determinants in evaluating the toxicology

database.

Figure 1. A dverse Outcome Pathway for OPs.

Consistent with risk assessment s for other AChE

- inhibiting compounds, OPP has used a benchmark response (BMR) level of 10% and has thus calculated BMD 10 

### ’ s and BMDL 10 

### ’ s (see

6 Available: ( http://epa.gov/compliance/ej/resources/po licy/exec_order_12898.pdf 

# Target
Tissue
Dose Phosphorylation

of the active site


## of AChE Neurotoxicity

Accumulation
of 

## acetylcholinePage 15 of 94



### Appendix 1 for summary of OPP’s AChE policy)

. The BMD 10 

### is the estimated dose where

AChE is inhibited by 10% compared to background. The BMDL 10 

### is the lower confidence

bound on the BMD 10



### . As a matter of science policy, the a gen cy uses the BMDL, not the BMD,

for use as the POD (USEPA, 2012)

. All BMD/BMDL modeling for all individual datasets was completed using USEPA BMD Software, version 2.2 and an exponential model was used to fit

the data

. Summary tables of the BMD analyses c an be found in Appendix B

.

4.1 Toxicology Studies Available for Analysis

The toxicology database for ethoprop is complete for risk assessment. There are acceptable studies available for toxicity endpoint selection; they include:

 subchronic oral toxici ty stud y in the dog

 chronic oral toxicity studies in rats and dogs

 carcinogenicity studies in rats and mice

 developmental studies in rats and rabbits

 reproduction study in rats

 acute and subchronic neurotoxicity studies in rats

 developmental neurotoxicity (DNT) study in rats

 acute and repeated comparative cholinesterase AChE studies in juvenile and

adult rats

 delayed neurotoxicity study in hens

 subchronic dermal toxicity in rats and rabbits

 repeated dosing inhalation studies i n rats

 immunotoxicity study in rats

 complete mutagenicity study battery

 metabolism study in rats

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME)

Ethoprop, unlike some other OPs, does not require metabolic activation to the oxon metaboli te to
inhibit AChE. In a metabolism study, ethoprop was administered to Crl:CD(SD)BR rats as a single IV bolus (males and females); single oral bolus (females, metabolism and pharmacokinetic studies; males, metabolism only); or by multiple oral doses (MRI D 41804301)

. Oral absorption of ethoprop is rapid and essentially complete by 48 hours. The principal route of excretion was in urine (>50% of dose). Radioactivity was also found in feces (7

- 16%) and respiratory air (11

- 19%). Terminal elimination half

- l ife in blood was 92

- 135 hours. Metabolism was by dealkylation of one or both S

- propyl groups, followed by hydroxylation and conjugation. The main urinary metabolites were O

- ethyl

- S

- methyl

- S

- propyl phosphorodithioate (SME), O

ethyl

- O

- methyl

- S

- propyl phosp horodithioate (OME), and O

- ethyl

- S

- propyl phosphorodithioate (M1).

.

4.2.1 Dermal Absorption

No dermal absorption study is avai lable for ethoprop. A dermal absorption factor is not required

since POD s for dermal exposure w ere selected from rout e

- specific dermal toxicity studiesPage 16 of 94



### for both the liquid and granular formulations. These dermal toxicity studies provided quality

AChE inhibition data, which were evaluated using BMD modeling techniques and are being used

for dermal risk assessment (see Se ction 4.5).

4.3 Toxicological Effects

Ethoprop has dose

- response data across multiple lifestages, durations, and routes for both RBC and brain AChE inhibition. Many of these studies have been evaluated with BMD techniques. However, it should be noted t hat some of the data did not model well

, and these data did not

have BMD values that could be used in the risk assessment. The CCA studies (acute and repeat phases), which were conducted at time to peak inhibition (24 hours

– adults; 8 hours

– pups),

prov ided the best data to examine temporality. Studies conducted by the dietary routes of exposure, e.g., the SCN and DNT studies

, did not report when AChE activity was measured, so it is not certain if measurements were performed consistently (at the same ti me of day) within a study. The ACN study reported that measurements were done at time to peak inhibition, however, no adequate fits were obtained with either brain or RBC AChE data from this study because of dose spacing issues.

Signs of neurotoxicity related to inhibition of AChE by ethoprop have been noted at higher doses

in a number of studies. In the ACN study, salivation

, lip smacking, ataxia, negative pupillary response and/or tremors were noted at 25 mg/kg. At doses > 25 mg/kg, the incidence a nd frequency of these signs increased and

, in addition, negative corneal response, negative air drop reflex, negative startle response, increased latency until first step, paralytic gait abnormalities, reduced activity, prostration and labored or gasping r espiration were observed. Decreased hindlimb grip strength, motor activity and analgesic response time were noted in the SCN study (LOAEL = 27 mg/kg/day; the NOAEL = 2.6 mg/kg/day)

. For the DNT study, t he maternal LOAEL for ethoprop in rats was 180 ppm (38.2 mg/kg/day during lactation) based on clinical signs (coarse tremors, repetitive chewing, muscle fasciculations). The PoDs selected are prote c tive of these clinical signs. There were no clinical sign s of toxicity in the CCA repeat study in adults and PND11 pups administered doses up to 1 mg/kg/day. Hen studies were negative for indications of organophosphate induced delayed neuropathy.

The CCA acute and repeated dose studies suggest quantitative sen sitivity to ethoprop with respect to RBC AChE inhibition. In both the CCA acute single

- dose and repeat

- dose studies, there was no apparent dose

- response in adults with respect to ethoprop administration and brain AChE inhibition, whereas this was not the case for PND11 pups. BMD values were obtained for pups based on the dose response brain AChE inhibition data. With respect to RBC AChE inhibition, pups were also more sensitive than the adults. There is confidence in the design of

the CCA studies in tha t time to peak inhibition for both adults and pups were established. In the CCA studies, AChE measurements were performed at time to peak effect for adults (24 hours) and pups (8 hours). A gestational component was not included in the CCA study, but inc luded in the DNT studies (discussed below).

In the DNT definitive study, the dams were more sensitive than PND 21 pups to RBC AChE inhibition. In the range

- finding DNT study, the dams were also more sensitive than gestation day 20 (GD20) fetus to RBC AChE inhibition. The DNT studies were conducted by the dietaryPage 17 of 94



### route of exposure, and it is difficult to relate the results to time to peak effect (which the CCA studies indicated a significant difference between adults and pups).

Ethoprop is classified "likely to be carcinogenic to humans" based o n malignant adrenal pheochromocytomas in male rats and is regulated with a Q 1 

### *. The Q 1 

### * for ethoprop is 2.81x10

- 2


### mg/kg/day

- 1



### .

The acute toxicity data for ethoprop show that ethoprop has a high acute toxicity category for

acute oral and acute inhalation toxicity (Category I/II, respectively). It is a Toxicity Category I/II for acute dermal toxicity, depending on the study. The data show severe acute eye irritation (Category I) and is a strong dermal irritant (Category I)

.

4.3.1 Critical Durations of Ex posure

One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments. One advantage of an AOP understanding is that human health risk assessments can be refined, and focused on the mo st relevant durations of

exposure. The following text provides an analysis of the temporal pattern of AChE inhibition from acute, single dosing and repeated dosing studies in laboratory animals for ethoprop

. This analysis provides the basis for determini ng which exposure durations are appropriate for assessing human health risk. Tables 4.3. 1 .1 and 4.3. 1

. 2 provide a summary of the selected results from experimental toxicology studies with ethoprop. The high quality, well

- designed CCA studies (acute and repeat phases), which were conducted at time to peak inhibition, provided the best data to examine temporality. The CCA studies revealed significant differences in the time to peak inhibiti on between adults (24 hours) and pups (8 hours). Some of the data sets from other studies (e.g., ACN and reproductive toxicity studies) did not model well or were less reliable for various reasons (low number of animals; questionable model variance; and d ose spacing issues).

Table 4.3. 1 .1

– Ethoprop BMD 10 Results (mg/kg/day) for Brain and RBC AChE Inhibition Over Time in Male and Female

Adult Rats

Days of dosing BMD 10 - RBC BMD 10 - Brain

Males Females Males Females

1 a 0.649 1.095 no dose response no dose response

1 1 b 0.553 0.247 no dose response no dose response

14 c not applicable 0.164 not applicable 2.411

28 d 0.238 0.454 not measured not measured

37 e not applicable 0.252 not applicable 5.012

a MRID 46278701 CCA Acute Study

– Single Dose (Adults)

b MRID 46636401 CCA Repeat Study

– Repeat Dose

c MRID 46364802 RF DNT study (Dams treated GD6

– GD20)

d MRID 45388502 28

- day oral study in the rat

e MRID 46364801 Developmental Neurotoxicity Study (LD 21 dams) ; maternal rats exposed from GD 6 through 21 days and 21
days during lactation.Page 18 of 94 Table 4.3. 1 .2

– Ethoprop BMD 10 Results (mg/kg/day) for Brain and RBC AChE Inhibition Over Time in Male and Female
Pup Rats

Days of dosing RBC Brain

Males Females Males Females

1 a 0.570 0.549 0.962 0.817

1 1 b 0.106 0.154 0.187 0.151

a MRID 46278701 CCA Acute Study

– Single Dose (Adults)

b MRID 46636401 CCA Repeat Study

– Repeat Dose



### As shown in Tables 4.3. 1 .1 and 4.3. 1 .2, the BMD values for adult and pup RBC were highest after a single oral dose (CCA acute study) and were lower after repeated exposures within these populations. RBC AChE inhibition was similar (0.549

– 1.095 mg/kg/day) for adults and pups following acut e (single oral) exposure. RBC AChE inhibition was also comparable (0.106

– 0.553 mg/kg/day) for adults and pups after repeated oral dosing. In comparing compartments,

RBC AChE inhibition in adults was more sensitive than brain AChE inhibition in this

pop ulation. For the pups, there was slight sensitivity between the compartments after a single dose but not with 11 days of dosing. The definitive and the range

- finding DNT dietary exposure studies yielded BMD 10 

### values of 5.012 mg/kg/day (lactational day 20 dams) and 2.411 mg/kg/day (GD20 dams), respectively

. Studies for the dermal and inhalation routes in adult

animals allow for route

- specific evaluations. For the dermal and inhalation studies, RBC and brain AChE inhibition were comparable.

OPs exhibit a biological response known as steady state AChE inhibition. After repeated dosing at the same dose level, the degree of inhibition comes into equilibrium with the production of new, uninhibited enzyme. At this point, the amount of AChE inhibition at a given dose remains consistent across duration. In general, OPs reach steady state within 2

- 3 weeks but this can vary among OPs. In the case of ethoprop

, the results in Table s 4.3. 1 .1 and 4.3. 1 .2 indicate that steady

state may be reached by 11 ─ 14 days o f exposure. Given the results in Tables 4.3. 1 .1 and

4.3. 1 .2, f or ethoprop , acute (single day) and steady state durations are appropriate for human health risk assessment. As such, endpoint selection discussed below focuses on acute, single day effects and steady state effects.

Although there are rat data at a shorter time period (i.e., 1 1 days) than 21 days, exposure assessments of 21 days and longer will be conducted for all routes of exposure (i.e., oral, dermal and inhalation) for all single chemical OP assessments. Although the durations of the toxicity and exposure as sessments may differ, an exact match is not necessary and would suggest a level of precision that the toxicity data do not support. Given this, the 21

- day and longer exposure assessment is scientifically supportable and also provides consistency with the O P cumulative

risk assessment across the OPs.

4.4 Literature Review on Neurodevelopment Effects

For the OPs, historically the Agency has used inhibition of AChE as the POD for human health risk assessment; at present time, this policy continues. This sc ience policy is based on decadesPage 19 of 94



### of work which shows that AChE inhibition is the initial event in the pathway to acute cholinergic neurotoxicity. The use of AChE inhibition data for deriving PODs was supported by the FIFRA SAP (2008, 2012) for chlorpyrifo s as the most robust source of dose

- response data for extrapolating risk and is the source of data for PODs for ethoprop. A detailed review of the epidemiological studies used in this review can be found either in the 2014 chlorpyrifos revised

draft human health risk assessment (D424485, D. Drew et al, 12/29/2014) or in the 2015 literature review for other organophosphates (OPP/USEPA; D331251; 9/15/15).

Newer lines of research on OPs in the areas of potential AOPs, in vivo animal studies, and notably ep idemiological studies in mothers and children, have raised some uncertainty about the agency’s risk assessment approach with regard to the potential for neurodevelopmental effects in fetuses and children. Many of these studies have been the subject of rev iew by the agency over the last several years as part of efforts to develop a risk assessment for chlorpyrifos (D424485, D. Drew et al, 12/29/2014). Initially, t he agency focused on studies from three US cohorts: 1) The Mothers and Newborn Study of North Manhattan and South Bronx performed by the Columbia Children’s Center for Environmental Health (CCCEH) at Columbia University; 2) the

Mt. Sinai Inner

- City Toxicants, Child Growth and Development Study or the “Mt. Sinai Child Growth and Development Study;” and 3) the Center for Health Assessment of Mothers and Children of Salinas Valley (CHAMACOS) conducted by researchers at University of California Berkeley. The agency has evaluated these studies and sought external peer review (FIFRA SAP

reviews in 2008 and 2012; federal panel, 2013 7 

### ) and concludes they are of high quality. In the

three US epidemiology cohort studies, mother

- infant pairs were recruited for the purpose of studying the potential health effects of environmental exposures during pregnancy on subsequent child development. Each of these cohorts evaluated the association between prenatal chlorpyrifos and/or OP exposure (with adverse neurodevelopmental outcomes in children through age 7 years). For the 2014 chlorpyrifos revised human health risk assessment (D424485, D. Drew et al, 12/29/2014) , EPA included epidemiologic research results from these three US prospective birth cohort studies but primarily focused on the results of CCCEH since this cohort has published studies on the association betwe en cord blood levels of chlorpyrifos and neurodevelopmental outcomes. The agency retained the FQPA 10X Safety Factor (SF) in the 2014 chlorpyrifos revised risk assessment, in large part, based on the findings of these studies.

In the 2015 updated literatu re review (OPP/USEPA; D331251; 9/15/15), the agency conducted a systematic review expanding the scope of the 2012/2014 review focused on US cohort studies with particular emphasis on chlorpyrifos. The expanded 2015 review includes consideration of the epi demiological data on any OP pesticide, study designs beyond prospective cohort studies,

and non

- U.S. based studies. The updated literature review identified seven studies which were

relevant (Bouchard et al., 2010; Fortenberry et al., 2014; Furlong et al., 2014; Guodong et al., 2012; Oulhote and Bouchard , 2013; Zhang et al., 2014; Shelton et al., 2014). These seven studies have been evaluated in context with studies from the 2012/2014 review ( D424485, D. Drew et al, 12/29/2014 ). Only a brief summary is p rovided below.

The OP exposure being assessed in many of these studies used concentrations of urinary dialkyl phosphate metabolites (DAPs) as the urinary biomarker. Total DAPs is a non

- specific measure of OP exposure and is the sum of six separate molecu les

- three dimethyl alkylphosphate

7 http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2008

- 0850

- 0170Page 20 of 94



### (DMAP) molecules of DMP, DMTP, DMDTP, and three diethyl alkylphosphate (DEAP) molecules of DEP, DETP, and DEDTP. Each metabolite is a breakdown product from multiple OPs (Table 4.4.1; CDC, 2008) 8 

### . Specifically, DMP, DMTP, and DMDTP are associated with 18, 13, and 5 OPs, whereas DEP, DETP, and DEDTP are associated with 10, 10, and 4 OPs, respectively. Thus, using urinary DAPs alone as an exposure measure, it is not possible to separate the exposu re and associated effects for single, specific OPs.

Table 4.4.1.CDC Table of organophosphate pesticides and their dialkyl phosphate metabolites (2008).

Pesticide DMP DMTP DMDTP DEP DETP DEDTP

Azinphos methyl X X X
Chlorethoxyphos X X Chlorpyrifos X X Chlorpyrifos methyl X X Coumaphos X X Dichlorvos (DDVP) X

Diazinon X X Dicrotophos X

Dimethoate X X X

Disulfoton X X X

Ethion X X X

Fenitrothion X X

Fenthion X X Isazaphos

- methyl X X

Malathion X X X

Methidathion X X X Methyl parathion X X

Naled X Oxydemeton

- methyl X X

Parathion X X

Phorate X X X

Phosmet X X X Pirimiphos

- methyl X X Sulfotepp X X Temephos X X

Terbufos X X X Tetrachlorviphos X

Trichlorfon X
DMP = dimethylphosphate; DEP = diethylphosphate; DMTP = dimethylthiophosphate; DMDTP = dimethyldithiophosphate; DETP = diethylthiophosphate; DEDTP = diethyldithiophosphate.



### For studies which measured urinary 3,5,6

- trichloro

- 2

- pyridinol ( TCPy) (e.g., Fortenberry et al, 2014; Eskenazi et al, 2007; Whyatt et al, 2009), this metabolite can be derived from chlorpyrifos, chlorpyrifos

- methyl, and the herbicide triclopyr. TCPy is also the primary environmental degradate of chlorpyrifos, chlorpyr ifos

- methyl, and triclopyr; thus exposure can be found

8 http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l26opd_c_met_organophosphorus_pesticides.pdfPage 21 of 94



### directly on food treated with these pesticides. CCCEH studies have largely used chlorpyrifos measured in cord blood as the specific biomarker (e.g., Lovasi et al, 2010; Whyatt et al, 2004; Rauh et al, 2011). The CHARGE study (Shelton et al, 2015) did not measure biomarkers but instead used geospatial analysis to focus on the residential proximity to OP exposure using data from the California Department of Pesticide Regulation, with five OPs accounting for a total of 73% of the pesticide applied near residential settings (chlorpyrifos, acephate, diazinon, bensulide, and dimethoate).

Similarly, DAPs can be found directly on food following OP applications (Zhang et al, 2008; Chen et al, 2012). Specifi cally, studies have shown that DAPs may form as environmental degradates from abiotic hydrolysis, photolysis, and plant metabolism (Zhang et al, 2008; Chen et al, 2012; Racke et al, 1994). Furthermore, since these DAPs are excreted more rapidly and

extens ively than the parent OPs (Zhang et al, 2008; Forsberg et al, 2008), direct exposure to DAPs may lead to an overestimate of OP exposure when using urinary DAPs as a biomarker of OP exposure. The agency recognizes that this is a source of uncertainty when using DAPs for assessing OP exposure and will continue to monitor this issue in future assessments.

With respect to neurological effects near birth, the CHAMACOS and Mt. Sinai cohorts measured neurological effects at birth, and observed a putative assoc iation with total DEAP, total DMAP, and total DAP exposure (Engel et al., 2007; Young et al., 2005) . Similarly, a Chinese study (Zhang et al., 2014) reported statistically significant associations between for total DEAPs, total DMAPs, and total DAPs from prenatal OP pesticide exposure and neonatal neurodevelopme nt assessed 3 days after birth. However, another cross

- sectional Chinese study, Guodong et al (2012), observed no association with urinary DAPs and a developmental quotient score for 23

- 25

month old children.

The 3 US cohorts (CCCEH, Mt. Sinai, CHAMACOS) each reported evidence of impaired mental and psychomotor development, albeit not consistent by age at time of testing (ranging from 6 month to 36 months across the three cohorts). Attentional problems and ADHD were reported by three prospective cohorts [Rauh et al, 2006; Eskenazi et al., 2007; Marks et al, 2010 ; and Fortenberry et al (2014)] investigators with additional support from a case control study, Bouchard et al. (2010). The exposure metric varied among these studies. Specifically, Fortenberry et al (2014) found suggestive evidence of an association with TCPy and ADHD in boys whereas statistically significant associations were observed by Rauh et al (2006) with chlorpyrifos exposure and ADHD

. Eskenazi et al (2007) reported associations with tot al DMAPs and total DAPs and ADHD; Marks et al (2010) reported associations with total DEAP, DMAP, and total DAP exposure and ADHD. In a national cross

- sectional study of Canadian

children , using 2007

- 2009 data for children age 6

- 11 years (Oulhote and Bouc hard , 2013), there were no overall statistically significant associations observed between child urinary DEAP, DMAP, or total DAP metabolite levels and parentally reported behavioral problems. In contrast, Bouchard et al. (2010), looking at U.S. children age 8

- 15 years in the 2000

- 2004 National Health and Nutrition Examination Survey (NHANES), observed a positive association between attention and behavior problems and total DAPs and DMAPs, but not DEAPs. As part of their analysis, Oulhote and Bouchard (20 13) noted that their outcome assessment for behavioral problems may not have been as sensitive as Bouchard et al (2010), which may in part account for

the difference in the observed results from these studies.Page 22 of 94



### In addition, the 3 US cohorts and the CHARG E study have reported suggestive or positive associations between OP exposure and autism spectrum disorders (Rauh et al., 2006; Shelton et al., 2014; Eskenazi et al, 2007; Furlong et al., 2014). Specifically, Furlong et al (2014) documented suggestive evi dence of an association between total DEAP exposure and reciprocal social responsiveness among blacks and boys. Eskenazi et al (2007) reported a statistically significant association between pervasive developmental disorder (PDD) and total DAP

exposure, w hereas Eskenazi et al (2010) reported non

- significant, but suggestive, increased odds of PDD of 2.0 (0.8 to 5.1; p=0.14). Rauh et al (2006) documented a significant association between PDD and specifically chlorpyrifos exposure. Both PDD and reciprocal s ocial responsiveness are related to the autism spectrum disorder. Using a different exposure assessment method (geospatial analysis and residential proximity to total OP exposure), Shelton et al (2014) also showed statistically significant associations be tween total OP exposure and ASD. While these studies vary in the magnitude of the overall strength of association, they have consistently observed a positive association between OP exposure and ASD. Finally, CCCEH, Mt. Sinai, CHAMACOS have reported an in verse relation between the respective prenatal measures of chlorpyrifos and intelligence measures at age 7 years (Rauh et al. ,2011; Engel et al., 2011; Bouchard et al., 2011 )

.

Across the epidemiology database of studies, the maternal urine, cord blood, and other (meconium) measures provide evidence that exposure did occur to the fetus during gestation but the actual level of such exposure during the critical window(s) of susceptibility is not known. While significant uncertainties remain about the actual exposure levels experienced by mothers

and infant participants in the children’s health cohorts, it is unlikely that these exposures resulted in AChE inhibition. As part of the CHAMACOS study, Eskenazi et al. (2004) measured AChE activity and showed that no differences in AChE activity were observed. Th e biomarker data (chlorpyrifos) from the Columbia University studies are supported by the agency’s dose reconstruction analysis using the PBPK

- PD model (D424485, D. Drew et al, 12/29/2014)

. Following the recommendation of the FIFRA SAP (2012), the agency conducted a dose reconstruction analysis of residential uses available prior to 2000 for pregnant women and young

children inside the home. The PBPK

- PD model results indicate for the highest exposure considered (i.e., indoor broadcast use of a 1% chlorpyr ifos formulation) <1% RBC AChE inhibition was produced in pregnant women. While uncertainty exists as to actual OP exposure at (unknown) critical windows of exposure, EPA believes it is unlikely individuals in the epidemiology studies experienced RBC AChE inhibition.

A review of the scientific literature on potential modes of action/adverse outcome pathways (MOA/AOP) 9 

### leading to effects on the developing brain was conducted for the 2012 FIFRA SAP meeting (USEPA, 2012) and updated for the December 2014 chl orpyrifos revised risk assessment (D424485, D. Drew et al, 12/29/2014). In short, multiple biologically plausible hypotheses and pathways are being pursued by researchers that include targets other than AChE inhibition, including cholinergic and non

- choli nergic systems, signaling pathways, proteins, and others. However, no one pathway has sufficient data to be considered more credible than the

others. The fact that there are, however, sparse AOP data to support the in vitro to in vivo

9 Mode of action (MOA) and adverse outcome pathways (AOPs) describe a set of measureable key events that make up the biological processes leading to an adverse outcome and the causal linkages between such events.Page 23 of 94



### extrapolation, or t he extrapolation from biological perturbation to adverse consequence significantly limits their quantitative use in risk assessment. The SAP concurred with the agency in 2008 and 2012 about the lack of definable key events in a MOA/AOP leading to developm ental neurobehavioral effects. However, since the 2014 literature review, there are no substantive changes in the ability to define and quantitate steps in an MOA/AOP leading from exposure to effects on the developing brain. Published and submitted guide line DNT laboratory animal studies have been reviewed for OPs as part of the 2012/2014 review (D424485, D. Drew et al, 12/29/2014) and the updated 2015 review (OPP/USEPA; D331251; 9/15/15). Neurobehavioral alterations in laboratory animals were often repo rted, albeit at AChE inhibiting doses, but there was generally a lack of consistency in terms of pattern, timing, or dose

- response for these effects, and a number of studies were of lower quality. However, this information does provide evidence of long

- la sting neurodevelopmental disorders in rats and mice following gestational exposure.

At this time, a MOA(s)/AOP(s) has/have not been established for neurodevelopmental outcomes. This growing body of literature does demonstrate, however, that OPs are biologically active on a number of processes that affect the developing brain. Moreover, there is a large body of in vivo laboratory studies which show long

- term behavioral effects from early life exposure, albeit at doses which cause AChE inhibition. EPA considers the results of the toxicological studies relevant to the human population, as qualitatively supported by the results of epidemiology studies. The agency acknowledges the lack of established MOA/AOP pathway and uncertainties associated lack of ability to make strong causal linkages and unknown window(s) of susceptibility. These unce rtainties do not undermine or reduce the confidence in the findings of the epidemiology studies. The epidemiology studies reviewed in the 2012/2014 and 2015 literature reviews represent different investigators, locations, points in time, exposure assessme nt procedures, and outcome measurements. Despite all these differences in study design, with the exception of two negative studies in the 2015 literature review (Guodong et al, 2012; Oulhote

and Bouchard , 2013), authors have identified associations with n eurodevelopmental outcomes associated with OP exposure across four cohorts and twelve study citations. Specifically, there is evidence of delays in mental development in infants (24

- 36 months), attention problems and autism spectrum disorder in early child hood, and intelligence decrements in school age children who were exposed to OPs during gestation. Investigators reported strong measures of statistical association across several of these evaluations (odds ratios 2

- 4 fold increased in some instances),

and observed evidence of exposures

- response trends in some instances, e.g. , intelligence

measures.

As section 408(b)(2)(C) of the FFDCA instructs EPA, in making its “reasonable certainty of no harm” finding, that in “the case of threshold effects, an additio nal tenfold margin of safety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children

to take into account potential pre

- and postnatal toxicity and completeness of data with respect to exposure and toxicit y to infants and children .” Section 408 (b)(2)(C) further states that “the Administrator may use a different margin of safety for the pesticide chemical residue only if, on the basis of reliable data, such margin will be safe for infants and children.” Gi ven the totality of the evidence, there is sufficient uncertainty in the human dose

- response relationship for neurodevelopmental effects which prevents the agency from reducing or removing the statutory 10X FQPA Safety Factor. For the ethoprop DRA, a valu e of 10X has been applied. Similarly, aPage 24 of 94



### database uncertainty factor of 10X will be retained for occupational risk assessments. The agency will continue to evaluate the epidemiology studies and pursue approaches for quantitative

or semi

- quantitative compa risons between doses which elicit AChE inhibition and those which are associated with neurodevelopmental outcomes prior to a revised human health risk

assessment.

4.5 Safety Factor for Infants and Children (FQPA SF)

As noted above, the lack of an establi shed MOA/AOP makes quantitative use of the epidemiology studies in risk assessment challenging, particularly with respect to determining

dose

- response, critical duration of exposure, and window(s) of susceptibility. However, exposure levels in the range measured in the epidemiology studies are likely low enough that they are unlikely to result in AChE inhibition. Epidemiology studies consistently identified associations with neurodevelopmental outcomes associated with OP exposure such as delays in

menta l development in infants (24

- 36 months), attention problems and autism spectrum disorder in early childhood, and intelligence decrements in school age children. Therefore, there is a need to protect children from exposures that may cause these effects; th is need prevents the agency from reducing or removing the statutory FQPA Safety Factor. Thus, the FQPA 10X Safety Factor will be retained for ethoprop for the population subgroups that include infants, children, youths, and women of childbearing age for a ll exposure scenarios.

4.5.1 Completeness of the Toxicology Database

The database of toxicology studies for ethoprop is complete and adequate for characterizing ethoprop toxicity. The ethoprop toxicity database includes developmental studies in rat and rabbit, a reproductive toxicity study, neurotoxicity studies (acute, subchronic, and developmental) and comparative cholinesterase studies (acute and repeat

- dosing in adults and pups).

As discussed in Section 4.4, there is uncertainty in the human dose

- response relationship for neurodevelopmental effects and this warrants retention of the FQPA Safety Factor for the population subgroups that include infants, childr en, youths, and women of childbearing age for all exposure scenarios.

4.5.2 Evidence of Neurotoxicity

Ethoprop is an OP with a neurotoxic AOP ; neurotoxicity is the most sensitive effect across all species, routes, and lifestages and is being used in deri ving PODs

. N eurotoxicity related to inhibition of AChE by ethoprop have been noted in a number of studies including the ACN, SCN, and the DNT studies. Neurotoxicity included numerous clinical signs, and motor abnormalities as discussed above. The point s of departures selected for this risk assessment are protective of these effects.

4.5.3 Evidence of Sensitivity/Susceptibility in the Developing or Young AnimalPage 25 of 94



### Rat and rabbit developmental toxicity studies are available and do not show any susceptibil ity, although cholinesterase activity was not monitored in those studies. Similarly , the rat reproductive toxicity study does not show any life stage susceptibility. Well

- conducted CCA studies (single and repeat dose phases) with time to peak AChE measure ments were available, and provided dose

- response data from potentially susceptible lifestages; i.e., pregnant dams and

post

- natal pups . The CCA studies indicated quantitative sensitivity (both acute and repeat dosing) in the pups for brain AChE i nhibition compared with adult rats, and also did not reveal any significant differences (as shown by the range of BMD values) between RBC and brain AChE inhibition in the pups.

Comparisons across studies (e.g., DNT vs CCA) are problematic for a number of reasons, but can reveal patterns in a qualitative, but not quantitative, sense. Based on the overall results from BMD modeling, the BMD estimates for pups from the CCA studies a re lower than the estimates for the dams from the DNT study, and has been used for acute and steady

- state points of departure.

As discussed in Section 4.4, there is uncertainty in the human dose

- response relationship for neurodevelopmental effects and th is warrants retention of the FQPA Safety Factor for the population subgroups that include infants, children, youths, and women of childbearing age for all exposure scenarios.

4. 5.4 Residual Uncertainty in the Exposure Database

There are no residual unce rtainties with regard to the exposure databases

. The unrefined acute dietary assessment incorporated tolerance level residues, default processing factors and 100% crop treated. The unrefined steady

- state dietary exposure assessments are not expected to

u nderestimate dietary (food and water) exposures.

4. 6 Toxicity Endpoint and Point of Departure Selections

4. 6 .1 Dose

- Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the ethoprop toxicity endpoints and POD s selected from an

evaluation of the da tabase. This endpoint selection was based on a weight of the evidence evaluation using the following considerations:

 Relative sensitivity of the brain and RBC compartments : For ethoprop, the RBC
compartment was consistently more sensitive than the brain compartment as
evident from the well

- conducted CCA studies (acute and repeat dose phases). The results of the DNT study provide support for the greater sensitivity of the RBC compartment. As such, OPP has emphasized the RBC AChE data in P O D derivation.

Potentially susceptible populations (fetuses, juveniles, pregnancy ): The well

- conducted CCA studies (acute and repeat dosing in adults and pups) revealed lifestage sensitivity with regard to AChE inhibition. Overall, pups were found to be more sensitiv e than adults to RBC cholinesterase inhibition by a factor of >2

- fold. The relative sensitivity of pups toPage 26 of 94



### adults to brain cholinesterase inhibition could not be accurately determined because of lack of dose response in adults. There was no gestational c omponent to the CCA study. It is important to note that the results of the dietary DNT study cannot readily be compared with the CCA study which was performed by the gavage route of exposure, inclusion of time to peak inhibition measurements (different fo r pups vs. adults), and the lack of lactational exposure of pups to ethoprop. For example, the differences in magnitude between AChE measurements of PND21 pups in the DNT study vs. PND 11 pups in the CCA study can be explained by the following considerati ons: (1) exposure to ethoprop in the DNT study

derives from lactation and 8

- days of food consumption, while the CCA study involves 11

- days of direct gavage dosing. It takes a longer time to reach an internal concentration with

the diet and another possi ble explanation could be minimal chemical absorption from in utero/lactational exposures . The CCA study with gavage dosing is more protective and matches a bolus dose from exposure via a baby bottle; (2) in the CCA study, AChE measurements were made at pea k exposure while the DNT AChE measurements were most likely the day after treatment; and (3) pups recover faster than adults due to their increased protein synthesis. However, both studies do show patterns in a qualitative, rather than quantitative sense . In this regard, the CCA studies indicated that PND11 pups were more sensitive than adults (including nonpregnant females) with respect to AChE inhibition.

 Route of exposure: It is preferred to match, to the degree possible, the route of exposure in the toxicity study with that of the exposure scenario(s) of interest

. In the case of ethoprop , there are oral , dermal, and inhalation studies which contain quality dose response AChE data.

 Duration of exposure: It is preferred to match, to the degree possible, the duration of toxicity study with that of the exposure duration of interest. In the case of ethoprop , there are single

- day and steady

- state oral studies . For the dermal and inhalation toxicity studies, there were no single

- day AChE measurements; however, there were

measurements at steady

- state

.

 Consistency across studies: In cases where multiple datasets are available for a single duration, it is important to evaluate the extent to which data are consistent (or not) across

studies. The ethoprop database has striking consistency across studies which allows for

POD s to be de rived from multiple critical studies thereby increasing the confidence in

such values.

Acute Dietary ( all populations )

As shown in Appendix Table A. 2.1, results from single dosing exposures with ethoprop provide only one dat a set appropriate for thi s exposure scenario (RBC and brain AChE data in pups for postnatal day 11 (PND 11 )

, in addition to adult male and female rats.

A PoD for the acute dietary (all populations) exposure scenario was derived from the results of a high quality, well

- conducted acut e CCA rat study (MRID 4627801). A BMDL 10 

### of ≈ 0. 42 mg/kg/day associated with RBC AChE inhibition in female pups (PND11) was selected as aPage 27 of 94



### suitable PoD for the acute dietary (all populations) exposure scenario. The corresponding

BMD 10 

### was ≈ 0.55 mg/ kg/day.

RBC A ChE inhibition in pups was selected for the POD because BMDL 10 

### ′s for this compartment were slightly lower than that estimated from t he pup brain AChE data . In addition, the brain AChE data (in contrast to RBC AChE) for the adult rats did not provide reliable fit s from benchmark dose analyse s because of a lack of a dose

- response relationship

. For the adults, the RBC compartment is more sensitive than the brain compartment. The B MDL 10 

### based on

RBC AChE inhibition in PND 11 fe males is protective of effects observed in adult rats in the

ACN , SCN and DNT stud ies, the male PND11 (CCA studies) and the PND21 pups in the DNT study. Data from the PND11 pups represent highly exposed sub

- populations (infants and young children) and are appropri ate for the POD derivation.

An uncertainty factor of 100 0 X (10X to account for interspecies extrapolation

, 10X for intraspecies variation and, 10x for FQPA SF due to uncertainty in the human dose

- response relationship for neurodevelopmental effects (S ee section 4.4) ) is applied to the BMDL 10 

### to obtain

an acute population adjusted dose (aPAD) of 0. 0 00 42 mg/kg/day. The only population subgroup that the FQPA safety factor is not retained is adults 50

- 99; therefore, the a PAD for this population subgroup is 0.0042 mg/kg/day.

Steady

- State Dietary (all populations)

A POD for the steady

- state dietary (all populations) exposure scenario was derived from the

results of high quality, well

- conducted CCA (repeat dosing) rat study (MRID 46636401)

. A

BMDL 10 

### of ≈ 0.07 mg/kg/day associated with RBC AChE inhibition in PND 11 m ale pups was

selected as a suitable PoD for the steady

- state dietary (all populations) exposure scenario. The corresponding BMD 10 

### was ≈ 0.11 mg/kg/day.

This endpoint is considered appropriat e for steady

- state dietary exposure due to the oral route of administration and the duration of exposure. The study and endpoint s were selected because they are protective of effects observed in all of the other avail able studies for all lifestages. The

P ND 1 1 pup was selected because th is age group and lifestage is more sensitive than adults to ethoprop

- induced RBC and brain AChE inhibition following repeated exposure.

The POD of 0.07 mg/kg/day for RBC AChE inhibition is supported by several other studies including:

 BMDL 10 

### of 0.11 mg/kg/day for RBC AChE inhibition in PND 1 1 fe male pups in the CCA (repeat dosing) rat study (MRID 46636401)

.

 BMDL 10 

### ′s of 0.12 and 0.16 mg/kg/day for brain AChE inhibition in PND11 male and female pups, respectively, in the CCA (repeat dosing) rat study (MRID 46636401)

.

 BMDL 10 

### of 0.13 mg/kg/day for RBC AChE in dams dosed from GD 6

- 20 in the range

finding DNT study (MRID 46364802).

An uncertainty factor of 1 0 0 0X (10X to account for interspecies extrapolation

, 10X for intraspecies variation , and 10X for FQPA SF due to uncertainty in the human dose

- responsePage 28 of 94



### relationship for neurodevelopmental effects (See section 4.4) ) is applied to the BMDL 10 

### to obtain

a n population adjusted dose ( ss PAD ) of 0. 0 000 65 mg/kg/day. The only population subgroup that the FQPA SF is not retained is adults 50

- 99; therefore, the ssPAD for this population subgroup is 0.00065 mg/kg/day.

Incidental Oral, Short

- Term

Same as Steady State Dietary Endpoint. A total uncertainty factor of 1

, 0 0 0 X (level of concern, LOC=1,000) is appropriate for non

- occupational incidental oral exposure ( i.e., 10X for interspecies extrapolation, 10X for intraspecies variation, and a 1 0 X FQPA SF due to uncertainty

in the human dose

- response relationship for neurodevelopmental effects (See section 4.4))

.

Dermal, Steady State

Two dermal toxicity studies on liquid (70% a.i.) ethoprop, one in rabbits and the other in rats, were available. There was a study (MRID 45034801) on the granular formulation (19.34% a.i.) that was also available. Since the occupational handler assessment may involve exposures to either the granular or the liquid formulations, depending on the pest and/or crop treated, two separate steady

- state dermal POD s were selected for the differ ent formulations. For the liquid formulation, a steady

- state d ermal POD was selected from a 3

- week dermal toxicity study (MRID 4 1304404 ) on technical ethoprop in rabbit s based on RBC A ChE inhibition ( BMDL 10 

### ≈
0.16 mg/kg/day ; BMD 10 ≈ 

### 0.20 mg/kg/day ) i n the adult female rabbit

. This selection was supported by comparable BMDL 10 

### ′s (0.2

– 0.3 mg/kg/day) obtained from the analyses of the

RBC AChE data from a 3

- week dermal toxicity study (MRID 45074602) in the rat. The RBC compartment, which provided BMD e stimates comparable to the brain, was selected to be consistent with other routes (i.e

. , oral and inhalation) in which RBC was the chosen compartment. The BMDL 10 

### of 0.16 mg/kg/day from the dermal rabbit toxicity study is lower

than the acute dermal LD 50 

### of 7.9 mg/kg in the male rabbit for the liquid formulation.

For the granular formulation, a steady

- state dermal POD was selected from the 4

- week dermal toxicity study of this formulation in the rat. The lowest BMDL 10 

### was 10.4 mg/kg/day based on

RBC AC hE inhibition in the female rat. Comparable BMD estimates were obtained for this compartment in the male rat. BMD estimates were based on doses corrected for percent active ingredient. No adequate BMD fits were obtained with the brain AChE data. The BM DL 10 

### of 10.4 mg/kg/day from the dermal study in the rat is lower than the acute dermal LD 50 

### of 31.36 mg/kg in the rabbit for a similar formulation (an acute dermal LD 50 

### study in the rat was not available for the granular formulation). Although an acute de rmal LD 50 

### study in the rat was not available for the granular formulation, the rabbit is more sensitive than the rat with regard to acute toxicity based on data on the technical form of ethoprop. This study is appropriate for the route and duration of expo sure.

A total uncertainty factor of 1000X is appropriate for dermal exposures (10X for interspecies extrapolation, 10X for intraspecies variation, a nd 10X FQPA SF for residential assessments or a database uncertainty factor in occupational assessments d ue to uncertainty in the human dose

response relationship for neurodevelopmental effects (See section 4.4 ) )

.Page 29 of 94



### Inhalation , Steady State

A steady state inhalation POD was selected from a 3

- week inhalation toxicity study (MRID 48779601) in rats, based on R BC AChE inhibition (BMDL 10 

### ≈ 0.82 μg/L/day; BMD 10 ≈ 

### 1.3 μg/ day/ L) in the adult male rat

. The particle size distribution from this study suggests that most particles were well belo w the respirable range for an aerosol, suggesting that the exposure was mainly via a gas. Human equivalent concentrations (HEC s ) and Human Equivalent Doses were calculated from the BMDL 10 

### value for various scenarios ( See Table 4.5.1) for extrarespiratory

e ffects of a gas. For steady state inhalation exposures, a total uncertainty factor of 300 X was applied [ 3 X for interspecies extr apolation, 10X for intraspecies variation, and 1 0X database uncertainty factor incorporating uncertainty in the human dose

- resp onse relationship for neurodevelopmental effects (See section 4.4)).

Table 4. 6 .1. Ethoprop inhalation BMDL10 values adjusted for toxicity duration and specific
breathing rates for various exposure scenarios

Population Scenario Tox 

### icity Duration 

### Adjustment BMDL 10



### (mg/L



### or mg/m 3 

### ) BMDL 10



### (mg/kg/day; breathing rate

specific)
hr/day day/wk 8.3

L/min 16.7



### L /min 29

L/min

O ccupational Handler 8 5 0.000825
mg/L 0.035

mg/kg/day 0.071

mg/kg/day 0.123

mg/kg/day

Residential Bystander 24 7 0.147
mg/m 3 NA NA NA



### Biomonitoring, Multi

- route exposure, Steady State Occupational handler b iomonitoring data are available for use in the ethoprop occupational handler assessment, where a urinary metabolite ( O

- ethyl

- S

- propylphosphorothioate ) was converted to ethoprop equivalents. Because the biomonitoring data allows for total ethoprop exposure without distinguishing between exposure routes (i.e., dermal vs. inhalation), a BMDL 10 

### of ≈ 0.065 mg/kg/day associated with RBC AChE inhibition in PN D11 pups was selected as a suitable PoD for the biomonitoring exposure scenario. The corresponding BMD 10 

### was ≈ 0.11 mg/kg/day.

A total uncertainty factor of 10 0 0X (level of concern, LOC=1,000) is appropriate for the biomonitoring risk estimation [ i.e., 10X for interspecies extrapolation, 10X for intraspecies variation, and a 1 0 X database uncertainty factor incorporating uncertainty in the human dose

response relationship for neurodevelopmental effects (See section 4.4) ]

.

4. 6 .2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources (oral, dermal, and inhalation) and

determine whether the individual exposures can be combined if they have the same toxicological effects. PODs for the incidental oral, dermal, and inhalation routes are all derived from RBCPage 30 of 94



### AChE inhibition. As a result, it is appropriate to combine dermal and inhalation expos ures in the occupational handler assessment (See Section 9 .1.1 for additional information).

4. 6 .3 Cancer Classification and Risk Assessment Recommendation

Ethoprop is classified "likely to be carcinogenic to humans" based on malignant adrenal pheochro mocytomas in male rats and is regulated with a Q 1 

### *. A quantitative cancer risk assessment is required; The Q 1 

### * for ethoprop is 2.81x10

- 2 

### mg/kg/day

- 1



### .

4. 6 .4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4.1 identifies the PODs and UF used in non

- occ upational (dietary , volatilization, and spray drift assessments ).

Table 4.5.4.2 identifies the PODs and UFs used in the occupational handler risk assessment.

Table 4. 6

. 4

. 1 Summary of Toxicological Doses and Endpoints for Ethoprop for Use in Non

- o ccupational

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty /

FQPA Safety

Factors a RfD, PAD, Level

of Concern for

Risk Assessment Study and Toxicological Effects

Acute Dietary

( All
Populations
including

f emales 13

- 49
years of age) BMDL 10 =

0. 4187
mg/kg/day UF A = 10x

UF H =10x
FQPA SF= 1 0 x Acute PAD =

0.0 0 0 42 mg/kg/day Acute CCA Study (MRID 46 27801 )

in the rat

– PND 11.

BMD 10 = 0. 5498 mg/kg/day

Inhibition of RBC AChE in PND11

pups.

Acute Dietary
(Adults 50

- 99) BMDL 10 =

0. 4187
mg/kg/day UF A = 10x

UF H =10x
FQPA SF= 1x Acute PAD =

0.0 042 mg/kg/day Acute CCA Study (MRID 46 27801 )

in the rat

– PND 11.

BMD 10 = 0. 5498 mg/kg/day

Inhibition of RBC AChE in PND11

pups.

Steady

- State
Dietary (all
populations BMDL 10 =

0.0 653
mg/kg/day UF A = 10x

UF H =10x
FQPA SF= 10 x Steady State PAD

= 0.0000 65
mg/kg/day Repeat CCA Study (MRID

46636401) in the rat

– PND 11.

BMD 10 = 0.1056 mg/kg/day

Inhibition of RBC AChE in PND11

pups

Steady

- State
Dietary
(Adults 50

- 99) BMDL 10 =

0.0 653
mg/kg/day UF A = 10x

UF H =10x
FQPA SF= 1x Steady State PAD

= 0.00065
mg/kg/day Repeat CCA Study (MRID

46636401) in the rat

– PND 11.

BMD 10 = 0.1056 mg/kg/day

Inhibition of RBC AChE in PND11

pupsPage 31 of 94

Table 4. 6

. 4

. 1 Summary of Toxicological Doses and Endpoints for Ethoprop for Use in Non

- o ccupational

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty /

FQPA Safety

Factors a RfD, PAD, Level

of Concern for

Risk Assessment Study and Toxicological Effects

Incidental

Oral Steady

State ( 3 weeks
& longer ) BMDL 10 =

0.0 653
mg/kg/day UF A = 10x

UF H =10x
FQPA SF= 10 x Residential LOC =

1,000 Repeat CCA Study (MRID

46636401) in the rat

– PND 11.

BMD 10 = 0.1056 mg/kg/day

Inhibition of RBC AChE in PND11

pups

Dermal
Steady

- State
( 3 weeks &
longer )

Technical

- Liquid

formulation a BMDL 10 =

0.1625
mg/kg/day UF A =10x

UF H =10x
FQPA SF= 10 x Residential LOC = 1,000 3

- week dermal toxicity study

(MRID 4 1304404 ) in ra bbits

BMD 10 = 0.2035 mg/kg/day

Inhibition of RBC AChE in adult

female ra bbits

.

Inhalation
Steady

- State
( 3 weeks &
longer ) BMDL 10 =

0. 8245
μg/L/day b UF A = 3 x

UF H =10x
FQPA SF= 10 x Residential LOC =
300 4

- week inhalation toxicity study

(MRID 4 8779601 )

BMD 10 = 1. 296 μg/L/day

Inhibition of RBC AChE in adult

male rat.
Cancer (oral,

dermal,
inhalation) Classification: "likely to be carcinogenic to humans" based on malignant adrenal

pheochromocytomas in male rats and is regulated with a Q 1 *. The Q 1 * for ethoprop is 2.81x10

-

2 mg/kg/day

- 1

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant huma n exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). aPAD = acute population adjusted dose. ssPAD = Steady state population adjusted dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

a While there is a separate endpoint and POD selected for the ethoprop granular formulation, it is applicable only to the

occupational assessment. The steady

- state dermal endpoint and POD is identified here for the spray drift assessment.

b See Appendix A; Table A3 for adjusted inhalation BMDL 10 val ues for toxicity duration and specific breathing rates for various
exposure scenarios

.

a FQPA SF retained for infants, children, youths, and women of childbearing age for all exposure scenarios due to uncertainty i n the human dose

- response relationship for neurodevelopmental effects (see Section 4.4). This includes all exposure scenarios, except the dietary exposure scenarios for the population subgroup adults 50

- 99 for which the FQPA SF has been reduced to 1X.Page 32 of 94

Table 4. 6

. 4 .2 Summary of Toxicological Doses and Endpoints for Ethoprop for Use in Occupational

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal

– Steady

- State ( 3
weeks & longer )

Technical

- Liquid

formulation BMDL 10 =

0.1625
mg/kg/day UF A =10x

UF H =10x

UF DB =10x b Occupational

LOC for MOE =

1

, 00 0 3

- week dermal toxicity study (MRID

4 1304404 ) in ra bbits

BMD 10 = 0.2035 mg/kg/day

Inhibition of RBC AChE in adult female

ra bbits

.

Dermal

– Steady

- State ( 3
weeks & longer )

Granular

formulation
(19.3% a.i.) BMDL 10 =

10.4
mg/kg/day UF A =10x

UF H =10x

UF DB = 10x b Occupational

LOC for MOE =

1

, 00 0 4

- week dermal toxicity study (MRID

45034801 ) in rats

BMD 10 = 15.7 mg/kg/day
(BMD modeling based on doses adjusted
for a.i.)

Inhibition of RBC AChE in adult female

rat.

Inhalation
Steady

- State (3
weeks & longer) BMDL 10 =

0. 8245
μg/L/day a UF A = 3 x

UF H =10x

UF DB = 10x b Occupational

LOC for MOE =

3 0 0 4

- week inhalation toxicity study (MRID

4 8779601 )

BMD 10 = 1. 296 μg/L/day

Inhibition of RBC AChE in adult male

rat.

Biomonitoring
Exposure

Assessment

– Multi

- route Steady

- State (3
weeks & longer) BMDL 10 =

0.0 653
mg/kg/day UF A = 10x

UF H =10x

UF DB = 10x Occupational

LOC = 1,000 Repeat Oral CCA Study (MRID

46636401) in the rat

– PND 11.

BMD 10 = 0.1056 mg/kg/day

Cancer (oral,

dermal,
inhalation) Ethoprop is classified "likely to be carcinogenic to humans" based on malignant adrenal

pheochromocytomas in male rats and is regulated with a Q 1 *. The Q 1 * for ethoprop is

2.81x10

- 2 mg/kg/day

- 1

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

- response data and used to mark the beginning of extrapolation to deter mine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = p otential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

a See Appendix A; Table A3 for adjusted inhalation BMDL 10 values for toxicity duration and specific breathing rates for various
exposure scenarios

. b UF DB for occupational dermal and inhalation exposures = database uncertainty factor for uncertainty in the human

dose

- response relationship for neurodevelopmental effects (see Section 4.4).Page 33 of 94



### 4. 7 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, development al and reproductive effects in different taxonomic groups. As part of its most recent registration decision for ethoprop, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard data base. However, as required by FFDCA section 408(p), ethoprop is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

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

active a nd other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statu torily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screen ing and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designe d to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

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

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

October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 20 13 10 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

Ethoprop is on List 1 for which EPA has received all of the re quired Tier 1 assay data

. The Agency has reviewed all of the assay data received for the appropriate List 1 chemicals and the

conclusions of those reviews are available in the chemical

- specific public dockets (see EPA

- HQ

OPP

- 2008

- 0560 for ethoprop). For fu rther information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and Tier 1 screening battery, please visit our website 11



### .

10 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

11 Available: http://www.epa.gov/endo/Page 34 of 94



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The metabolism of ethoprop in plants and livestock was extensively discussed in the residue chemistry chapter of the ethoprop RED ( DP# D239294, J. Abbo t ts, 3/27/199 8 ). The degradation of ethoprop in the environment is discussed in a memo by M. Barrett ( DP Barcodes D428028,

09

- 15

- 2015 ).

The residues of concern for the acute and steady state risk assessments in crops are parent and Metabolites II and III (S

- ME and O

- ME) ; for cancer dietary risk, the residues of concern are parent and Metabolites II through IV (S

- ME, O

- ME and M

- 1). For water, the only residue of concern is parent, ethoprop. Metabolites II and III are AChE inhibitors, but Metabolite IV is not.

The envi ronmental degradate SSDP is also of concern for cancer risk assessment. These metabolites are also rat metabolites. Structures of the parent and metabolites may be found in

Table 2.2.

Since field trial data on the metabolites are not available, metabol ite ratios were estimated from metabolism and rotational crop studies. Further information on the development of the ratios may be found in the anticipated residue memo (C. Olinger, DP Barcodes 352476 and 352477

, 07/03/2008 ).

5.1.2 Summary of Environment al Degradation

Ethoprop degrades primarily by microbial metabolism as well as the abiotic process of hydrolysis. The aerobic soil metabolism half

- life is 100 days in the guideline study. Field dissipation half

- lives are 3 to 60 days at approximately 24 different sites. There are no acceptable anaerobic aquatic metabolism studies available but a 100 day half

- life was observed in an anaerobic soil metabolism study. Degradation due to hydrolysis varies with pH, with

estimated half

- lives at 25 °C of 205 day s for acidic (pH 5) waters, 150

- 155 days for waters with neutral pH (pH 7), and 39 days for alkaline waters (pH 9). Ethoprop is not subject to photolysis. Ethoprop is classified as highly mobile with a median K
oc 

### of 109 in five test soils [1]



### .

No degradat e of ethoprop in soil and water laboratory studies was observed at >10% of the applied parent at any time during the studies. O

- ethyl

- S

- propyl phosphorodithioate (also known

as metabolite M

- 1) is a common metabolite found in soil and water and is a hydroly sis product; subsequent to the formation of M

- 1 further degradation and mineralization is observed. For the purposes of drinking water exposure evaluation for the human health risk assessment parent ethoprop is the only residue of concern.

[1] McCall, P. J., Swann, R. L., Laskowski, D. A., Unger, S. M., Vrona, S. A. and Dishburger, H. J. 1980. Estimation of chemical mobility in soil from liquid chromatographic retention times, Bull. Environ. Contam. Toxicol., 24, 190

– 195.Page 35 of 94



### 5.1.3 Compariso n of Metabolic Pathways

For reregistration and risk assessment purposes, adequate plant and livestock metabolism data

are available. The metabolism of ethoprop in plants and livestock was extensively discussed in the residue chemistry chapter of the ethop rop RED (DP# D239294, J. Abbotts, 3/27/1998).

For plants, ethoprop is metabolized primarily to parent and metabolites II and III and water is metabolized into parent ; for cancer dietary risk, the residues of concern are parent and metabolites II, III, a nd IV. See Table 3.1 for additional information on the metabolites.

For livestock, ethoprop is metabolized primarily to metabolites III and/or IV which together

accounted for < 2% of the total radioactive residues in liver of hens and goats (J. Abbotts,

D2 39294, 03/27/1998).

For drinking water, ethoprop is the only residue of concern that exceed s 10% in the environment.

Metabolites III and IV are both found in rat metabolism studies however it is likely that

Metabolite II also forms.

5.1.4 Residues of Concern Summary and Rationale

The Health Effects Division (HED) Metabolism Committee found that for plants , acute and steady state non

- cancer dietary risk, the residues of concern in crops were parent and metabolites II and III. For plants

, cancer dietary risk residues of concern are parent and metabolites II, III,

and IV. Table 5.1.4.1 summarizes the metabolites and degradates to be included in the human health risk assessment and in the tolerance expression. Drinking water residues of concern were

parent only, ethoprop for both tolerance and risk assessment.

Ta b le 5.1.4.1. Su mm a r y o f Me tabolit e s a n d D e g r a d at e s to be i n c l ud e d in t h e Risk Ass e s s m e n t and Tole r a n c e Ex p re ss i on.

M a trix R esi d u es i n cl u d ed in R i s k As s e ss m e n t

Non

- Cancer (Cancer) R esi d u es i n cl u d ed in T o l e r a n ce E x pr es s i o n

P la n ts P r i m

a r y C ro p Metabolites II and III (II, III & IV) Ethoprop

R o tati o n al C ro p Metabolites II and III (II, III & IV) Ethoprop

L i v esto c k R u m i n a n t Metabolites II and III (II, III & IV) Ethoprop

P o u ltry Metabolites II and III (II, III & IV) Ethoprop

D r i n k i n g W ater Ethoprop Ethoprop



### 5.2 Food Residue Profile

H E D h a s p r e vious l y e v a l u a ted re sidue d a ta d e p i c t i ng the m a g ni t ude o f ethoprop r e sidues of

concern in banana; bean, lima; snap, succulent; cabbage; field corn (forage, stover, and grain); sweet corn (forage, stover, and kernel plus cob with husk removed); cucumber; hop, dried cones,Page 36 of 94



### peppermint tops; pineapple; spearmint tops; sugarcane, cane; and sweet pot ato roots 12



### . The Nature of the Residue (NOR) in plants is adequately understood based on cabbage, corn, and potato metabolism studies. The HED Metabolism Committee (K. Farwell, 02/06/1998) found

that for acute and chronic non

- cancer dietary risk, the residu es of concern in crops were parent and metabolites II and III; for cancer dietary risk, residues of concern are parent and metabolites II, III, and IV. The NOR in livestock is adequate based on ruminant and poultry metabolism

studies. The Agency (R. Perfet ti, 06/22/1994) concluded that the data from the metabolism studies indicate that a Category 3 situation [40 CFR 180.6 (a) (3)] exists for livestock commodities. Ethoprop was not detected in milk, eggs, or tissues from goats and hens dosed orally for seven consecutive days with ethoprop at levels equivalent to 32 ppm and 2.09 ppm, respectively in the diet.

An adequate confined rotational crop study is available and indicates that residues of ethoprop in rotational crops are qualitatively similar to the re sidues resulting from the direct application of ethoprop to the primary crops. Ethoprop residues of concern were detected at >0.01 ppm in/on spinach from the 31

- day plant

- back interval, radish roots and wheat straw from 31

- and 123

- day PBIs, and wheat for age from 31

- , 123, and 365

- day PBIs. Based upon results of the confined rotational crop study, limited field accumulation studies in rotational crops were required (D239294, J. Abbots, 03/27/1998). Adequate data are available from limited rotational crop field trials complete this deficiency (D394590, C. Olinger, 12/10/2008).

5.3 Water Residue Profile
Drinking Water Exposure Assessment; M

. Barrett ; 09

- 15

- 201 5 ; D428 028



### The drinking water residues used in the dietary risk assessment were provided by EFED and incorporated directly into this dietary assessment.

There were no degradates of ethoprop in soil and water laboratory studies that exceeded 10% of the applied parent at any time during the st udies. For the purposes of drinking water exposure evaluation, the parent ethoprop is the only residue of concern. EFED provided groundwater (Pesticide Root Zone Model for Groundwater (PRZM

- GW), version 1.0, August 31, 2012) EDWC s . EFED stated that the ground water EDWC was appropriate to use in the acute dietary exposure assessment. For the steady

- state dietary

exposure assessment, EFED provided daily time

- series outputs that simulate 29 years of residues

of ethoprop in drinking water. These distributi ons were adjusted so that the data points were 21

- day rolling averages . These values were incorporated into RDFs for use in DEEM.

5.4 Dietary Risk Assessment

Ethoprop acute

, steady

- state , and cancer dietary risk assessments were conducted using DEEM

FCID, Version 3.16, which incorporates consumption data from USDA’s N HANES/WWEIA. This dietary survey was conducted from 2003 to 2008. The analyses were performed to support

the Re gistration R eview of ethoprop

.

12 Available: CFR §180.262Page 37 of 94



### Because the estimated drinking water concentration from EFED exceeded HED’s level of concern, a Drinking Water Level of Comparison (DWLOC) was calculated for acute, steady state, and cancer assessments assuming that the DWLOC was equal to 0% and 100% of th e available risk cup. The body weight and water consumption of the subpopulation that was expected to be exposed with the highest level of ethoprop residue was incorporated in a DWLOC calculation. Each respective population adjusted dose for acute (aPAD), steady state (ssPAD), and cancer (Q 1 

### *) was used to represent the available risk cup.

5.4.1 Description of Residue Data Used in Dietary Assessment

The dietary assessments completed for ethoprop used tolerance level residue values. Applicable default proc essing factors for commodities for which processing studies are required and are not available, were used in this assessment. All tolerance values for registered crops were at 0.02 ppm and can be found in the 40 Code of Federal Regulations (CFR) §180.262

. Tolerances are not required for residues in livestock commodities since there is no reasonable expectation of detectable residues, 40 CFR §180.6(a)3. Because general tolerances are established for ethoprop ( O

- ethyl

- S,S

- dipropylphosphorodithioate) and not t he metabolites, metabolite ratios were applied to the tolerances before residue values were included in the dietary assessment modeling

program.

Table 5.4.1.1 Summary of Metabolite Ratios used for each Dietary Run

Dietary Run Type Metabolite Ratio (ppm) *

Acute 4.9 Steady State 2.4

Cancer 3.3



### * Metabolite Ratios are averages , “Ethoprop Dietary Memo. C. Olinger ; D 352232



### Water residues were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources”. The most conservative exposure model was used to assess the contributions from drinking water and the Estimated Drin king Water Concentrations (EDWCs) used PRZM

- GW.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The unrefined assessment included 100% crop treated for all crops in the acute, steady state, and

cancer dietary analyses

.

5.4.3 Acute Dietary Risk Assessment
Dietary Assessment; K. King; 0 8

- 04

- 2015 ; D428313



### The acute assessment is un refined ; t olerance level residues, DEEM (ver. 7.81) default processing factors, and 100% crop treated data were utilized

.

The acute dietary (food only + drinking water only ) exposure analysis is > 100 % aPAD at the 95th percentile of exposure for the general population and all population subgroups , except
adults 50

- 99 years of age (Table 5.4.3.1)

.Page 38 of 94



### The DEEM

- FCID analysis of food only for the general US population and the population subgroup with the highest % aPAD value (All Infants), are 260% and 630% reported at the 95 th


### percentile, respectively. The majority of subpopulations exceeded the Health Effects Division ’s (HED) level of concern and the commodities with the highest percent of total exposure are

banana and banana

- babyfood.

The DEEM

- FCID analysis of water only for the general US population and the population subgroup with the highest % aPAD value (All Infants), are 3,200% and >10,000% reported at the

95 th 

### per centile, respectively. All subpopulations exceeded the HED level of concern.

Table 5.4.3.1. Results of Food Only & Water Only Exposure and Risk Analyses

Population Subgroup Acute (Food Only)

95 th Percentile Acute (Water Only)

95 th Percentile Exposure (mg/kg/day) % a PAD Exposure (mg/kg/day) % a PAD

General U.S. Population 0.001098 260 0.013499 3,200 All Infants (<1 year old) * 0.002655 630 0.042824 >10,000

Children 1

- 2 years old 0.002525 600 0.020770 5,000

Children 3

- 5 years old 0.002078 500 0.016902 4,000

Children 6

- 12 years old 0.001447 350 0.012484 3,000

Youth 13

- 19 years old 0.000947 230 0.010940 2,600

Adults 20

- 49 years old 0.000799 190 0.013406 3,200

Adults 50

- 99 years old 0.000634 15 0.012182 2,900

Females 13

- 49 years old 0.000763 180 0.013641 3,300 *The subpopulation(s) with the highest risk estimates

.



### 5.4.4 Steady

- State Dietary Risk Assessment
Dietary Assessment; K. King; 0 8

- 04

- 2015 ; D428313



### The DEEM acute module was used to conduct steady

- state assessments using the steady

- state endpoint, two

- day average dietary exposure, and 21

- day rolling water averages. The steady

- state

assessments are un refined using tolerance level residues, 100% crop treated, and default processing factors. Food residues cannot confidently be refined because all tolerances are all

non

- detectable residues which cannot be confidently used for assessment

. EFED provided daily

time

- series outputs that simulate 29 years of residue s of ethoprop in water for one scenario (Delmarva sweet corn). These distributions were converted into 21

- day rolling averages and incorporated into R esidue D istribution F ile s (RDFs) that were used in DEEM for water, direct all

sources and water, indirect all sources.

For the steady state assessment, the food alone and water alone exposure estimates exceed HED’s level of concern for the U.S. population and all population subgroups except adults 50

- 99 for food only. The results of the steady

- state dietary exposure and risk analysis are reported in

the T able 5.4.4.1 for food only and water only

. The DEEM

- FCID analysis results of food alone for the general US population and the population subgroup with the highest % ssPAD value (All Infants), are 780% and 1,800% , respectively, reported at the 95 th 

### percentile. The DEEM

- FCID analysis results of water alone for the general US population and the population subgroup withPage 39 of 94



### the highest % ssPAD value (All Infants), are 3,000% and > 10,000% reported at the 95 th


### percentile respectively.

Table 5.4. 4 .1. Resul ts of Food Only & Water Only Exposure and Risk Analyses

Population Subgroup Steady State (Food Only)

95 th Percentile Steady State (Water Only)

95 th Percentile Exposure (mg/kg/day) % ss PAD Exposure (mg/kg/day) % ss PAD

General U.S. Population 0.000510 780 0.012684 3,000 All Infants (<1 year old) * 0.001190 1,800 0.040883 >10,000

Children 1

- 2 years old 0.001143 1,800 0.019195 >10,000

Children 3

- 5 years old 0.000907 1,400 0.015321 >10,000

Children 6

- 12 years old 0.000653 1,000 0.011423 >10,000

Youth 13

- 19 years old 0.000406 630 0.010287 >10,000

Adults 20

- 49 years old 0.000349 540 0.012543 >10,000

Adults 50

- 99 years old 0.000274 42 0.011665 1,800

Females 13

- 49 years old 0.000335 520 0.012884 >10,000 *The subpopulation(s) with the highest risk estimates

.



### 5.4.5 Cancer Dietary Risk Assessment

In accordance with the Agency ’ s Cancer Risk Assessment Guidelines ( March, 2005 ), e thoprop is classified “likely to be carcinogenic to humans” based on malignant adrenal pheochromocytomas

in male rats and is regulated with a Q 1 

### *. Applying the Q 1 

### * of 0.0281 (mg/kg/day)

- 1 

### to the exposure value results in a cancer risk estimate of 7 x 10

- 6 

### for food only . For water only , the exposure value results in a cancer risk estimate of 5 x 10

- 5



### .

Table 5.4.5.1. Results of Food & Water Cancer Risk

Population Subgroup Cancer (Food Only) Cancer (Water Only)

Exposure (mg/kg/day) Cancer

Risk

Estimate Exposure

(mg/kg/day) Cancer Risk

Estimate

General U.S. Population 0.000261 7 x 10

- 6 0.001746 5 x 10

- 5
All Infants (<1 year old)

N/A N/A N/A N/A Children 1

- 2 years old

Children 3

- 5 years old

Children 6

- 12 years old

Youth 13

- 19 years old

Adults 20

- 49 years old

Adults 50

- 99 years old

Females 13

- 49 years old



### 5.4.6 Characterization of Uncertainties in the Dietary Risk Assessment

Assessment of dietary risk for food is conservative utilizing tolerance level residues (based on method detection limits), 100% crop treated, and default processing factors. However, because

most residue level s found in foods were less than the analytical method detection limit, useful refinement of the risk estimates is not possible. The food only risk estimates therefore reflect a worst case estimate of risks; the degree to which actual risks are lower than these estimates cannot be determined in the absence of residue data utilizing more sensitive analytical methods.Page 40 of 94



### Metabolite ratios were multiplied by tolerances to determine residues that incorporated parent and metabolites. Ratios for acute (4.9x), stead y state (2.4x), and cancer (3.3) were averaged from C. Olinger’s memo (D382076 & D299884, C. Olinger, 07/03/2008).

Drinking water risk estimates are also highly conservative since conservative modeled residues

were assumed. Based on the Delmarva sweet corn drinking water scenario, HED’s level of concern was exceeded. Therefore, HED calculated a drinking water level of comparison (DWLOC) to help characterize the dietary risk estimates. The DWLOC calculation is a function

of the P A D and daily water consu mption used to provide the EDWC at the targeted level of concern for dietary assessment (100% of the PAD). Typically, the DWLOC would indicate the residue level allowable in drinking water considering contributions to the total risk cup (i.e., 100% PAD) f

rom food and residential exposures. However, since there are no contributions to the risk cup from residential sources, and since food exposures already fill the total risk cup (i.e., exceed 100% of the PAD), HED has calculated a DWLOC assuming the entire risk cup is available for drinking water. This was done to provide some characterization of risk estimates

derived from drinking water

.

Because the population subgroup A ll I nfants <1 year old has the highest exposures to residues in drinking water, mitigating the acute, steady

- state, and cancer risks for this population subgroup would be protective of all others. Table 5.4.6.1 summarizes the DWLOC calculations for the acute, steady state, and cancer assessments.

Table 5.4.6.1. Summary of DWLOC for Acute, Steady State, and Cancer Assessments Population Acute DWLOC (ppb) 1 Steady State DWLOC (ppb) 1 Cancer DWLOC (ppb) 2

US General Population N/A 4.68

All Infants <1 years old 2. 93 0. 453 N/A

1 DWLOC= (% aPAD or % ssPAD mg/kg/day) * (Subpopulation Bodyweight kg) * (1000)/ ( DW Consumption L/day)

2 Cancer DWLOC= (Allowed Exposure ) * ( Bodyweight kg ) * ( 1000)/ ( DW Consumption L/day )



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are currently no registered or proposed residential uses for ethoprop ; therefore, a quantitative residential handler and post

- application assessment was not performed. Section 6.1/6.2 addresses the potential for non

- occupational bystander post

- appli cation inhalation exposure (from nearby treated fields). Section 6.3 addresses non

- occupational exposure potential from spray drift.

6.1 Non

- Occupational Bystander Post

- A pplication Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). ThePage 41 of 94



### agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 13



### .

The Agency has developed a preliminary bystander volatilization inhalation exposure assessment for ethoprop utilizing the currently available inhalation toxicity and air monitoring data. There is

an availa ble air monitoring stud y with two components relevant to the residential bystander

assessment

. These components include:

 A pplication site monitoring conducted in Siskiyou County, CA by the California Air Resource Board (CARB), and

 A mbient air monitoring also conducted in Siskiyou County, CA by the California Air Resource Board (CARB)

.

Details of the CARB study are provided in the ORE disciplinary memo 14



### . Inhalation risk estimates are presented below using both air concentrations measured during applicati on site monitoring and during ambient air monitoring. Application site air monitoring (i.e., also known as field volatility) refers to the collection of air samples around the edges of a treated field during and after a pesticide application. Samples are generally collected for short intervals (e.g., < 8 hours), for at least the first day or two after application with subsequent samples increasing in duration. In this type of study, it is typically known when an application occurred, the equipment used f

or the application, and the application rate. Application site monitoring data represents an exposure to vapors at or near the field edge resulting from an application.

Ambient air monitoring typically is focused on characterizing the airborne pesticide levels within a localized airshed or community structure of some definition (e.g., city, township, or municipality). This type of monitoring effort also can be focused on capturing chronic background levels or other temporal characteristics of interest su ch as focusing on seasonal pesticide use patterns. Typically, samples are generally taken for 24 consecutive hours and collected at the same site over an extended period of time (e.g., several weeks or months). In contrast to application site air monitor ing, information on the precise timing and location of pesticide applications are rarely collected in ambient air monitoring studies. However, this does not mean that an application did not occur near an ambient sampler during the monitoring period.

For adults, when an endpoint is not sex

- specific (i.e., the endpoints are based on developmental or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case,

a female

- specific body weight of 69 kg was used. While the e ndpoint of concern, RBC AChE inhibition, is not sex

- specific, the female

- specific body weight was used to protect for pregnant women due to uncertainty in the human dose

- response relationship for neurodevelopmental effects (see Section 4.4).

Table 6.1 .1 provides ethoprop inhalation risk estimates resulting from volatilization for each site. The ethoprop bystander volatilization inhalation exposure assessment compares the maximum and average air concentration s detected in each of the monitoring studies to the steady state HEC for residential bystanders, as no acute HEC is available for ethoprop. This comparison of the

13 Available: http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219

14 M. Lloyd; 09

- 15

- 2015 ; D421954Page 42 of 94



### steady state HEC and the available application site monitoring data is a conservative representation of a potential resident who lives ne xt to a treated field and may be exposed to the peak or average concentration of ethoprop volatilizing off the field over a 24

- hour period. In addition, both the single peak air concentration per site and the arithmetic mean ethoprop air

concentration fro m the ambient air monitoring study was compared to the steady

- state HEC for residential bystanders. Again, because no acute HEC value is available, the comparison of the peak ambient concentrations against the steady state endpoint is a conservative repre sentation of a potential resident of an agricultural area where ethoprop is being applied in multiple field

locations.

Even with the conservative use of the steady state endpoint to evaluate peak exposures from the application site and ambient monitoring

, none of the application site monitoring locations results in single day risks of concern. None of the air concentrations from either the ambient or application site data available resulted in risk estimates of concern for the steady state analysis.Page 43 of 94

Table 6.1.1 . Residential Bystander : Preliminary Volatilization Risk Analysis

.

Study Year

of Study Sampler/Site Location Number of samples c Duration of

samples Duration of

sampling period Maximum Air

Concentration (mg/m 3 ) Arithmetic

Mean Air

Concentration (mg/m 3 ) Single

- Day

MOEs a (LOC = 3 0 0) Steady

- state

MOEs b
(LOC = 30 0 )

Ambient Air Monitoring d

Siskiyou County, CA (CARB) 1998 MacDoel School

– MacDoel, CA 28 (3 above the MDL)

24

- hour 1 month 2.0E

- 06 5.0E

- 07 74 ,000 2 9 0,000

Doris School

– Doris, CA 29 (1 above the MDL) 3.0E

- 06 3.5E

- 07 49 ,000 410 ,000

Tule Lake School Bus

Barn

– Tule Lake, CA 29 (none above MDL) 1.3E

- 06 6. 1 E

- 07 110 ,000 240 ,000

Newell School

– Tule Lake, CA 29 (none above MDL) 1.3E

- 06 3. 4 E

- 07 110 ,000 440 ,000

Application Site Monitoring d

Siskiyou County, CA (CARB) e 1998 East

Each site included 8 samples (including background sample) Ranged from 3.4

-

hour to 24

- hour samples; taken

pre

- application &

at post

application 3 days 1.3E

- 04 8.1E

- 05 1,800 1, 1 00 East (co

- located sampler ) 1.4E

- 04 8.6E

- 05 1,700 1,100

North 5.4E

- 05 2.4E

- 05 2,700 6,100

South 2.1E

- 04 1. 2 E

- 04 700 1,400

West 6.8E

- 05 2.1E

- 05 2,200 7,200

a. Single Day MOE = Steady

- state HEC (0. 147 mg/m 3 ) / Study maximum air concentration (ng/m 3 ). LOC = 10 0 0

. b. Steady

- state MOE = Steady

- state HEC (0. 147 mg/m 3 ) / Study arithmetic mean air concentration (mg/m 3 ). LOC = 1 0 00

.

c. All non

- detects and trace concentrations reported. For non

- detects, assumed 1/2 Method Detection Limit (MDL) of 0.947 ng/sample

– 1.33 ng/m 3 . For trace concentrations, assumed

concentration halfway between MDL and Estimated Quantitation Limit (4.74 ng/m 3 )

. d

. Samples analyzed by ARB testing Laboratory Section Laboratory

. Additional details on lab analysis available: http://www.cdpr.ca.gov/docs/emon/pubs/tac/tacpdfs/ethoamap.pdf

.

All of the “application site” sampling sites were adjacent to an 80 acre potato field. The ambient site data were collected a t various areas adjacent to agricultural activity in Siskiyou County,

CA.

e

. Prevailing wind direction was generally from the North west

.Page 44 of 94



### 6

. 2 Residential Bystander Post

- Application Inhalation Risk Characterization

The ethoprop bystander volatilization inhalation exposure assessment compares the maximum and average air concentration s detected in each of the monitoring studies to the steady state HEC for residential bystanders, as no acute HEC is available for ethoprop. This comparison of the steady state HEC and the available application site monitoring data is a conservative

represe ntation of a potential resident who lives next to a treated field and may be exposed to the peak or average concentration of ethoprop volatilizing off the field over a 24

- hour period. In addition, both the single peak air concentration per site and the ar ithmetic mean ethoprop air concentration from the ambient air monitoring study was compared to the steady

- state HEC for residential bystanders. T he comparison of the peak ambient concentrations against the steady state endpoint is a conservative represent ation of a potential resident of an agricultural area where ethoprop is being applied in multiple field locations.

Some of the limitations and considerations that have been identified that should be considered in the interpretation of these results inclu de:

 The application site data were collected based on an application of a 10% granular formulation of ethoprop. There is uncertainty in extrapolating application site field measurements from the formulation applied in the study to the alternative EC form ulation that is currently available on the market.

 Most of the data utilized in this preliminary assessment are 24

- hour (or less) air samples.

When th ese data are used, an assumption is made that an individual is exposed to the

same air concentration f

or 24

- hours every day. However, this is not always the case as

real world time

- activity data indicate that many parts of the population move from site to site on a daily basis (e.g., go to work and back).

 This assessment is only representative of outdoor concentrations at locations similar to the monitoring sites (i.e., the exposure and risk estimates assume an individual is outdoors all the time). It does not take into account potential effects of air conditioning systems and similar air filtration syst ems which could potentially reduce air concentrations of ethoprop indoors. The assessment assumes that indoor concentrations will be at worst equivalent to outdoor concentrations and may potentially be lower.

 The available exposure data used for this ana lysis have been generated in California; however, ethoprop is used in many regions of the country. Therefore, the results based on the limited available air monitoring data were used to represent the rest of the country due to a lack of adequate informati on for any other region. It is unclear what potential impacts this extrapolation might have on the risk assessment. Factors such as meteorology and cultural practices may impact the overall amounts of ethoprop that

volatilize from a treated field as well as the rate at which it volatilizes.

 The residential bystander estimated exposure should not be included in the human health risk assessment aggregate due to the fact that this is only a preliminary assessment and is

not considered a refined assessment for the reasons noted above. There are limitationsPage 45 of 94



### associated with the air monitoring data that are available, such as the fact that most are air sampling and measurement techniques do not distinguish between aerosols and vapors. In addition, as noted in the above bullet, this assessment assum es residents are outdoors during the entire exposure duration.

6.3 Non

- Occupational Spray Drift Exposures and Risk Estimates

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to indirect exposures (e.g., children playing on lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label langu age and other regulatory requirements intended to prevent them. 15 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted ar eas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to <2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect exposure are the focus of this analysis analogous to how exposures to turf products are

considered in risk assessment.

In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to

address drift from th e agricultural applications of ethoprop . In the spray drift scena rio, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift ® 

### (v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedure s Addenda 1: Consideration of Spray Drift Policy

. Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Proce dures For Residential Risk Assessment (SOPs)

.

For ethoprop , chemical

- specific turf transferable residue (TTR) data are not available, therefore, the estimated TTR are based on a default assumption from the 2012 Residential SOPs that the

transferable resi due available for exposure is 1% of the total deposited residue, which is assumed to be equivalent to the maximum application rate.

A screening approach was developed based on the use of the AgDrift ® 

### model in situations where specific label guidance tha t defines application parameters is not available. 16 

### AgDrift ® 

### is

15 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

16 http://www.agdrift.com/Page 46 of 94



### appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and groundboom sprayers. When AgDrift ® 

### was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening options specifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bou nd level of drift for common application methods in agriculture. These screening options are consistent with how spray drift is considered in a number of ecological risk assessments and in the process used to develop drinking water concentrations used for risk assessment. In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are

no t allowed). Table s 8.0.1 and 8

. 0 .2 provide the screening level drift related risk estimates for adults and children, respectively

. In many cases, risk estimates are of concern when the screening level estimates for spray drift are used as the basis for the analysis. In order to better

characterize risk estimates related to drift , additional spray drift deposition fractions were also

considered.

Combined Risk Estimates from Lawn Deposition Adjacent to Applications

The spray drift risk estimates are b ased on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. Ethoprop is registered on a variety of agricultural crops 17 

### , and can be applied as an emulsifiable concentrate via enclosed cab

grou ndboom equipment at application rates between 3 and 12 lbs ai/A . The recommended drift scenario screening level options are listed below:

 Groundboom applications are based on the AgDrift option for low boom height and using fine to medium/coarse spray t ype using the 90 th 

### percentile results.

The recommended drift scenario screening level option diverges from the default selection in the

drift SOP based on the nature of the ethoprop emulsifiable concentrate applications (pre

- plant) and the registered use sites. The default screening level options involves the “high boom” as the default scenario. As ethoprop is applied pre

- plant to bare soil, the “low boom” spray type/nozzle configurations was selected to represent the screening level option for emulsifiab le concentrate applications of ethoprop.

In addition to the screening level spray drift scenarios described above, additional results are provided using viable drift reduction technologies (DRTs)

. In particular, different spray qualities

have been consid ered as well as the impact of other application conditions (e.g., boom height and crop canopy conditions).

Dermal risk estimates were calculated for adults. For adults, when an endpoint is not sex

specific (i.e., the endpoints are based on developmental or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case, a female

- specific body weight of 69 kg

was used. While the endpoint of concern, RBC AChE inhibition, is not sex

- specific, the female

specific body weight was used to protect for pregnant women due to uncertainty in the human

dose

- response relationship for neurodevelopmental effects (see Section 4.4). Dermal and

17 See Section 3.3 for additional detail on the full range of registered use sites and application ratesPage 47 of 94



### incidental oral risk estimates for children (1 to < 2 years old) were combined because the toxicity endpoint for each route of exposure is the same (RBC AChE inhibition). The total applicable LOC is 1000, so MOEs <1000 represent risk estimates of concern.

Risk estimates related to spray drift are of concern at various distances from the edge of the field for adults and children (1 to <2 years) depending on the spray drift scenario. Adult and children

risk esti mates are summarized in Table s 6

. 3 .1 and 6

. 3 .2

, respectively . For adults, the screening

level scenario of low boom height and using fine to medium/coarse spray type requires a
distance of over 300 feet to reach a dermal MOE ≥ 1000 for the range of crops assessed

. For children, the screening level sce nario also requires a distance of over 300 feet to reach a combined (dermal and incidental oral) MOE ≥1000 for the range of crops assessed . Drift reduction technologies, such as using coarser sprays and lowering boom height for groundboom

sprayers, can re duce risk concerns . In the case of ethoprop, the screening scenario assumes a low boom height because of the use pattern (pre

- plant applications). Regardless, there are still risk estimates of concern at the field edge. Further, c hemical

- specific TTR data could be submitted to help refine the spray drift assessment.Page 48 of 94

Table 6

. 3 .1

. Adult Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Ethoprop for the Dermal Route of Exposure

. Crop/Rate Group Spray Type/

Nozzle Configuration 1 Appl

.

Rate (lb ai/A) TTR

(ug/cm2) At

Edge 10

Feet 25

Feet 50

Feet 75

Feet 100

Feet 125

Feet 150

Feet 200

Feet 250

Feet 300

Feet

Potatoes

- west

Groundboom High Boom

Very fine to

Fine

12 1.3338 <1 <1 1 1 1 2 2 2 3 4 4

Low Boom Very

fine to Fine <1 1 2 2 3 4 4 5 6 8 10

High Boom Fine

to
Medium/Coarse 1 2 2 3 4 5 6 6 8 10 10

Low Boom Fine

to
Medium/Coarse 1 3 4 5 6 8 10 10 16 16 16

Potatoes

- east

Groundboom High Boom

Very fine to

Fine

9 1.00035 <1 <1 1 1 2 2 2 3 4 5 6

Low Boom Very

fine to Fine <1 1 2 3 4 5 6 7 8 10 14

High Boom Fine

to
Medium/Coarse 1 2 3 5 6 7 8 8 10 14 14

Low Boom Fine

to
Medium/Coarse 1 3 5 7 8 10 14 14 21 21 21

Mint

Groundboom High Boom

Very fine to

Fine

4 0.4446 <1 1 2 3 4 5 5 7 8 12 13

Low Boom Very

fine to Fine 1 3 5 7 9 12 13 16 19 23 31

High Boom

Fine to

Medium/Coarse 2 5 7 10 13 16 19 19 23 31 31

Low Boom Fine

to
Medium/Coarse 3 8 12 16 19 23 31 31 47 47 47

HopsPage 49 of 94

Table 6

. 3 .1

. Adult Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Ethoprop for the Dermal Route of Exposure

. Crop/Rate Group Spray Type/

Nozzle Configuration 1 Appl

.

Rate (lb ai/A) TTR

(ug/cm2) At

Edge 10

Feet 25

Feet 50

Feet 75

Feet 100

Feet 125

Feet 150

Feet 200

Feet 250

Feet 300

Feet

Groundboom High Boom

Very fine to

Fine

3 0.33345 1 1 2 4 5 6 7 9 11 16 18

Low Boom Very

fine to Fine 1 4 6 10 12 16 18 21 25 31 41

High Boom

Fine to

Medium/Coarse 3 7 10 14 18 21 25 25 31 41 41

Low Boom Fine

to
Medium/Coarse 4 10 16 21 25 31 41 41 62 62 62

1

- Bolded Spray type/nozzle configuration is the representative screening scenario for ethopropPage 50 of 94

Table 6

. 3 .2

. Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Ethoprop for the Combined Dermal and Oral Routes of Exposure

. Crop/Rate Group Spray Type/

Nozzle Configuration 1 Appl

.

Rate (lb ai/A) TTR

(ug/cm2) At

Edge 10

Feet 25

Feet 50

Feet 75

Feet 100

Feet 125

Feet 150

Feet 200

Feet 250

Feet 300

Feet

Potatoes

- west

Groundboom High Boom

Very fine to

Fine

12 1.3338 <1 <1 <1 1 1 1 1 1 2 2 3

Low Boom Very

fine to Fine <1 1 1 1 2 2 3 3 4 4 6

High Boom Fine

to
Medium/Coarse <1 1 1 2 3 3 4 4 4 6 6

Low Boom Fine

to
Medium/Coarse 1 1 2 3 4 4 6 6 9 9 9

Potatoes

- east

Groundboom High Boom

Very fine to

Fine

9 1.00035 <1 <1 <1 1 1 1 1 2 2 3 3

Low Boom Very

fine to Fine <1 1 1 2 2 3 3 4 5 6 8

High Boom Fine

to
Medium/Coarse <1 1 2 3 3 4 5 5 6 8 8

Low Boom Fine

to
Medium/Coarse 1 2 3 4 5 6 8 8 12 12 12

Mint

Groundboom High Boom

Very fine to

Fine

6 0.4446 <1 1 1 2 2 3 3 4 5 7 7

Low Boom Very

fine to Fine 1 2 3 4 5 7 8 9 11 13 17

High Boom Fine

to
Medium/Coarse 1 3 4 6 8 9 11 11 13 18 17

Low Boom Fine

to
Medium/Coarse 2 4 7 9 11 13 18 18 27 27 26

HopsPage 51 of 94

Table 6

. 3 .2

. Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Ethoprop for the Combined Dermal and Oral Routes of Exposure

. Crop/Rate Group Spray Type/

Nozzle Configuration 1 Appl

.

Rate (lb ai/A) TTR

(ug/cm2) At

Edge 10

Feet 25

Feet 50

Feet 75

Feet 100

Feet 125

Feet 150

Feet 200

Feet 250

Feet 300

Feet

Groundboom High Boom

Very fine to

Fine

3 0.33345 <1 1 1 2 3 4 4 5 6 9 10

Low Boom Very

fine to Fine 1 2 4 5 7 9 10 12 14 18 24

High Boom Fine

to
Medium/Coarse 1 4 5 8 10 12 14 14 18 24 24

Low Boom Fine

to
Medium/Coarse 2 6 9 12 14 18 24 24 36 36 35

1

- Bolded Spray type/nozzle configuration is the representative screening scenario for ethoprop

### Page 52 of 94

7 .0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. The registered uses of ethop rop are not anticipated to result in a residential contribution to the aggregate risk assessment. Therefore, the aggregate assessment consists of dietary (food and drinking water) exposure and risk. In the case of ethoprop, since both the food

alone and w ater alone dietary risk estimates exceed HED’s level of concern, HED did not combine (i.e., aggregate) these exposure as the result would further exceed HED’s level of

concern. The acute and steady

- state non

- cancer dietary exposure estimates are detailed in

Section 5.4.3 and 5.4.4

.

Ethoprop is classified "likely to be carcinogenic to humans" based on malignant adrenal pheochromocytomas in male rats and is regulated with a Q 1 

### *. Applying the Q 1 

### * of 0.0281 (mg/kg/day)

- 1 

### to the exposure value results in a cancer risk estimate of 7 x 10

- 6 

### for food only . For water only , the exposure value results in a cancer risk estimate of 5 x 10

- 5



### .

Food only and water only dietary risk concerns are typically combined to estimate a dietary cancer risk assessment. The food only dietary cancer assessment is unrefined and based on tolerance level residues, default processing factors, and 100% crop treated assumptions. In the

ca se of ethoprop, a dietary cancer risk for food and drinking water together (i.e., the aggregate cancer dietary assessment) was not completed because even though the food only cancer risk estimate could be refined, the water only cancer risk estimate drives the dietary cancer risk

estimate. Refinements of the water only cancer risk estimates are not available at this time.

8.0 Cumulative Exposure/Risk Characterization

OPs, like ethoprop, share the ability to inhibit AChE through phosphorylation of the seri ne residue on the enzyme leading to accumulation of acetylcholine and ultimately cholinergic neurotoxicity. This shared MOA/AOP is the basis for the OP common mechanism grouping per

OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances t hat have a Common Mechanism of Toxicity (USEPA, 1999). The 2002 and 2006 CRAs used brain AChE inhibition in female rats as the source of dose response data for the relative potency factors and PODs for each OP, including ethoprop. Prior to the completion of Registration Review, OPP will update the OP CRA on AChE inhibition to incorporate new toxicity and exposure information available

since 2006.

As described in Section 4.4, OPP has retained the FQPA Safety Factor for OPs, including ethoprop, due to unc ertainties associated with neurodevelopmental effects in children and exposure to OPs. There is a lack of an established MOA/AOP for the neurodevelopment

outcomes which precludes the agency from formally establishing a common mechanism group per the Guida nce For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) based on that outcome. Moreover, the lack of a recognized MOA/AOP and other uncertainties with exposure assessment in the epidemiology

stud ies prevent the agency from establishing a causal relationship between OP exposure and neurodevelopmental outcomes. The agency will continue to evaluate the epidemiology studies

### Page 53 of 94

associated with neurodevelopmental outcomes and OP exposure prior to the release of the revised DRA. During this period, the agency will determine whether or not it is appropriate to apply the draft guidance document entitled, Pesticide Cumulative Risk As sessment: Framework for Screening Analysis for the neurodevelopment outcomes.

9 .0 Occupational Exposure/Risk Characterization

9 .1 Occupational Handler

Occupational handler exposure is anticipated from the registered uses of ethoprop. The occupationa l handler section is laid out in three sections. Section 9 .1 .1 addresses the ethoprop occupational handler non

- cancer assessment based on surrogate unit exposure data. Section

9 .1.2 addresses the non

- cancer occupational handler assessment based on an ava ilable biomonitoring study. The ethoprop biomonitoring study was performed with the sole purpose of quantifying professional applicator exposure during the use of ethoprop in Pacific Northwest potato fields. As the original biomonitoring study occurred in a large portion of the occupational handler group for ethoprop occupational handlers in a discrete geographic location, there is uncertainty bridging the use of the data to other occupational handler groups with different agricultural practices and geogra phic variations. It is unclear how different agricultural and climate conditions would affect the resulting handler exposure estimates. It is also important to note that individuals in the Washington State study often wore personal protective equipment b eyond the label requirements, limiting personal exposures. Section 9 .1.3 addresses the occupational handler cancer assessment. Regardless of data source, non

- cancer occupational handler risk estimates are of concern for ethoprop for mixer/loaders, loaders, and applicators for all handler scenarios assessed based on the LOC of 1,000.

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks rel ated to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can c ause exposure levels to differ in a manner specific to each application event.

Based on current product labels, the scenarios which should serve as the basis for the quantitative exposure and risk assessment (cancer and non

- cancer) , are as follows:

 Loading granulars for tractor drawn spreader application;

 Mixing/loading EC (liquid) formulation for chemigation;

 Mixing/loading EC (liquid) formulation for groundboom application;

 Applying gran ules with a tractor drawn spreader;

 Loading/applying granules with a backpack spreader; and,

 Applying liquids with a groundboom sprayer

.

The above exposure scenarios best represent the registered use pattern (i.e., soil incorporation of EC and granular end use formulations) for ethoprop

.

9 .1.1 Occupational Handler Exposure/Risk Estimates (Surrogate Unit Exposure Scenarios)

### Page 54 of 94

The potential absorbed doses and margins of exposure for ethoprop were calculated using standard EPA exposure algorithms and generic PHED/AHETF unit exposure values.

Occupational Handler Expo sure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Assumptions and factors, as well as algorithms used to estimate non

cancer exposure and dose for occupatio nal handlers are detailed in the most recent occupational and residential exposure ( ORE ) assessment memo ( M

. Lloyd ; 09

- 15

- 2015 ; D 421954 ).

The steady

- state approach is appropriate for ethoprop given the toxicological and exposure profile. The steady

- state endpoint selection for ethoprop overlaps with HED’s traditional short

term exposure duration endpoint selection and is considered health protective for occupational handlers that apply commerc ially over longer periods of time (i.e., intermediate

- term exposures).

The currently registered application rates for ethoprop generally range from 3 lbs ai/A to 12 lbs

ai /A via ground application. The applications are specified to be conducted with engi neering controls (lock

- N

- load equipment and closed cab applications ), with the exception of backpack granular application for bananas

. Typically, HED would also assess the use of handheld equipment, particularly for field grown ornamentals ; however, c urre ntly registered ethoprop products prohibit the use of handheld equipment for treating field grown ornamentals and allow only ground

- based application methods. The 15G product is the only registered ethoprop product that allows for backpack granular applic ations around the base of the banana tree that are then soil incorporated (presumably by hand by the loader/applicators). Th is particular application pattern requires use of double layer PPE, gloves, and PF10 respiratory protection. For the other register ed uses, i n addition to the engineering controls/closed system , mixer, loaders, applicators, and other handlers must also wear long sleeved shirt, long pants, shoes plus socks, chemical

resistant gloves, chemical

- resistant apron (for mixing and loading), a nd protective eyewear.

For adults, when an endpoint is not sex

- specific (i.e., the endpoints are based on developmental or fetal effects) a body weight of 80 kg is typically used in risk assessment; however, in this case,

a female

- specific body weight o f 69 kg was used. While the endpoint of concern, RBC AChE inhibition, is not sex

- specific, the female

- specific body weight was used to protect for pregnant women due to uncertainty in the human dose

- response relationship for neurodevelopmental effects (se e Section 4.4).

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were similar , although there are separate dermal POD s for the different ethoprop formulations . Dermal and inhalation risk estimates were combined using the following formula:

Total MOE = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE)



### Summary of Occupational Handler Non

- Ca ncer Exposure and Risk Estimates

HED relied on both chemical

- specific biomonitoring data and surrogate unit exposure data in order to complete the ethoprop handler assessment. This section presents the risk estimates based

on the surrogate unit exposure da ta

. Risk estimates for the emulsifiable concentrate (EC) and granular (G) formulations are calculated separately because different dermal POD s were selected according to formulation type

. All combined risk estimates are of concern for occupational

### Page 55 of 94

handler mixer/loaders, loaders, and applicators , assuming label

- defined engineering controls

.

For mixer/loaders using the label

- defined engineering controls, t otal MOEs (dermal + inhalation) range from <1

- 1 1 for the liquid formulation and 19

- 190 for the granul ar formulation. For applicators using the label defined engineering controls, t otal MOEs range from <1

- 18 for the liquid formulation and 1 4

- 1 4 0 for the granular formulation, respectively. Of the evaluated exposure scenarios, the lowest combined MOE s are for mixing and loading for chemigation and groundboom application at application rates >5 lbs ai/A. Total non

- cancer risk estimates are generally of greater concern (i.e., lower MOEs) for the liquid formulatio n than the granular

formulation.

Tables 9 .1 .1 .1 and 9 .1. 1. 2 present the risk estimates for the ethoprop liquid and granular formulations, respectively based on surrogate or chemical

- specific unit exposure data.

### Page 56 of 94

Table 9 .1.1. 1 Occupational Handler Non

- Cancer Exposure and Risk Estimates for Ethoprop [Liquid Formulation].

Scenario 1 

### Representative

Application/Crops Application

Rate (lbs ai/A) 2 

### Area

Treated (A/day) 3 

### Dermal Dose

(mg/kg/day) 4 

### Dermal

MOE 5


### (LOC = 1000) Inhalation

Dose (mg/kg/day)

6 

### Inhalation

MOE 7


### (LOC = 1000) Total

MOE 8


### (LOC = 1000)

Mixer/Loaders

M/L liquids: Chemigation Cabbage: Field crop, typical 5.1

350 0.223 <1 0.00 214 57 <1

Hops: Orchard 3 0.131 1.2 0.00126 98 1.2

Potatoes (west): Field crop, high

- acreage 12 0.523 <1 0.00506 24 <1

Potatoes (east): Field crop, high

- acreage 9 0.393 <1 0.00378 33 <1

Sweet Potato: Field crop, typical 3.9 0.17 <1 0.00164 75 <1

M/L liquids:

Groundboom Cabbage: Field crop, typical 5.1

80 0.0509 3.2 0.000491 250 3.2

Sweet Potato: Field crop, typical 3.9 0.0388 4.2 0.000375 330 4.1

Field crop, typical 3 0.0299 5.4 0.000288 430 5.3

Field Grown Ornamental Crops 3

40 0.0149 11 0.000144 850 11

Field Grown Ornamental Crops 6 0.0299 5.4 0.000288 430 5.3

Potatoes (west): Field crop, high

- acreage 12

200 0.299 0.54 0.00288 43 <1

Potatoes (east): Field crop, high

- acreage 9 0.225 0.72 0.00216 57 <1

Mint: Field crop, high

- acreage 6 0.149 1.1 0.00144 85 1.1



### Applicators
Cabbage: Field crop, typical 5.1 80 0.0301 5.4 0.000254 480 5.3

### Page 57 of 94

Table 9 .1.1. 1 Occupational Handler Non

- Cancer Exposure and Risk Estimates for Ethoprop [Liquid Formulation].

Scenario 1 

### Representative

Application/Crops Application

Rate (lbs ai/A) 2 

### Area

Treated (A/day) 3 

### Dermal Dose

(mg/kg/day) 4 

### Dermal

MOE 5


### (LOC = 1000) Inhalation

Dose (mg/kg/day)

6 

### Inhalation

MOE 7


### (LOC = 1000) Total

MOE 8


### (LOC = 1000)

Applicator: liquid sprays Sweet Potato: Field

crop, typical 3.9 0.023 7 0.000194 630 6.9

Field crop, typical 3 0.0177 9.2 0.000149 830 9.1

Field Grown Ornamental Crops 3 40 0.00887 18 0.0000748 1600 18

Potatoes (west): Field crop, high

- acreage 12

200 0.177 0.92 0.00149 83 <1

Potatoes ( east ): Field crop, high

- acreage 9 0.133 1.2 0.00112 110 1.2

Mint: Field crop, high

- acreage 6 0.0887 1.8 0.000748 160 1.8

1 Engineering Control Unit Exposures for each exposure scenario b ased on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table ” ( [March, 2013] ); Level of mitigation: Eng. Controls.

2 Based on registered label s (Reg. No. 5481

- 9041/5481

- 9040/5481

- 9042).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated (A/day) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal BMDL 10 ( 0.1625 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated (A/day) ÷ BW ( 69 kg).

7 Inhalation MOE = Inhalation BMDL 10 (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). HEDs = 0.035 mg/kg/day (8.3L/min); 0.071 mg/kg/day (16.7 L/min); 0.123 mg/kg/day (29 L/min)

8 Total MOE = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) . LOC = 1,000



### Table 9 .1 .1 .2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Ethoprop [Granular Formulations].

Scenario Representative

Application/Cr

ops Application

Rate (lbs ai/A) Area

Treated (A/day) Dermal Dose

(mg/kg/day) Dermal

MOE (LOC = 1000) Inhalation

Dose (mg/kg/day ) Inhalation

MOE (LOC = 1000) Total

MOE (LOC = 1000)

Loaders

Tractor

- drawn spreader Field crop, typical 3

80 0.0299 350 0.000288 430 190

Sweet potato: Field crop, typical 3.9 0.0388 270 0.000375 330 150

Cabbage: Field crop, typical 5.1 0.0509 200 0.000491 250 110

Tobacco: Field crop, typical 6 0.0599 170 0.000577 210 94

### Page 58 of 94

Table 9 .1 .1 .2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Ethoprop [Granular Formulations].

Scenario Representative

Application/Cr

ops Application

Rate (lbs ai/A) Area

Treated (A/day) Dermal Dose

(mg/kg/day) Dermal

MOE (LOC = 1000) Inhalation

Dose (mg/kg/day ) Inhalation

MOE (LOC = 1000) Total

MOE (LOC = 1000)

Beans: Field crop, typical 8.1 0.0807 130 0.00078 160 72

Corn: Field crop, high

- acreage 3

200 0.0748 140 0.000722 170 77

Corn: Field crop, high

- acreage 4 0.0997 100 0.000962 130 57

Mint: Field crop, high

- acreage 6 0.149 70 0.00144 85 38

Potatoes ( east ): Field crop, high

acreage 9 0.225 46 0.00216 57 25

Potatoes ( west ): Field crop, high

acreage 12 0.299 35 0.00288 43 19



### Applicators

Applicator: broadcast granules Field crop, typical 3

80 0.00696 1500 0.000765 160 140

Field crop, typical 4 0.00928 1100 0.00102 120 110 Cabbage: Field crop, typical 5.1 0.0118 880 0.0013 95 86

Tobacco: Field crop, typical 6 0.0139 750 0.00154 80 72

Beans: Field crop, typical 8 .1 0.0188 550 0.00207 59 53

Corn: Field crop, high

- acreage 3

200 0.0174 600 0.00191 64 58

Corn: Field crop, high

- acreage 4 0.0232 450 0.00255 48 43

Sugarcane: Field crop, high

- acreage 5.88 0.0341 300 0.00375 33 30

Mint: Field crop, high

- acreage 6 0.0348 300 0.00383 32 29

Potatoes ( east ): Field crop, high

acreage 9 0.0522 200 0.00574 21 19

### Page 59 of 94

Table 9 .1 .1 .2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Ethoprop [Granular Formulations].

Scenario Representative

Application/Cr

ops Application

Rate (lbs ai/A) Area

Treated (A/day) Dermal Dose

(mg/kg/day) Dermal

MOE (LOC = 1000) Inhalation

Dose (mg/kg/day ) Inhalation

MOE (LOC = 1000) Total

MOE (LOC = 1000)
Potatoes ( west ): Field crop, high

acreage 12 0.0696 150 0.00765 16 14



### Loader/Applicators
Backpack application Banana: Orchard 121 1 .127 82 0.0042 17 16

1 Engineering Control Unit Exposures for each exposure scenario b ased on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table ” ( [March, 2013] ); Level of mitigation: Eng. Controls , except for Loader/applicator: backpack applications.

2 Based on registered label s (Reg. No. 5481

- 9041/5481

- 9040/5481

- 9042).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated ( A /day) ÷ BW ( 69 kg).

5 Derma l MOE = Dermal BMDL 10 ( 10.4 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW ( 69 kg).

7 Inhalation MOE = Inhalation BMDL 10 (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). HEDs = 0.035 mg/kg/day (8.3L/min); 0.071 mg/kg/day (16.7 L/min); 0.123 mg/kg/day (29 L/min)

8 Total MOE = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE)

.

### Page 6 0 of 94 9 .1 .2 Occupational Handler Exposure/Risk Estimates ( Based on Biomonitoring Data )

Occupational Handler Exposure Data and Assumptions

The observational biomonitoring study (MRID 45621501) us ed the Mocap® 6EC formulation [EPA Reg. No. 5481

- 09041] of ethoprop with

mecha nical ground application equipment to treat potato fields in the Central Basin of Washington State in the United States. This study was used in multiple previous HED risk assessments 18 

### , which

18 Dawson, 2005; D281648 / Lloyd, 2010, D 375925

### Page 61 of 94

assessed exposure from the application of ethoprop on potatoes for handlers in the Northwest and

also extrapolated the biomonitoring results to similar crop/application patterns. The application methodology on the registered labels is substantively similar to the application equipment used in the biomonitoring study (i.e., closed cab tractors pulling sweep injection booms followed by rotary cultivators and specialized groundboom rigs for surface spray applications). A complete

characterization of the biomon itoring study is detailed in the most recent occupational and residential exposure (ORE) assessment memo (M. Lloyd; 09

- 15

- 2015 ; D421954).

Chemical

- specific handler exposure data are available to support this registration review

assessment. HED evaluate d the potential exposure to ethoprop using urinary concentrations of

M1 ( O

- ethyl

- S

- propylphosphorothioate), as an exposure biomarker in the available biomonitoring study. Occupational handler r isk estimates were calculated using the biological monitoring data in two distinct manners: (1) a daily dose approach ; and (2) a cumulative dose approach. While the individual results varied widely, risk estimates from both approaches result in risk estimates of concern (i.e, MOEs below the LOC of 1,000).

The biom onitoring study data are appropriate to bridge for the currently registered ethoprop use patterns registered with both the emulsifiable concentrate (for the ethoprop MOCAP® EC formulation) and the two granular formulations (15G and 20G) , although the resul ts should be interpreted with caution because individuals in the Washington State study often wore personal protective equipment beyond the label requirements, that are consistent with climates conditions

in the Pacific Northwest. The biomonitoring risk es timates are scaled to the various registered rates for the EC formulation. For the granular formulations, the risk estimate results are extrapolated from the EC formulation (in the study) to the existing granular formulation and scaled to the various regis tered rates for the granular formulations. The formulation extrapolation is appropriate and conservative based on the toxicity information available for ethoprop. In this biomonitoring study, it is not possible to parse the occupational handler exposure co ntribution by route (i.e, dermal, inhalation). While the same oral endpoint and point of departure (a BMDL 10 

### POD of 0.065 mg/kg/day based on inhibition of red blood cell cholinesterase 19 

### ) is used for both the emulsifiable concentrate and granular formulations, examining the difference between the

route

- specific points of departure can help characterize the conservatism of extrapolating the emulsifiable concentrate results to the granular formulation. The occupational handler assessment relies on th e same steady

- state inhalation endpoint and point of departure for the emulsifiable concentrate and granular formulation, while the steady

state dermal points of departure are different for the two formulations. The effect is the same (inhibition of red bl ood cell cholinesterase) for both formulations, although the point of departure

is 65x lower 20 

### for the granular formulation versus the emulsifiable concentration. Studies have shown that farmworkers receive the bulk of their potential pesticide exposure thr ough the dermal route of exposure 21 

### . Based on the differential toxicity between the two formulations and the lower exposure profile of occupational handlers using granular formulations, HED finds it appropriate and conservative to extrapolate the results of the available biomonitoring study from the emulsifiable concentrate (monitored in the study) to the granular formulation.

19 See Table 4.5.4.2 for additional detail

20 See Table 3.2

– POD of 0.1625 mg/kg /day for the EC formulation vs. 10.4 mg/kg/day for granular

21 Available: [Spear et al., 1977; Popendorf et al., 1979; Davis et al., 1982, 1983; Everhart and Holt, 1982; Herman et al., 1985]; http://onlinelibrary.wiley.com/doi/10.1002/ajim.1122/pdf

### Page 62 of 94

All of the risk estimates based on the biomonitoring data reflect the use of engineering controls plus the use of additional PPE reflected in the biomonitoring study report

. HED analyzed the ethoprop biomonitoring data by scaling the calculated daily dose and cumulative dose (in mg/kg/day) from the application rate applied in the biomonitoring study based on the existing applicatio n rates ( 2.1 to 12 lbs ai/A) on the product label

. MOEs calculated from the arithmetic mean daily exposure for mixer/loaders are of concern for each individual ( day s 1

- 4 ). Mixer/loader MOEs ranged from 9

- 36 , based on single day output for the higher appl ication

rates. For applicators, MOEs calculated from the arithmetic mean daily exposure for applicators

are also of concern on any individual day (MOEs range from 34

- 210 for days 1

- 4

. For mixer/loader/applicators (where individuals monitored in the study completed a variety of job tasks) MOEs calculated from the arithmetic mean daily exposure for that job category were also

of concern. Mixer/loader/applicator MOEs ranged from 9

– 64 for the highest registered ethoprop application rate.

For all application rates, MOEs calculated from the cumulative doses are of concern for each occupational handler group [mixer/loader, applicator, mixer/loader/applicator] with MOEs ranging from 4

- 83, depending on the job activity and application rate

.

Table 9

. 1. 2 .1. Risk Estimates For Ethoprop Handlers Based On Daily And Cumulative Dose

Estimates From MRID 45621501

.

Occupational Handler Monitoring Category Margins of Exposure (MOEs) Based On Single Day & Cumulative [M1] In

Urine 4 (LOC = 1000)

Day 1 Day 2 Day 3 Day 4 Cumulative

Based on ethoprop 5 scaled to 3 lbs ai/A

Mixer/Loader 1 35 58 140 76 15

Applicators 2 850 140 580 560 83

Mixer/Loader/Applicators 3 260 53 35 61 14

Based on ethoprop 5 scaled to 4 lbs ai/A

Mixer/Loader 1 26 43 110 57 11

Applicators 2 640 100 430 420 62
Mixer/Loader/Applicators 3 650 260 480 430 83

Based on ethoprop 5 scaled to 5.1 lbs ai/A

Mixer/Loader 1 21 34 84 45 9

Applicators 2 500 80 340 330 49
Mixer/Loader/Applicators 3 150 31 21 36 8

Based on ethoprop 5 scaled to 6 lbs ai/A

Mixer/Loader 1 18 29 72 38 8

Applicators 2 420 68 290 280 41
Mixer/Loader/Applicators 3 130 27 18 30 7

Based on ethoprop 5 scaled to 9 lbs ai/A

Mixer/Loader 1 12 19 48 25 5

Applicators 2 280 45 190 190 28
Mixer/Loader/Applicators 3 85 18 12 20 5

Based on ethoprop 5 scaled to 12 lbs ai/A

### Page 63 of 94

Table 9

. 1. 2 .1. Risk Estimates For Ethoprop Handlers Based On Daily And Cumulative Dose

Estimates From MRID 45621501

.

Occupational Handler Monitoring Category Margins of Exposure (MOEs) Based On Single Day & Cumulative [M1] In

Urine 4 (LOC = 1000)

Day 1 Day 2 Day 3 Day 4 Cumulative

Mixer/Loader 1 9 14 36 19 4

Applicators 2 210 34 140 140 21
Mixer/Loader/Applicators 3 64 13 9 15 4

1

– Mixer/Loader = Margin of Exposure calculated from Arithmetic mean exposure of study participants (ML1, ML2, ML3, AP11).

2

– Applicators = Margin of Exposure calculated from Arithmetic mean exposure of study participants (AP6, AP12, AP14).

3

– Mixer/Loader/Applicators = Margin of Exposure calculated from Arithmetic mean exposure of study participants (AP1, AP2, AP3, AP4, AP5 AP13, AP15, AP16, AP17, AP18, AP19, AP20, AP21, AP22, AP24). *AP1 Urines were also collected on days 5 & 6. AP2 urine was also collected on Day 5. MOEs are not presented here.

4

– MOEs calculated per exposure day and with cumulative 4 day exposure based on inhibition of RBC AChE in adult male rats; POD =

BMDL 10 = 0.065 mg/kg/day.

5

- In the biomonitoring study, MOCAP EC . See Section 9 .1.2 for additional information



### The MOEs calculated from the daily doses in the biomonitoring study ranged widely among

individual handlers. The Agency believes that these results are to be expected when considering the actual work practices of multiple individuals monitored over several days. The hazard concerns are a key driver of occupational risk from handling the liquid formulation of ethoprop. The study screened for very low levels of exposure (i.e., low ppb); therefore, the smallest

incr ease in exposure significantly affected (lowered) the risk estimate ( MOE )

. The level of care with which an individual handles a pesticide greatly influences the overall exposure to the pesticide. Given this study monitored the actual work practices of 23 handlers, degrees of

caution will differ.

T he exposure data from the biological monitoring study (MRID #45621501) on users in Washington State potato fields is appropriate to be bridged to the existing registered uses

. The ethoprop biomonitoring study was performed with the sole purpose of quantifying professional applicator exposure during the use of ethoprop in Pacific Northwest potato fields. As the original biomonitoring study occurred in a large portion of the occu pational handler group for ethoprop occupational handlers in a discrete geographic location, there is uncertainty bridging the use of the data to other occupational handler groups with different agricultural practices and geographic variations. It is uncl ear how different agricultural and climate conditions would affect the resulting handler exposure estimates. It is also important to note that individuals in the Washington State study often wore personal protective equipment beyond the label requirements , limiting personal exposures. This is an important detail to consider when interpreting the biomonitoring results

.

The study protocol required that potential adverse effects of ethoprop be explained to each of the study participants. The study report p rovides detailed descriptions of observations by the study monitors of both the workers’ work practices and other observations. There is no mention of any worker exhibiting any adverse effects or anything that would be suggestive of cholinergic

clinical s igns in the original biomonitoring study. It is important when interpreting the results of this study to note that approximately 50 percent of the samples collected were less than the quantification limit. Application rates in the original study ranged f rom 4

- 12 lbs ai/A (i.e., comparable with the range of the currently registered ethoprop labels )

.

### Page 64 of 94

There is one additional risk characterization piece to consider as it relates to biological monitoring. HED evaluated Washington State’s annual cholinesterase monitoring report for

2013 22 

### . Washington State evaluates a number of agricultural chemicals that can result in cholinesterase inhibition; ethoprop is among those that have been monitored. The report is valuable because Washington State represents: 1) an area with both high overall usage of both formulations of ethoprop (granular and EC) ; 2) a region that represents multiple crops where ethoprop is applied; and 3) a region with a high percentage of the highest application rate of ethoprop (12 lbs ai/A).

The report highlighted a few important pieces of information that relate to the risk characterization for ethoprop use:

 Only 6% of handlers (n=1994) had cholinesterase depression (from any OP/n

- methyl carbamate)

.

 No handlers reported pesticide illness/symptoms in 201 3

.

 Only 4% (n=9) had cholinesterase depression to the point of “ exposure removal ” level defined by WA state

.

 Only 2% (n=2) had cholinesterase depression to the point of “ work evaluation ” level defined by WA state

.

 The 2013 WA state results are in line with ann ual monitoring results since 2008

.

Unfortunately, the Washington State program does not differentiate the individual agricultural

chemicals where worker exposure may have occurred. Still, even if one was to assume that all

the adverse incidents identi fied in the 2013 results of the Washington State program were due to ethoprop exposure, the overall report provides another line of evidence that

, at least in the Pacific

Northwest where monitoring takes place , that workers are not exposed to ethoprop to t he point of cholinesterase depression.

9 .1

. 3 Occupational Handler Exposure/Risk Estimates ( Cancer Risk Estimation )

9 .1.3.1 Occupational Handler Cancer Risk Estimates ( Standard LADD Approach)

Occupational Handler Cancer Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational

handler cancer risk assessments. Assumptions and factors, as well as algorithms used to estimate

the cancer exposure and dose for occupational handlers are de tailed in the most recent occupational and residential exposure (ORE) assessment memo (M. Lloyd; 09

- 15

- 2015 ; D421954).

One point that departs from standard cancer assessment practices is noteworthy for the human health risk assessment. The majority of a pplications of ethoprop are restricted to 1 application per year, and HED typically assesses “private” and “commercial” applicators at 10 and 30 days per year, respectively. HED worked in consultation with BEAD and PRD to refine the default “private” and “ commercial” handler days per year of exposure input for Pacific Northwest potatoes to 5 and 8 days per year, respectively. Complete details on deriving the refinements can be found in the BEAD memo, “BEAD Estimates for Applicator Exposure to Ethoprop From Applications Made to Potatoes in the Pacific Northwest”.

22 Available: http://www.lni.wa.gov/Safety/Topics/AtoZ/Cholinesterase/files/2013Report.pdf

### Page 65 of 94

Rate Information for use in Cancer Risk Assessment : For the occupational handler cancer risk assessment, HED consulted with BEAD and obtained seasonal average application rate information. Seasonal average application rates are appropriate

for us e in the cancer risk assessment because the assessment assumes use every year over a 30 year working lifetime. Where seasonal rate information was not available, HED used the average of the high and low appli cation rates for each crop presented on the label. Since ethoprop is used as both an insecticide and a nematicide, occupational handler cancer risk estimates are presented for both cases to help risk managers identify the potential range in the cancer risk estimates for each crop. Additional detail on the rate information used in the cancer assessment is detailed in the ORE disciplinary memo ( M. Lloyd; 09

- 15

- 2015 ; D421954 ).

Summary of Occupational Handler Cancer Exposure and Risk Estimates

Cancer risk est imates resulting from exposures to ethoprop were calculated using a linear low

dose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated and then compared with a Q 1 

### * 

### that has been calculated for ethoprop based on dose r esponse data ( Q 1 

### * 

### = 2.8 x 10

- 2 

### (mg/kg/day)

- 1 

### ).

Tables 9 .1.3.1.1 and 9 .1.2.1.2 summarize the occupational handler cancer assessment for the emulsifiable concentrate and granular formulations, respectively. The quantitative cancer risk assessment also calculated separate cancer risk assessment estimates for the liquid and granular formulations, for both private handlers and commercial handlers, respectively. All of the cancer risk estimates presented reflect the use of engineering controls except the loader/applicator for backpack granule application for bananas; the range in the cancer risk estimates considers the typical application rate per crop and formulation

. For the emulsifiable concentrate formulatio n, the private handler cancer risk estimates range from 3.5 x 10

- 6 

### to 9.6 x 10

- 5 

### for mixer/loaders and

2.0 x 10

- 6 

### to 3.2 x 10

- 5 

### for applicators. The commercial handler cancer risk estimates range from

1.0 x 10

- 5 

### to 2.9 x 10

- 4 

### for mixer/loaders and 6.1 x 1 0

- 6 

### to 9.7 x 10

- 5 

### for applicators

. For the granular formulation, the private handler cancer risk estimates ranged from 3.9 x 10

- 6 

### to 5.5 x

10

- 5 

### for mixer/loaders and 1.0 x 10

- 6 

### to 1.4 x 10

- 5 

### for applicators

. The commercial handler cancer risk estimates ranged from 1.2 x 10

- 5 

### to 1.7 x 10

- 4 

### for mixer/loaders and 3.0 x 10

- 6 

### to 4.2 x 10

- 5


### for applicators

.

Typically, cancer risk estimates that are not based on the use of engineering controls present a range of risk estimates to reflect increasing PPE and/or the use of engineering controls. In the case of the backpack granular application for bananas, the cancer risk estimates reflects the current label PPE. Based on the available surrogate exposure data for th at exposure scenario, no additional PPE is available for that exposure scenario. Additionally, the use of engineering controls is not available for the granular application to banana trees.

### Page 66 of 94

Table 9 .1.3.1

. 1 Occupational Handler Cancer Expo sure and Risk Estimates for Ethoprop [Liquid Formulation]

.

Crop or Target Exposure Scenario Private Handler Commercial Handler LADD (mg/kg/day)

Total LADD 3 Cancer

Risk

Estimate 4 LADD (mg/kg/day)

Total LADD 3 Cancer Risk

Estimate 4 Dermal 1 Inhalation 2 Dermal 1 Inhalation 2

Hops: Orchard M/L: Chemigation

2.3 lbs ai/A 0.00106 0.000010 0.0011 3.0E

- 05 0.0032 0.0000308 0.0032 9.1E

- 05

Cabbage: Field crop, typical M/L: Chemigation

3.7 lbs ai/A 0.00171 0.000017 0.0017 4.8E

- 05 0.0051 0.0000494 0.0052 1.5E

- 04

Sweet Potato: Field crop, typical M/L : Chemigation

3 .5 lbs ai/A 0.00161 0.000016 0.0016 4.6E

- 05 0.0048 0.0000472 0.0049 1.4E

- 04

Potatoes: Field crop, high

acreage M/L: Chemigation

4.5 lbs ai/A 0.00104 0.0000101 0.00105 3.0E

- 05 0.00166 0.0000161 0.00168 4.7E

- 05

Potatoes: Field crop, high

acreage M/L: Chemigation

7.3 lbs ai/A 0.00169 0.0000163 0.00171 4.8E

- 05 0.0027 0.0000261 0.00273 7.7E

- 05

Cabbage: Field crop, typical M/L : Groundboom

3.7 lbs ai/A 0.0004 0.00000 0.000374 1.1E

- 05 0.0011 0.00001 0.00112 3.2E

- 05

Sweet Potato: Field crop, typical M/L : Groundboom

3 .5 lbs ai/A 0.0004 0.00000 0.000396 1.1E

- 05 0.0012 0.00001 0.00119 3.3E

- 05

Field Grown

Ornamental Crops M/L : Groundboom

2. 3 lbs ai/A 0.000111 0.00000107 0.000112 3.2.E

- 06 0.000333 0.00000321 0.000336 9.4.E

- 06

Potatoes: Field crop, high

acreage [ M/L: Groundboom

4.5 lbs ai/A 0.000595 0.00000574 0.000601 1.7E

- 05 0.000952 0.00000919 0.000961 2.7E

- 05

Potatoes: Field crop, high

acreage M/L: Groundboom

7.3 lbs ai/A 0.000971 0.00000928 0.000983 2.8E

- 05 0.00155 0.0000149 0.00157 4.4E

- 05

Mint: Field crop, high

acreage M/L Groundboom

4.5 lbs ai/A 0.00119 0.000012 0.0012 3.4E

- 05 0.0036 0.0000344 0.0036 1.0E

- 04

### Page 67 of 94

Table 9 .1.3.1

. 1 Occupational Handler Cancer Expo sure and Risk Estimates for Ethoprop [Liquid Formulation]

.

Crop or Target Exposure Scenario Private Handler Commercial Handler LADD (mg/kg/day)

Total LADD 3 Cancer

Risk

Estimate 4 LADD (mg/kg/day)

Total LADD 3 Cancer Risk

Estimate 4 Dermal 1 Inhalation 2 Dermal 1 Inhalation 2

Field Grown

Ornamental Crops Applicator

Groundboom

2. 3 lbs ai/A 0.0000658 0.000000554 0.0000664 1.9.E

- 06 0.000197 0.00000166 0.000199 5.6.E

- 06

Cabbage: Field crop, typical Applicator

Groundboom

3.7 lbs ai/A 0.00023 0.000002 0.0002 6.6E

- 06 0.0007 5.86E

- 06 0.0007 2.0E

- 05

Sweet Potato: Field crop, typical Applicator

Groundboom

3.5 lbs ai/A 0.00022 0.000002 0.0002 6.3E

- 06 0.0007 5.53E

- 06 0.0007 1.9E

- 05

Potatoes: Field crop, high

acreage [insecticide] Applicator:

Groundboom

4.5 lbs ai/A 0.000353 0.00000298 0.000356 1.0E

- 05 0.000565 0.00000476 0.000569 1.6E

- 05

Potatoes:

Field crop, high

acreage [nematicide] Applicator

Groundboom

7.3 lbs ai/A 0.000572 0.00000483 0.000577 1.6E

- 05 0.000916 0.00000772 0.000923 2.6E

- 05

Mint: Field crop, high

- acreage Applicator

4.5 lbs ai/A 0.00071 0.000006 0.0007 2.0E

- 05 0.0021 0.0000179 0.0021 6.0E

- 05

1 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure ( 10/30 days/yr) ÷ 365 days/year] × [Years per lifetime of exposure ( 35 yrs) ÷ Lifetime expectancy ( 78 yrs)].

2 Inhalation LADD (mg/kg/day) = Inhalation Dose (mg/kg/day) × [Days per year of exposure (days/yr) / 365 days/year] × [Years per lifetime of exposure ( 35 yrs) ÷ Lifetime expectancy ( 78 yrs)].

3 Total LADD (mg/kg/day) = Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/day).

4 Cancer risk estimates = Total LADD × Q 1 * , where Q 1 * = 2.81x10

- 2 (mg/kg/day)

- 1

.

Table 9 .1.3.1.2 . Occupational Handler Cancer Exposure and Risk Estimates for Ethoprop [Granular Formulation]

.

Crop or Target Exposure Scenario Private Handler Commercial Handler

LADD (mg/kg/day)

Total LADD 3 Cancer

Risk

Estimate 4 LADD (mg/kg/day)

Total LADD 3 Cancer Risk

Estimate 4 Dermal 1 Inhalation 2 Dermal 1 Inhalation 2

Sweet potato: Field crop, typical M/L: Tractor

Spreader

3 .5 lbs ai/A 0.0004 0.000004 0.000374 1.1E

- 05 0.0011 0.00001 0.00112 3.2E

- 05

Cabbage: Field crop, typical M/L: Tractor

Spreader 0.0004 0.000004 0.000396 1.1E

- 05 0.0012 0.00001 0.00119 3.3E

- 05

### Page 68 of 94

Table 9 .1.3.1.2 . Occupational Handler Cancer Exposure and Risk Estimates for Ethoprop [Granular Formulation]

.

Crop or Target Exposure Scenario Private Handler Commercial Handler

LADD (mg/kg/day)

Total LADD 3 Cancer

Risk

Estimate 4 LADD (mg/kg/day)

Total LADD 3 Cancer Risk

Estimate 4 Dermal 1 Inhalation 2 Dermal 1 Inhalation 2

3.7 lbs ai/A

Tobacco: Field crop, typical M/L: Tractor

Spreader

5.7 lbs ai/A 0.0006 0.000006 0.000609 1.7E

- 05 0.0018 0.00002 0.00183 5.1E

- 05

Beans (Snap, etc): Field crop, typical M/L: Tractor

Spreader

2.2 lbs ai/A 0.0002 0.000002 0.000235 6.6E

- 06 0.0007 0.00001 0.000704 2.0E

- 05

Beans (Snap, etc): Field crop, typical M/L: Tractor

Spreader

2.8 lbs ai/A 0.0003 0.000003 0.000299 8.4E

- 06 0.0009 0.00001 0.000896 2.5E

- 05

Beans (Dry/Pea): Field crop, typical M/L: Tractor

Spreader

3 lbs ai/A 0.0003 0.000003 0.00032 9.0E

- 06 0.0010 0.00001 0.000959 2.7E

- 05

Mint: Field crop, high

acreage M/L: Tractor

Spreader

4.5 lbs ai/A 0.0012 0.000012 0.0012 3.4E

- 05 0.0036 0.00003 0.0036 1.0E

- 04

Potatoes: Field crop, high

acreage M/L: Tractor

Spreader

4.5 lbs ai/A 0.000595 0.00000574 0.000601 1.7E

- 05 0.000952 0.00000919 0.000961 2.7E

- 05

Potatoes: Field crop, high

acreage M/L: Tractor

Spreader

7.3 lbs ai/A 0.000971 0.00000928 0.000983 2.8E

- 05 0.00155 0.0000149 0.00157 4.4E

- 05

Sugarcane: Field crop, high

acreage M/L: Tractor

Spreader

4 lbs ai/A 0.0011 0.000010 0.00107 3.0E

- 05 0.0032 0.00003 0.0032 9.0E

- 05

Sweet corn:

Field crop, typical [insecticide use] M/L: Tractor

Spreader

1.3 lbs ai/A 0.0001 0.000001 0.000139 3.9E

- 06 0.0004 0.00000 0.000417 1.2E

- 05

Sweet corn: Field crop, typical [nematicide use] M/L: Tractor

Spreader

2.3 lbs ai/A 0.0002 0.000002 0.000246 6.9E

- 06 0.0007 0.00001 0.000738 2.1E

- 05

### Page 69 of 94

Table 9 .1.3.1.2 . Occupational Handler Cancer Exposure and Risk Estimates for Ethoprop [Granular Formulation]

.

Crop or Target Exposure Scenario Private Handler Commercial Handler

LADD (mg/kg/day)

Total LADD 3 Cancer

Risk

Estimate 4 LADD (mg/kg/day)

Total LADD 3 Cancer Risk

Estimate 4 Dermal 1 Inhalation 2 Dermal 1 Inhalation 2

Sweet corn: Field crop, typical [insecticide use] Applicator: Tractor

Spreader

1.3 lbs ai/A 0.0000 0.000004 0.0000355 1.0E

- 06 0.0001 0.00001 0.000107 3.0E

- 06

Sweet corn: Field crop, typical [nematicide use] Applicator: Tractor

Spreader

2.3 lbs ai/A 0.0001 0.000006 0.0000628 1.8E

- 06 0.0002 0.00002 0.000188 5.3E

- 06

Sugarcane: Field crop, high

acreage Applicator

4 lbs ai/A 0.0002 0.000027 0.000273 7.7E

- 06 0.0007 0.00008 0.000819 2.3E

- 05

Mint: Field crop, high

- acreage Applicator

4.5 lbs ai/A 0.0003 0.000031 0.000307 8.6E

- 06 0.0008 0.00009 0.000922 2.6E

- 05

Potatoes: Field crop, high

acreage Applicator

4.5 lbs ai/A 0.000138 0.0000152 0.000154 4.3E

- 06 0.000221 0.0000244 0.000246 6.9E

- 06

Potatoes: Field crop, high

acreage Applicator

7.3 lbs ai/A 0.000224 0.0000246 0.000249 7.0E

- 06 0.000359 0.0000394 0.000398 1.1E

- 05

Beans (Dry/Pea): Field crop, typical Applicator : Tractor

Spreader

3 lbs ai/A 0.0001 0.000008 0.0000819 2.3E

- 06 0.0002 0.00002 0.000246 6.9E

- 06

Sweet potato: Field crop, typical Applicator : Tractor

Spreader

3 .5 lbs ai/A 0.0001 0.000009 0.0000955 2.7E

- 06 0.0003 0.00003 0.000287 8.1E

- 06

Cabbage: Field crop, typical Applicator : Tractor

Spreader

3.7 lbs ai/A 0.0001 0.000010 0.000101 2.8E

- 06 0.0003 0.00003 0.000303 8.5E

- 06

Tobacco: Field crop, typical Applicator : Tractor

Spreader

5.7 lbs ai/A 0.0001 0.000015 0.000156 4.4E

- 06 0.0004 0.00005 0.000468 1.3E

- 05

Beans (Snap, etc): Field crop, typical Applicator : Tractor

Spreader

2.2 lbs ai/A 0.0001 0.000006 0.00006 1.7E

- 06 0.0002 0.00002 0.00018 5.1E

- 06

### Page 70 of 94

Table 9 .1.3.1.2 . Occupational Handler Cancer Exposure and Risk Estimates for Ethoprop [Granular Formulation]

.

Crop or Target Exposure Scenario Private Handler Commercial Handler

LADD (mg/kg/day)

Total LADD 3 Cancer

Risk

Estimate 4 LADD (mg/kg/day)

Total LADD 3 Cancer Risk

Estimate 4 Dermal 1 Inhalation 2 Dermal 1 Inhalation 2

Beans (Snap, etc): Field crop, typical Applicator : Tractor

Spreader

2.8 lbs ai/A 0.0001 0.000008 0.0000765 2.2E

- 06 0.0002 0.00002 0.000229 6.4E

- 06

Banana/plantain:

orchard 5 Loader/applicator

90.8 lbs ai/A . 001 0.00 00332 0.00 0242 3. 0 .E

- 05 0.00 3 0.000 0996 0.00 314 8.8 E

- 05

1 Dermal LADD (mg/kg/day) = Dermal dose (mg/kg/day) × [Days per year of exposure ( 10/30 days/yr) ÷ 365 days/year] × [Years per lifetime of exposure 35 (yrs) ÷ Lifetime expectancy ( 78 yrs)].

2 Inhalation LADD (mg/kg/day) = Inhalation Dose (mg/kg/day) × [Days per year of exposure ( 10/30 days/yr) / 365 days/year] × [Years per lifetime of exposure ( 35 yrs) ÷ Lifetime expectancy 78 (yrs)].

3 Total LADD (mg/kg/day) = Dermal LADD (mg/kg/day) + Inhalation LADD (mg/kg/d ay).

4 Cancer risk estimates = Total LADD × Q 1 * , where Q 1 * = 2.81x10

- 2 (mg/kg/day)

- 1 5 Reflects Double Layer PPE with gloves, & a PF10 respirator; not engineering controls like the other scenarios assessed

### Page 71 of 94

9 .1.3.2 Occupational Handler Ca ncer Risk Estimates (Based on Biomonitoring Data)

While HED’s standard cancer assessment risk estimates are detailed in Section 9 .1.3.1 , a cancer risk estimate screen can also be performed based on the worker exposure profile from the biomonitoring study outlined in Section 9 .1.2 . For the same reasons identified in Section 9 .1 , it is appropriate to consider this occupational handler cance r risk estimation based on both the granular and EC formulations, with the caveats about the use of extra PPE in the study.

Summary of Occupational Handler Cancer Exposure and Risk Estimates

Table 9 .1.3.2.1 summarize the occupational handler cancer asse ssment based on the biomonitoring study. All of the cancer risk estimates presented reflect the use of engineering

controls plus the use of additional PPE reflected in the biomonitoring study report . While current label requirements indicate engineering c ontrols are required, the biomonitoring study report details a number of additional PPE items worn by study subjects including Tyvek suits, coveralls, hats, and various head coverings.

The private handler cancer risk estimates range from 3.2 x 10

- 6 

### to 5.2 x 10

- 6 

### for mixer/loaders

and 8.3 x 10

- 7 

### to 1.3 x 10

- 6 

### for applicators, depending on the crop/rate combination. The commercial handler cancer risk estimates range from 9.6 x 10

- 6 

### to 1.6x 10

- 5 

### for mixer/loaders and

2.5 x 10

- 6 

### to 4.0 x 10

- 6 

### for applicators depending on the crop/rate combination. The mixer/loader scenarios for both crop/rate combinations are in the cancer risk estimate range between 1x10

- 6



### and 1x10

- 4



### .

Table 9

. 1

. 3.2.1 . Occupational Handler Cancer Exposure and Risk Estimates for Ethoprop [Biomonitoring Screen]

.

Crop or Target Exposure Scenario Private Handler Commercial Handler

Total LADD (mg/kg/day) 3 Cancer Risk

Estimate 4 Total LADD

(mg/kg/day) Cancer Risk

Estimate 4

Potatoes M/L: 7.3 lbs ai/A 0.00018 5.2E

- 06 0.00055 1.6E

- 05

Potatoes Applicator: 7.3 lbs

ai/A 0.00005 1.3E

- 06 0.00014 4.0E

- 06

Mint M/L: 4.5 lbs ai/A 0.00011 3.2E

- 06 0.00034 9.6E

- 06

Mint Applicator: 4.5 lbs

ai/A 0.00003 8.3E

- 07 0.00009 2.5E

- 06



### The above occupational cancer risk estimates are based on data derived from the biomonitoring study; specifically, the use of engineering controls plus the use of additional dermal PPE (e.g., Tyvek suits, coveralls, head coverings). Therefore, these results cannot be directly compared

with the standard cancer ris k estimates presented in Section 9 .1.3.1

. Additionally, because the study monitoring units had differential exposure based on the number of ethoprop uses over the course of monitoring, the highest cumulative dose per worker group (M/L and applicators) was used as a surrogate for the average daily dose (ADD). There are other potential surrogates for the

ADD such as 1) the highest single dose per individual per worker group, or 2) the arithmetic mean exposure per worker group. HED selected the highest cumulat ive dose value per worker group as the surrogate for ADD because of the uncertainties surrounding the kinetics of the M1 metabolite and the extrapolation of 4 days of exposure (in the biomonitoring study) to a seasonal and then lifetime exposure estimation

.

### Page 72 of 94

9 .2 Occupational Post

- application Exposure/Risk Estimates

9 .2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application ac tivities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of

pe sticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March
2, 2010 23 

### . The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 24



### . During Reg istration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies ) or further analysis is required for ethoprop

.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by ARTF . Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the A gency's risk assessments.

A summary of the non

- occupational bystander post

- application inhalation exposure assessment for ethoprop is detailed in Section 6.1

.

9 .2.2 Occupational Post

- A pplication Dermal Expo sure/Risk Estimates

A quantitative post

- application dermal exposure assessment has not been conducted for ethoprop because ethoprop is typically applied pre

- plant/pre

- emergent in the growing season. E thoprop is used in pre

- plant and pre

- emergent applicat ions and is normally soil incorporated or watered

- in. For both granular and EC formulations of ethoprop, HED believes the potential for post

application exposure is low because of limited contact with the soil

. Therefore, a post

application dermal exposu re assessment was not conducted.

Restricted

- Entry Interval (REI)

The current product

- label REI is 48 hours (72 hours in areas where rainfall is less than 25 inches per year). Under 40 CFR 156.208 (c) (2) (i), ai’s classified as Acute toxicity category I for acute dermal, eye irritation or primary skin irritation are assigned a 48

- hour REI. In addition, for organophosphates that may be applied outdoors in an area where the average annual rainfall for the site is less than 25 inches per year, the REI is 72 hours. Ethoprop is extremely acutely toxic. Ethoprop is classified as Toxicity Category I via the dermal route and was classified as Toxicity Category 1 for eye irritation, as well (with 0.1 ml resulting in 100% mortality).

No quantitative postapp lication assessment is necessary for the registered uses of ethoprop. The

interim REI based on the criteria laid out in 40 CFR 156.208 (c) (2) (i) meets the minimum requirements to be protective of potential post

- application exposure.

23 http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

24 http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219.

### Page 73 of 94

10.0 Incident Repo rt
S. Recore et al., 12/02/14, D421955



### One component of the Agency’s registration review program is consideration of human observational information including incident data, medical case reports, general medical information, and epidemiology studies. In c onjunction with a human health risk assessment based on other data sources, such human incident and other human data can assist the Agency in better defining and characterizing the risk of pesticides/pesticide products.

Based on the low frequency and severity of incident cases reported for ethoprop in both IDS and

NIOSH SENSOR

- Pesticides, there does not appear to be a concern at this time with respect to incident cases that would warrant further investigation. Additionally, the findings of the researc h reviewed from the Agricultural Health Study do not support any changes to OPP's approach to quantitative risk assessment for ethoprop . However, OPP will continue to monitor the AHS and other epidemiologic results and will re

- evaluate these conclusions a s needed.

HED has prepared an ethoprop incident report review (S. Recore et al

., 12 / 02 /14, D42195 5

, Ethoprop : Updated Tier I Review of Human Incidents for Preliminary Risk Assessment). The review considers a variety of types and sources of human observational information including human incident data, medical data/case report information, and epidemiological information in

an ef fort to inform the re

- evaluation of ethoprop in this phase of registration review. The human

incident databases that were reviewed are:

 the OPP Incident Data System (IDS);

 NIOSH’s Sentinel Event Notification System for Occupational Risks (SENSOR);

OPP’ s IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports from registrants, other federal and state health and environmental agencie s, and individual

consumers. Overall, there are few incidents involving ethoprop reported to IDS. Incidents in the IDS system include:

 For the Main IDS, from January 1, 200 7 to August , 2014, there were 2 incidents reported for single chemical only in the database. There w as one additional incident reported involving more than one chemical. These incident s were classified as moderate severity.

 In Aggregate IDS, from January 1, 2009 to August , 2014, there were 2 reported incidents involving ethoprop . Thes e incidents were classified as minor severity.

The SENSOR

- Pesticides database covers 11 states from 1998

- 2010, although reporting varies from state to state. Cases of pesticide

- related illnesses are ascertained from a variety of sources, including: repor ts from local Poison Control Centers, state Department of Labor workers’ compensation claims when reported by physicians, reports from State Departments of Agriculture, and physician reports to state Departments of Health. A query of SENSOR

Pesticides 1998

- 2010 identifies a total of nine cases, from five events, involving ethoprop. All nine cases experienced respiratory symptoms. Five cases experienced potential nervous system symptoms (mainly dizziness), and the moderate severity case also experienced pot ential cardiovascular symptoms.

In addition to the incident/poisoning data and medical case reports, epidemiological research can be an important source for human observational data and can potentially assist in identifying,

### Page 74 of 94

characterizing, and (ideally) quantifying linkages between human exposures and resulting health

effects. For ethoprop , epidemiological data is available from the Agricultural Health Study (AHS). Across numerous evaluations of pesticide use in relation to different anatomical cancer endpoints, ethoprop was either not included or the statistical association was neither strong nor significant (p>0.10). Similarly, ethoprop use was either not measured or was not associated with

the evaluations of non

- cancer endpoints.

To date, there is one positive statistically significant association between ethoprop use and neurobehavioral performance. Starks et al. (2012) investigated neurobehavioral performance i n relation to pesticide use in a sub

- sample of male AHS participants (n=701). The purpose of this investigation was to examine associations between OP pesticide use and measures of neurobehavioral function in a large cohort of pesticide applicators with we ll characterized pesticide use histories. The primary hypothesis tested was whether long

- term OP pesticide use was associated with adverse neurobehavioral (NB) outcomes. In this study, investigators evaluated the associations between (i) ever/never use bas ed on any positive report at any
i nterview and (ii) lifetime days of use based on the sum of lifetime days of use reported at each interview for each of 16 different organophosphate pesticides with performance on a series of 9 neurobehavioral tests, contro lling for age, education, state and other neurological parameters which were selected from a list of 16 variables by using a stepwise selection process. From the analysis in which pesticide use is dichotomized as "ever/never use", authors reported signific antly decreased ability to complete three (of the nine) neurobehavioral tasks that relate to motor speed, verbal learning and memory, and visual processing among those who reported ever use of ethoprop over the working lifetime. However, in the analysis wh ere the pesticide use was set as the number of lifetime use days, only the association between the number of lifetime days using ethoprop and one NB task (motor speed and scanning) was significant. The authors conclude, overall, that they found "no consist ent evidence of an association between OP use and

adverse neurobehavioral performance tests among this older sample of pesticide applicators

. "

During the time frame that AHS conducted their analyses, OPP implemented a number of measures designed to reduce worker and environmental exposure as a result of ethoprop use

. Subsequent to the 2001 IRED, all registered ethoprop labels (5481

- 9040 [formerly 2 64

- 452 ],

5481

- 9042 [formerly 264

- 469] , and 5481

- 9041 [formerly 264

- 458] ) were updated to reflect

additional control measures

. Important changes for granulars (5481

- 9040 & 5481

- 9042) implemented worker protections including enclosed cab, prohibition of certain applications (aerial, push

- type spreaders, applic ations to peanuts, slit treatment, all hand applications) and lock and load (for 5481

- 9042). For the emulsifiable concentrate formulation of ethoprop, the changes included prohibition of certain application types (backpack, handwand, etc) and certain

use sites (sugar cane). All ethoprop formulations increased restrictions on number of

app lications and the maximum application rates.

In summary, the available incident report details available incident and epidemiological data.

The available incident data identified few incidents involving ethoprop that were reported to IDS

or NIOSH SENSOR

- Pesticides. The incidents involved cardiac, neurological

, gastrointestinal, or respiratory symptoms. The available epidemiological data from the AHS do not support any

ch anges to OPP's approach to quantitative risk assessment for ethoprop . OPP implemented significant worker exposure mitigations during the same time frame as the AHS epidemiological analyses were being conducted. OPP will continue to monitor incident data, t he AHS and other epidemiologic results and will re

- evaluate these conclusions as needed.

### Page 75 of 94

11.0 References

Bouchard MF, Chevrier J, Harley KG, Kogut K, Vedar M, Calderon N, et al. Prenatal Exposure to Organophosphate Pesticides and IQ in 7

- Year

- Old Childr en. Environ Health Perspectives. 2011;119:1189

- 1195.

Bouchard M.F., Bellinger D.C., Wright R.O., Weisskopf M.G., (2010). Attention

Deficit/Hyperactivity Disorder and Urinary Metabolites of Organophosphate Pesticides.

PEDIATRICS

. DOI:10.1542/peds.2009

- 3058.

Engel SM, Berkowitz GS, Barr DB, Teitelbaum SL, Siskind J, Meisel SJ, Wetmur JG, Wolff MS. Prenatal Organophosphate Metabolite and Organochlorine Levels and Performance on the Brazelton Neonatal Behavioral Assessment Scale in a Multiethnic Pregnancy Cohort. American Journal of Epidemiology. 2007;165:1397

- 1404.

Engel SM, Wetmur J, Chen J, Zhu C, Barr DB, Canfield RL, Wolff MS. Prenatal Exposure to Organophosphates, Paraoxonase 1, and Cognitive Development in Childhood. Environmental Health Perspectives . 2011;119:1182

- 1188.

Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, Furlong CE, Holland NT. Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of Gestation in an Agricultural Population. Environmental Health Perspectives. 2004;115:792

– 798.

Eskenazi B, Marks AR, Bradman A, Harley K, Barr DB, Johnson C, Morga N, Jewell NP. Organophosphate Pesticide Exposure and Neurodevelopment in Young Mexican

- American Children. Environmental Health Perspectives. 2007;1 15:792

– 798.

FIFRA Scientific Advisory Panel. (2012). Transmittal of the Meeting Minutes from the FIFRA Scientific Advisory Panel Meeting of April 10

- 12, 2012. FIFRA Scientific Advisory Panel, Office of Science Coordination and Policy, Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency. Washington, DC. Available: http://www.epa.gov/scipoly/sap/meetings/2012/041012meeting.htmll

Fortenberry, GZ, Mee ker, JD, Sánchez, BN, Barr, DB, Panuwet, P, Bellinger, D, Schnaas, L,

Solano

- González, M, Ettingera, AS, Hernandez

- Avila, M, Hu, H, Tellez

- Rojoj, MM. Urinary 3,5,6

- trichloro

- 2

- pyridinol (TCPY) in pregnant women from Mexico City: Distribution, temporal

vari ability, and relationship with child attention and hyperactivity. International Journal of Hygiene and Environmental Health 217 (2014): 405

– 412.

Furlong, Melissa A., Engel, Stephanie M., Boyd Barr, Dana, Wolff, Mary S. Prenatal exposure to organophosphate pesticides and reciprocal social behavior in childhood. 2014. Environment

International 70:125

- 131.

Guodong, Ding, Pei, Wang, Ying, Tian, Jun, Zhang, Yu, Gao, Xiaojin, Wang, Rong, Shi, Guoquan, Wang, and Xiaoming, Shen. Organophosphate Pesticide Exposure a nd Neurodevelopment in Young Shanghai Children. Environmental Science and Technology

46:2911

- 2917, 2012.

Oulhote, Youssef and Bouchard, Maryse F. Urinary Metabolites of Organophosphate and Pyrethroid Pesticides and Behavioral Problems in Canadian Children. Environmental Health Perspectives. 121:1378

- 1384 (2013)

Rauh VA, Garfinkel R, Perera FP, Andrews HF, Ho epner L, Barr DB, Whitehead R, Tang D, Whyatt RW. Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life Among Inner

- City Children. Pediatrics. 2006;18(6): 1835

- 1859.

### Page 76 of 94

Rauh V, Arunajadai S, Horton M, Perera F, Hoepner L, B arr DB, et al. 2011. Seven

- Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural Pesticide. Environmental Health Perspectives. 2011;119:1196

- 1201.

Shelton, Janie F., Geraghty, Estella M., Tancredi, Daniel J., Delwiche, Lora D., Schmidt, Rebecca J., Ritz, Beate, Hansen, Robin L., and Hertz

- Picciotto, Irva. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE Study. Environmental Health Perspectives 122:1103

– 1109, 2014.

U. S. Environmental Protection Agency. (2008). Science Issue Paper: Chlorpyrifos Hazard and Dose Response Characterization

. http://www.epa.gov/scipoly/sap/meetings/2008/091608_mtg.htm

U.S. Environmental Protection Agency. (2012). Draft Issue Paper: Scient ific Issues Concerning Health Effects of Chlorpyrifos. http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

2012

- 0040

- 0002

Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, Barr DB, Furlong CE, Holland NT. Association Between In Ut ero Organophosphate Pesticide Exposure and Abnormal Reflexes in Neonates. NeuroToxicology. 2005;26:199

– 209.

Zhang, Ying, Han, Song, Liang, Duohong, Shi, Xinzhu, Wang, Fengzhi, Wei Liu, Zhang, Li, Chen, Lixin, Gu, Yingzi, Tian, Ying. Prenatal exposure to or ganophosphate pesticides and neurobehavioral development of neonates: A birth cohort study in Shenyang, China. PlosOne

47:80

– 85, 2014.

### Page 77 of 94

Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for the food use for e thoprop are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21/28

- Day Dermal

................................ ......................... 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

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

yes

yes

no

yes yes

yes

yes

870.3700a Developmental Toxicity (rodent)

................................ .. 870.3700b Developmental Toxicity (nonrodent)

............................ 870.3800 Reproduction

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ ................... 870.4300 Chronic/Oncogenicity

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

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... 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 Develop. Neurotoxicity

................................ ................. CR

no

yes

yes

CR yes

yes

yes

yes

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................
870.7800 Immunotoxicity

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

CR

yes yes

yes

yes

Special Studies

Comparative Cholinesterase (rat)

............................... - yes

1 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.

2 Subchronic 90

- day and 6

- month studies are available; therefore, a longer term study is not required.

### Page 78 of 94

A.2. Toxicity Profiles

Table A.2.1 Acute Toxicity Profile

- Ethoprop

Guideline No. Study Type MRID(s) Results Toxicity
Category

870.1100 Acute oral

- Rat 00078035 M LD 50 = 56.2 m g/kg

F LD 50 = 30.2 mg/kg I

870.1100 Acute oral

– Rat 44472501 F LD 50 = 56 mg/kg II

870.1200 Acute dermal

– Rabbit

(technical form) 00078035 LD 50 = 25.74 mg/kg I

870.1200 Acute dermal

– Rabbit

(technical form) 42979502 M LD 50 = 7

. 9 mg/kg

F LD 50 = 9

. 3 mg/kg I

870.1200 Acute dermal

– Rat

(technical form) 42979501 M LD 50 = 1280 mg/kg

F LD 50 = 424 mg/kg II

870.1200 Acute dermal

– Rabbit

(20% granular form) 00132267 M LD 50 = 45.5 mg/kg

F LD 50 = 31.4 mg/kg I

870.1300 Acute inhalation

- Rat 070060 LC 50 = 0.123 mg/L II

870.2400 Acute eye irritation

- Rabbit 00078036 0.1 mL resulted in
100% mortality -

870.2500 Acute dermal irritation

- Rabbit 00048774 0.5 mL resulted in
100% mortality -

870.2600 Skin sensitization

– guinea pig N/A 1 N/A N/A

1 Requirement for dermal sensitization study waived in 1987 Registration Standard due to high acute dermal toxicity.

### Page 79 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3050 28

- Day oral

toxicity rodents

Crl:CD(SD)IGS

BR 45388501 (2001)

acceptable/nonguideline

0, 0.2, 0.5, 1.0 ppm

M 0,0.018, 0.045, 0.090
mg/kg/day

F 0, 0.021, 0.052, 0.099
mg/kg/day Systemic NOAEL = 0.09/0.099 (M/F).
Systemic LOAEL = not identified.

RBC AChE inhibition NOAEL = 0.09/0.099
(M/F).

RBC AChE inhibition LOAEL = not

identified.

870.3050 28

- Day oral

toxicity rodents

Crl:CD(SD)IGS

BR 45388502 (2001)

acceptable/nonguideline

0, 7.5, 15, 30 ppm

M: 0, 0.567, 1.159, 2.363
mg/kg/day

F: 0, 0.707, 1.366, 2.677
mg/kg/day Systemic NOAEL = 2.363/2.677 (M/F)
mg/kg/day).
Systemic LOAEL = not identified.

LOAEL for erythrocyte cholinesterase

inhibition = 7.5 ppm (

- 22%; 0.567 mg/kg/day)
in males and 30 ppm (

- 40%; 2.677 mg/ kg/day)
in females).

NOAEL for erythrocyte cholinesterase

inhibition was not established in males and is
15 ppm (1.366 mg/kg/day) in females.

870.3150 90

- Day oral

toxicity in

nonrodents 00075240 (1967)

acceptable/guideline

0, 1, 3, 100 ppm

0, 0.025, 0.075, 2.5
mg/kg/day RBC AChE inhibition NOAEL = 0.075
mg/kg/day

RBC AChE inhibition LOAEL = 2.5
mg/kg/day

Note: Brain AChE not measured. Old DER.
Only 3 dogs/group.

870.3200 21

- Day dermal

toxicity rabbits

TECHNICAL MRID 41304404 (1989)

0.03, 0.1, 1 mg/kg/day Brain and RBC AChE inhibition LOAEL = 1
mg/kg/day

Brain and RBC AChE inhibition NOAEL = 0.1
mg/kg/day

870.3200 21

- Day dermal

toxicity rats

TECHNICAL 45074602 (1990)

0.3, 1, 10 mg/kg/day RBC AChE inhibition LOAEL = 1 mg/kg/day

RBC AChE inhibition NOAEL = 0.3
mg/kg/day

Brain AChE inhibition LOAEL = 10 mg/kg/day

Brain AChE inhibition NOAEL = 1 mg/kg/day

### Page 80 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3200 28

- D ay dermal

toxicity rat

GRANULAR

FORMULATION

19.34% 45034801 (2000)

0, 100, 500, or 2000
mg/kg/day

[ 0, 19.34, 96.7, 387
mg/kg/day (corrected for
% a.i.) ] RBC AChE inhibition LOAEL = 1 9.34 mg/kg/day (♂)

RBC AChE inhibition NOAEL = not identified (♂)

RBC AChE inhibition LOAEL = 96.7 mg/kg/day (♀)

RBC AChE inhibition NOAEL = 19.34 (♀)

Brain AChE inhibition LOAEL = 96.7 mg/kg/day (♂/♀)

Brain AChE inhibition NOAEL = 19.34 mg/kg/day (♂/♀)

870.3465 4

- Week inhalation

toxicity rat

Technical 48779601 (2012)

0, 0.498, 2.05, & 6.36
μg/L RBC AChE inhibition LOAEL = 0.498 μg/L (♂/♀)

RBC AChE inhibition NOAEL = not identified ♂/♀)

Brain AChE inhibition LOAEL = 2.05 μg/L (♂/♀)

Brain AChE inhibition NOAEL = 0.498 μg/L (♂/♀)

870.3700a Prenatal

developmental in

rodents 41304402 (1989)

MATERNAL
2, 9, 18 mg/kg/day maternal NOAEL = 2 mg/kg/day

maternal LOAEL = 9 mg/kg/day based on
decreased body weight gain and increased

incidence of soft stool.

developmental toxicity NOAEL was  18
mg/kg/day, the highest dose tested

.

870.3700b Prenatal

developmental in

rabbits 41304403 (1989)

MATERNAL

0.625, 1.25, 2.5
mg/kg/day maternal and developmental NOAELs were  2.5 mg/kg/day, the highest dose tested.

870.3800 Reproduction and

fertility effects MRID 41921201 (1991)

PARENTAL parental LOAEL for systemic toxicity = 13
mg/kg/day, based on decreased body weights.

parental N OAEL for systemic toxicity = 2.3

### Page 81 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

rats 0, 1, 30, 300/150 ppm

0.08, 2.3, 24/13 mkd. ↓dose: excess mortality in

F1a pups. mg/kg/day

parental LOAEL for brain cholinesterase

inhibition = 2.3 mg/kg/day.

parental NOAEL for brain cholinesterase

inhibition = 0.08 mg/kg/day

parental NOAEL for red blood cell

cholinesterase inhibition  13 mg/kg/day, the
highest dose tested.

offspring LOAEL = 13 mg/kg/day, based on
body weight decrement.

offspring NOAEL = 2.3 mg/kg/day

870.4100b Chronic toxicity

dogs

COMBINED 1

- YEAR + 5

MONTH DOG 00 160179 , 41498601

(1986, 1990)

M: 0, 0.01, 0.025, 1.0,
10.0 mg/kg/day

F: 0, 0.01, 0.025, 1.0, 10.0
mg/kg/day RBC AChE inhibition LOAEL = 1 mg/kg/day

RBC AChE inhibition NOAEL = 0.025

mg/kg/day

Brain AChE inhibition LOAEL = 10 mg/kg/day

Brain AChE inhibition NOAEL = 1 mg/kg/day

Systemic LOAEL = 1.0 mg/kg/day, based on
decreases in red blood cell parameters in males

and females and elevations in SGPT in males.

Systemic LOAEL = 0.025 mg/kg/day

870.4200a Chronic toxicity/

Carcinogenicity

rat

Crl:CD 42530201 (1992)

M: 0, 1, 60, 600/400 ppm

0.04, 2.44, 18.38 mkd. ↓dose: signs, death, major
↓BW in 1st 2 wks.

F: 0, 1, 60, 600/400 ppm

0, 0.06, 3.56, 23.98 Systemic LOAEL = 400 ppm (18.38
mg/kg/day in males and 23.98 mg/kg/day in
females), based on reduced body weight gain,
reduced food consumption, reduced erythrocyte
count, reduced hemoglobin, and reduced

hematocrit.

Systemic NOAEL = 60 ppm (2.44 mg/kg/day

in males and 3.56 mg/kg/day in females)

LOAEL for red blood cell and brain

cholinesterase inhibition = 60 ppm (2.44
mg/kg/day in males and 3.56 mg/kg/day in
females).

### Page 82 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

NOAEL for red blood cell and brain

cholinesterase inhibition = 1 ppm (0.04
mg/kg/day in males and 0.06 mg/kg/day in
females)

870.4200b Carcinogenicity

mice 40356301, 43326001

M: 0, 0.2, 2, 30 ppm

0, 0.026, 0.254, 3.96
mg/kg/day

F: 0, 0.2, 2, 30 ppm

0, 0.032, 0.318, 4.9
mg/kg/day Systemic LOAEL = 3.96 mg/kg/day (♂) and
4.91 mg/kg/day (♀ ) based on body weight and
body weigh t gain decreases.

Systemic NOAEL = 0.254 (♂), 0.318 (♀)

870.6100b Delayed

Neurotoxicity
Study

Hen 40609401

6.5 mg/kg initially,
followed by a second oral
dose 5.3 mg/kg 21

- days

later. no clinical signs or neurohistopathology.

870.6200a Acute

Neurotoxicity

Rat (Oral gavage)

Crl:CD BR

VAF/Plus 43197701 ( 1994 )

M: 0, 5, 50, 75 mg/kg

F: 0, 5, 25, 50 mg/kg

tested blood AChE on day
2, brain on day 15 neurotoxicity LOAEL = 25 mg/kg, based on
neurobehavioral signs ( sa livation, lip
smacking, ataxia, negative pupillary
response and/or tremors) in females related

to cholinesterase inhibition.

neurotoxicity NOAEL = 5 mg/kg.

LOAEL inhibition RBC cholinesteras e = 5 mg/kg (♂)

NOAEL inhibition RBC cholinesteras e = <5 mg/kg (♂)

Note: no inhibition of brain AChE observed

870.6200a Acute

Neurotoxicity

- Rat

time course 43442402 (1994)

males: 0, 30 or 60 mg/kg
target; 0, 24.2 or 52 mg/kg

actual;

females: 0, 20 or 40 mg/kg
target; 0, 15.7 or 33 mg/kg

actual. AChE inhibition NOAEL = not identified.

AChE inhibition LOAEL < 15.7 mg/kg (20
mg/kg dose), based on inhibition of plasma,

RBC and brain AChE in females.

Neurotoxicity NOAEL = 15.7 mg/kg .

### Page 83 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

Neurotoxicity LOAE L =33 mg/kg, based on
cholinergic symptoms (tremors, excessive
salivation) in females.

870.6200b Subchronic

Neurotoxicity

Rat (Oral dietary) 43442401 (1994)

0, 4, 40 or 400 ppm
(0, 0.260, 2.648 or 27.113
mg/kg/day for males and

0, 0.306, 2.989 or 31.311
mg/kg/day for females,
respectively Systemic/n eurotoxicity NOAEL = 40 ppm (2.648
mg/kg/day).

Systemic/n eurotoxicity LOAEL = 400 ppm
(27.113 mg/kg/day) based on decreased body
weight gain/food consumption, decreased
hindlimb grip strength, motor ac tivity and
analgesic response time in males, and possible
cholinergic signs.

RBC AChE inhibition NOAEL = 4 ppm (♂/♀)

.

RBC AChE inhibition LOAEL = 40 ppm (♂/♀).

Brain AChE inhibition NOAEL = not identified (♀)

.

Brain AChE inhibition LOAEL = 4 ppm (♀).

870.6300 Developmental

Neurotoxicity

– Main Study

Rat (Oral gavage) 46364801 (2004)

0, 3, 30 and 180 ppm from

GD6

- LD21. Average

doses to the animals were

0, 0.3, 2.8 and 16.6
mg/kg/day during
gestation and 0, 0.7, 6.2
and 38.2 mg/kg/day
during lactation for the 0,
3, 30 and 180 ppm
groups, respectively. maternal LOAEL for systemic t oxicity = 180
ppm (38.2 mg/kg/day during lactation) based
on clinical signs (coarse tremors, repetitive
chewing, muscle fasciculations, and nasal
stains) and decreased body weight and body
weight gain during lactation.

maternal NOAELfor systemic toxicit y = 30
ppm (6.2 mg/kg/day during lactation)

.

maternal LOAEL for plasma AChE and RBC

AChE inhibition = 3 ppm (0.7 mg/kg/day
during lactation based on enzyme inhibition on

LD 21. T

maternal NOAEL for plasma AChE and RBC

AChE inhibition was not establish ed.

maternal LOAEL for brain AChE inhibition for
Ethoprop = 30 ppm (6.2 mg/kg/day during

### Page 84 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

lactation) based on enzyme inhibition on LD

21.

maternal NOAEL for brain AChE inhibition = 3 ppm (0.7 mg/kg/day during lactation).

offspring LOAEL for systemic toxicity = not

identified.

offspring NOAEL for systemic toxicity = 180
ppm (38.2 mg/kg/day during lactation).

offspring LOAEL for RBC AChE inhibition = 180 ppm (38.2 mg/kg/day during lactation,
respectively) based on enzyme inhibition on

PND21.

offspring NOAEL for RBC AChE inhibition = 30 ppm (6.2 mg/kg/day during lactation).

offspring LOAEL for plasma AChE and brain

AChE inhibition = 30 ppm (6.2 mg/kg/day
during lactation) based on enzyme inhibition on

PND21.

offspring NOAEL for plasma AChE and brain

AChE inhibition = 3 ppm (0.7 mg/kg/day
during lactation).

870.6300 Developmental

Neurotoxicity

– Range Finding

Rat (Oral gavage) 46364802 (2004)

0, 3, 30 or 240 ppm from

GD 6

- GD 20 (inclusive).

Mean intake based on
average consumption
during gestation weeks 2

and 3 was 0, 0.3, 2.5 and
21.4 mg/kg/day at 0, 3, 30
and 240 ppm,
respectively. maternal LOAEL for RBC and brain AChE
activity = 30 ppm. The maternal NOAEL for
RBC and brain AChE activity was 3 ppm.

fetal LOAEL = 240 ppm based on inhibition of
plasma AChE and RBC AChE activity.

fetal NOAEL = 30 ppm.

870.7485 Metabolism and

pharmacokinetics 41804301

acceptable E thoprop was administered to Crl:CD(SD)BR
rats as a single IV bolus (males and females);
single oral bolus (females, metabolism and
pharmacokinetic studies; males, metabolism
only); or by multiple oral doses. Following
oral administration, ethoprop was com pletely

### Page 85 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

absorbed and completely metabolized.
Excretion was by urinary (  50% administered
dose), fecal (7

- 16%), and respiratory (11

- 19%)
routes and was essentially complete by 48

hours. Terminal elimination t 1/2 in blood was

92

- 135 hours. Metabolism was by dealkylation

of one or both S

- propyl groups, followed by
hydroxylation and probably conjugation. Two
urinary metabolites were identified by HPLC
while 3 others were believed to be possible
conjugates of those metabolites. The TLC
profiles of fecal met abolites were similar to the
profiles for urinary metabolites.

870.7800 Immunotoxicity

male Sprague

Dawley
(Crl:CD(SD)) rats 48632501

acceptable

dietary: 0, 5, 15, or 30
ppm (equivalent to 0.4,
1.2, or 2.43 mg/kg/day,
respectively) for 4 weeks. systemic toxicity LOAEL = 5 ppm (0.4
mg/kg/day) based on reduced red blood cell
cholinesterase activity

systemic toxicity NOAEL =< 0.4 mg/kg/day.

immunotoxicity NOAEL = 30 ppm (equivalent
to 2.43 mg/kg/day), the highest tested dose.

Non

guideline Acute Comparative

Cholinesterase

-

Rat 46278701 (2004)

administered to 6 adult

rats/sex/dose at dose

levels of 0, 0.5, 1, 2, and 4
mg/kg and to 10 rat
pups/sex/dose at dose

levels of 0, 0.5, 1, and 2
mg/kg. adult LOAEL for erythrocyte cholinesterase

inhibition = 2 mg/kg (

- 22% inhibition in
males)

,

adult N OAEL for erythrocyte cholinesterase

inhibition = 1 mg/kg

.

pup LOAEL for erythrocyte cholinesterase

inhibition = 1 mg/kg (

- 17% in males)

pup N OAEL for erythrocyte cholinesterase

inhibition = 0 .5 mg/kg

.

adults NOAEL for brain cholinesterase

inhibition = 4 mg/kg , the highest dose tested.

pup LOAEL for brain cholinesterase inhibition

= 1 mg/kg (

- 10% in both males and females)

,

pup NOAEL for brain cholinesterase inhibition

= 0.5 mg/kg

.

### Page 86 of 94

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Ethoprop

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

Non

guideline Repeat

- dosing

Comparative

Cholinesterase

-

Rat 46636401 (2005)

administered to 6 young
adult Wistar rats (8

- 10
weeks old) /sex/group and
to 10 Wistar preweanling
rat pups (11 days
old)/sex/group for 11
consecutive days.

Nominal doses for a dults

were 0, 0.25, 0.5, or 1
mg/kg/day and for pups

were 0, 0.25, 0.5, or 1
mg/kg/day. In adults , the LOAEL for plasma

cholinesterase inhibition was 0.5 mg/kg/day (

- 44% in females) , the lowest dose tested. The

NOAEL in adults was <0.5 mg/kg/day . In pups
, the LOAEL for plasma cholinesterase inhibition

was 0.25 mg/kg/day (

- 24% in females) , the
lowest dose tested. The NOAEL in pups was

<0.25 mg/kg/day

.

In adults , the LOAEL for erythrocyte

cholinesterase inhibition was 1 mg/kg/day (

- 53% in males and

- 28% in females) , with a

NOAEL of 0.5 mg/kg/day . In pups , the LOAEL
for erythrocyte cholinesterase inhibition was 0.5
mg/kg/day (

- 39% in males) , with a NOAEL of

0.25 mg/kg/day

.

In adults , the LOAEL for brain cholinesterase

inhibition was 2 mg/kg/day (

- 12% in females)

, with a NOAEL of 1 mg/kg/day. In pups , the

LOAEL for brain cholinesterase inhibition was

0.25 mg/kg/day (

- 10% in males and

- 15% in
females) , the lowest dose tested. The NOAEL

was <0.25 mg/kg/day

.

### Page 87 of 94

Appendix A3. Summary of Occupational and Residential BMDL10 Values Adjusted for Toxicity Duration and Breathing Rates.

Table A 3 . Ethoprop inhalation BMDL10 values adjusted for toxicity duration and specific
breathing rates for various exposure scenarios

Population Scenario Tox 

### icity Duration 

### Adjustment BMDL 10



### (mg/L



### or mg/m 3 

### ) BMDL 10



### (mg/kg/day; breathing rate

specific)
hr/day day/wk 8.3

L/min 16.7



### L /min 29

L/min

O ccupational Handler 8 5 0.000825
mg/L 0.035

mg/kg/day 0.071

mg/kg/day 0.123

mg/kg/day

Residential Handler NA NA NA NA NA NA

Outdoor

post

- applic NA NA 0.825
mg/m 3 NA NA NA

Indoor

post

- applic NA NA NA NA NA NA

Bystander 24 7 0.147
mg/m 3 NA NA NA



### NA = not applicable

### Page 88 of 94

Appendix B. Summary of OPP’s Cholinesterase Policy & Use of BMD Modeling

OPP’s AChE policy (USEPA, 2000 25 

### ) describes the manner in which AChE data are used in human health risk assessment. The following text provides a brief summary of that document to provide context to points of departure selected.

AChE inhibition can be inhibited in the central or peripheral nervous tissue. Measurements of

AChE or AChE inhibition in peripheral tissues (e.g., liver, diaphragm, heart, lung

, etc.) are rare. As such, experimental laboratory studies generally measure b rain (central) and blood (plasma and red blood cell, RBC) AChE . Blood measures do not represent the target tissue, per se , but are instead used as surrogate measures for peripheral toxicity in studies with laboratory animals or for peripheral and/or centr al toxicity in humans. In addition, RBC measures represent AChE, whereas plasma measures are predominately butyryl

- AChE (BuChE). Thus, RBC AChE data may provide a better representation of the inhibition in target tissues. As part of the dose

response as sessment, evaluations of neurobehavior and clinical signs are performed to consider the dose response linkage between AChE inhibition and apical outcomes.

Refinements to OPP’s use of AChE data have come in the implementation of BMD approaches in dose resp onse assessment. Beginning with the OP CRA, OPP has increased its use of BMD modeling to derive PODs for AChE inhibiting compounds. Most often the decreasing exponential empirical model has been used.

OPP does have not a defined BMR for OPs. However , the 10% level has been used in the majority of dose response analyses conducted to date. This 10% level represents a 10% reduction in AChE activity (i.e., inhibition) compared to background (i.e., controls). Specifically, the BMD 10 

### is the estimated dos e where AChE is inhibited by 10% compared to background. The BMDL 10 

### is the lower confidence bound on the BMD 10



### .

The use of the 10% BMR is derived from a combination of statistical and biological considerations. A power analysis was conducted by EPA’s Office of Research and Development on over 100 brain AChE datasets across more than 25 OPs as part of the OP CRA (USEPA, 2002). This analysis demonstrated that 10% is a level that can be reliably measured in the majority of rat toxicity studies. In addi tion, the 10% level is generally at or near the limit of sensitivity for discerning a statistically significant decrease in AChE activity in the brain compartment and is a response level close to the background brain AChE level. With respect to biological considerations, a change in 10% brain AChE inhibition is protective for downstream clinical signs and apical neurotoxic outcomes. With respect to RBC AChE inhibition, these data tend to be more variable than brain AChE data. OPP begins its BMD analyses using the 10% BMR for RBC AChE inhibition but BMRs up to 20% could be considered on a case

- by

- case basis as long as such PODs are protective for brain AChE inhibition, potential peripheral inhibition, and clinical signs of neurotoxicity.

25 USEPA (2000) Office of Pesticide Programs, US Environmental Protection Agency, Washington DC 20460. August 18, 2000 Office of Pesticide Programs Science Policy of The Use of Data on Ch olinesterase Inhibition for Risk Assessments of Organophosphorous and Carbamate Pesticides.

### Page 89 of 94

Appendix C. Sum mary Tables of Benchmark Dose (BMD) Analyses

Toxicity studies with AChE data were analyzed using the most recent version of EPA’s Benchmark Dose Software (Version 2.4). Full results and technical details for these analyses can

be found in the latest BMD memo ( J

. Liccione ; 09

- 15

- 2015 ; TXR 0057238 ).

Ethoprop /Study Sex/age Compartment BMD Results

BMD 10 

### (mg/kg) BMDL 10



### (mg/kg)

MRID 46278701
CCA Acute Study

Single Dose Female

Adult Brain no dose response

Male

Adult Brain no dose response

MRID 46278701
CCA Acute Study

Single Dose Female

Adult RBC 1.09451 0.719828

Male

Adult RBC 0.649245 0.468507

MRID 46278701
CCA Acute Study

Single Dose Female

PND11 Brain 0.817231 0.624816

Male

PND11 Brain 0.961856 0.642672

MRID 46278701
CCA Acute Study

Single Dose Female

PND11 RBC 0.5498 0.4187

Male

PND11 RBC 0.570495 0.440426

Appendix Table 2.2 BMD results of repeated dosing studies ranging in duration from 11 to 37 days.



### Ethoprop /Study Sex/age Compartment BMD Results

BMD 10 

### (mg/kg/day) BMDL 10



### (mg/kg/day)

MRID 46636401
CCA Repeat
Study

- 11 days Female

Adult Brain no dose response

Male

Adult Brain no dose response

MRID 46636401
CCA Repeat
Study

- 11 days Female

Adult RBC 0.247409 0.190533

Male

Adult RBC 0.552759 0.382568

MRID 46636401
CCA Repeat
Study

- 11 days Female

PND11 Brain 0.150686 0.116861

Male Brain 0.18691 0.160026

### Page 90 of 94

Ethoprop /Study Sex/age Compartment BMD Results

BMD 10 

### (mg/kg/day) BMDL 10



### (mg/kg/day)

PND11

MRID 46636401
CCA Repeat
Study

- 11 days Female

PND11 RBC 0.1536 0.1082

Male

PND11 RBC 0.105645 0.065269

MRID 46364802
RF DNT Study

– 14 days Dams Brain 2.41108 1.84917

Dams RBC 0.163555 0.128748

MRID 46364802
RF DNT Study

– 14 days GD20 fetus Brain no adequate fit no adequate fit

GD20 fetus RBC 5.46166 1.86428

MRID 45388502

28

- day rat toxicity
study Female

Adult Brain not measured

Male

Adult Brain not measured

MRID 45388502

28

- day rat toxicity
study Female

Adult RBC 0.453912 0.349179

Male

Adult RBC 0.237535 0.207944

MRID 46364801
Main DNT Study

– 37 days Dams Brain 5.01245 1.57613

MRID 46364801
Main DNT Study

– 37 days Dams RBC 0.251676 0.22383

MRID 46364801
Main DNT Study

– 37 days Female

PND21

pups Brain 8.75985 6.40739

Male

PND21

pups Brain 5.46684 4.32517

### Page 91 of 94

Ethoprop /Study Sex/age Compartment BMD Results

BMD 10 

### (mg/kg/day) BMDL 10



### (mg/kg/day)

MRID 46364801
Main DNT Study

– 37 days Female

PND21

pups RBC 2.96579 1.88126

Male

PND21

pups RBC 4.41733 2.52439

Appendix Table 2.2 BMD results of repeated exposure studies via the dermal and inhalation routes.



### Ethoprop /Study Sex/age Compartment BMD Results

BMD 10 

### BMDL 10


### MRID 45074602

21

- Day Dermal
Toxicity

– Rats

Technical (liquid) Fem ale Brain 0.4406 0.1942

Male Brain no reliable fits

MRID 45074602

21

- Day Dermal
Toxicity

– Rats

Technical (liquid) Fem ale RBC 0.274287 0.214247

M ale RBC 0.4047 0.2702

MRID 41304404

21

- Day Dermal
Toxicity

– Rabbits

Technical (liquid) Fem ale Brain 0.901831 0.163516

M ale Brain 0.142702 0.115131

MRID 441304404

21

- Day Dermal
Toxicity

– Rabbits

Technical (liquid) Fem ale RBC 0.2035 0.1625

Male RBC no reliable fits

MRID 45034801

28

- Day Dermal
Toxicity

– Rats Fem ale Brain no reliable fits

Male Brain no reliable fits

### Page 92 of 94

Ethoprop /Study Sex/age Compartment BMD Results

BMD 10 

### BMDL 10


### Granular

formulation
(19.34% a.i.)

MRID 45034801

28

- Day Dermal
Toxicity

– Rats

Granular

formulation
(19.34% a.i.) Fem ale RBC 15.7 10.4

M ale RBC 14.8 11.1

MRID 48779601

4

- Week Inhalation
Toxicity

– Rats

Technical Fem ale Brain 1.5988 1.46858

Male Brain 1.98637 1.38417

MRID 48779601

4

- Week Inhalation
Toxicity

– Rats

Technical Fem ale RBC 2.42513 1.30211

M ale RBC 1.296 0.8245

### Page 93 of 94

Appendix D . Physical/Chemical Properties

Table D.1 Physicochemical Properties of Technical Grade Ethoprop.

Parameter Value Reference

Boiling point 86

- 91oC at 0.2 mmHg Ethoprop Registration Standard (10/20/87) pH 6.65 in saturated aqueous solution at 21oC

Density 1.097 g/mL at 15oC

Water solubility 843 ppm at 21oC

Solvent solubility Completely miscible in hexane, xylene, acetone, and ethanol

Vapor pressure 3.89 x 10

- 4 Torr at 24oC

Dissociation constant, pK a not available

Octanol/water partition coefficient, Log(K OW ) 3.59 at 21oC

UV/visible absorption spectrum not available

### Page 94 of 94

Appendix E

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

### Codex 3

§ 180.262 (a) General

. (1) ethoprop,

O

- ethyl S,S

- dipropyl phosphorodithioate O

- ethyl S,S

- dipropyl phosphorodithioate ethoprophos



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

US Canada Mexico 2 

### Codex 3

Banana 0. 02 0.02 0.02
Bean, lima 0. 02 0.09 (edible

- podded) Bean, snap, succulent 0 .02 0.09 Cabbage 0 .02 0.02 Corn, field, forage 0.02 Corn, field, grain 0. 02 0.02
Corn, field, stover 0.02 Corn, sweet, forage 0.02 Corn, sweet, kernel plus cob with husks

removed 0. 02 0.02

Corn, sweet, stover 0.02

Cucumber 0. 02 0.02 0.01 Hop, dried cones 0. 02 0.02 Peppermint, tops 0.02 0.02 Pineapple 1 0.02

Potato 0. 02 0.02 0.05 Spearmint, tops 0.02 0.02 Sugarcane, cane 0.02 0.02 0.02 Sweet potato, roots 0. 02 0.02 0.05 sweet potato MRLs with No US Equivalent Edible offal (mammalian) 0.01 (*) Meat (from mammals other than marine mammals) 0.01 (*)

Melons, except watermelon 0.02

Milks 0.01 (*) Peppers chili , dried 0.2 Peppers, sweet (including pimento or pimiento) 0.05

Strawberry 0. 02 (*) Sugar cane fodder 0. 02 (*)

Tomato 0.01 (*) Turnip, garden 0.02 (*) Completed : M. Negussie; 0 7 / 29 /201 5

1 There are no U.S. registrations as of July 23, 2009, except for existing stocks bearing old labeling whose sale, distribution , and use is allowed, provided it is consistent with the terms of the cancellation order of July 9, 2009; i.e. , the EPA will allow the technical registrant to continue to sell and distribute existing stocks of the amended registered product bearing old labelin g for use on pineapple for 18 months (until January 9, 2011) and persons other than the registrant may continue to sell and/or use existing stocks of product bearing the old labeling until such stocks are exhausted, provided that such use is consistent wit h the terms of the previously approved labeling on, or that accompanied, the modified product.

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

3 * = absent at the limit of quantitation