UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

DATE: September 15, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Ethoprop: Draft Human Health Risk Assessment for Registration Review. 

PC Code: 041101 

Decision No.: 476334 

Petition No.: NA 

Risk Assessment Type: Single Chemical/Aggregate 

TXR No.: NA 

MRID No.: 4562 15-01 

DP Barcode: D4 10028 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: NA 

CAS No.: 13194-48-4 

40 CFR: § 180.262 

Matthew Lloyd, CTH, Risk Assessor w i( ~ Katelynn King, Chemist . FROM: 

John Liccione, T ox ico 1 ogist ' c____,,~?'":::""Z:_'-:::..__-..:::..._-R..__ 

Risk Assessment Branch VIVI 

Health Effects Division (HE 

& 

Michael Barrett, Chemist 

Environmental Fate and Effect 

THROUGH: Michael Metzger, Chief '. I ~ ~ () RAB V & VJl/HED (75~)"{_ ;\, 

*hurston Morton, RARC Reviewer IJJ l. ~ Charles Smith, RARC Reviewer }-QR- ? , 

TO : Eric Miederhoff 

Chemical Review Manager 

Risk Management and Implementation Branch Il I 

Pesticide Re-Evaluation Division (PRD) (7508P) 

This document provides the HED's human health risk assessment for the Registration Review of 

Ethoprop [S,S-dipropyl 0 -ethyl phosphorodithioate]. The occupational and residential exposure 

assessment/risk assessment were provided by Matthew Lloyd (RAB57); the residue chemistry 

assessment and dietary exposure assessments were provided by Katelynn King (RAB57); and the 

hazard characterization and endpoi nt selection was provided by John Liccione (RAB57). 

Page I of93 
Page 2 of 94

Table of Contents

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

2.0 HED Recommendations.................................................................................................... 8

2.1 Data 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 Dose-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................................................................................... 37
Page 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-Occupational 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 Report ................................................................................................................. 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. Physical/Chemical Properties................................................................................. 93

Appendix E. International Residue Limits .................................................................................. 94
Page 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. The end use products are 

applied in the field using ground and soil incorporated equipment once early in the season 

(typically pre-plant). All the available 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 since ethoprop may be applied directly to growing crops and application may result in 

ethoprop reaching surface and ground water sources of drinking water. Dermal and inhalation 

exposures are anticipated for occupational handlers. There are currently no registered residential 

uses of ethoprop. There 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 database in multiple species, durations, lifestages, 

and routes. Ethoprop, unlike some other OPs, does not require metabolic activation to the oxon 

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 steady 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 the exposure scenarios. For the purposes of the nonoccupational 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 

acceptable 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-specific evaluation. There are 

two separate steady-state dermal PODs 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. Additionally, the Food Quality Protection Act 
Page 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 

exposures 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 Q1*. A quantitative cancer risk 

assessment is required (dietary and occupational handler); the Q1* for ethoprop is 2.81x10-2

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 & ssPAD), 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 subgroups1. Dietary exposure 

from food only at the 95th 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 population subgroup. 

Dietary exposure from drinking water only at the 95th 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 steadystate 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 unrefined 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 95th percentile of exposure1. 

At the 95

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 completed because even though the food only

cancer risk estimate could be refined, the water only cancer risk estimate drives the dietary 

cancer risk estimation. 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 the ethoprop Q1* of 0.0281 (mg/kg/day)-1, the cancer risk estimate for the 

U.S. general population is 7 x 10-6for food alone (based on incorporated tolerance level residues, 

DEEM default processing factors, and 100% crop treated (PCT)) and 5 x 10-5for 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 bystander 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 formulation2. HED believes a quantitative spray 

drift assessment is applicable only for pre-plant groundboom 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 scenario of a high boom and fine 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, risk estimates for the 

emulsifiable concentrate (EC) and granular (G) formulations are calculated separately because 

different dermal PODs 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 label-defined engineering controls for occupational handler mixer/loaders, 

loaders, and applicators. For mixer/loaders using the label-defined engineering controls, total 

MOEs (dermal + inhalation) range from <1-11 for the liquid formulation and 19-190 for the 

granular formulation. 

HED also evaluated the potential exposure to ethoprop using urinary concentrations of M1 (Oethyl-S-propylphosphorothioate), as an exposure biomarker in an available observational 

biomonitoring study. While the individual results 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 workers 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 with 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. Using 

the surrogate unit exposure approach, the cancer risk estimates representing label-defined 

engineering controls range from 10-4to 10-6depending 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 10-4to 10-6depending 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. 

The 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 practices, 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 Populations3".

Human Studies Review:

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 Agricultural Handler Exposure Task 

Force (AHETF) database; the Residential SOPs (Turf/Incidental Oral SOP), other registrantsubmitted 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 website4. 

 

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.html
Page 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 using 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. Abbotts, 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)

HEDRecommended 

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

Pineapple5 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 product 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 until 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.

P

O

O S

CH3

S

CH3

H3C
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 

P

S

O

S

O

H

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 Physical/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 86-91o 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 Use 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 purchased 

H3C

P

O

O S

CH3

S

CH3

H3C

P

O

O S

CH3

O

CH3

H3C

P

O

O S

CH3

OH
Page 11 of 94

and used only by certified applicators (or persons under their direct supervision). The 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 handheld 

applications are prohibited on the existing registered labels (with the exception of a backpack 

granular 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 longsleeve shirt and long pants, chemical-resistant gloves, chemical-resistant footwear plus socks, 

and a non-powered air-purifying respirator 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.

Formulation 

[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

Cucumber
Page 12 of 94

Table 3.3.1. Summary of Directions for Use of Ethoprop.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[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/preemergence

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/preemergence

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/preemergence

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 activities 
Page 13 of 94

Table 3.3.1. Summary of Directions for Use of Ethoprop.

Applic. 

Timing, Type, 

and Equip.

Formulation 

[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. There 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 and 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 Populations6." As a 

part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups 

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

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

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

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

under the National Health and Nutrition 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 circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

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 acetylcholine 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; the availability of reliable

AChE inhibition dose response data is one of the key determinants in evaluating the toxicology 

database. 

Figure 1. Adverse Outcome Pathway for OPs.

Consistent with risk assessments for other AChE-inhibiting compounds, OPP has used a 

benchmark response (BMR) level of 10% and has thus calculated BMD10’s and BMDL10’s (see 

 

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

Target 

Tissue 

Dose

Phosphorylation 

of the active site 

of AChE

Neurotoxicity

Accumulation 

of 

acetylcholine
Page 15 of 94

Appendix 1 for summary of OPP’s AChE policy). The BMD10 is the estimated dose where 

AChE is inhibited by 10% compared to background. The BMDL10 is the lower confidence 

bound on the BMD10. As a matter of science policy, the agency 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 can 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 toxicity study 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 in 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 metabolite 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 (MRID 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-life 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), Oethyl-O-methyl-S-propyl phosphorodithioate (OME), and O-ethyl-S-propyl phosphorodithioate 

(M1). . 

4.2.1 Dermal Absorption

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

since PODs for dermal exposure were selected from route-specific dermal toxicity studies
Page 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 Section 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 that 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), 

provided 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 time 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 and 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 respiration 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, the 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 protective of these 

clinical signs. There were no clinical signs 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 sensitivity 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 that 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 included 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 dietary 
Page 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 on malignant adrenal 

pheochromocytomas in male rats and is regulated with a Q1*. The Q1* 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 Exposure

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 most 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 determining 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 inhibition 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 dose 

spacing issues). 

Table 4.3.1.1 –Ethoprop BMD10 Results (mg/kg/day) for Brain and RBC AChE Inhibition Over Time in Male and Female 

Adult Rats 

Days of dosing BMD10 - RBC BMD10 - Brain

Males Females Males Females 

1

a 0.649 1.095 no dose response no dose response

11

b 0.553 0.247 no dose response no dose response

14c not applicable 0.164 not applicable 2.411

28d 0.238 0.454 not measured not measured

37e 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 BMD10 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

11

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 acute (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 

population. 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 BMD10 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 Tables 4.3.1.1 and 4.3.1.2 indicate that steady 

state may be reached by 11 ─ 14 days of exposure. Given the results in Tables 4.3.1.1 and 

4.3.1.2, for 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., 11 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 assessments 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 OP 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 science policy is based on decades 
Page 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 chlorpyrifos 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 epidemiological 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 review 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, the 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, 20137) 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 between 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 literature 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 epidemiological 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 provided 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 molecules - three dimethyl alkylphosphate 

 

7 http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0170
Page 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 exposure 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, chlorpyrifos-methyl, and triclopyr; thus exposure can be found 

 

8 http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l26opd_c_met_organophosphorus_pesticides.pdf
Page 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). Specifically, 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 

extensively 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 association 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 neurodevelopment 

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 total 

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 Bouchard, 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 (2013) 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 CHARGE 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 evidence 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, whereas 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 social 

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 between 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 inverse 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. The 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% chlorpyrifos 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)9leading to effects on the developing brain was conducted for the 2012 FIFRA SAP 

meeting (USEPA, 2012) and updated for the December 2014 chlorpyrifos 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-cholinergic 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 the 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 

developmental 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 guideline 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 reported, 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-lasting 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 uncertainties 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 assessment 

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 neurodevelopmental 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 childhood, 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 additional 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 toxicity 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.” Given 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 value of 10X has been applied. Similarly, a 
Page 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 comparisons 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 established 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 

mental 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; this 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 all 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, children, 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 deriving PODs. Neurotoxicity 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 points of departures selected for this risk assessment are 

protective of these effects. 

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

Rat and rabbit developmental toxicity studies are available and do not show any susceptibility, 

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 measurements 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 inhibition 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 are 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 this 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 uncertainties 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 

underestimate 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 PODs selected from an 

evaluation of the database. 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 POD 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 sensitive than adults to

RBC cholinesterase inhibition by a factor of >2-fold. The relative sensitivity of pups to 
Page 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 component 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 for 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 considerations: (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 possible 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 peak 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 

PODs to be derived 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 dataset appropriate for this exposure scenario (RBC and brain AChE data in pups for 

postnatal day 11 (PND11), 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 acute CCA rat study (MRID 4627801). A BMDL10 of ≈ 0.42

mg/kg/day associated with RBC AChE inhibition in female pups (PND11) was selected as a 
Page 27 of 94

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

BMD10 was ≈ 0.55 mg/kg/day. 

RBC AChE inhibition in pups was selected for the POD because BMDL10 ′s for this 

compartment were slightly lower than that estimated from the pup brain AChE data. In addition, 

the brain AChE data (in contrast to RBC AChE) for the adult rats did not provide reliable fits 

from benchmark dose analyses because of a lack of a dose-response relationship. For the adults, 

the RBC compartment is more sensitive than the brain compartment. The BMDL10 based on 

RBC AChE inhibition in PND11 females is protective of effects observed in adult rats in the 

ACN, SCN and DNT studies, 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 appropriate for the POD derivation. 

An uncertainty factor of 1000X (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 (See section 4.4)) is applied to the BMDL10 to obtain 

an acute population adjusted dose (aPAD) of 0.00042 mg/kg/day. The only population subgroup 

that the FQPA safety factor is not retained is adults 50-99; therefore, the aPAD 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 

BMDL10 of ≈ 0.07 mg/kg/day associated with RBC AChE inhibition in PND11 male pups was 

selected as a suitable PoD for the steady-state dietary (all populations) exposure scenario. The 

corresponding BMD10 was ≈ 0.11 mg/kg/day. 

This endpoint is considered appropriate for steady-state dietary exposure due to the oral route of 

administration and the duration of exposure. The study and endpoints were selected because they 

are protective of effects observed in all of the other available studies for all lifestages. The 

PND11 pup was selected because this 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:

 BMDL10 of 0.11 mg/kg/day for RBC AChE inhibition in PND11 female pups in the CCA 

(repeat dosing) rat study (MRID 46636401). 

 BMDL10′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). 

 BMDL10 of 0.13 mg/kg/day for RBC AChE in dams dosed from GD 6-20 in the rangefinding DNT study (MRID 46364802).

An uncertainty factor of 1000X (10X to account for interspecies extrapolation, 10X for 

intraspecies variation, and 10X for FQPA SF due to uncertainty in the human dose-response 
Page 28 of 94

relationship for neurodevelopmental effects (See section 4.4)) is applied to the BMDL10 to obtain 

an population adjusted dose (ssPAD) of 0.000065 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 1,000X (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 10X 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 PODs were selected for the different formulations. For the liquid 

formulation, a steady-state dermal POD was selected from a 3-week dermal toxicity study 

(MRID 41304404) on technical ethoprop in rabbits based on RBC AChE inhibition (BMDL10 ≈ 

0.16 mg/kg/day; BMD10 ≈ 0.20 mg/kg/day) in the adult female rabbit. This selection was 

supported by comparable BMDL10′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 estimates 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 BMDL10 of 0.16 mg/kg/day from the dermal rabbit toxicity study is lower 

than the acute dermal LD50 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 BMDL10 was 10.4 mg/kg/day based on 

RBC AChE 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 BMDL10 of 

10.4 mg/kg/day from the dermal study in the rat is lower than the acute dermal LD50 of 31.36 

mg/kg in the rabbit for a similar formulation (an acute dermal LD50 study in the rat was not 

available for the granular formulation). Although an acute dermal LD50 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 exposure. 

A total uncertainty factor of 1000X is appropriate for dermal exposures (10X for interspecies 

extrapolation, 10X for intraspecies variation, and 10X FQPA SF for residential assessments or a 

database uncertainty factor in occupational assessments due to uncertainty in the human doseresponse 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 RBC AChE inhibition (BMDL10 ≈ 0.82 μg/L/day; BMD10 ≈ 1.3 

μg/day/L) in the adult male rat. The particle size distribution from this study suggests that most 

particles were well below the respirable range for an aerosol, suggesting that the exposure was 

mainly via a gas. Human equivalent concentrations (HECs) and Human Equivalent Doses were 

calculated from the BMDL10 value for various scenarios (See Table 4.5.1) for extrarespiratory 

effects of a gas. For steady state inhalation exposures, a total uncertainty factor of 300X was 

applied [3X for interspecies extrapolation, 10X for intraspecies variation, and 10X database 

uncertainty factor incorporating uncertainty in the human dose-response 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

Toxicity Duration

Adjustment BMDL10

(mg/L

or 

mg/m3)

BMDL10

(mg/kg/day; breathing rate 

specific)

hr/day day/wk 8.3

L/min

16.7 

L/min

29

L/min

Occupational 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/m3

NA NA NA

Biomonitoring, Multi-route exposure, Steady State

Occupational handler biomonitoring 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 BMDL10 

of ≈ 0.065 mg/kg/day associated with RBC AChE inhibition in PND11 pups was selected as a 

suitable PoD for the biomonitoring exposure scenario. The corresponding BMD10 was ≈ 0.11 

mg/kg/day. 

A total uncertainty factor of 1000X (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 10X database uncertainty factor incorporating uncertainty in the human doseresponse 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 RBC 
Page 30 of 94

AChE inhibition. As a result, it is appropriate to combine dermal and inhalation exposures 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 

pheochromocytomas in male rats and is regulated with a Q1*. A quantitative cancer risk 

assessment is required; The Q1* 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-occupational (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-occupational 

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty /

FQPA Safety 

Factorsa

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary 

(All 

Populations 

including 

females 13-49 

years of age)

BMDL10 = 

0.4187 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 10x

Acute PAD = 

0.00042 mg/kg/day

Acute CCA Study (MRID 4627801) 

in the rat – PND11.

BMD10 = 0.5498 mg/kg/day

Inhibition of RBC AChE in PND11 

pups. 

Acute Dietary 

(Adults 50-99)

BMDL10 = 

0.4187 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute PAD = 

0.0042 mg/kg/day

Acute CCA Study (MRID 4627801) 

in the rat – PND11.

BMD10 = 0.5498 mg/kg/day

Inhibition of RBC AChE in PND11 

pups. 

Steady-State 

Dietary (all 

populations

BMDL10 = 

0.0653

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 10x

Steady State PAD 

= 0.000065

mg/kg/day

Repeat CCA Study (MRID 

46636401) in the rat – PND11.

BMD10 = 0.1056 mg/kg/day

Inhibition of RBC AChE in PND11 

pups

Steady-State 

Dietary 

(Adults 50-99)

BMDL10 = 

0.0653

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Steady State PAD 

= 0.00065

mg/kg/day

Repeat CCA Study (MRID 

46636401) in the rat – PND11.

BMD10 = 0.1056 mg/kg/day

Inhibition of RBC AChE in PND11 

pups
Page 31 of 94

Table 4.6.4.1 Summary of Toxicological Doses and Endpoints for Ethoprop for Use in Non-occupational 

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty /

FQPA Safety 

Factorsa

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Incidental 

Oral SteadyState (3 weeks 

& longer)

BMDL10 = 

0.0653

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 10x

Residential LOC = 

1,000

Repeat CCA Study (MRID 

46636401) in the rat – PND11.

BMD10 = 0.1056 mg/kg/day

Inhibition of RBC AChE in PND11 

pups

Dermal 

Steady-State

(3 weeks & 

longer)

Technical -

Liquid 

formulationa

BMDL10 = 

0.1625

mg/kg/day

UFA=10x

UFH=10x

FQPA SF= 10x

Residential LOC = 

1,000

3-week dermal toxicity study 

(MRID 41304404) in rabbits

BMD10 = 0.2035 mg/kg/day

Inhibition of RBC AChE in adult

female rabbits.

Inhalation 

Steady-State

(3 weeks & 

longer)

BMDL10 = 

0.8245

μg/L/dayb

UFA=3x

UFH=10x

FQPA SF= 10x

Residential LOC = 

300

4-week inhalation toxicity study 

(MRID 48779601)

BMD10 = 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 Q1*. The Q1* 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 human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). 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 BMDL10 values 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 in 

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

BMDL10 = 

0.1625

mg/kg/day

UFA=10x

UFH=10x

UFDB=10xb

Occupational 

LOC for MOE = 

1,000

3-week dermal toxicity study (MRID 

41304404) in rabbits

BMD10 = 0.2035 mg/kg/day

Inhibition of RBC AChE in adult female

rabbits.

Dermal –

Steady-State (3 

weeks & longer)

Granular 

formulation 

(19.3% a.i.)

BMDL10 = 

10.4 

mg/kg/day

UFA=10x

UFH=10x

UFDB = 10xb

Occupational 

LOC for MOE = 

1,000

4-week dermal toxicity study (MRID

45034801) in rats 

BMD10 = 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)

BMDL10 = 

0.8245

μg/L/daya

UFA=3x

UFH=10x

UFDB = 10xb

Occupational 

LOC for MOE = 

300

4-week inhalation toxicity study (MRID 

48779601)

BMD10 = 1.296 μg/L/day

Inhibition of RBC AChE in adult male

rat.

Biomonitoring 

Exposure 

Assessment –

Multi-route

Steady-State (3 

weeks & longer)

BMDL10 = 

0.0653

mg/kg/day

UFA= 10x

UFH=10x

UFDB = 10x Occupational 

LOC = 1,000

Repeat Oral CCA Study (MRID 

46636401) in the rat – PND11.

BMD10 = 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 Q1*. The Q1* 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 human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

a See Appendix A; Table A3 for adjusted inhalation BMDL10 values for toxicity duration and specific breathing rates for various 

exposure scenarios.

b UFDB 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, developmental 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 database. 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 and other ingredients) may have an effect in humans or wildlife similar to an effect 

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

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

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

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

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

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

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

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

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

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

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

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

chemicals identified for EDSP screening was published on June 14, 201310 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 required 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-HQOPP-2008-0560 for ethoprop). For further 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 website11.

 

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. Abbotts, 3/27/1998). 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 environmental 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, metabolite 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 Environmental 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 days 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 Koc of 109 in five test soils[1].

No degradate 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 hydrolysis 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 Comparison 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 ethoprop 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, and 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, 

D239294, 03/27/1998).

For drinking water, ethoprop is the only residue of concern that exceeds 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. 

Table 5.1.4.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance

Expression.

Matrix Residues included in Risk Assessment

Non-Cancer (Cancer) Residues included in Tolerance Expression

Plants

Primary Crop Metabolites II and III (II, III & IV) Ethoprop

Rotational Crop Metabolites II and III (II, III & IV) Ethoprop

Livestock

Ruminant Metabolites II and III (II, III & IV) Ethoprop

Poultry Metabolites II and III (II, III & IV) Ethoprop

Drinking Water Ethoprop Ethoprop

5.2 Food Residue Profile

HED has previously evaluated residue data depicting the magnitude of ethoprop residues 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 potato roots12. 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 residues 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. Perfetti, 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 residues 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 forage 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; 09-15-2015; D428028

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 studies. 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) EDWCs. EFED stated that the groundwater 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 distributions 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 DEEMFCID, Version 3.16, which incorporates consumption data from USDA’s NHANES/WWEIA. 

This dietary survey was conducted from 2003 to 2008. The analyses were performed to support 

the Registration Review of ethoprop. 

 

12 Available: CFR §180.262
Page 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 the 

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 (Q1*) 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 processing 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 the 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; D352232

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 Drinking 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; 08-04-2015; D428313

The acute assessment is unrefined; tolerance 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 95th

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 

95th percentile, 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)

95th Percentile

Acute (Water Only)

95th Percentile

Exposure 

(mg/kg/day) % aPAD Exposure (mg/kg/day) % aPAD

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; 08-04-2015; 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 unrefined 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 residues of ethoprop in water for one scenario 

(Delmarva sweet corn). These distributions were converted into 21-day rolling averages and 

incorporated into Residue Distribution Files (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 Table 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 95th percentile. The DEEM-FCID 

analysis results of water alone for the general US population and the population subgroup with 
Page 39 of 94

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

percentile respectively. 

Table 5.4.4.1. Results of Food Only & Water Only Exposure and Risk Analyses

Population Subgroup

Steady State (Food Only)

95th Percentile

Steady State (Water Only)

95th Percentile

Exposure 

(mg/kg/day) % ssPAD Exposure (mg/kg/day) % ssPAD

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), ethoprop is 

classified “likely to be carcinogenic to humans” based on malignant adrenal pheochromocytomas 

in male rats and is regulated with a Q1*. Applying the Q1* of 0.0281 (mg/kg/day)-1to the 

exposure value results in a cancer risk estimate of 7 x 10-6for 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 levels 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), steady 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 PAD and daily water consumption 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) from 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 All Infants <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-application 

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

exposure potential from spray drift.

6.1 Non-Occupational Bystander Post-Application Inhalation Exposure

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

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

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

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

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 
Page 41 of 94

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis13. 

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 available air monitoring study with two components relevant to the residential bystander 

assessment. These components include:

 Application site monitoring conducted in Siskiyou County, CA by the California Air 

Resource Board (CARB), and 

 Ambient 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 memo14. Inhalation risk 

estimates are presented below using both air concentrations measured during application 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 for 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 such 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 monitoring, 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 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).

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 concentrations 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; D421954
Page 42 of 94

steady state HEC and the available application site monitoring data is a conservative 

representation 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 arithmetic mean ethoprop air 

concentration from 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 representation 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 

samplesc

Duration of 

samples

Duration of 

sampling 

period

Maximum Air 

Concentration 

(mg/m3)

Arithmetic 

Mean Air 

Concentration 

(mg/m3)

Single-Day 

MOEsa

(LOC = 300)

Steady-state 

MOEsb

(LOC = 300)

Ambient Air Monitoringd

Siskiyou 

County, CA 

(CARB)

1998

MacDoel School –

MacDoel, CA

28

(3 above the MDL)

24-hour 1 month

2.0E-06 5.0E-07 74,000 290,000

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 6.1E-07 110,000 240,000

Newell School – Tule 

Lake, CA

29 

(none above MDL) 1.3E-06 3.4E-07 110,000 440,000

Application Site Monitoringd

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 postapplication

3 days

1.3E-04 8.1E-05 1,800 1,100

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 1.2E-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/m3) / Study maximum air concentration (ng/m3). LOC = 1000.

b. Steady-state MOE = Steady-state HEC (0.147 mg/m3) / Study arithmetic mean air concentration (mg/m3). LOC = 1000.

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/m3. For trace concentrations, assumed 

concentration halfway between MDL and Estimated Quantitation Limit (4.74 ng/m3).

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 at various areas adjacent to agricultural activity in Siskiyou County, 

CA.

e. Prevailing wind direction was generally from the Northwest.
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 concentrations 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 

representation 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 arithmetic mean ethoprop air 

concentration from the ambient air monitoring study was compared to the steady-state HEC for 

residential bystanders. The comparison of the peak ambient concentrations against the steady 

state endpoint is a conservative representation 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 include:

 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 formulation 

that is currently available on the market. 

 Most of the data utilized in this preliminary assessment are 24-hour (or less) air samples. 

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

same air concentration for 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 systems 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 analysis 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 information 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 limitations 
Page 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 assumes 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 offtarget 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 language 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 areas, 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 the agricultural applications of ethoprop. In the spray drift scenario, 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 Procedures 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 Procedures 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 residue 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 that 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 bound 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 

not allowed). Tables 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 based on an estimated deposited residue concentration as a 

result of the screening level agricultural application scenarios. Ethoprop is registered on a 

variety of agricultural crops17, and can be applied as an emulsifiable concentrate via enclosed cab 

groundboom 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 type using the 90th 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 emulsifiable 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 considered 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 sexspecific (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 femalespecific 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 rates
Page 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 estimates are summarized in Tables 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 scenario 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 reduce 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, chemical-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 

Configuration1

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

Hops
Page 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 

Configuration1

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 ethoprop
Page 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 

Configuration1

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

Hops
Page 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 

Configuration1

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 ethoprop 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 water 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 Q1*. Applying the Q1* of 0.0281

(mg/kg/day)-1to the exposure value results in a cancer risk estimate of 7 x 10-6for 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 

case 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 serine 

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 that 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 uncertainties 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 Guidance 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 

studies 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 Assessment: 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 

occupational 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 available 

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 geographic 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 beyond 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 related 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 cause 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 granules 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 Exposure 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 noncancer exposure and dose for occupational handlers are detailed in the most recent occupational 

and residential exposure (ORE) assessment memo (M. Lloyd; 09-15-2015; D421954). 

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 shortterm exposure duration endpoint selection and is considered health protective for occupational 

handlers that apply commercially 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 engineering 

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, currently 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 applications around the base of the banana tree that are 

then soil incorporated (presumably by hand by the loader/applicators). This particular application 

pattern requires use of double layer PPE, gloves, and PF10 respiratory protection. For the other 

registered uses, in addition to the engineering controls/closed system, mixer, loaders, applicators, 

and other handlers must also wear long sleeved shirt, long pants, shoes plus socks, chemicalresistant gloves, chemical-resistant apron (for mixing and loading), and 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 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). 

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 PODs 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-Cancer 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 data. Risk estimates for the emulsifiable concentrate (EC) and 

granular (G) formulations are calculated separately because different dermal PODs 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, total MOEs (dermal + inhalation) 

range from <1-11 for the liquid formulation and 19-190 for the granular formulation. For 

applicators using the label defined engineering controls, total MOEs range from <1-18 for the 

liquid formulation and 14-140 for the granular formulation, respectively. Of the evaluated 

exposure scenarios, the lowest combined MOEs 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 formulation 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].

Scenario1 Representative 

Application/Crops

Application 

Rate

(lbs ai/A)2

Area 

Treated 

(A/day)3

Dermal Dose 

(mg/kg/day)4

Dermal 

MOE5

(LOC = 

1000)

Inhalation 

Dose 

(mg/kg/day)

6

Inhalation 

MOE7

(LOC = 

1000)

Total

MOE8

(LOC = 

1000)

Mixer/Loaders

M/L

liquids: 

Chemigation

Cabbage: Field crop, 

typical 5.1

350

0.223 <1 0.00214 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].

Scenario1 Representative 

Application/Crops

Application 

Rate

(lbs ai/A)2

Area 

Treated 

(A/day)3

Dermal Dose 

(mg/kg/day)4

Dermal 

MOE5

(LOC = 

1000)

Inhalation 

Dose 

(mg/kg/day)

6

Inhalation 

MOE7

(LOC = 

1000)

Total

MOE8

(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 based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ([March, 2013]); Level of mitigation: Eng. Controls.

2 Based on registered labels (Reg. No. 5481-9041/5481-9040/5481-9042).

3 Exposure Science Advisory Council Policy #9.1.

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

5 Dermal MOE = Dermal BMDL10 (0.1625 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

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

7 Inhalation MOE = Inhalation BMDL10 (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, highacreage9 0.225 46 0.00216 57 25

Potatoes (west): 

Field crop, highacreage12 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, highacreage

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, highacreage

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 based 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 labels (Reg. No. 5481-9041/5481-9040/5481-9042).

3 Exposure Science Advisory Council Policy #9.1.

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

5 Dermal MOE = Dermal BMDL10 (10.4 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

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

7 Inhalation MOE = Inhalation BMDL10 (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 60 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) used the Mocap® 6EC formulation [EPA Reg. No. 5481-09041] of ethoprop with 

mechanical 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 assessments18, which 

 

18 Dawson, 2005; D281648 / Lloyd, 2010, D375925
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 biomonitoring 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 evaluated 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 risk 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 biomonitoring 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 results 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 estimates 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 registered 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 contribution by 

route (i.e, dermal, inhalation). While the same oral endpoint and point of departure (a BMDL10

POD of 0.065 mg/kg/day based on inhibition of red blood cell cholinesterase19) 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 the same steady-state inhalation endpoint and 

point of departure for the emulsifiable concentrate and granular formulation, while the steadystate dermal points of departure are different for the two formulations. The effect is the same 

(inhibition of red blood cell cholinesterase) for both formulations, although the point of departure 

is 65x lower20 for the granular formulation versus the emulsifiable concentration. Studies have 

shown that farmworkers receive the bulk of their potential pesticide exposure through the dermal 

route of exposure21. 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

application 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 (days 1-4). 

Mixer/loader MOEs ranged from 9-36, based on single day output for the higher application 

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 

Urine4(LOC = 1000)

Day 1 Day 2 Day 3 Day 4 Cumulative

Based on ethoprop5scaled to 3 lbs ai/A

Mixer/Loader1 35 58 140 76 15

Applicators2 850 140 580 560 83

Mixer/Loader/Applicators3

260 53 35 61 14

Based on ethoprop5scaled to 4 lbs ai/A

Mixer/Loader1 26 43 110 57 11

Applicators2 640 100 430 420 62

Mixer/Loader/Applicators3

650 260 480 430 83

Based on ethoprop5scaled to 5.1 lbs ai/A

Mixer/Loader1 21 34 84 45 9

Applicators2 500 80 340 330 49

Mixer/Loader/Applicators3

150 31 21 36 8

Based on ethoprop5scaled to 6 lbs ai/A

Mixer/Loader1 18 29 72 38 8

Applicators2 420 68 290 280 41

Mixer/Loader/Applicators3

130 27 18 30 7

Based on ethoprop5scaled to 9 lbs ai/A

Mixer/Loader1 12 19 48 25 5

Applicators2 280 45 190 190 28

Mixer/Loader/Applicators3

85 18 12 20 5

Based on ethoprop5scaled 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 

Urine4(LOC = 1000)

Day 1 Day 2 Day 3 Day 4 Cumulative

Mixer/Loader1 9 14 36 19 4

Applicators2 210 34 140 140 21

Mixer/Loader/Applicators3

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 = 

BMDL10=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 

increase 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.

The 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 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 

geographic 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 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 provides 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 signs 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 from 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 

201322. 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 2013.

 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 annual 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 identified 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 the 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 detailed 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 applications 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 use 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 application 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 estimates resulting from exposures to ethoprop were calculated using a linear lowdose extrapolation approach in which a Lifetime Average Daily Dose (LADD) is first calculated 

and then compared with a Q1* that has been calculated for ethoprop based on dose response data 

(Q1* = 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 formulation, 

the private handler cancer risk estimates range from 3.5 x 10-6to 9.6 x 10-5for mixer/loaders and 

2.0 x 10-6to 3.2 x 10-5for applicators. The commercial handler cancer risk estimates range from 

1.0 x 10-5to 2.9 x 10-4for mixer/loaders and 6.1 x 10

-6

to 9.7 x 10-5for applicators. For the 

granular formulation, the private handler cancer risk estimates ranged from 3.9 x 10-6to 5.5 x 

10-5for mixer/loaders and 1.0 x 10-6to 1.4 x 10-5for applicators. The commercial handler cancer 

risk estimates ranged from 1.2 x 10-5to 1.7 x 10-4for mixer/loaders and 3.0 x 10-6to 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 that 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 Exposure and Risk Estimates for Ethoprop [Liquid Formulation]. 

Crop or Target Exposure Scenario

Private Handler Commercial Handler

LADD (mg/kg/day)

Total LADD3

Cancer 

Risk 

Estimate4

LADD (mg/kg/day)

Total LADD3 Cancer Risk 

Estimate4 Dermal1

Inhalation2 Dermal1Inhalation2

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, highacreage

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, highacreage

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, highacreage

[

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, highacreage

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, highacreage

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 Exposure and Risk Estimates for Ethoprop [Liquid Formulation]. 

Crop or Target Exposure Scenario

Private Handler Commercial Handler

LADD (mg/kg/day)

Total LADD3

Cancer 

Risk 

Estimate4

LADD (mg/kg/day)

Total LADD3 Cancer Risk 

Estimate4 Dermal1

Inhalation2 Dermal1Inhalation2

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, highacreage

[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, highacreage

[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 × Q1

*

, where Q1

* = 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 LADD3

Cancer 

Risk 

Estimate4

LADD (mg/kg/day)

Total LADD3 Cancer Risk 

Estimate4 Dermal1

Inhalation2 Dermal1Inhalation2

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 LADD3

Cancer 

Risk 

Estimate4

LADD (mg/kg/day)

Total LADD3 Cancer Risk 

Estimate4 Dermal1

Inhalation2 Dermal1Inhalation2

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, highacreage

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, highacreage

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, highacreage

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, highacreage

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 LADD3

Cancer 

Risk 

Estimate4

LADD (mg/kg/day)

Total LADD3 Cancer Risk 

Estimate4 Dermal1

Inhalation2 Dermal1Inhalation2

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, highacreage

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, highacreage

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, highacreage

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 LADD3

Cancer 

Risk 

Estimate4

LADD (mg/kg/day)

Total LADD3 Cancer Risk 

Estimate4 Dermal1

Inhalation2 Dermal1Inhalation2

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: 

orchard5

Loader/applicator

90.8 lbs ai/A .001 0.0000332 0.000242 3.0.E-05 0.003 0.0000996 0.00314 8.8E-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 (10/30days/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 × Q1

*

, where Q1

* = 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 Cancer 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 cancer 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 assessment 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 controls 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 10-6to 5.2 x 10-6for mixer/loaders 

and 8.3 x 10-7to 1.3 x 10-6for applicators, depending on the crop/rate combination. The 

commercial handler cancer risk estimates range from 9.6 x 10-6to 1.6x 10-5for mixer/loaders and 

2.5 x 10-6to 4.0 x 10-6for 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 

Estimate4

Total LADD

(mg/kg/day)

Cancer Risk 

Estimate4

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 risk 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 cumulative 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 activities 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 

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

2, 201023. The Agency has evaluated the SAP report and has developed a Volatilization 

Screening Tool and a subsequent Volatilization Screening Analysis24. During Registration 

Review, the Agency 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 Agency'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-Application Dermal Exposure/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. Ethoprop is 

used in pre-plant and pre-emergent applications and is normally soil incorporated or watered-in. 

For both granular and EC formulations of ethoprop, HED believes the potential for postapplication exposure is low because of limited contact with the soil. Therefore, a postapplication dermal exposure 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 postapplication 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 Report

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 conjunction 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 research 

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 as needed.

HED has prepared an ethoprop incident report review (S. Recore et al., 12/02/14, D421955, 

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 effort 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 agencies, 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, 2007 to August, 2014, there were 2 incidents reported 

for single chemical only in the database. There was one additional incident reported 

involving more than one chemical. These incidents were classified as moderate severity. 

 In Aggregate IDS, from January 1, 2009 to August, 2014, there were 2 reported incidents 

involving ethoprop. These 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: reports 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 SENSORPesticides 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 potential 

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 in 

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 well 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 based on any positive report at any 

interview 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, controlling 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

significantly 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 where 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 consistent 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 264-452], 

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, applications 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 

applications 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 

changes 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, the 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 Children. Environ Health Perspectives. 

2011;119:1189-1195.

Bouchard M.F., Bellinger D.C., Wright R.O., Weisskopf M.G., (2010). AttentionDeficit/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;115:792–798.

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, Meeker, 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 

variability, 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 and 

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, Hoepner 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, Barr 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: Scientific Issues Concerning 

Health Effects of Chlorpyrifos. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP2012-0040-0002

Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, Barr DB, Furlong 

CE, Holland NT. Association Between In Utero 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 organophosphate 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 ethoprop 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 LD50 = 56.2 mg/kg

F LD50 = 30.2 mg/kg

I

870.1100 Acute oral – Rat 44472501 F LD50 = 56 mg/kg II

870.1200 Acute dermal – Rabbit

(technical form)

00078035 LD50 = 25.74 mg/kg I

870.1200 Acute dermal – Rabbit 

(technical form)

42979502 M LD50 = 7.9 mg/kg

F LD50 = 9.3 mg/kg

I

870.1200 Acute dermal – Rat

(technical form)

42979501 M LD50 = 1280 mg/kg

F LD50 = 424 mg/kg

II

870.1200 Acute dermal – Rabbit

(20% granular form)

00132267 M LD50 = 45.5 mg/kg

F LD50 = 31.4 mg/kg

I

870.1300 Acute inhalation -Rat 070060 LC50 = 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/A1 N/A N/A

1Requirement 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-Day 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 = 19.34

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 NOAEL 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

00160179, 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 weight 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 (salivation, lip 

smacking, ataxia, negative pupillary 

response and/or tremors) in females related 

to cholinesterase inhibition. 

neurotoxicity NOAEL = 5 mg/kg.

LOAEL inhibition RBC cholinesterase = 5 mg/kg

(♂)

NOAELinhibition RBC cholinesterase = <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 LOAEL =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/neurotoxicity NOAEL = 40 ppm (2.648 

mg/kg/day).

Systemic/neurotoxicity LOAEL = 400 ppm 

(27.113 mg/kg/day) based on decreased body 

weight gain/food consumption, decreased 

hindlimb grip strength, motor activity 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 toxicity = 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 toxicity = 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 established.

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

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. Following 

oral administration, ethoprop was completely 
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 t1/2 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 metabolites were similar to the 

profiles for urinary metabolites. 

870.7800 Immunotoxicity

male SpragueDawley 

(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.

Nonguideline 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 NOAEL for erythrocyte cholinesterase 

inhibition = 1 mg/kg. 

pup LOAEL for erythrocyte cholinesterase 

inhibition = 1 mg/kg (-17% in males)

pup NOAEL 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

Nonguideline 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 adults 

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 A3. Ethoprop inhalation BMDL10 values adjusted for toxicity duration and specific 

breathing rates for various exposure scenarios

Population Scenario

Toxicity Duration

Adjustment BMDL10

(mg/L

or 

mg/m3)

BMDL10

(mg/kg/day; breathing rate 

specific)

hr/day day/wk 8.3

L/min

16.7 

L/min

29

L/min

Occupational 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/m3

NA NA NA

Indoor 

post-applic

NA NA NA NA NA NA

Bystander 24 7 0.147

mg/m3

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, 200025) 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 brain (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 central 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 assessment, 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 response 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 BMD10 is the estimated dose where AChE is inhibited by 10% compared to 

background. The BMDL10 is the lower confidence bound on the BMD10. 

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 addition, 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 Cholinesterase Inhibition

for Risk Assessments of Organophosphorous and Carbamate Pesticides.
Page 89 of 94

Appendix C. Summary 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

BMD10 (mg/kg) BMDL10

(mg/kg)

MRID 46278701

CCA Acute StudySingle Dose 

Female

Adult

Brain no dose response

Male

Adult

Brain no dose response

MRID 46278701

CCA Acute StudySingle Dose 

Female

Adult

RBC 1.09451 0.719828

Male

Adult

RBC 0.649245 0.468507

MRID 46278701

CCA Acute StudySingle Dose 

Female

PND11

Brain 0.817231 0.624816

Male

PND11

Brain 0.961856 0.642672

MRID 46278701

CCA Acute StudySingle 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

BMD10

(mg/kg/day)

BMDL10 

(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

BMD10

(mg/kg/day)

BMDL10 

(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

BMD10

(mg/kg/day)

BMDL10 

(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

BMD10 BMDL10

MRID 45074602

21-Day Dermal 

Toxicity – Rats

Technical (liquid) 

Female Brain 0.4406 0.1942

Male Brain no reliable fits

MRID 45074602

21-Day Dermal 

Toxicity – Rats

Technical (liquid)

Female RBC 0.274287 0.214247

Male RBC 0.4047 0.2702

MRID 41304404

21-Day Dermal 

Toxicity – Rabbits

Technical (liquid) 

Female Brain 0.901831 0.163516

Male Brain 0.142702 0.115131

MRID 441304404

21-Day Dermal 

Toxicity – Rabbits

Technical (liquid)

Female RBC 0.2035 0.1625

Male RBC no reliable fits

MRID 45034801

28-Day Dermal 

Toxicity – Rats

Female Brain no reliable fits

Male Brain no reliable fits
Page 92 of 94

Ethoprop/Study Sex/age Compartment

BMD Results

BMD10 BMDL10

Granular 

formulation 

(19.34% a.i.) 

MRID 45034801

28-Day Dermal 

Toxicity – Rats

Granular 

formulation 

(19.34% a.i.)

Female RBC 15.7 10.4

Male RBC 14.8 11.1

MRID 48779601

4-Week Inhalation 

Toxicity – Rats

Technical 

Female Brain 1.5988 1.46858

Male Brain 1.98637 1.38417

MRID 48779601

4-Week Inhalation 

Toxicity – Rats

Technical

Female RBC 2.42513 1.30211

Male 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, pKa not available

Octanol/water partition coefficient, Log(KOW) 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 Mexico2 Codex3

§ 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 Mexico2 Codex3

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

Pineapple1 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; 07/29/2015

1There 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 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 until 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.

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

3 * = absent at the limit of quantitation