UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: March 22, 2016 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

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

PC Code: 036501 

Decision No.: 475453 

Petition No.: NA 

DP Barcode: D409347 

Registration No.: NA 

Regulatory Action: Registration Review 

Risk Assessment Type: Human Health Risk Case No.: NA 

Assessment 

TXRNo.: NA CAS No.: 95266-40-3 

MRIDNo.: NA 40 CFR: §180.189 

FROM: She~la Piper, Risk A~sesso~*~ _ 

Chns Schlosser, Tox1cologi;t r'%v ~­ Bridgett 

Registration 

Bobowiec

Action 

, Biologist 

Branch VI 

~ ~ 

Health Effects Division (7509P) 

THROUGH: Jeff Dawson, RARC Detail Reviewer 

PV Shah, RARC Detail Reviewer 

Risk Assessment Review Committee (RARC) 

Donna Davis, Branch Chief (/\,.. • . 

Risk Assessment Branch VI VJ>!U--t 

Health Effects Division (7509P) 

TO: Brian Kettl, Chemical Review Manager 

Tom Myers, Team Leader 

Kevin Costello, Branch Chief 

Risk Management and Implementation Branch IV 

Pesticide Re-evaluation Division (7508P) 

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

coumaphos ( 0, 0-diethyl 0-3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl phosphorothioate ). 

The most recent quantitative human health risk assessment was conducted in 2007 (D315769, K. 

Schumacher, 02/28/2007). The hazard characterization and endpoint selection were provided by 

Chris Schlosser; the residue chemistry assessment, dietary exposure assessments, and risk 

assessment were provided by Sheila Piper; the occupational and residential exposure assessment 
Coumaphos Human Health Risk Assessment DP#409347

Page 2 of 77

were provided by Bridgett Bobowiec; and the drinking water assessment was provided by 

Faruque Khan of the Environmental Fate and Effects Division (EFED).
Coumaphos Human Health Risk Assessment DP#409347

Page 3 of 77

Table of Contents

1.0 Executive Summary.......................................................................................................... 5

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

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

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

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

2.2.2 International Harmonization................................................................... 9

2.2.3 Recommended Tolerances........................................................................ 9

2.3 Label Recommendations.................................................................................... 10

2.3.1 Recommendations from Residue Reviews............................................ 10

2.3.2 Recommendations from Occupational Assessment............................. 10

2.3.3 Recommendations from Residential Assessment................................. 10

3.0 Introduction..................................................................................................................... 10

3.1 Chemical Identity................................................................................................ 10

3.2 Physical/Chemical Characteristics.................................................................... 11

3.3 Pesticide Use Pattern .......................................................................................... 11

3.4 Anticipated Exposure Pathways........................................................................ 15

3.5 Consideration of Environmental Justice .......................................................... 15

4.0 Hazard Characterization and Dose-Response Assessment......................................... 15

4.1 Toxicology Studies Available for Analysis........................................................ 16

4.2 Absorption, Distribution, Metabolism, & Excretion (ADME) ....................... 17

4.2.1 Dermal Absorption ................................................................................. 17

4.3 Toxicological Effects........................................................................................... 17

4.3.2 Critical Durations of Exposure.............................................................. 18

4.4 Literature Review on Neurodevelopment Effects............................................ 20

4.5 Safety Factor for Infants and Children (FQPA Safety Factor)...................... 25

4.5.1 Completeness of the Toxicology Database............................................ 25

4.5.2 Evidence of Neurotoxicity ...................................................................... 25

4.5.3 Evidence of Sensitivity/Susceptibility in the Developing or Young 

Animal.................................................................................................................. 25

4.5.4 Residual Uncertainty in the Exposure Database.................................. 26

4.6 Toxicity Endpoint and Point of Depature Selections....................................... 26

4.6.1 Dose-Response Assessment .................................................................... 26

4.6.2 Oxon Toxicity Adjustment Factor......................................................... 30

4.6.3 Recommendations for Combining Routes of Exposures for Risk...... 31

4.6.4 Cancer Classification and Risk Assessment Recommendation .......... 31

4.6.5 Summary of Points of Departure and Toxicity Endpoints Used in 

Human Risk Assessment .................................................................................... 32

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 Metabolite Pathways.................................................... 34

5.1.4 Residues of Concern Summary and Rationale..................................... 35
Coumaphos Human Health Risk Assessment DP#409347

Page 4 of 77

5.2 Food Residue Profile........................................................................................... 35

5.3 Water Residue Profile......................................................................................... 35

5.4 Dietary Risk Assessment .................................................................................... 37

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

5.4.4 Steady State Dietary Risk Assessment.................................................. 39

5.4.5 Cancer Dietary Risk Assessment........................................................... 40

6.0 Residential and Other Non-Occupational Exposure and Risk Estimates................. 41

6.1 Residential Risk Estimates for Use in Aggregate Assessment ........................ 41

6.2 Non Occupational Spray Drift Exposures and Risk Estimates...................... 41

6.3 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates.......................................................................................................................... 41

7.0 Aggregate Risk Assessments and Risk Characterization............................................ 41

7.1 Acute Aggregate Risk ......................................................................................... 42

7.2 Steady State Aggregate Risk.............................................................................. 42

7.3 Cancer Aggregate Risk....................................................................................... 42

8.0 Cumulative Risk Characterization/Assessment........................................................... 42

9.0 Occupational Exposure/Risk Characterization ........................................................... 43

9.1 Occupational Handler Exposure/Risk Estimates............................................. 43

9.2 Occupational Post-application Exposure/Risk Estimates............................... 55

9.2.1 Occupational Post-Application Inhalation and Dermal Exposure..... 55

10.0 Incident Report ............................................................................................................... 56

11.0 References........................................................................................................................ 57

Appendix A: Toxicology............................................................................................................. 58

A.1 Toxicity Profile .................................................................................................... 58

A.2: Toxicology Profile and Executive Summaries.............................................................. 62

A.2.1 Toxicology Data Requirements.......................................................................... 62

A.2.2 Toxicity Profiles .................................................................................................. 63

A.3: Hazard Identification and Toxicity Endpoint Selection.............................................. 69

A.4: Executive Summaries for Studies Selected as Basis of PoDs ...................................... 71

Appendix B: Physical/Chemical ................................................................................................ 74

Appendix B.1: Physical/Chemical Properties........................................................................... 74

Appendix B.2: International Residue Limits for Coumaphos................................................ 75

Appendix C: Summary of Occupational Non-Cancer Algorithms ........................................ 76

Appendix D: Review of Human Research ................................................................................ 77
Coumaphos Human Health Risk Assessment DP#409347

Page 5 of 77

1.0 Executive Summary

Coumaphos is a broad spectrum organophosphate (OP) insecticide/acaricide used to control 

arthropod pests on beef cattle, dairy cows, goats, horses, sheep, swine and swine bedding. The 

chemical is also embedded into livestock ear tags and bee hive strips. There are currently no 

registered residential (non-occupational) uses for coumaphos.

Coumaphos is formulated as a technical 96% active ingredient (a.i.), as well as a dust 

formulation intermediate (25% a.i.), a dust (1% a.i.), an emulsifiable concentrate (6.15 and 11.6 

% a.i.), and a flowable concentrate (42% a.i.). Coumaphos is also embedded into cattle ear tags, 

(20% a.i) and bee hive pest control strips (10% a.i). The bee hive pest control strips can be 

applied year around, including during honey flow (honey accumulation) and can remain in the 

hive for up to 45 days. The application of coumaphos to livestock can include use of the 

following equipment: swim and hydraulic dip vats, shaker cans, dust bags, back oilers/rubbers, 

mechanically and manually pressurized handguns, backpacks, and ear tags. Use of coumaphos 

in dip vats to control pests on cattle livestock is limited to employees of the U.S. Department of 

Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) and are enrolled in a

cholinesterase monitoring program. Mechanical dusting is prohibited and there are label 

restrictions on the number of livestock and area per day. Applicators are restricted to spraying 

no more than 100 animals in one day at maximum application rate and 200 animals a day at one 

half the maximum application rate. In addition, applicators are limited to dusting no more than 

25 animals in one day and no more than 1,000 square feet of swine bedding in one day. 

Coumaphos, like other OPs, binds to and phosphorylates the enzyme, acetylcholinesterase 

(AChE), in both the central brain and peripheral nervous systems leading to accumulation of 

acetylcholine and, ultimately, to clinical signs of toxicity. Coumaphos requires metabolic 

activation of the oxon metabolite to inhibit AChE. For coumaphos, AChE inhibition is the most 

sensitive endpoint in the toxicology database in multiple species, durations, lifestages, and 

routes. 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. Therefore, steady state exposure assessments of 21 days 

and longer were conducted instead of the traditional short and intermediate term assessments. 

The toxicology database for coumaphos is complete, with the exception of a subchronic 

inhalation study and a coumaphos oxon comparative cholinesterase assay (CCA) study. HED’s 

Hazard Science Policy Council (HASPOC) determined, based on a weight of evidence (WOE) 

approach that a subchronic inhalation toxicity study is required for coumaphos due to 

unacceptable inhalation risk estimates using the current point of departure (PoD) from an oral 

study. The toxicological PoDs are based on the results of benchmark dose (BMD) analyses 

where appropriate, and WOE consideration of all reliable data. A PoD for the acute dietary (all 

populations) exposure scenario was derived from the results of an acute CCA rat study

conducted with coumaphos. A benchmark dose lower limit for 10% response (BMDL10) of 0.19 

mg/kg/day associated with RBC ChE inhibition in adult males was selected. No sensitivity was 

observed to PND 11 pups following acute exposure. Therefore, this BMDL10 is protective of 

RBC AChE inhibition in PND11 pups, as the BMDL10 for pups was 0.25 mg/kg. A PoD for the 

steady state dietary (all populations) exposure scenario was derived from the results of a 2 
Coumaphos Human Health Risk Assessment DP#409347

Page 6 of 77

generation rat reproduction study. The BMDL10 is 0.04 mg/kg/day for RBC ChE inhibition in 

both sexes of the F0 and F1 generations. The acute and steady state PoDs are based on the most 

sensitive BMDL10s for RBC AChE (the most sensitive compartment), and thus are protective of 

the observed sensitivity of juvenile rats following repeated exposure.

Coumaphos requires bioactivation to the oxon to allow AChE inhibition; however, no data were 

submitted regarding the toxicity of the oxon. Although oxon CCA data are not available for 

coumaphos, EPA plans to move forward with the coumaphos human health risk assessment 

without toxicity data for coumaphos’s oxon degradate. Due to the lack of coumaphos-specific 

oxon CCA data, EPA has used an oxon toxicity adjustment factor of 50X in its calculations (See 

Section 4.6.2). Also, there is uncertainty in the human dose-response relationship for 

neurodevelopmental effects and this warrants retention of the FQPA Safety Factor (10X) for the 

population subgroups that include infants, children, youth, and women of childbearing age for all 

exposure scenarios. Additionally, there is a data gap for coumaphos for a subchronic inhalation 

study. Therefore, a total database uncertainty factor of 30X, to account for the uncertainty in the 

human dose-response relationship for neurodevelopmental effects and the lack of an inhalation

study, will be used for coumaphos for the population subgroups that include infants, children, 

youth, and women of childbearing age for inhalation exposure scenarios. 

Coumaphos is classified as “not likely to be carcinogenic in humans” based on lack of evidence 

of carcinogenicity in rats and mice. A quantitative cancer risk assessment is not required.

The existing residue chemistry database for coumaphos is adequate for risk assessment purposes. 

The residue of concern in plants and animals for both tolerance expression and risk assessment 

includes coumaphos and its oxygen analog, coumaphoxon. The residue of concern for risk 

assessment purposes in drinking water is coumaphos and coumaphoxon. The Environmental Fate 

and Effects Division (EFED) performed surface water and groundwater modeling using the 

highest application rates. The highest estimated drinking water concentrations were from surface 

water modelling. The drinking water assessment assumed that during a rain event, coumaphos 

wash-off from treated cattle can be potentially adsorbed into manure as well as transported as 

effluent from concentrated animal feeding operations and pasture/rangeland. 

The acute and steady state dietary exposure and risk assessment incorporated PDP monitoring 

data for honey, milk and livestock commodities, assumes a 50x toxicity adjustment factor (TAF) 

for coumaphoxon in drinking water only, DEEM default processing factors, and assumed all 

hives and livestock are treated (100% crop treated (CT)). Acute assessments exposure estimates 

are below HED’s level of concern (LOC; <100% of the acute population adjusted dose (aPAD)) 

for the U.S. population and all population subgroups. The food only dietary exposure estimate is 

50% of the acute population adjusted dose (aPAD) for the U.S. population, and 98% of the 

aPAD for children 3-5 years old, the most highly exposed population subgroup at the 99.9th

percentile. Combined dietary exposure from food and drinking water at the 99.9th percentile of 

exposure is 51% of the aPAD for the U.S. population and 99% of the aPAD for children 3-5 

years, the most highly exposed population subgroup.

Steady-state assessments were conducted in the DEEM acute module using the steady-state 

endpoint, monitored food residues, and 21-day rolling water averages to provide an estimate of 
Coumaphos Human Health Risk Assessment DP#409347

Page 7 of 77

21-day (“steady-state”) average daily exposures. Steady-state assessments exposure estimates are 

above HED’s LOC (>100% of the steady state population adjusted dose (ssPAD)) for the U.S. 

population and all population subgroups, except adults 50-99 years old. The food only dietary 

exposure estimate is 210% of ssPAD for the U.S. population, and 380% of the ssPAD for 

children 1-2 years old, the most highly exposed population subgroup at the 99.9th percentile. 

Combined dietary exposure from food and drinking water is 210% of the ssPAD for the U.S. 

population and 390% of the ssPAD for children 1-2 years, the most highly exposed population 

subgroup. Beef meat is the risk driver when combining food in the steady state assessment for 

coumaphos, accounting for approximately 90% of estimated exposure in the dietary assessment 

based upon critical exposure contribution analysis.

There are currently no registered uses of coumaphos in or around residences; therefore, risk 

assessments for residential (non-occupational) exposure are not warranted at this time. A nonoccupational bystander spray drift assessment was not performed for coumaphos at the time 

because of the limited use pattern on livestock.

The acute and steady state aggregate assessment for coumaphos includes only food and water 

exposures. Residential aggregate exposure assessments are not required since none of the 

currently registered uses result in residential exposure. Because coumaphos has been classified 

as a “not likely human carcinogen”, a cancer aggregate risk assessment is not required. 

Occupational exposure is possible with use of products containing coumaphos applied as both 

liquid sprays/solutions and as solids. The “steady state” endpoint selection for coumaphos 

overlaps with HED’s traditional short-term 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). Chronic exposure is not expected for the 

registered uses. 

Based on the use patterns of coumaphos, there are eight major handler exposure scenarios 

assessed in this memorandum: mixing/loading liquids for hydraulic type dip vats; mixing/loading 

liquids for swim type dip vats; mixing/loading liquids for back rubber/oilers; loading dust into 

bags; applying dusts with a shaker can to livestock or swine bedding; mixing/loading/applying 

liquids for backpack, mechanically pressurized handguns, and manually pressurized hand-wands. 

Exposure to applying ear tags and bee hive control strips were not quantitatively assessed.

Personal protective equipment, or PPE, mandated on coumaphos labels varies depending on the 

type of formulation (liquid or dust) and maximum application rate. Coumaphos labels require 

gloves for handlers however respirator requirement is inconsistent across labels. A total 

aggregated risk index (ARI) was used as a risk metric to account for the different LOCs between 

dermal (LOC = 1,000) and inhalation (LOC = 3,000) exposure. Occupational exposure scenarios 

for all formulations types and application rates were of concern (ARIs < 1) at both label required 

PPE and additional mitigation PPE levels. The one exception of this was mixing and loading 

liquid products EPA registration numbers 11556-115 and 11556-23 for livestock back oil rubbers 

(ARI = 1 with double layer dermal protection and PF5 respirator).
Coumaphos Human Health Risk Assessment DP#409347

Page 8 of 77

A quantitative dermal post-application exposure was not conducted for coumaphos uses. The 

amount of dermal exposure to post-application workers is likely to be substantially lower than 

the exposure to handlers, therefore, the handler assessment would also be protective of risks to 

post-application workers. In addition, coumaphos labels include the language, "Do not contact 

treated animals until sprays have dried and dusts have settled on the coat."

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for coumaphos 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 coumaphos.

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 studies from 

Pesticide Handler Exposure Database (PHED) 1.1; and the Agricultural Handlers Exposure Task 

Force (AHETF) database; submitted to the Agency by the registrant 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 website1

. 

2.0 HED Recommendations

2.1 Data Deficiencies

The database of toxicology studies for coumaphos is complete, with the exception of a 

subchronic inhalation study and a coumaphos oxon comparative cholinesterase assay (CCA) 

study.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical 

For the purpose of registration review, adequate methods are available for the enforcement of the 

established tolerances for residues in/on honey and honeycomb. Adequate LC/MS/MS methods

(Bayer Methods 75043 and 75044) are available for enforcing tolerances for coumaphos and its 

oxygen analog (coumaphoxon, also referred to as coumaphos-PO) residues in honey and 

beeswax. Additionally, the FDA multi-residue methods are also adequate for determining 

residues of coumaphos and its oxygen analog in honey. It is not known whether the methods are 

adequate for determining either coumaphos or its oxygen analog in beeswax (honeycomb).

 1 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data

and http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-post-applicationexposure
Coumaphos Human Health Risk Assessment DP#409347

Page 9 of 77

For the purpose of registration review, an adequate method is available to enforce the established 

milk and livestock tolerances. The GC-NPD enforcement method 74310 adequately recovers

residues of coumaphos and coumaphoxon from milk and livestock tissues.

2.2.2 International Harmonization 

There are currently no Mexican or Codex maximum residue limits (MRLs) for coumaphos; there 

are Canadian MRLs set at 0.5 mg/kg (calculated on the fat content) for coumaphos (defined as 

coumaphos, per se) in meat, meat byproducts, and fat of cattle, goats, horses, hogs, poultry, and 

sheep. The U.S. tolerances for residues in livestock commodities are set at 1.0 ppm to account 

for the parent and its oxygen metabolite at the limit of quantitation (LOQ). A Canada MRL of 

1.0 ppm was proposed based on the method limit of quantitation for beeswax. A U.S. tolerance 

is based on the use of coumaphos-impregnated strips in beehives, and HED recommends in favor 

of the establishment of permanent tolerances for the combined residues of coumaphos and its 

oxygen analog at 0.15 ppm in honey, and 45 ppm in honeycomb. A U.S. tolerance on 

honeycomb adequately covers beeswax; therefore, a tolerance was not recommended for 

beeswax. Refer to Appendix B.2 for complete summary of international tolerances.

2.2.3 Recommended Tolerances 

Permanent tolerances have been established in 40 CFR §180.189 for the combined residues of 

coumaphos (O,O-diethyl O-3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl phosphorothioate 

and its oxygen analog (O,O-diethyl O-3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 

phosphate). The established tolerances shown below have not be changed and only the tolerance 

expression should be revised.

The tolerance expression for coumaphos has been reviewed and should be updated as follows 

based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

Tolerances are established for residues of the insecticide coumaphos, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only the 

sum of coumaphos (0,0-diethyl 0-(3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl) 

phosphorothioate) and its oxygen analog (0,0-diethyl 0-(3-chloro-4-methyl-2-oxo-2H1-benzopyran-7-yl phosphate, calculated as the stoichiometric equivalent of 

coumaphos.

Honey.................................................................................................0.15 ppm

Honeycomb........................................................................................45 ppm

Cattle, fat............................................................................................1.0 ppm

Goat, fat..............................................................................................1.0 ppm

Hog, fat ..............................................................................................1.0 ppm

Horse, fat............................................................................................1.0 ppm

Sheep, fat............................................................................................1.0 ppm

Cattle, meat ........................................................................................1.0 ppm

Goat, meat..........................................................................................1.0 ppm
Coumaphos Human Health Risk Assessment DP#409347

Page 10 of 77

Hog, meat...........................................................................................1.0 ppm

Horse, meat ........................................................................................1.0 ppm

Sheep, meat........................................................................................1.0 ppm

Cattle, byproducts..............................................................................1.0 ppm

Goat, byproducts................................................................................1.0 ppm

Hog, byproducts.................................................................................1.0 ppm

Horse, byproducts..............................................................................1.0 ppm

Sheep, byproducts..............................................................................1.0 ppm

Milk Fat..............................................................................................0.5 ppm

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews 

None

2.3.2 Recommendations from Occupational Assessment 

A summary of the risk estimates have been provided, and shows that there are risk estimates of 

concern for registered uses of coumaphos based on the label-required personal protective 

equipment for occupational workers. Mechanical dusting is prohibited yet appears on some of 

the dust formulated labels (Co-Ral Bulk Dust (1%) [34704-267, and Co-Ral (1%) [960-184].

Label corrections/revisions should be made to remove all mechanical dusting and inconsistent 

respirator requirements including the TC21C respirator nomenclature.

HED continues to recommend that registrants submit more information on quarantine dipping 

practices to comply with 40 CFR 158.1070 post-application guidelines including use pattern 

information (e.g., cattle dipped per day, number of days dipping takes place per year, and etc.) in 

order to clarify and refine exposure scenarios. 

2.3.3 Recommendations from Residential Assessment 

None

3.0 Introduction

3.1 Chemical Identity

Coumaphos is an organophosphate insecticide/acaricide currently used for the control of mites 

and insects on livestock. The chemical structure and nomenclature of coumaphos are presented 

in Table 3.1.
Coumaphos Human Health Risk Assessment DP#409347

Page 11 of 77

Table 3.1. Coumaphos Nomenclature.

Chemical Structure

Common Name Coumaphos

Molecular Formula C14H16ClO5PS

Molecular Weight 362.78

IUPAC Name O-3-chloro-4-methyl-2-oxo-2H-chromen-7-yl O,O-diethyl phosphorothioate

CAS Name O-(3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl) O,O-diethyl phosphorothioate

CAS Registry Number 56-72-4

Chemical Class Organophosphate

Coumaphos-oxon

Molecular Formula C14H16ClO6P

Molecular Weight 346.7

CAS Name 0,0-diethyl 0-(3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl phosphate

CAS Registry Number 321-54-0

3.2 Physical/Chemical Characteristics

The physiochemical properties of coumaphos are summarized in Appendix B.1. Technical 

coumaphos is a grey to tan powder with a slight sulfur odor. Volatilization from moist and dry 

soil surfaces is not expected to be an important fate process based upon an estimated Henry's 

Law constant of 3.1 X 10-8 atm-cu m/mole and this compound's vapor pressure (9.7 x 10-8 mm 

Hg), respectively. Although it is stable in water, coumaphos hydrolyzes slowly in alkaline 

conditions. If released into water, coumaphos is expected to adsorb to suspended solids and 

sediment in water based upon the estimated Koc (1874-10297 L/kg

3.3 Pesticide Use Pattern

Coumaphos is formulated as a technical 96% active ingredient, (a.i.) as well as a dust 

formulation intermediate (25% a.i.), a dust (1% a.i.), an emulsifiable concentrate (6.15 and 11.6

%a.i.), and a flowable concentrate (42%a.i.). Coumaphos is also embedded into cattle ear tags, 

(20%a.i.) and bee hive pest control strips (10%a.i.). Multiple applications to livestock and/or 

livestock areas are permitted during a one year period. There are, however, label restrictions on 

the amount of livestock and livestock area treated per day. Applicators are restricted to spraying 

no more than 100 animals in one day at maximum rate or 200 animals a day at half of the 

maximum rate. There are also limits on dusting no more than 25 animals in one day and 

applying coumaphos to no more than 1,000 square feet of swine bedding in one day. 

O O

Cl

O

P

S

H5C2O

OC2H5

CH3
Coumaphos Human Health Risk Assessment DP#409347

Page 12 of 77

Application of coumaphos to livestock can include the use of the following equipment: swim and 

hydraulic dip vats, shaker cans, dust bags, back oilers/rubbers, mechanically and manually 

pressurized handguns, backpacks, and ear tags. Application rates range from 0.005 to 0.025 lbs

a.i. per gallon for sprays or dips, 0.076 lbs a.i. per gallon of oil for back-rubbers, 0.000625 to 

0.013 lbs a.i. per animal for dust application, and 0.000042 lbs a.i. per 1000 square feet of swine 

bedding treatment. 

Labels vary considerably with respect to requirements for work attire and personal protective 

equipment (PPE). The product Co-Ral Flowable, EPA registration number 11556-98, which has 

the highest maximum spray application rate requires single layer dermal attire with the addition 

of gloves and a PF10 respirator. This product is restricted to employees of the USDA-APHIS2

who are enrolled in the USDA-APHIS cholinesterase monitoring program. The USDA’s Cattle 

Fever Tick Eradication Program (CFTEP) uses this product solely in Texas. The products EPA 

registration numbers 11556-115 and 11556-23 have lower spray application rates however do not 

require respirators for handlers. The dust coumaphos formulations products require dermal 

baseline attire (long sleeved shirt, pants, shoes and socks) along with gloves and at least a PF5 

respirator. Table 3.3 provides a summary of the registered uses of coumaphos for each of the 

formulated products sorted by livestock type.

 2 APHIS- Animal and Plant Health Inspection Service
Coumaphos Human Health Risk Assessment DP#409347

Page 13 of 77

Table 3.3. Summary of Directions for Use of Coumaphos.

Application

Timing, Type, 

and Equip.

Formulation 

(% ai.)

[EPA Reg. No.]

Maximum 

Application

Rate 

Max. No. 

Application

per Season

Max. 

Application 

Rate or 

Treatment 

Interval

Use Directions and Limitations

Cattle/Horses

Swim Dip Vat

Cattle only

Co-Ral Flowable Concentrate 

(42%)

[11556-98 ]

0.025 lbs 

ai/gallon of 

spray

2 times/year Do not make 

applications less 

than 10 days 

apart.

RUP1 and use is restricted to employees of the USDA APHIS2 who 

are enrolled in the USDA-APHIS cholinesterase monitoring 

program. For beef and non-lactating dairy cattle and horses. Charge 

dip vats with concentration of product and volume of water. Do not 

tip excessively thirsty animals. Applicators using handheld sprayers 

are limited to 100 animals are day at maximum application rate and 

200 animals a day at 1⁄2 the maximum application rate. Apply as high 

pressure spray to wet the skin to run-off. Repeat applications as 

necessary. Respirator requirement. 

Hydraulic Dip 

Vats

Cattle only

Manual and 

Mechanical Spray 

Cattle and Horses

0.021 lbs 

ai/gallon of 

spray

6 times/year

Manual and 

Mechanical Spray 

Cattle and Horses

Co-Ral Fly and Tick Spray (6.15%) 

[11556-115], 

And

Co-Ral Emulsifiable Livestock 

Insecticide (11.6%) [11556-23]

0.01 lbs 

ai/gallon of 

spray

6 times/year

Do not make 

applications less 

than 10 days 

apart.

Re-treatment 

only necessary 

when insects 

reappear.

11.6 % is a RUP. Lactating and young cattle are subject to lower 

application rates. Do not apply rate above 0.0025 lb ai/gallon within 

14 days of freshening. Do not apply on animals less than 3 months 

old. Do not spray animals for 10 day before shipping or weaning. 

Label limits handler to 100 applications to cattle a day and 200 a day 

if treated at 1⁄2 the maximum application rate. Apply for complete 

wetting to run-off. Do not contact treated animal until coats are dry. 

Do not spray in confined area. Do not use in conjunction with other 

OPs.

Back Rubbers Oil

Cattle 

Co-Ral Fly and Tick Spray (6.15% 

ai) [11556-115],

And 

Co-Ral Emulsifiable Livestock 

Insecticide (11.6%) [11556-23]

0.076 lbs ai/ 

gallon of 

fuel 

unknown

Re-treatment 

only necessary 

when insects 

reappear and 

constitute a 

problem.

For dairy cattle suspend at height that will prevent straddling. No 

interval needed between treatment and slaughter or use of milk. 

Back rubber application for horn files and face flies. Mix specified 

dosage in 1 gallon of No. 2 fuel oil. Hang so no dairy cattle can 

straddle. No interval required between treatment and slaughter or 

milk use.

Dust Bags and 

Shaker Can 

Cattle, Horses, 

Swine, Swine 

Bedding

Co-Ral Animal Insecticide (1%) 

Bulk Dust [11556-14], 

Co-Ral Shaker Can (1%) [11556-4], 

Co-Ral Bulk Dust (1%) [34704-267], 

Shaker Duster (1%) [69208-1]

Y-Tex Co-Ral (1%) [39039-15],

D- Louse (1%) [34704-306],

Diolice (1%) [2393-378], 

Co-Ral (1%) [960-184], 

Zipcide Dust Bag (1%) [960-169]

0.125 lbs 

ai/bag 

0.0013 lbs 

of ai/cattle

Shaker can: 

12 

times/year 

cows 

6 times/year 

horses

unknown

10 days apart. 

No interval 

required 

between 

treatment and 

slaughter or 

between 

treatment and 

use of milk. 

Mechanical dusters are prohibited. For lactating dairy cows suspend 

bags in exit of milking barn. Limit number of animals can treat/day 

to no more than 25 animals and 1,000 feet of swine bedding. One 

12.5 lb duster per 25 animals. For direct application by shaker can 

animals dusted using no more 2 oz. of dust per animal. PPE baseline 

plus gloves.
Coumaphos Human Health Risk Assessment DP#409347

Page 14 of 77

Table 3.3. Summary of Directions for Use of Coumaphos.

Application

Timing, Type, 

and Equip.

Formulation 

(% ai.)

[EPA Reg. No.]

Maximum 

Application

Rate 

Max. No. 

Application

per Season

Max. 

Application 

Rate or 

Treatment 

Interval

Use Directions and Limitations

Ear Tags

Beef and Non 

Lactating Dairy 

Cattle 

Corathon (15%) [11556-148], 

And

Co-Ral Plus Insecticide Cattle Ear 

Tag (20%) [11556-123]

20%a.i., 

15% Replace as necessary

0.5 oz (14 grams ) per tag. Wear chemical resistant glove when 

applying tags. All mature animals should be tagged. Attach one tag 

to each ear. Do not use on cattle less than 3 months old.

Remove tags at end of fly season prior to slaughter.

Swine

Shaker Can

Co-Ral Emulsifiable Livestock 

Insecticide (11.6%) [11556-14], 

Co-Ral Shaker Can (1%) [11556-4], 

Co-Ral Bulk Dust (1%) [34704-267], 

Shaker Duster (1%) [69208-1], 

Y-Tex Co-Ral (1%) [39039-15], 

D- Louse (1%) [34704-306], 

Diolice (1%) [2393-378], 

Co-Ral (1%) [960-184]

0.000625 

lbs ai/pig

6 times a 

year

Do not make 

applications less 

than 10 days 

apart. 

Mechanical dusters are prohibited. Limit number of pig can treat 

per day to 25. Do not enter allow contact with animals until dust has 

settled.

Mechanical and 

Manual Spray 

Co-Ral Fly and Tick Spray (6.15% 

ai) [11556-115], and Co-Ral 

Emulsifiable Livestock Insecticide 

(11.6%) [11556-23]

0.005 lbs ai/ 

gallon of 

spray

6 times a 

year

Do not make 

applications less 

than 10 days 

apart.

Label limits handler to 100 applications to swine a day at maximum 

application rate. Do not contact treated animal until coats are dry.

Do not spray animals for 10 days before shipping or weaning. Do 

not spray in confined area. Do not use in conjunction with other 

OPs.

Swine Bedding

Shaker Can

Co-Ral Emulsifiable Livestock 

Insecticide (11.6%) [11556-14], 

Co-Ral Bulk Dust (1%) [34704-267, 

Shaker Duster (1%) [69208-1],

D- Louse (1%) [34704-306], 

Diolice (1%) [2393-378],

Co-Ral (1%) [960-184]

4.5 x 10-

5 lbs ai/ft2

6 times a 

year

Do not make 

applications less 

than 10 days 

apart.

Apply 2 oz. uniformly over 30 square feet of fresh dry bedding. 

Limit area of swine bedding treated per day to 1000 ft2.

Bee Hives

Bee Hive Strips Checkmite + Bee Hive Pest Control 

Strip (10%ai) [11556-138]

10%ai by 

weight

Twice a year for Varroa mites 

and no more than four times 

for small hive beetle.

Leave strips in hive for at least 42 days but not over 45 days.

1 Restricted Use Pesticide (RUP)

2 U.S. Department of Agriculture Animal and Plant Health Inspection Service (USDA-APHIS)
Coumaphos Human Health Risk Assessment DP#409347

Page 15 of 77

3.4 Anticipated Exposure Pathways

The Pesticide Re-Evaluation Division (PRD) has requested an assessment of human health risk 

to support the registration review of all existing registered uses of coumaphos. Humans may be 

exposed to coumaphos in food since coumaphos may be applied directly to animals resulting in 

secondary residues in milk and livestock commodities for human consumption and may be used 

in strips in hives resulting in residues in honey and honeycomb. Additionally, humans may be 

exposed to coumaphos in drinking water since coumaphos wash-off from treated cattle can come 

into contact with and be adsorbed onto manure as well as transported as runoff, reaching surface 

and ground water sources of drinking water. There are no residential uses of coumaphos, so 

there is not likely to be exposure in residential or non-occupational settings. In an occupational 

setting, applicators may be exposed while handling the pesticide prior to application, as well as 

during application. Occupational post-application exposure is not expected due to the use pattern 

on livestock and embedded product formulations for ear tags and beehive strips. This risk 

assessment considers all of the aforementioned exposure pathways based on the existing uses of 

coumaphos.

3.5 Consideration of Environmental Justice

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

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled from the U.S. Department of 

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

(NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

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

Coumaphos is a member of the organophosphate class of pesticides. Like other OPs, the 

initiating event in the adverse outcome pathway (AOP), also often called the mode of action 

(MOA), for coumaphos involves inhibition of the enzyme acetylcholinesterase (AChE) via 

phosphorylation of the serine residue at the active site of the enzyme. This inhibition leads to 
Coumaphos Human Health Risk Assessment DP#409347

Page 16 of 77

accumulation of acetylcholine and ultimately to neurotoxicity in the central and/or peripheral 

nervous system (see Figure 1). Coumaphos requires metabolic activation to the oxon metabolite 

to inhibit AChE. For coumaphos, AChE inhibition is the most sensitive endpoint in the 

toxicology database in 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 this toxicology database. 

Figure 1. Adverse outcome pathway for OPs

4.1 Toxicology Studies Available for Analysis

The toxicology database for coumaphos is complete, with the exception of a subchronic 

inhalation study and a coumaphos oxon comparative cholinesterase assay (CCA) study. The 

Health Effect Divisions (HED’s) Hazard Science Policy Council (HASPOC) determined, based 

on a weight of evidence (WOE) approach that a subchronic inhalation toxicity study is required 

for coumaphos due to unacceptable inhalation risk estimates using the current PoD from an oral 

study (April 29, 2013, TXR 0056625). Coumaphos requires bioactivation to the oxon to allow 

AChE inhibition; however, no data were submitted regarding the toxicity of the oxon. Although 

oxon CCA data are not available for coumaphos, EPA plans to move forward with the 

coumaphos human health risk assessment without toxicity data for coumaphos’s oxon degradate. 

In lieu of coumaphos-specific oxon CCA data, EPA has used an oxon toxicity adjustment factor 

of 50X in its calculations. This value considers the data derived toxicity adjustment factor (TAF) 

that EPA has identified among oxon metabolites for other organophosphates, with an additional 

margin of safety included due to the uncertainty in extrapolating oxon potency data across 

chemicals (See Section 4.6.2 for details). The toxicology database includes the following 

toxicity studies:

• subchronic oral toxicity studies in rats,

• 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 (ChE) studies in juvenile and adult 

rats,

• repeated, gestational ChE study in pregnant rat and fetuses,

• delayed neurotoxicity study in hens,

• 2, 5 and 21 day dermal toxicity in rats,

• immunotoxicity study in rats, 

• complete mutagenicity study battery, and 

Target 

Tissue Dose

Phosphorylation 

of the active site 

of AChE

Neurotoxicity Accumulation 

of acetylcholine
Coumaphos Human Health Risk Assessment DP#409347

Page 17 of 77

• metabolism study in rats.

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

Coumaphos, like some other OPs, requires metabolic activation to the oxon metabolite to inhibit 

AChE, with subsequent metabolism that leads to detoxification. Following oral administration,

coumaphos was rapidly absorbed and eliminated in urine and feces with no evidence of 

bioaccumulation. 

In a metabolism study, rats were administered [14C] coumaphos as a single dose at levels of 1 

mg/kg intravenously, and 1 and 15 mg/kg orally (MRID 00138596; Accession No. 25227074). 

A fourth group received 1 mg/kg coumaphos by the oral route daily for 14 days. 

Following oral administration, the plasma half-life ranged from 2.35 to 3.3 hours at 1 mg/kg and 

2.93 and 5.3 hours at 15 mg/kg (includes both single and repeated dose groups). Oral absorption 

was estimated to be 80% and 90% for the 1 mg/kg/day groups (single and repeat dosing, 

respectively), and 50% for the 15 mg/kg/day group. Urinary excretion was rapid with 63%-87% 

of the administered dose being excreted within 24 hours. For both doses, 76-96% of the 

administered dose was excreted within 168 hours following a single exposure. Tissue residues 

were highest in fat, kidney, liver and muscle. The urine contained 5 to 8 metabolites and the 

feces contained 5 to 7 metabolites. The major metabolite is chlorferon (dephosphorylated 

coumaphos). Coumaphos represented 0.1% of the urinary metabolites. Coumaphos represented 

0.2% of the fecal metabolites when administered intravenously. However, when administered 

orally, coumaphos represented approximately 15 to 55% of the fecal metabolites. The range 

varies depending on whether coumaphos was administered as a single dose or as repeated doses. 

Sex differences were observed that suggest less complete oral absorption of coumaphos in 

female rats following single or repeated doses. Sex differences were not noted in high dose rats 

(15 mg/kg).

4.2.1 Dermal Absorption 

There are no dermal absorption studies available. However, a dermal absorption factor is not 

needed for coumaphos because a route-specific dermal toxicity study was used to assess dermal 

exposure scenarios (see Section 4.5).

4.3 Toxicological Effects 

Coumaphos is an OP with a neurotoxic AOP; neurotoxicity is the most sensitive effect in all 

species, routes and life stages, and is being used in deriving PoDs. Coumaphos has quality dose 

response data across multiple life stages, durations, and routes for both RBC and brain AChE 

inhibition. Many of these studies have been evaluated using benchmark dose (BMD) modeling 

techniques. Based on Table 4.3.2.1, and Tables 2.1.1-2.2.2 in Appendix A2, RBC AChE 

inhibition is substantially more sensitive than brain AChE inhibition for all life stages evaluated 

(adults, juveniles, pregnant dams, and fetuses) in oral and dermal studies. Available studies with 

adult animals show similar findings in gavage and dietary studies. All of the oral studies 

modeled for BMD analysis were based on dietary administration except for the acute and 11 day 
Coumaphos Human Health Risk Assessment DP#409347

Page 18 of 77

repeat CCA studies, which were based on gavage administration. Studies for the dermal route

are available for route-specific evaluation. As mentioned previously, inhalation studies are not 

available for coumaphos. 

No sensitivity to coumaphos was observed in developmental and reproduction guideline studies 

or following acute exposure in the CCA study. However, brain AChE (approximately 4-fold) 

and RBC AChE inhibition (approximately 2-fold) were more sensitive in PND 11 pups 

following repeated exposure in the CCA studies. Following gestational exposure, no fetal 

sensitivity was observed. However, in both the CCA and DNT studies, pregnant animals were 

approximately 2-fold more sensitive than non-pregnant females in repeat exposure studies. No 

sex-specific differences were observed at doses relevant for risk assessment. However, at higher 

doses adult female rats appear to be more sensitive than male rats. 

Clinical signs of neurotoxicity can be found throughout the database of experimental toxicity 

studies at doses higher (10-fold) than those causing inhibition of AChE. In the subchronic 

neurotoxicity study, neurobehavioral effects such as decreased open field activity in males and 

decreased forelimb grip strength in females were observed. In the developmental studies, 

tremors were observed in maternal rats, and cholinergic signs and mortality (2/17 rabbits) were 

noted in maternal rabbits. 

In acute lethality studies, coumaphos is highly toxic (Category I for the oral route and Category

II for the inhalation route). Coumaphos is Category III for dermal toxicity, and is Category IV 

for eye and dermal irritation. It is not a dermal sensitizer. 

Coumaphos requires bioactivation to the oxon to allow AChE inhibition; however, as stated 

above, no data were submitted regarding the toxicity of the oxon. In the absence of oxon toxicity 

data, exposure to coumaphos oxon is considered to be 50X as toxic as exposure to the parent

(See Section 4.6.2 for details). 

4.3.2 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. This analysis provides the basis 

for determining which exposure durations are appropriate for assessing the human health risk. 

Table 4.3.2.1 provides a summary of the representative results from experimental toxicology 

studies with coumaphos for adult rats.
Coumaphos Human Health Risk Assessment DP#409347

Page 19 of 77

Table 4.3.2.1 – Coumaphos BMD10 Results (mg/kg/day) for RBC AChE Inhibition 

Over Time in Female and Male Adult Rats Following Oral Exposure 

Days of dosing RBC 

Males Females

1a 0.31 0.57

11 b 0.127 0.106

28 e 0.096 0.085

42 c NT 0.08 h

57 d 0.16 0.17

90d 0.15 0.10

90 e 0.11 0.25

91 f (F1) 0.048 0.05

91 g (F0) NRF 0.07

NRF = No Reliable Fit; NT= not tested;

a MRID 46258301 CCA Acute Study – Single Dose b

MRID 46502201 CCA Repeat Study – 11 days c MRID 45912101 Developmental Neurotoxicity Study (i.e., gestational and lactational CCA data from lactation day 21); Results 

for maternal rats exposed 21 days during gestation and 21 days during lactation 

d MRID 00126527 Subchronic Oral Study (lower doses than SCN and more inhibition at lower doses). Both 8 week and 13 week 

measures are available.

e MRID 44775901, subchronic neurotoxicity study; 4 week interim measures and 90 day final measures f

 MRID 43061701 2 generation reproductive study; F1 generation. g MRID 43061701 2 generation reproductive study; F0 generation based on visual inspection and taking into account the 

observed dose spacing issues this model fit is adequate and these data are reported for characterization purposes. h p=0.03 model fit; based on visual inspection and taking into account the observed dose spacing issues this model fit is adequate 

and these data are reported for characterization purposes.

As shown in Table 4.3.2.1, the acute BMD values for adults are the highest in this table. With 

respect to BMD values from 11 days of dosing up to 90 days, there is remarkable similarity in 

the RBC BMD estimates across multiple studies (i.e., BMDs with a 3X range) in both sexes with 

the 2-generation reproduction study F0 and F1 generation rats providing the lowest values. In 

adults, OPs exhibit a phenomenon known as steady state cholinesterase (AChE) inhibition. After 

repeated dosing at the same 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. For coumaphos, the results in Table 4.3.2.1 show a clear pattern of 

steady state reached by 11 days of exposure. In addition to the consistency across durations, the 

data across multiple studies are similar. The data are also consistent with the OP cumulative risk 

assessment which included subchronic and chronic data for coumaphos. 

Although the durations of the toxicity and exposure assessments may differ among the OPs, 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 (OP Cumulative Risk 

Assessment (CRA); 2002, 2006) and across the single chemical risk assessment for the OPs. As 

such, the single chemical OP assessment will evaluate steady state (a 21-day assessment) instead 

of the typical chronic duration dietary assessment. The steady state point of departure is 

protective of any exposure duration longer than 21-days, including chronic exposure, since 

cholinesterase inhibition does not increase after reaching maximum inhibition or steady state. 
Coumaphos Human Health Risk Assessment DP#409347

Page 20 of 77

Given the results in Table 4.3.2.1, for coumaphos, single day and steady state durations are 

appropriate for human health risk assessment. As such, the endpoint selection for coumaphos 

focuses on acute, single day effects, and steady state effects (21 days and longer).

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 

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 coumaphos. 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, 20133) 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; 9/15/2015), 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 

 3 http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2008-0850-0170
Coumaphos Human Health Risk Assessment DP#409347

Page 21 of 77

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 

(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)4

. 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 

 4 http://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l26opd_c_met_organophosphorus_pesticides.pdf
Coumaphos Human Health Risk Assessment DP#409347

Page 22 of 77

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 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, and 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 
Coumaphos Human Health Risk Assessment DP#409347

Page 23 of 77

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. 

In addition, the three 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)5 leading 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 

 5 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. 
Coumaphos Human Health Risk Assessment DP#409347

Page 24 of 77

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

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; 

9/15/2015). 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 with the 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 
Coumaphos Human Health Risk Assessment DP#409347

Page 25 of 77

neurodevelopmental effects which prevents the agency from reducing or removing the statutory 

10X FQPA Safety Factor. For the coumaphos PRA, a value of 10X has been applied. Similarly, 

a 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 Safety Factor) 

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 critical 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 coumaphos for the population subgroups that include infants, 

children, youth, and women of childbearing age for all exposure scenarios. 

Additionally, there is a data gap for coumaphos for a subchronic inhalation study. 

Therefore, a total database uncertainty factor of 30X, to account for the uncertainty in the 

human dose-response relationship for neurodevelopmental effects and the lack of an 

inhalation, will be used for coumaphos for the population subgroups that include infants, 

children, youth, and women of childbearing age for inhalation exposure scenarios. 

4.5.1 Completeness of the Toxicology Database 

The database of toxicology studies for coumaphos is complete, with the exception of a 

subchronic inhalation study and a coumaphos oxon CCA study. Available studies include 

developmental studies in rat and rabbit, a reproductive toxicity study, a DNT, and a comparative 

ChE study with three components (acute, repeated, and gestational). A CCA study for the oxon 

is not available, and exposure to the oxon is considered to be 50X as toxic as exposure to the 

parent in the absence of this study (See Section 4.6.2 for details). 

4.5.2 Evidence of Neurotoxicity 

Coumaphos is an OP with a neurotoxic MOA/AOP; neurotoxicity is the most sensitive effect in 

all species, routes, and lifestages and is being used in deriving PoDs for risk assessment.

4.5.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal 
Coumaphos Human Health Risk Assessment DP#409347

Page 26 of 77

Comparative AChE studies are available and provide quality AChE dose response data from 

potentially susceptible lifestages (i.e., fetuses, pregnant dams, post-natal pups). In the acute and 

repeat CCA rat studies juvenile animals were more sensitive than adults to both RBC and brain 

AChE inhibition at peak time of inhibition at high doses (i.e., > 1 mg/kg/day), but not at low 

doses near the PoDs for 10% RBC AChE inhibition. In addition, the gestational dosing CCA 

study does not show any lifestage sensitivity to coumaphos-induced AChE inhibition. Rat and 

rabbit developmental studies are also available that do not show any susceptibility (although they 

did not measure AChE inhibition). Similarly, the reproductive toxicity study and developmental 

neurotoxicity (DNT) study provide no evidence of quantitative lifestage susceptibility. In the 2-

generation reproduction and DNT studies, the parental animals had more robust AChE inhibition 

than the offspring at similar doses; however, the parental animal measurements and BMD 

analysis have greater uncertainty and are only provided for characterization purposes. 

Qualitative susceptibility (morphometric brain changes in offspring) recorded in the DNT study 

was only observed at much higher doses (70 fold higher) than those selected for PoD derivation. 

Moreover, BMD results using RBC AChE inhibition are protective for the effects on the pups 

observed in the DNT and repeat CCA studies.

The acute and steady state PoDs are based on the most sensitive BMDL10s for RBC AChE (the 

most sensitive compartment), and thus are protective of the observed sensitivity of juvenile rats. 

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, youth, and women of childbearing age for all 

exposure scenarios.

4.5.4 Residual Uncertainty in the Exposure Database 

There are no residual uncertainties in the exposure database. The partially refined dietary risk 

assessment uses anticipated residues from monitoring data, estimated drinking water 

concentrations from maximum application rate, and 100% crop treated and will not 

underestimate dietary (food and water) exposure to coumaphos. All of the exposure and risk 

estimates are based on conservative assumptions that do not underestimate risk. There are no 

registered residential uses for coumaphos.

4.6 Toxicity Endpoint and Point of Departure Selections 

4.6.1 Dose-Response Assessment 

Table 4.6.5.1 summarizes the coumaphos 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 coumaphos, across all 

studies, durations, lifestages, and routes, the RBC AChE is more sensitive than the brain 

compartment. As such, OPP has emphasized the RBC data in PoD derivation as these 

data tend to be less variable than brain data because of a lack of brain AChE inhibition in 
Coumaphos Human Health Risk Assessment DP#409347

Page 27 of 77

many studies, and thus a majority of brain data were not suitable for BMD analysis, or 

had a poor dose response. 

• Potentially susceptible populations (fetuses, juveniles, pregnancy): The available oral 

AChE data across multiple lifestages (adults, pregnant adults, fetuses, juveniles) show 

lifestage sensitivity for acute and repeat oral exposures at doses > 1 mg/kg/day, but not 

for gestational exposure. However, there is no sensitivity at low doses near the PoDs 

used for risk assessment (0.04-0.19 mg/kg/day). Based on the oral studies, lifestage 

sensitivity is not expected for dermal and inhalation routes of exposure.

• 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 

coumaphos, there are oral and dermal studies that contain quality dose response AChE 

data. The majority of oral studies are via dietary exposure. 

• 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 coumaphos, 

there are single day and repeated dosing oral studies, and 2-, 5-, and 21-day dermal 

studies are available. 

• 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 across studies. 

The coumaphos database demonstrates a striking consistency across studies which allows 

for PoDs to be derived from multiple critical studies, thereby, increasing the confidence 

in such values. 

Descriptions of the primary toxicity studies used for selecting toxicity endpoints and points of 

departure for various exposure scenarios are presented in Appendix 3. Summary tables of BMD 

analyses can be found in Appendix 2 and the technical details of the analysis can be found in the 

BMD memo (Liccione & Holman, 8/5/2014, TXR #0057001) 

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

benchmark response (BMR) level of 10% and has thus calculated BMD10s and BMDL10s. 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 was completed using USEPA BMD Software, version 2.2; an exponential model was 

used to fit the data, with the assumption of constant variance across each dataset. 

Acute Dietary (all populations)

As shown in Appendix Table 2.1, results of the single dosing CCA study with coumaphos are 

comparable for RBC AChE data in pups ages post-natal day (PND) 11 and adult male and 

female rats. A PoD for the acute dietary (all populations) exposure scenario was derived from 

the results of a well-conducted acute CCA rat study (MRID 46258301). A BMDL10 of 0.19 

mg/kg/day associated with RBC AChE inhibition in adult males was selected as a suitable PoD

for the acute dietary (all populations) exposure scenario. The corresponding BMD10 was 0.31 

mg/kg/day. This BMDL10 is protective of RBC AChE inhibition in PND11 pups, as the BMDL10 

for pups is 0.25 mg/kg, and the PND 11 pups represent the most highly exposed sub-populations 

(infants and young children). 
Coumaphos Human Health Risk Assessment DP#409347

Page 28 of 77

The acute neurotoxicity study was not selected because it did not measure AChE at the peak time 

of inhibition (4 hours for adults and 8 hours for pups). RBC AChE inhibition was selected for 

the PoD because it was more sensitive than brain AChE inhibition in pups, and the brain ChE 

data for adults did not provide a reliable fit in the benchmark dose analysis, due to the lack of a 

response. 

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

intraspecies variation, and 10X for FQPA safety/ database uncertainty factor due to uncertainty 

in the human dose-response relationship for neurodevelopmental effects (see Section 4.4)) is 

applied to the BMDL10 to obtain an aPAD of 0.00019 mg/kg/day for exposure scenarios with 

infants, children, youth, and women of childbearing age. The only population subgroup for 

which the FQPA SF is not retained is adults 50-99; therefore, the aPAD for this population 

subgroup is 0.0019 mg/kg/day. 

Steady-State Dietary (all populations)

Table 4.3.2.1 and Appendix Table 2.2 show remarkable similarity in RBC BMD estimates across 

multiple studies and durations for adults in studies 11 days and longer (i.e., BMDs within 3X 

range). A PoD for the steady state dietary (all populations) exposure scenario was derived from 

the results of a 2 generation reproduction study (MRID 43061701). A BMDL10 of 0.04 

mg/kg/day (0.036 mg/kg/day rounded) associated with RBC AChE inhibition in both male and 

female adult rats of the F0 and F1 generation was selected as a suitable PoD for the steady-state 

dietary (all populations) exposure scenario. The corresponding BMD10s were 0.05/0.07 

mg/kg/day in females and males, respectively.

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

administration and the chronic duration of exposure. The study and endpoint were selected 

because they are protective of effects observed in all the other available studies for all lifestages, 

including offspring effects seen in the DNT study, and RBC AChE inhibition in the PND 11 

pups of the repeat CCA study. 

The PoD of 0.04 mg/kg/day for RBC AChE inhibition is supported by several other studies 

including:

• BMDL10 of 0.041/0.042 mg/kg/day (males/females) in PND 11 pups in repeat CCA 

study via gavage (11 days) (MRID 46502201)

• BMDL10 of 0.03 mg/kg/day in dams of the DNT study following gestational and 

lactation exposure via diet (42 days) (MRID 45912101)

The female data in the DNT study and F0 generation did not yield statistically acceptable results 

with a p-value of 0.05 using a log-likelihood ratio test. However, visual observation of the data 

shows a good fit and comparable findings to the F1 generation data, which were selected as the 

PoD. 
Coumaphos Human Health Risk Assessment DP#409347

Page 29 of 77

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

intraspecies variation, and 10X for FQPA safety/ database uncertainty factor due to uncertainty 

in the human dose-response relationship for neurodevelopmental effects (see Section 4.4)) is 

applied to the BMDL10 to obtain a ssPAD6 of 0.00004 mg/kg/day for exposure scenarios with 

infants, children, youth, and women of childbearing age. The only population subgroup for 

which the FQPA SF is not retained is adults 50-99; therefore, the ssPAD for this population 

subgroup is 0.0004 mg/kg/day. 

Dermal, Steady State

Based on the use pattern for coumaphos, only a repeated exposure dermal PoD is required. 

Therefore, the two available 21-day dermal studies were used for the steady state dermal 

assessment. 

A steady state dermal PoD was selected from a 21-day dermal toxicity study (MRID 42666401) 

in rats based on RBC AChE inhibition (BMDL10 = 0.5 mg/kg/day; BMD10 = 0.72 mg/kg/day) in 

the female rat. It is noted that the female and male data for the second dermal study (that tested 

higher doses of 2, 4, 20 and 100 mg/kg/day) did not provide statistically acceptable results with a 

p-value of 0.05 using a log-likelihood ratio test for RBC AChE inhibition; however, visual 

observation of the data show good fit and similar findings were obtained in females in this study 

(BMDL10 of 0.71 mg/kg/day). RBC AChE inhibition was significantly more sensitive than brain 

AChE inhibition (between 6 and 8.3 fold) in the dermal toxicity study. 

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

extrapolation, 10X for intraspecies variation, and a 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)), allowing a level of 

concern (LOC) of 1000X.

Inhalation, Steady State

Based on the use pattern for coumaphos, only a steady-state inhalation PoD is required to assess 

occupational exposure and risk. In the absence of a repeat dose inhalation study, an oral study 

was used. In addition, it was assumed that the time to reach steady state is comparable for oral 

and inhalation exposure.

A PoD for the steady state inhalation exposure scenario was derived from the results of a 2 

generation reproduction study (MRID 43061701). A BMD10 of 0.05 mg/kg/day associated with 

RBC AChE inhibition in both male and female adult rats of the F0 and F1 generations from the 2 

generation reproductive study was selected as a suitable PoD for the steady-state inhalation (all 

populations) exposure scenario. The corresponding BMDL10 was 0.04 (0.036 rounded) 

mg/kg/day. Toxicity by the inhalation route was considered to be equivalent to toxicity by the 

oral route. However, in some cases toxicity via the inhalation route is higher than toxicity via 

the oral exposure, which results in an underestimation of risks from inhalation exposure. In 

addition, there may be a potential for portal of entry effects via the inhalation route, which would 

 6 ssPAD: Population adjusted dose derived from steady state duration
Coumaphos Human Health Risk Assessment DP#409347

Page 30 of 77

not be accounted for in the oral studies. As a result, the HASPOC concluded that an inhalation 

study is needed for a more accurate assessment of inhalation risks.

The total uncertainty factor of 3000X was applied (10X for interspecies extrapolation, 10X for 

intraspecies variation, and 30X database uncertainty factor incorporating uncertainty in the 

human dose-response relationship for neurodevelopmental effects (see Section 4.4) and because 

there is an unfulfilled inhalation study requirement for coumaphos), allowing a LOC of 3000X.

4.6.2 Oxon Toxicity Adjustment Factor 

In the 2006 updated OP cumulative risk assessment (CRA), the Agency characterized the 

potential impacts of the conversion of OP pesticides to oxon transformation products during 

standard drinking water treatment processes. For those OP pesticides that could potentially 

transform into more toxic oxons, the Agency assumed a complete transformation as a result of 

drinking water treatment. Based on limited data (documented in the 2002 OP CRA), the Agency 

assumed that the oxons would persist for a sufficient time to travel through the distribution 

system. 

The Agency used submitted data to characterize the relative toxicity differences between the 

oxon and the parent for some of the OP pesticides; information from published literature was also 

available to inform relative potency for a few OP Pesticides[1]. For those OP pesticides without 

sufficient oxon data, the Agency initially used upper bound oxon adjustment factors of 10X and 

100X for estimating potential oxon potency. The 100X was used considering the highest relative 

toxicity difference observed (61X) for malathion/maloxon, based on the data available at the 

time. However, since then, acute and repeat dose CCA studies have been submitted for both 

malathion and malaoxon. The new data allows a direct comparison of relative toxicity for the 

two chemicals and therefore, reduces uncertainty; an oxon adjustment factor of 22X was 

determined based on this data. As a result, a 50X oxon adjustment factor has been used for the 

OP draft risk assessments for registration review to estimate potential oxon potency. The 50X 

accounts for the highest oxon adjustment factor of 22X with an additional safety margin to 

protect for potential oxon toxicity for chemicals without oxon data. The adjustment factors were 

applied to residues for risk assessment of all exposure durations, routes, and scenarios.

 [1] Chambers JE, Carr RL. 1993. “Inhibition patterns of brain acetylcholinesterase and hepatic and plasma 

aliesterases following exposures to three phosphorothionate insecticides and their oxons in rats.” Fundamental and 

Applied Toxicology. Jul; 21(1):111_9.
Coumaphos Human Health Risk Assessment DP#409347

Page 31 of 77

OP PESTICIDE OXON ADJUSTMENT FACTOR

Azinphos-Methyl No data

Bensulide No data

Chlorethoxyfos No data

Chlorpyrifos 11.9X (acute); 18X (repeated): RBC 

Coumaphos No data

Diazinon 12.1X (acute); 9.0X (repeated):RBC

Dimethoate 8 X (acute); 3X (repeated): Brain

Disulfoton No data

Malathion 22X (acute); 22X (repeated): RBC

+-Methidathion No data

Methyl Parathion <10X (Chambers and Carr, 1993)*

Phostebupirim No data

Propetamphos No data

Temephos No data

Oxon toxicity adjustment factors are based on a comparison of the most sensitive compartment (i.e., RBC or brain) determined 

for the chemical. 

4.6.3 Recommendations for Combining Routes of Exposures for Risk 

PoDs for the oral, dermal, and inhalation routes are all derived from RBC AChE 

inhibition. Thus, all routes can be combined.

4.6.4 Cancer Classification and Risk Assessment Recommendation 

There is no evidence of carcinogenicity in adequate studies in rats and mice and no evidence of 

mutagenicity. Therefore, coumaphos is classified as “not likely to be carcinogenic in humans.”
Coumaphos Human Health Risk Assessment DP#409347

Page 32 of 77

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

Assessment 

Table 4.6.5.1 Summary of Toxicological Doses and Endpoints and Points of Departure for Coumaphos in 

Dietary Human Health Risk Assessments

Exposure

Scenario

Point of Departure

(mg/kg/day)

Uncertainty/

FQPA Factors5

RFD, PAD, & LOC

for Risk Assessment

Study and Toxicological

Effects

Acute Dietary

(All Populations 

Except Adults 50-

99 Years)

BMDL10 = 0.19 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 10x

Acute RfD =0.0019 

mg/kg

aPAD = 0.00019 

mg/kg

CCA Study (MRID 

46258301) in the rat

BMD10 = 0.31 mg/kg 

(adult males) for inhibition 

of RBC AChE in adult 

male rats.

Acute Dietary

(Adults 50-99 

Years)

BMDL10 = 0.19 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Acute RfD = 0.0019 

mg/kg

aPAD = 0.0019 

mg/kg

CCA Study (MRID 

46258301) in the rat

BMD10 = 0.31 mg/kg 

(adult males) for inhibition 

of RBC AChE in adult 

male rats.

Steady-State 

Dietary

(All Populations 

Except Adults 50-

99 Years)

BMDL10 = 0.04 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 10x

ssRfD = 0.0004 

mg/kg

ssPAD = 0.00004 

mg/kg/day

2 generation reproductive 

study (MRID 43061701)

BMD10 = 0.05 

mg/kg/day for Inhibition 

of RBC AChE in in F0 and 

F1 young adults at 90 days 

in both males and females

Steady-State 

Dietary

(Adults 50-99 

Years)

BMDL10 = 0.04 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

ssRfD = 0.0004 

mg/kg

ssPAD = 0.0004 

mg/kg/day

2 generation reproductive 

study (MRID 43061701)

BMD10 = 0.05 

mg/kg/day for Inhibition 

of RBC AChE in in F0 and 

F1 young adults at 90 days 

in both males and females

Cancer (oral, 

dermal, inhalation) Classification: not likely to be carcinogenic in humans

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. BMDL10 = lower confidence interval on the 

benchmark dose for 10% response. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential 

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

dose (a = acute, ss = steady state or maximal AChE inhibition which occurs around 2-3 weeks for OPs and is a specific exposure assessment 

conducted for OPs instead of the traditional short, intermediate, or chronic assessments. The SS assessment is protective of longer durations of 

exposure, including chronic). RfD = reference dose. 
Coumaphos Human Health Risk Assessment DP#409347

Page 33 of 77

Table 4.6.5.2 Summary of Toxicological Doses and Endpoints for Coumaphos 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 (21 

days and longer)

BMDL10 = 0.5 

mg/kg/day

UFA=10x

UFH=10x 

UFDB = 

10xa

Occupational LOC for 

MOE = 1000

21-day dermal toxicity study (MRID 

42666401) in female rats

BMD10 = 0.72 mg/kg/day for 

inhibition of RBC AChE in adult 

female rats.

Inhalation

Steady State (21 

days and longer)

BMDL10 = 0.04 

mg/kg/day

Inhalation 

absorption 100% of 

oral absorption

UFA=10x

UFH=10x

UFDB= 30xb

Occupational LOC for 

MOE = 3000

2 generation reproductive study 

(MRID 43061701)

BMD10 = 0.05 mg/kg/day for 

Inhibition of RBC AChE in F0 and F1

young adults at 90 days in both males 

and females

Cancer (oral, 

dermal, 

inhalation)

Classification: not likely to be carcinogenic in humans

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. BMDL10 = lower confidence interval on the 

benchmark dose for 10% response. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential 

variation in sensitivity among members of the human population (intraspecies). UFDB = database uncertainty factor. MOE = margin of 

exposure. LOC = level of concern. N/A = not applicable. Steady state = maximal AChE inhibition which occurs around 2-3 weeks for OPs and 

is a specific exposure assessment conducted for OPs instead of the traditional short, intermediate, or chronic assessments. The steady state 

assessment is protective of longer durations including chronic.

a UFDB for occupational dermal exposures = database uncertainty factor for uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4). b UFDB for occupational inhalation exposures = database uncertainty factor incorporating uncertainty in the human dose-response relationship for 

neurodevelopmental effects (see Section 4.4) and the UFL due to lack of a NOAEL in the sub-chronic inhalation toxicity study.

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 reregistration decision for coumaphos, 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), coumaphos 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 
Coumaphos Human Health Risk Assessment DP#409347

Page 34 of 77

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, 20136 and includes some 

pesticides including coumaphos 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.

Coumaphos is on List 2. List 2 represents the next set of chemicals for which EPA intends to 

issue test orders/data call-ins in the near future. For further information on the status of the

EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the

Tier 1 screening battery, please visit our website7

.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile 

5.1.1 Summary of Plant and Animal Metabolism Studies 

No primary crop metabolism data are required, as coumaphos is not registered for use on plants.

In honeybee products (honey and honeycomb), the residues of concern are coumaphos and its 

oxygen analog, coumaphoxon. The nature of the residue in ruminants has been established, 

based on an adequate ruminant metabolism study reflecting dermal dosing. In livestock, the 

residues of concern for risk assessment and for tolerance enforcement are coumaphos and 

coumaphoxon. The registrant has canceled uses on poultry; therefore, there is no requirement for 

poultry metabolism data.

5.1.2 Summary of Environmental Degradation 

Coumaphos is persistent in the environment and slightly mobile to hardly mobile in soil. The 

major pathway of coumaphos degradation appears to be photodegradation in water. Results of 

the field dissipation study support the finding that coumaphos is persistent; however, coumaphos 

moved to greater depths than expected based on its Kd values. A major degradate, the oxygen 

analog, coumaphoxon, was detected in an aqueous photodegradation study at a maximum of 

10.2% of applied chemical. Limited environmental fate data are available for coumaphoxon, 

which suggests that it is not persistent in the terrestrial environment, but it is mobile in soil. 

Coumaphos accounted for 0.4% of leachate from a sandy loam column and less than 2% of 

leachate from columns of sand, silt loam, and silty clay loam.

5.1.3 Comparison of Metabolite Pathways 
Coumaphos Human Health Risk Assessment DP#409347

Page 35 of 77

There are no direct uses of coumaphos on plants; therefore, a discussion of comparative 

metabolic pathways is not pertinent to this assessment. Coumaphos, like some other OPs,

requires metabolic activation to the oxon metabolite to inhibit AChE, with subsequent 

metabolism that leads to detoxification. Coumaphos is metabolized in animals by oxidation to 

its hydrolysis product chlorferon (dephosphorylated coumaphos). Following oral administration

in the rat metabolism study, coumaphos was rapidly absorbed and eliminated in urine and feces 

with no evidence of bioaccumulation and the major metabolite is chlorferon (See Section 4.2). 

5.1.4 Residues of Concern Summary and Rationale 

Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment and 

Tolerance Expression.

Matrix Residues included in Risk 

Assessment

Residues included in Tolerance 

Expression

Plants

Primary Crop Not Applicable 1 Not Applicable1

Rotational Crop Not Applicable1 Not Applicable1

Livestock

Ruminant Parent and oxygen analog 

(coumaphoxon)

Parent and oxygen analog 

(coumaphoxon)

Poultry Not Applicable 2 Not Applicable 2

Drinking Water

Parent and oxygen analog 

(coumaphoxon)

Parent and oxygen analog 

(coumaphoxon)

1 There are currently no registered uses of coumaphos on plants. Honey and beeswax (honeycomb) residue of concern are 

coumaphos and its oxygen analog coumaphoxon (coumaphos-PO). 2 There are currently no registered uses of coumaphos on poultry.

5.2 Food Residue Profile 

Coumaphos is an insecticide used to control arthropod pests on livestock and used in beehives 

(impregnated strips) for the control of mites and small hive beetles. Plant metabolism data are 

not available for coumaphos. Based on the ruminant metabolism study, coumaphos was the 

major residue accounting for 70-96% of the residue in tissues and its metabolite, coumaphoxon 

was not detected in the muscle or fat. Accumulation of coumaphos residues in honey and 

beeswax following treatment of hives with coumaphos-impregnated strips were shown to be 

considerably higher in beeswax than in honey. Field trial data looked for the parent and 

coumaphoxon in honey/beeswax and found no detectable resides of coumaphoxon. Magnitude 

of residue studies reflecting the current types of registered external uses (dusts, sprays, dips, 

pour-ons, backrubbers, and bedding treatments) and feeding studies were reviewed. The feeding 

study looked for the combined residue of parent and coumaphoxon in livestock and found 

detectable residues in livestock tissues (primarily fat samples). However, PDP monitoring data 

for honey and livestock commodities looked for the parent separately from the oxon and found 

detectable parent residues, but no coumaphoxon. Therefore, coumaphoxon is not expected to be 

found in food and a TAF of 50x was not used for food and was only applied to drinking water.

5.3 Water Residue Profile 
Coumaphos Human Health Risk Assessment DP#409347

Page 36 of 77

Coumaphos indoor use (e.g. to treat swine bedding) and the placement of coumaphos-treated 

strips in bee hives were not considered in the drinking water assessment because they do not 

provide complete routes of exposure to surface water or groundwater. However, during a rain 

event, a certain fraction of coumaphos wash-off from treated cattle can come into contact with 

and be adsorbed onto manure as well as transported as runoff from concentrated animal feeding 

operations and pasture/rangeland. 

The estimated drinking water concentration (EDWCs) of coumaphos and coumaphoxon were 

generated using the Tier II Pesticide Root Zone Model/Exposure Analysis Modeling System 

(PRZM/EXAMS) model for surface water and Tier I SCIGROW (Screening Concentration in 

Ground Water Program) for groundwater. Pesticide Root Zone Model-Ground Water model 

(PRZM-GW) was also used for ground water. The drinking water assessment assumed that during 

a rain event, coumaphos wash-off from treated cattle can be potentially adsorbed into manure as 

well as transported as effluent from concentrated animal feeding operations and 

pasture/rangeland. Use of this product is restricted to employees of the USDA-APHIS7 who are 

enrolled in the USDA-APHIS cholinesterase monitoring program. The USDA’s Cattle Fever 

Tick Eradication Program (CFTEP) uses this product solely in Texas. As a result, the TX Barton 

Springs Segment of the Edward Aquifer scenario with a 2% wash-off fraction after 24 hours dipvat treatment in the leaching study was used.

The residues of concern for drinking water are coumaphos and its oxygen analog, coumaphoxon. 

A maximum conversion efficiency of coumaphos to coumaphoxon of 10.2% was derived from 

available data on photodegradation in water. This conversion efficiency was used to estimate a 

coumaphoxon application rate of 0.0285 lbs ai/A for drinking water modeling. However, a more 

conservative estimate is to assume 100% conversion to oxygen analog if it was determined that 

oxygen analog is more toxic than its parent. Coumaphos exposed to chlorine in drinking water 

treatment facilities is expected to be rapidly and completely converted to coumaphoxon and is 

multiplied by the TAF of 50X to take into account conversion to coumaphoxon. Final time 

series provided to HED are multiplied by 1.05 to convert from coumaphos (362.76 g/mol) to 

coumaphoxon (346.7 g/mol). 

Table 5.3 summarizes recommended EDWCs for surface water and groundwater. However, for

acute and steady state assessments, the entire 30-year distribution of estimated daily 

concentrations was incorporated into the PRZM/EXAMS and used in the probabilistic analyses. 

For steady state, the TX scenario daily time series was also recalculated using the 21-day 

forward rolling averages. In the 21-day rolling average distributions, the first data point is the 

average of days 1-21, the second data point is the average of days 2-22, the third data point is the 

average of days 3-23, etc. 

 7 APHIS- Animal and Plant Health Inspection Service
Coumaphos Human Health Risk Assessment DP#409347

Page 37 of 77

Table 5.3. Maximum EDWCs for Drinking Water Sources for Coumaphos and Coumaphoxon 

Source of Drinking Water

Estimated Drinking Water concentration (μg/L)

Acute Chronic Average

chronic

Coumaphos

Surface Water1 0.10 0.05 0.03

Groundwater2 1.91 x 10-03 1.91 x 10-03 1.91 x 10-03

Coumaphoxon

Surface Water 0.002 0.0001 6.89 x 10-05

Groundwater,2 5.06 x 10-06 5.06 x 10-06 5.06 x 10-06

Coumaphos Equivalents (Coumaphos+Coumaphoxon) 3

Surface Water 0.102 0.05 0.03

Groundwater 1.92 x 10-03 1.92 x 10-03 1.92 x 10-03

1 EDWCs based on PRZM/EXAMS model

2 EDWCs derived from SCIGROW 

3 Coumaphos + Coumaphoxon- sum of surface water/and or groundwater for coumaphos and coumaphoxon, 

respectively

5.4 Dietary Risk Assessment 

Reference: D412870; S. Piper, February 4, 2016

5.4.1 Description of Residue Data Used in Dietary Assessment 

Partially refined acute and steady state dietary exposure and risk assessments for coumaphos 

were conducted using DEEM-FCID version 3.18. This model uses 2003-2008 food consumption 

data from USDA’s National Health and Nutrition Examination Survey, What We Eat in America

(NHANES/WWEIA). The dietary exposure assessments incorporated USDA Pesticide Data 

Program (PDP) monitoring data for coumaphos and its metabolite (coumaphoxon) in/on honey, 

milk, and livestock commodities and assumed 100% crop treated. The dietary exposure 

assessment assumes a 50x TAF for coumaphoxon in drinking water, DEEM default processing 

factors, and100% CT. Acute and steady-state assessments were conducted for food only, 

drinking water only, and food and drinking water. 

5.4.2 Percent Crop Treated Used in Dietary Assessment 

The dietary exposure assessment assumes 100% crop treated for honey for the acute and steady 

state dietary exposure assessments. BEAD has no information on honey (per conversation with 

D. Atwood and S. Smearman).

5.4.3 Acute Dietary Risk Assessment 

The acute dietary exposure estimates are summarized in Tables 5.4.3.1-5.4.3.3 and are below 

HED’s LOC (<100% of the aPAD) for the U.S. population and all population subgroups at the 

99.9th percentile. The food only dietary exposure estimate is 50% of the acute population 

adjusted dose (aPAD) for the U.S. population, and 98% of the aPAD for children 3-5 years old, 

the most highly exposed population subgroup at the 99.9th percentile. Combined dietary 

exposure from food and drinking water at the 99.9th percentile of exposure is 51% of the aPAD 

for the U.S. population and 99% of the aPAD for children 3-5 years, the most highly exposed 
Coumaphos Human Health Risk Assessment DP#409347

Page 38 of 77

population subgroup. The drinking water only dietary exposure estimate is 7% of the aPAD for 

the U.S. population, and 20% of the aPAD for all infants (<1 years old), the most highly-exposed 

population subgroup, at the 99.9th percentile. Beef meat is the risk driver when combining food 

in the acute assessment for coumaphos, accounting for approximately 80% of estimated exposure 

in the acute assessment based upon critical exposure contribution analysis.

Table 5.4.3.1. Summary of Acute Dietary (Food Only) Exposure and Risk for Coumaphos

Population Subgroup aPAD 

(mkd)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

General U.S. Population 0.00019 0.000029 16 0.000051 27 0.000096 50

All Infants (<1 year old) 0.00019 0.000034 18 0.000068 36 0.000158 83

Children 1-2 years old 0.00019 0.000061 32 0.000100 52 0.000168 88

Children 3-5 years old 0.00019 0.000054 29 0.000095 50 0.000187 98

Children 6-12 years old 0.00019 0.000039 21 0.000064 34 0.000106 56

Youth 13-19 years old 0.00019 0.000028 15 0.000045 24 0.000082 43

Adults 20-49 years old 0.00019 0.000026 13 0.000041 21 0.000066 34

Adults 50-99 years old 0.0019 0.000020 1.0 0.000033 1.8 0.000051 2.7

Females 13-49 years old 0.00019 0.000022 11 0.000036 19 0.000060 32

mkd = mg/kg/day. aPAD= acute population adjusted dose; Highest exposure at the 99.9th percentile is in bold font.

Table 5.4.3.2. Summary of Acute Dietary (Drinking Water Only) Exposure and Risk for 

Coumaphos

Population Subgroup aPAD 

(mkd)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

General U.S. Population 0.00019 0.000002 1.2 0.00004 2.3 0.000014 7.3

All Infants (<1 year old) 0.00019 0.000007 3.6 0.000011 6.1 0.000037 20

Children 1-2 years old 0.00019 0.000003 1.8 0.000006 3.4 0.000020 11

Children 3-5 years old 0.00019 0.000003 1.5 0.000005 2.6 0.000018 9.5

Children 6-12 years old 0.00019 0.000002 1.1 0.000004 2.1 0.000012 6.5

Youth 13-19 years old 0.00019 0.000002 <1 0.000003 1.8 0.000010 5.2

Adults 20-49 years old 0.00019 0.000002 1.2 0.000004 2.0 0.000013 7.0

Adults 50-99 years old 0.0019 0.000002 <1 0.000004 <1 0.000013 <1

Females 13-49 years old 0.00019 0.000002 1.2 0.000004 2.1 0.000013 7.0

mkd = mg/kg/day. aPAD= acute population adjusted dose; Highest exposure at the 99.9th percentile is in bold font.

Table 5.4.3.3. Summary of Acute Dietary (Food and TX Drinking Water) Exposure and Risk for 

Coumaphos

Population Subgroup aPAD 

(mkd)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

General U.S. Population 0.00019 0.000030 16 0.000052 27 0.000098 51

All Infants (<1 year old) 0.00019 0.000035 19 0.000070 37 0.000161 85

Children 1-2 years old 0.00019 0.000062 32 0.000100 53 0.000171 90

Children 3-5 years old 0.00019 0.000056 29 0.000096 51 0.000188 99

Children 6-12 years old 0.00019 0.000040 21 0.000065 34 0.000107 56

Youth 13-19 years old 0.00019 0.000029 15 0.000045 24 0.000083 44

Adults 20-49 years old 0.00019 0.000026 14 0.000041 22 0.000067 35

Adults 50-99 years old 0.0019 0.000021 1.1 0.000035 1.8 0.000055 2.9
Coumaphos Human Health Risk Assessment DP#409347

Page 39 of 77

Table 5.4.3.3. Summary of Acute Dietary (Food and TX Drinking Water) Exposure and Risk for 

Coumaphos

Population Subgroup aPAD 

(mkd)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

Exposure 

(mkd)

% 

aPAD

Females 13-49 years old 0.00019 0.000023 12 0.000038 20 0.000064 34

mkd = mg/kg/day. aPAD= acute population adjusted dose; Highest exposure at the 99.9th percentile is in bold font.

5.4.4 Steady State Dietary Risk Assessment 

Steady-state assessments were conducted in the DEEM acute module using the steady-state 

endpoint, PDP monitoring residue distributions and 21-day rolling water averages to provide an 

estimate of 21-day (“steady-state”) exposures. Steady-state assessments were conducted for 

drinking water alone, food alone, and food + drinking water. 

As shown in Tables 5.4.4.1-5.4.4.3 the steady state aggregate dietary (food alone, water alone 

and food plus drinking water) exposure estimates are above HED’s LOC (>100% of the PAD) 

for the U.S. population and all population subgroups, except adults 50-99 years old. The food 

only dietary exposure estimate is 210% of ssPAD for the U.S. population, and 380% of the 

ssPAD for children 1-2 years old, the most highly exposed population subgroup at the 99.9th

percentile. The drinking water only dietary exposure estimate is 36% of the ssPAD for the U.S. 

population and 110% of the ssPAD for all infants (<1 year old), the most highly-exposed 

population subgroup, at the 99.9th percentile. Combined dietary exposure from food and drinking 

water is 210% of the ssPAD for the U.S. population and 390% of the ssPAD for children 1-2 

years, the most highly exposed population subgroup. Beef meat is the risk driver when 

combining food in the steady state assessment for coumaphos, accounting for approximately 

90% of estimated exposure in the acute assessment based upon critical exposure contribution 

analysis.
Coumaphos Human Health Risk Assessment DP#409347

Page 40 of 77

Table 5.4.4.1. Summary of Steady State Dietary (Food Only) Exposure and Risk for Coumaphos

Population Subgroup ssPAD 

(mkd)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mkd)

% 

ssPAD

Exposure 

(mkd)

% 

ssPAD

Exposure 

(mkd)

% 

ssPAD

General U.S. Population 0.00004 0.000023 64 0.000037 100 0.000074 210

All Infants (<1 year old) 0.00004 0.000027 76 0.000050 140 0.000117 330

Children 1-2 years old 0.00004 0.000044 120 0.000066 180 0.000137 380

Children 3-5 years old 0.00004 0.000043 120 0.000073 200 0.000112 310

Children 6-12 years old 0.00004 0.000031 87 0.000045 130 0.000097 270

Youth 13-19 years old 0.00004 0.000022 62 0.000032 90 0.000054 150

Adults 20-49 years old 0.00004 0.000021 57 0.000030 84 0.000049 140

Adults 50-99 years old 0.0004 0.000016 4.6 0.000025 6.8 0.000034 9.4

Females 13-49 years old 0.00004 0.000018 49 0.000026 72 0.000049 140

mkd = mg/kg/day. ssPAD= steady state population adjusted dose; Highest exposure at the 99.9th percentile is in bold font

Table 5.4.4.2. Summary of Steady State Dietary (Drinking Water Only) Exposure and Risk for 

Coumaphos

Population Subgroup ssPAD 

(mkd)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mkd)

% 

ssPAD

Exposure 

(mkd)

% 

ssPAD

Exposure 

(mkd)

% 

ssPAD

General U.S. Population 0.00004 0.000007 5.9 0.00004 11 0.000013 36

All Infants (<1 year old) 0.00004 0.000003 18 0.000011 30 0.000039 110

Children 1-2 years old 0.00004 0.000003 8.8 0.000006 16 0.000018 51

Children 3-5 years old 0.00004 0.000003 7.1 0.000005 13 0.000015 42

Children 6-12 years old 0.00004 0.000002 5.3 0.000003 9.7 0.000011 31

Youth 13-19 years old 0.00004 0.000002 4.7 0.000003 8.2 0.000009 26

Adults 20-49 years old 0.00004 0.000002 5.7 0.000004 9.9 0.000013 35

Adults 50-99 years old 0.0004 0.000002 <1 0.000003 <1 0.000012 3.4

Females 13-49 years old 0.00004 0.000002 5.9 0.000004 9.8 0.000013 35

mkd = mg/kg/day. ssPAD= steady state population adjusted dose; Highest exposure at the 99.9th percentile is in bold font

Table 5.4.4.3. Summary of Steady State Dietary (Food and TX Drinking Water) Exposure and 

Risk for Coumaphos

Population Subgroup ssPAD 

(mkd)

95th Percentile 99th Percentile 99.9th Percentile

Exposure 

(mkd)

% 

ssPAD

Exposure 

(mkd)

% 

ssPAD

Exposure 

(mkd)

% 

ssPAD

General U.S. Population 0.00004 0.000024 67 0.000039 110 0.000075 210

All Infants (<1 year old) 0.00004 0.000029 81 0.000056 150 0.000123 340

Children 1-2 years old 0.00004 0.000046 130 0.000067 190 0.000140 390

Children 3-5 years old 0.00004 0.000044 120 0.000074 210 0.000114 320

Children 6-12 years old 0.00004 0.000032 89 0.000046 130 0.000098 270

Youth 13-19 years old 0.00004 0.000023 64 0.000033 91 0.000055 150

Adults 20-49 years old 0.00004 0.000021 59 0.000031 87 0.000051 140

Adults 50-99 years old 0.0004 0.000017 4.8 0.000026 7.1 0.000036 10

Females 13-49 years old 0.00004 0.000018 51 0.000028 77 0.000051 140

mkd = mg/kg/day. ssPAD= steady state population adjusted dose; Highest exposure at the 99.9th percentile is in bold font

5.4.5 Cancer Dietary Risk Assessment 
Coumaphos Human Health Risk Assessment DP#409347

Page 41 of 77

Coumaphos is classified as “no evidence” of carcinogenicity for humans. Therefore, a cancer 

dietary exposure analysis is not required. 

6.0 Residential and Other Non-Occupational Exposure and Risk Estimates

There are currently no registered non-occupational (residential) uses for coumaphos at this time. 

6.1 Residential Risk Estimates for Use in Aggregate Assessment

There are no currently registered residential (non-occupational) uses of coumaphos. Based on 

the labeled use pattern and the exposure profile of coumaphos, there is no recommended 

residential contribution to the aggregate risk assessment. 

6.2 Non Occupational Spray Drift Exposures and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast). The approach is outlined in the revised (2012) Standard Operating Procedures for 

Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. Coumaphos is not applied nor registered on use 

sites that are likely to result in spray drift. Therefore, a spray drift analysis is not included in this 

assessment. 

6.3 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates

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 

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

subsequent Volatilization Screening Analysis 

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

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

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

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, when there are potential residential exposures to a pesticide, 

aggregate risk assessment must consider exposures and risks from three major sources: food, 

drinking water, and residential exposures. In an aggregate assessment, exposures from dietary 

and residential sources are added together and compared to quantitative estimates of hazard (e.g., 
Coumaphos Human Health Risk Assessment DP#409347

Page 42 of 77

a NOAEL), or the risks themselves can be aggregated. When aggregating exposures and risks 

from various sources, HED considers both the route and duration of exposure. Because there are 

no residential uses for coumaphos at this time, the aggregate assessments include dietary 

exposures only.

7.1 Acute Aggregate Risk

The acute exposure estimates provided in the Dietary Exposure Section represent the acute 

aggregate exposure. See Section 5.4.3. The acute aggregate risks associated with the registered 

uses of coumaphos do not exceed HED’s level of concern for the general U.S. population or any 

population subgroup.

7.2 Steady State Aggregate Risk

Because there are no residential uses for coumaphos, the aggregate assessments include dietary

(food and water) exposures only. See Section 5.4.4. The steady state aggregate risks associated 

with the registered uses of coumaphos do exceed HED’s level of concern for the general U.S. 

population or any population subgroup.

7.3 Cancer Aggregate Risk

Coumaphos has been classified as “Not likely to be Carcinogenic to Humans”; therefore, a

cancer aggregate risk assessment is not required.

8.0 Cumulative Risk Characterization/Assessment

OPs, like coumaphos, 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 terbufos. 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 4.5, OPP has retained the FQPA Safety Factor for OPs, including 

coumaphos, 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 

associated with neurodevelopmental outcomes and OP exposure prior to the release of the 
Coumaphos Human Health Risk Assessment DP#409347

Page 43 of 77

revised PRA. 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 

Reference: D409347, D410244; B. Bobowiec, November 11, 2015

9.1 Occupational Handler Exposure/Risk Estimates

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

that can potentially be used, occupational dermal and inhalation handler exposure is expected 

from the proposed uses. Applying ear tags to cattle and inserting pest control strips into bee 

hives was not quantitatively assessed. The exposure to these tasks was considered negligible 

based on the product formulation and glove requirement. Therefore, the quantitative 

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

scenarios: 

• mixing/loading flowable concentrate for hydraulic type dip vats, 

• mixing/loading flowable concentrate for swim type dip vats,

• mixing/loading flowable and emulsifiable concentrate for back rubber/oilers, 

• loading dust into bags, 

• applying dust with a shaker can to cattle, horses,

• applying dust to swine bedding via shaker can,

• mixing/loading/applying liquid sprays for backpack application, 

• mixing/loading/applying liquid sprays for mechanically pressurized handguns,

and

• mixing/loading/applying liquid sprays for manually pressurized hand-wands. 

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. These are outlined in more detail in (B. Bobowiec, 20-March-2016, 

D409347, and D410244), but are summarized briefly below.

• Application Rate: Summary of the registered coumaphos products are outlined in the 

previous Table 3.3. In addition maximum application rates are presented in Tables 9.1.1 

- 9.1.9 organized by registration number.

• Unit Exposures: scenario/equipment/formulation-specific exposure factors known as 

“unit exposures” as well as their corresponding estimates for area treated or amount of 
Coumaphos Human Health Risk Assessment DP#409347

Page 44 of 77

solution handled are from HED’s ExpoSAC Policy #9.1 or standard assumptions for 

livestock treatment.

• Body Weight: A female-specific body weight of 69 kg was used to protect for pregnant 

women due to uncertainty in the human dose-response relationship for 

neurodevelopmental effects. See section 4.4 for more information.

• Absorption factors: A dermal toxicity study is the basis of dermal points of departure, a 

dermal absorption factor is not required. The inhalation route is considered to be 

equivalent to the estimated toxicity by the oral route of exposure.

• Area Treated or Amount Handled: There are label restrictions that Applicators are 

restricted to spraying no more than 100 animals in one day at the maximum application 

rate with handheld equipment and 200 animals a day at one half the maximum 

application rate. Dust applications to livestock via a shaker can is restricted to 25 animals 

a day and 1000 ft2 of bedding a day. The amount treated or amount handled was based 

on guidance in HED ExpoSAC Policy 9.1, language restrictions on the labels, and HED’s 

best professional judgement of tank and cattle herd sizes, as well as the previous 

assessment memo (D267778, R. Sandvig, August 3, 1999). Amount handled is 

summarized below.

o Swim dip vats are estimated to hold 4,000 gallons of solution. 

o Hydraulic-type dip vats are estimated to hold 1,800 gallons of solution.

o Back oil rubbers are estimated to hold 14 gallons of solution. 

o Livestock herd sizes were estimated as small (100 cows), medium (350 cows), 

and large (500 cows). 

o Mechanically pressurized handguns are estimated to hold 1,000 gallons of spray; 

however, using the language from the labels this amount was lowered to 400 and 

100 gallons of spray a day.

o Manually pressurized handwand and backpack application were assumed 40 

gallons of spray a day.

HED typically classifies exposures from 1 to 30 days as short-term and exposures 30 days to six 

months as intermediate-term. The endpoint selection for organophosphate pesticides including 

coumaphos involves a “steady state” approach based on an individual chemical’s cholinesterase 

inhibition. The “steady state” endpoint selection for coumaphos overlaps HED’s traditional 

short-term endpoint selection as well as being appropriately health protective for occupational 

handlers that apply commercially over longer periods of time (i.e., intermediate-term exposures). 

Coumaphos can be toxic to livestock if over applied so it is assumed most farmers will only 

apply when pests are an issue. However, there is no quantitative data such as number of cattle 

dipped per day, number of days dipping takes place per year, etc. HED continues to request 

more quantitative data, such as the number of cattle dipped per day, number of days dipping 

takes place per year, etc., to refine exposure to dip vat workers in quarantine areas under the 

animal and plant health inspection service, (APHIS) USDA program.

Product labels vary with respect to work attire and levels of personal protective equipment, with 

some labels not providing any specifications to others requiring use of chemical/water-resistant 

gloves or respirators. Estimates of dermal and inhalation exposure were calculated for various 

levels degrees of mitigation. Results are presented for “baseline,” defined as a single layer of 
Coumaphos Human Health Risk Assessment DP#409347

Page 45 of 77

clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and 

no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, 

etc). Co-Ral Flowable, EPA Reg. No. 11556-98 has the highest spray application rates and 

requires handlers to wear a PF10 respirator. EPA Reg. Nos.11556-115 and 11556-23 have lower 

spray application rates and do not require any respirators for handlers. The various dust 

formulations require baseline dermal attire along with gloves and PF5 respirator. Protective 

eyewear, shield, and apron are also listed on some of the labels. See Section 4.6.4 for acute 

toxicity coumaphos summary. HED does not consider a face shield equivalent to a respirator nor 

an apron over long sleeve shirt equivalent to double layer protection.

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be 

found in Appendix C. The toxicological PoDs for inputs can be found in the Section 4.6.4. A 

total aggregated risk index (ARI) approach was used since the toxicological effects for the

dermal and inhalation exposure routes were similar (RBC cholinesterase inhibition), but the LOC

values for dermal exposure (1000) and inhalation exposure (3000) are different. The target ARI 

is 1; therefore, ARIs of less than 1 are risk estimates of concern. 

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

Based on the labeled PPE for occupational handlers for the various formulations, there are risk 

estimates of concern identified (i.e., dermal MOEs < 1000 and inhalation MOEs < 3000) for the 

steady-state exposure assessment. Combined occupational handler risk estimates are presented 

using the ARI approach with a target of 1. 

There are dermal and inhalation risk estimates of concern for all formulation types and exposure 

scenarios except for back oil rubber applications. The products are sorted by formulation type

(e.g., flowable, emulsifiable concentrate, and dust) with corresponding registration numbers. 

Risk estimates are presented in Tables 9.1.1. –9.1.9 with the unit exposures for each formulation 

presented in a separate tables. The unit formulation tables are then followed by scenario specific 

inhalation and dermal exposure risk estimates and then lastly followed by the ARI estimate 

tables. The following list provides a summary of the scenarios that resulted in risk estimates of 

concern:

• The USDA cholinesterase monitoring program scenarios include gloves and PF10 

respirator and result in ARIs < 1. At label level PPE ARIs range from 0.003 to 0.06. 

ARIs range from 0.006 to 0.08 with PPE increased to double layer dermal protection and 

a PF10 respirator. 

• The liquid coumaphos products that require gloves but no respirator also result in risk 

estimates of concern. At label level of PPE ARIs range from 0.002 to 0.7. ARIs range 

from 0.03 to 1.1 with PPE increased to double layer dermal protection and a PF10 

respirator. 

• The dust formulations require gloves and at least a PF5 respirator and result in result in 

ARIs < 1. At label level PPE ARIs range from 0.003 to 0.28. ARIs range from 0.006 to 

0.46 with PPE increased to double layer dermal protection and a PF10 respirator.
Coumaphos Human Health Risk Assessment DP#409347

Page 46 of 77

Table 9.1.1. Dermal and Inhalation Unit Exposures for Dry Flowable Co-Ral Flowable Insecticide, REG # 11556-98

Application Equipment Application Rate2 Amount Handled / Area Treated3 Dermal Unit Exposures (ug/lb ai)1 Inhalation Unit Exposures (ug/lb ai)1

SL/No G SL/G DL/G EC No-R PF5 R PF10 R EC

Mixer/Loader

Swim Dip Vat 0.025

lb ai/gallon of dip

4000

gallons/day 220 37.6 29.1 8.6 0.219 0.0438 0.0219 0.083

Hydraulic Dip Vat 0.025

lb ai/gallon of dip

1800

gallons/day 220 37.6 29.1 8.6 0.219 0.0438 0.0219 0.083

Mixer/Loader/Applicator

Backpack 0.021

lb ai/gallon

40

gallons 2510 2500 1600 ND 30 6 3 ND

Manually-pressurized Handwand 0.021

lb ai/gallon

40

gallons 100000 430 365 ND 30 6 3 ND

Mechanically-pressurized Handgun 0.021

lb ai/gallon

100

gallons 1800 640 365 ND 79 15.8 7.9 ND

Mechanically-pressurized Handgun 0.021

lb ai/gallon

400

gallons 1800 640 365 ND 79 15.8 7.9 ND

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015). PPE represented includes SL= baseline dermal (long sleeved shirt, long pants, shoes 

and socks), SL/G baseline dermal plus gloves, DL/G= coverall over baseline dermal plus gloves, EC= closed system. NR = no respirator; PF5 = “Protection Factor 5”, indicating a reduction in 

exposure of 80%; PF10 = “Protection Factor 10” indicating a reduction in exposure of 90%. 

2. Based on registered label Co-Ral Flowable Insecticide Reg # 11556-98. Label is restricted use to employees enrolled in the USDA-APHIS cholinesterase monitoring program.

3. Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk for the Animal Spray and Dip Uses of Coumaphos June 10, 

1999 and EXPOSAC discussion 03/14/2013.
Coumaphos Human Health Risk Assessment DP#409347

Page 47 of 77

Table 9.1.2. Steady State-Term Duration Occupational Dermal and Inhalation Handler Non-Cancer Exposure and Risk Estimates for Co-Ral Flowable Insecticide, REG # 11556-98

Application 

Equipment

Application 

Rate1

Amount 

Handled 

/ Area 

Treated2

Dermal Dose (mg/kg/day)3 Dermal MOE7 (LOC=1000) Inhalation Dose (mg/kg-day)5 Inhalation MOE6 (LOC=3000)

SL/No G SL/G DL/G EC SL/No 

G SL/G DL/G EC No-R PF5 R PF10 R EC No-R PF5 R PF10 R EC

Mixer/Loader

Swim Dip Vat

0.025

lb ai/gallon 

of dip

4000

gallons 0.319 0.055 0.042 0.013 1.6 9.2 12 40 0.0003 6.35E-05 3.17E-05 0.00012 110 570 1100 300

Hydraulic Dip 

Vat

0.025

lb ai/gallon 

of dip

1800

gallons 0.143 0.025 0.019 0.006 3.5 20 26 89 0.0001 2.86E-05 1.43E-05 5.42E-05 250 1300 2500 660

Mixer/Loader/Applicator

Backpack 0.021

lb ai/gallon

40

gallons 0.031 0.030 0.019 ND 16 16 26 ND 0.0004 7.3E-05 3.65E-05 ND 99 490 990 ND

Manuallypressurized 

Handwand

0.021

lb ai/gallon

40

gallons 1.22 0.005 0.004 ND 0.41 96 110 ND 0.0004 7.3E-05 3.65E-05 ND 99 490 990 ND

Mechanicallypressurized 

Handgun

0.021

lb ai/gallon

100

gallons 0.055 0.019 0.011 ND 9.1 26 45 ND 0.002 4.8E-04 2E-04 ND 15 75 150 ND

Mechanicallypressurized 

Handgun

0.021

lb ai/gallon

400

gallons 0.219 0.078 0.045 ND 2.3 6.4 11 ND 0.01 0.002 0.001 ND 3.7 19 37 ND

1 Based on registered label Co-Ral Flowable Insecticide Reg # 11556-98. Label is restricted use to employees enrolled in the USDA-APHIS cholinesterase monitoring program.

2 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk for the Animal Spray and Dip Uses of Coumaphos June 10, 1999 and EXPOSAC 

discussion 03/14/2013

3 Dermal Dose= Dermal Unit Exposure (μg/lbs a.i.) × Application Rate (lbs a.i./acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (69 kg).

4 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day) 

5 Inhalation Dose = Inhalation Unit Exposure (μg/lbs a.i.) × Conversion Factor (0.001 mg/μg) × Application Rate (lbs a.i./acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (69 kg).

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
Coumaphos Human Health Risk Assessment DP#409347

Page 48 of 77

Table 9.1.3. Steady State-Term Duration Occupational ARI Handler Non-Cancer Exposure and Risk Estimates for Co-Ral Flowable Insecticide, REG # 11556-981

Application Equipment Application Rate2 Amount Handled 

/ Area Treated3

ARI4

SL/No G + 

No-R

SL/G + 

No-R

DL/G + 

No-R

SL/G + 

PF5 R

DL/G + 

PF5 R

SL/G + 

PF10 R

DL/G + 

PF10 R EC

Mixer/Loader

Swim Dip Vat 0.025

lb ai/gallon of dip

4000

gallons 0.0015 0.0074 0.009 0.0088 0.011 0.009 0.012 0.029

Hydraulic Dip Vat 0.025

lb ai/gallon of dip

1800

gallons 0.0034 0.016 0.02 0.019 0.025 0.02 0.025 0.063

Mixer/Loader/Applicator

Backpack 0.021

lb ai/gallon

40

gallons 0.011 0.011 0.015 0.015 0.022 0.015 0.024 ND

Manually-pressurized 

Handwand

0.021

lb ai/gallon

40

gallons 0.0004 0.025 0.025 0.06 0.066 0.074 0.083 ND

Mechanically-pressurized 

Handgun

0.021

lb ai/gallon

100

gallons 0.0032 0.0042 0.0045 0.013 0.016 0.017 0.024 ND

Mechanically-pressurized 

Handgun

0.021

lb ai/gallon

400

gallons 0.0008 0.001 0.0011 0.0032 0.004 0.0042 0.0058 ND

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015). Level of mitigation represented in table include: SL= baseline dermal (long sleeved 

shirt, long pants, shoes and socks), SL/G baseline dermal plus gloves, DL/G= coverall over baseline dermal plus gloves, EC= closed system. NR = no respirator; PF5 = “Protection Factor 5”, 

indicating a reduction in exposure of 80%; PF10 = “Protection Factor 10” indicating a reduction in exposure of 90%. 

2 Based on registered label Co-Ral Flowable Insecticide Reg # 11556-98. Label is restricted use to employees enrolled in the USDA-APHIS cholinesterase monitoring program

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk for the Animal Spray and Dip Uses of Coumaphos June 10, 

1999 and EXPOSAC discussion 03/14/2013

4 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)]. 
Coumaphos Human Health Risk Assessment DP#409347

Page 49 of 77

Table 9.1.4 Steady State-Term Duration Unit Exposures for Liquid Formulations (Reg #s. 11556-115, and 11556-23)

Application 

Equipment Target Animal Application 

Rate2

Amount Handled / 

Area Treated3

Dermal Unit Exposures (ug/lb ai)1 Inhalation Unit Exposures (ug/lb ai)1

SL/No G SL/G DL/G EC No-R PF5 R PF10 R EC

Mixer/Loader

Back Oil Rubbers Cattle 0.07617

lb ai/ gallon 

14

gallons/day 220 37.6 29.1 8.6 0.219 0.0438 0.0219 0.083

Mixer/Loader/Applicator

Backpack Cattle 0.01

lb ai/gallon 40

gallons 2510 2500 1600 ND 30 6 3 ND

Backpack Swine 0.005

lb ai/gallon

Manuallypressurized 

Handwand

Cattle 0.01

lb ai/gallon 40

gallons 100000 430 365 ND 30 6 3 ND Manuallypressurized 

Handwand

Swine 0.005

lb ai/gallon

Mechanicallypressurized 

Handgun

Cattle 0.01

lb ai/gallon

100

gallons 1800 640 365 ND 79 15.8 7.9 ND

Mechanicallypressurized 

Handgun

Swine 0.005

lb ai/gallon

100

gallons 1800 640 365 ND 79 15.8 7.9 ND

Mechanicallypressurized 

Handgun

Cattle 0.01

lb ai/gallon

400

gallons 1800 640 365 ND 79 15.8 7.9 ND

Mechanicallypressurized 

Handgun

Swine 0.005

lb ai/gallon

400

gallons 1800 640 365 ND 79 15.8 7.9 ND

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015). PPE represented includes SL= baseline dermal (long sleeved shirt, long pants, shoes 

and socks), SL/G baseline dermal plus gloves, DL/G= coverall over baseline dermal plus gloves, EC= closed system. NR = no respirator; PF5 = “Protection Factor 5”, indicating a reduction in 

exposure of 80%; PF10 = “Protection Factor 10” indicating a reduction in exposure of 90%. 

2 Based on registered label Co-Ral Flowable Insecticide Reg # 11556-98. Label is restricted use to employees enrolled in the USDA-APHIS cholinesterase monitoring program

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk for the Animal Spray and Dip Uses of Coumaphos June 10, 

1999 and EXPOSAC discussion 03/14/2013.
Coumaphos Human Health Risk Assessment DP#409347

Page 50 of 77

Table 9.1.5. Steady State-Term Duration Occupational Handler Non-Cancer Exposure and Risk Estimates for Liquid Formulations (Reg #s. 11556-115, and 11556-231)

Application 

Equipment

Target 

Animal

Application 

Rate2

Amount 

Handled 

/ Area 

Treated3

Dermal Dose (mg/kg/day)4 Dermal MOE5 (LOC=1000) Inhalation Dose (mg/kg-day)6 Inhalation MOE7 (LOC=3000)

SL/

No G SL/G DL/G EC

SL/

No 

G

SL/

G

DL/

G EC No-R PF5 R PF10 R EC No-R PF5 R PF10 R EC

Mixer/Loader

Back Oil 

Rubbers Cattle 0.07617lb ai/ gallon

14

gallons/

day

0.003 0.001 0.0005 0.0001 150 860 1100 3800 3.39E-06 6.77E-07 3.39E-07 1.28E06 11000 53000 110000 28000

Mixer/Loader/Applicator

Backpack Cattle 0.01

lb ai/gallon 40

gallons

0.015 0.015 0.009

ND

34 34 54

ND

1.7E-04 3.48E-05 1.74E-05

ND

210 1000 2100

ND

Backpack Swine 0.005

lb ai/gallon 0.007 0.007 0.005 69 69 110 9E-05 1.74E-05 8.7E-06 410 2100 4100

Manuallypressurized 

Handwand

Cattle 0.01

lb ai/gallon 40

gallons

0.58 0.003 0.002

ND

0.86 200 240

ND

1.74E-04 3.48E-05 1.74E-05

ND

210 1000 2100

ND Manuallypressurized 

Handwand

Swine 0.005

lb ai/gallon 0.146 ND 0.001 1.7 400 470 8.7E-05 1.74E-05 8.7E-06 410 2100 4100

Mechanical

pressurized

Handgun

Cattle 0.01

lb ai/gallon

100

gallons 0.026 0.009 0.005 ND 19 54 95 ND 1.14E-03 2.29E-04 1E-04 ND 32 160 320 ND

Mechanical 

pressurized

Handgun

Swine 0.005

lb ai/gallon

100

gallons 0.013 0.005 0.003 ND 38 110 190 ND 5.72E-04 1.14E-04 5.72E-05 ND 63 320 630 ND

Mechanical

pressurized

Handgun

Cattle 0.01

lb ai/gallon

400

gallons 0.104 0.037 0.021 ND 4.8 13 24 ND 4.58E-03 9.16E-04 4.58E-04 ND 7.9 39 79 ND

Mechanical

pressurized

Handgun

Swine 0.005

lb ai/gallon

400

gallons 0.052 0.019 0.011 ND 9.6 27 47 ND 2.29E-03 4.58E-04 2.29E-04 ND 16 79 160 ND

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015). PPE represented includes SL= baseline dermal (long sleeved shirt, long pants, shoes and socks), SL/G baseline 

dermal plus gloves, DL/G= coverall over baseline dermal plus gloves, EC= closed system. NR = no respirator; PF5 = “Protection Factor 5”, indicating a reduction in exposure of 80%; PF10 = “Protection Factor 10” 

indicating a reduction in exposure of 90%. 

2 Based on registered coumaphos labels Reg # 11556-115 and 11556-23.

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk for the Animal Spray and Dip Uses of Coumaphos June 10, 1997. EXPOSAC 

discussion 03/14/2013.

4 Dermal Dose= Dermal Unit Exposure (μg/lbs a.i.) × Application Rate (lbs a.i./acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg).

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

6 Inhalation Dose = Inhalation Unit Exposure (μg/lbs a.i.) × Conversion Factor (0.001 mg/μg) × Application Rate (lbs ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
Coumaphos Human Health Risk Assessment DP#409347

Page 51 of 77

Table 9.1.6. Steady State-Term Duration ARI Occupational Handler Non-Cancer Exposure and Risk Estimates for Liquid Formulations (Reg #s. 11556-115, and 11556-231)

Application 

Equipment

Application 

Type

Target 

Animal

Application 

Rate2

Amount Handled 

/ Area Treated3

ARI4

SL/No G + 

No-R

SL/G + 

No-R

DL/G + 

No-R

SL/G + 

PF5 R

DL/G + 

PF5 R

SL/G+ 

PF10 R

DL/G+ 

PF10 R EC

Mixer/Loader

Back Oil Rubbers Broadcast Cattle

0.076172

lb ai/ gallon 

mixture

14

gallons 0.14 0.7 0.85 0.82 1 0.84 1.1 2.7

Mixer/Loader/Applicator

Backpack Broadcast Cattle 0.01

lb ai/gallon

40

gallons 0.023 0.023 0.03 0.031 0.046 0.032 0.05 ND

Backpack Broadcast Swine 0.005

lb ai/gallon

40

gallons 0.046 0.046 0.061 0.063 0.095 0.066 0.1 ND

Manually-pressurized 

Handwand Broadcast Cattle 0.01lb ai/gallon

40

gallons 0.00085 0.052 0.054 0.13 0.14 0.16 0.18 ND

Manually-pressurized 

Handwand Broadcast Swine 0.005lb ai/gallon

40

gallons 0.0017 0.1 0.11 0.25 0.28 0.31 0.35 ND

Mechanicallypressurized Handgun Broadcast Cattle 0.01

lb ai/gallon

100

gallons 0.0068 0.0089 0.0096 0.027 0.034 0.036 0.05 ND

Mechanicallypressurized Handgun Broadcast Swine 0.005

lb ai/gallon

100

gallons 0.014 0.018 0.019 0.054 0.068 0.072 0.1 ND

Mechanicallypressurized Handgun Broadcast Cattle 0.01

lb ai/gallon

400

gallons 0.0017 0.0022 0.0024 0.0065 0.0084 0.0087 0.013 ND

Mechanicallypressurized Handgun Broadcast Swine 0.005

lb ai/gallon

400

gallons 0.0034 0.0045 0.0048 0.013 0.017 0.018 0.025 ND

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015). PPE represented includes SL= baseline dermal (long sleeved shirt, long pants, shoes 

and socks), SL/G baseline dermal plus gloves, DL/G= coverall over baseline dermal plus gloves, EC= closed system. NR = no respirator; PF5 = “Protection Factor 5”, indicating a reduction in 

exposure of 80%; PF10 = “Protection Factor 10” indicating a reduction in exposure of 90%. 

2 Based on registered coumaphos labels Reg # 11556-115 and 11556-23.

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk for the Animal Spray and Dip Uses of Coumaphos June 10, 

1997. EXPOSAC discussion 03/14/2013.

4 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)]. 
Coumaphos Human Health Risk Assessment DP#409347

Page 52 of 77

Table 9.1.7. Occupational Handler Dermal and Inhalation Unit Exposures for Dust Based Formulations and Impregnated Material 

Crop / Target Category Application Rate2 Amount Handled / 

Area Treated3

Dermal Unit Exposures (ug/lb ai)1 Inhalation Unit Exposures (ug/lb ai)1

Application Equipment SL/No G SL/G DL/G EC No-R PF5 R PF10 R EC

Mixer/Loader

Dust bag Small Cattle Farm 0.009615

lb ai/cattle

100

cattle 227 51.6 41.2 ND 8.96 1.792 0.896 ND

Dust bag Medium Cattle 

Farm

0.009615

lb ai/cattle

350

cattle 227 51.6 41.2 ND 8.96 1.792 0.896 ND

Dust bag Large Cattle Farm 0.009615

lb ai/cattle

500

cattle 227 51.6 41.2 ND 8.96 1.792 0.896 ND

Applicator

Shaker can Cattle or Horse 0.00125

lb ai/cow or horse

25

Cows or horses 4042000 110000 72600 ND 17500 3500 1750 ND

Shaker can Swine 0.000625

lb ai/pg

25

pigs 4042000 110000 72600 ND 17500 3500 1750 ND

Shaker can Swine Bedding 4.17E-05

lb ai/ft2

1000

ft2 4042000 110000 72600 ND 17500 3500 1750 ND

Impregnated Material Non Dust formulations

Ear Tag9 Cattle 20% a.i./tag Negligible exposure

Bee Mite Strip9 Bee hives 10% a.i./strip Negligible exposure

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015). PPE represented includes SL= baseline dermal (long sleeved shirt, long pants, shoes 

and socks), SL/G baseline dermal plus gloves, DL/G= coverall over baseline dermal plus gloves, EC= closed system. NR = no respirator; PF5 = “Protection Factor 5”, indicating a reduction in 

exposure of 80%; PF10 = “Protection Factor 10” indicating a reduction in exposure of 90%. 

2 Based on registered coumaphos dust and solid formulated labels.

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk for the Animal Spray and Dip Uses of Coumaphos June 10, 

1997. EXPOSAC discussion 03/14/2013.
Coumaphos Human Health Risk Assessment DP#409347

Page 53 of 77

Table 9.1.8. Steady State-Term Occupational Handler Non-Cancer Exposure and Risk Estimates for Dust Based Formulations and Impregnated Material1

Application 

Equipment

Crop / 

Target 

Category

Application 

Rate2

Amount 

Handled / 

Area 

Treated3

Dermal Dose (mg/kg/day)4 Dermal MOE5 (LOC=1000) Inhalation Dose (mg/kg-day)6 Inhalation MOE7

(LOC=3000)

SL/No G SL/G DL/G SL/No G SL/G DL/G No-R PF5 R PF10 R No-R PF5 R PF10 

R

Mixer/Loader

Dust bag Small 

Cattle Farm

0.009615

lb ai/cattle

100

cattle 0.00316 0.00072 0.0006 160 700 870 1.25E-04 2.49E-05 1.25E-05 290 1400 2900

Dust bag Medium 

Cattle Farm

0.009615

lb ai/cattle

350

cattle 0.0111 0.00252 0.0020 45 200 250 4.3E-04 8.74E-05 4.38E-05 82 410 820

Dust bag Large 

Cattle Farm

0.009615

lb ai/cattle

500

cattle 0.0158 0.00359 0.0029 32 140 170 6.25E-04 1.25E-04 6.25E-05 58 290 580

Applicator 

Shaker can Cattle and 

Horses

0.00125

lb ai/cow or 

horses

25

Cows or 

horses

1.83 0.0499 0.0329 0.27 10 15 7.93E-03 1.58E-03 7.93E-04 4.5 23 45

Shaker can Swine 0.000625

lb ai/pg

25

pigs 0.916 0.0249 0.0164 0.55 20 30 3.96E-03 7.93E-04 3.96E-04 9.1 45 91

Shaker can Swine 

Bedding

4.17E-05

lb ai/ft2

1000

ft2 2.43 0.0664 0.0439 0.21 7.5 11 1.06E-03 2.12E-03 1.06E-03 3.4 17 34

Impregnated Material Non Dust formulations

Ear Tag9 Cattle 20% a.i./tag Negligible exposure

Bee Mite 

Strip9 Bee hives 10% a.i./strip Negligible exposure

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015); Level of mitigation represented in table includes baseline inhalation and additional PPE 

required gloves (G) and PF5 respirator. It is noted that the labels suggests that handlers could utilized more protective equipment however it does not appear to be a requirement on various dust 

labels.

2 Based on registered coumaphos dust and solid formulated labels 

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. June 10, 1997. Dust bag estimates are best judgments utilizing farm surveys from memo. EXPOSAC 

discussion 03/14/2013

4 Dermal Dose= Dermal Unit Exposure (μg/lbs a.i.) × Application Rate (lbs a.i./acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (69kg).

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

6 Inhalation Dose = Inhalation Unit Exposure (μg/lbs a.i.) × Conversion Factor (0.001 mg/μg) × Application Rate (lbs a.i./ gal.) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW 

(69kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
Coumaphos Human Health Risk Assessment DP#409347

Page 54 of 77

Table 9.1.9. Steady State-Term ARI Occupational Handler Non-Cancer Exposure and Risk Estimates for Dust Based Formulations1

Application Equipment Target 

Category

Application 

Rate2

Amount Handled / Area 

Treated3

ARI4

SL/No G + 

No-R

SL/G + 

No-R

DL/G + 

No-R

SL/G + 

PF5 R

DL/G + 

PF5 R

SL/G + 

PF10 R

DL/G + 

PF10 R

Mixer/Loader

Dust bag Small Cattle 

Farm

0.009615

lb ai/cattle

100

cattle 0.06 0.085 0.087 0.28 0.3 0.41 0.46

Dust bag Medium 

Cattle Farm

0.009615

lb ai/cattle

350

cattle 0.017 0.024 0.025 0.081 0.088 0.12 0.13

Dust bag Large Cattle 

Farm

0.009615

lb ai/cattle

500

cattle 0.012 0.017 0.017 0.057 0.062 0.081 0.09

Applicator

Shaker can Cattle, and 

Horses

0.00125

lb ai/cow or 

horse

25

Cows or horses 0.00023 0.0013 0.0014 0.0043 0.0051 0.006 0.0075

Shaker can Swine 0.000625

lb ai/pg

25

pigs 0.00047 0.0026 0.0028 0.0086 0.01 0.012 0.015

Shaker can Swine 

Bedding

4.17E-05

lb ai/ft2

1000

ft2 0.00018 0.00098 0.001 0.0032 0.0037 0.0045 0.0056

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 2015); Level of mitigation represented in table includes 

baseline inhalation and additional PPE required gloves (G) and at least a PF5 respirator. It is noted that the labels suggests that handlers could utilized 

more protective equipment however it does not appear to be a requirement on various dust labels.

2 Based on registered coumaphos dust and solid formulated labels. 

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. June 10, 1997. Dust bag estimates are best judgments utilizing farm 

surveys from memo. EXPOSAC discussion 03/14/2013

4 ARI = Aggregate Risk Index
Coumaphos Human Health Risk Assessment DP#409347

Page 55 of 77

9.2 Occupational Post-application Exposure/Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure. 

9.2.1 Occupational Post-Application Inhalation Exposure 

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 Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

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

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

subsequent Volatilization Screening Analysis 

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

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

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

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

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

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

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

9.2.2 Occupational Post-Application Dermal Exposure 

Dermal post-application exposure is not anticipated due to the limited coumaphos use pattern on 

livestock and embedded ear and beehive strips, and therefore was not included in this 

assessment. 

Restricted Entry Interval

Coumaphos is classified as Toxicity Category III via the dermal route and Toxicity Category IV 

for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), a.i.’s 

classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are 

assigned a 12-hour REI. However, in the worker protection standard (WPS) (40 CFR 170.103: 

Exceptions), there is an exception for pesticides applied “on livestock or other animals, or in or 

about animal premises.” Therefore, coumaphos labels do not fall under WPS. Language on 
Coumaphos Human Health Risk Assessment DP#409347

Page 56 of 77

coumaphos end use product labels should retain statements such as, "Do not contact treated 

animals until sprays have dried and dusts have settled on the coat."

10.0 Incident Report 

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. 

For the Main Incident Data System (IDS) from January 1, 2009- May 6, 2014, there were 3 

incidents reported for coumaphos. One incident was classified as major severity and two were 

classified as moderate severity. SENSOR-Pesticides identified 5 cases from 1998 to 2010; three 

involved ingestion, one involved the misapplication of the product (intended for cattle) inside a 

home. Based on the low frequency and severity of incident cases reported for coumaphos in 

both IDS and National Institute of Occupational Safety and Health Sentinel Event Notification 

System for Occupational Risk (NIOSH SENSOR) Pesticides, there does not appear to be a 

concern at this time 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 coumaphos. However, OPP will continue to 

monitor the AHS and other epidemiologic results and will re-evaluate these conclusions as 

needed.
Coumaphos Human Health Risk Assessment DP#409347

Page 57 of 77

11.0 References 

Coumaphos: Acute and Steady State Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments to Support Registration Review. D412870, 02/04/2016, 

S. Piper.

Addendum to Revised Drinking Water Assessment for the Registration Review of 

Coumaphos. D420394, 06/02/2014, F. Khan.

Coumaphos: Registration Review Occupational Exposure Assessment for Use on Cattle,

Cattle Ear Tags, Horses, Swine, Swine Bedding, and Beehives. D409347, D410244, 

03/20/2015, B. Bobowiec.

Coumaphos: Updated Tier I Review of Human Incidents for Preliminary Risk 

Assessment. D413032, 05/27/2014, S. Recore.

Coumaphos: Registration Review Scoping Document for Human Health Assessment. 

D347381, 02/28/2008, S. Recore.

Coumaphos: Human Health Risk Assessment for Registration Review. D315769, 

02/28/2007, K. Schumacher.
Coumaphos Human Health Risk Assessment DP#409347

Page 58 of 77

Appendix A: Toxicology 

A.1 Toxicity Profile

A.1.1: Summary of OPP’s ChE Policy & Use of BMD Modeling

OPP’s ChE policy (USEPA, 20008

) describes the manner in which ChE 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 (PoD) selected. 

AChE inhibition can be inhibited in the central or peripheral nervous tissue. Measurements of 

AChE or cholinesterase (ChE) 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) ChE. 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-ChE (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 ChE 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 benchmark response (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 ChE 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 the Office of Research and Development 

(ORD) 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 ChE activity in the brain 

compartment and is a response level close to the background brain ChE 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 

 8 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.
Coumaphos Human Health Risk Assessment DP#409347

Page 59 of 77

basis as long as such PoDs are protective for brain AChE inhibition, potential peripheral 

inhibition, and clinical signs of neurotoxicity.

A.1.2: Results for BMD/BMDL Modeling for Coumaphos 

Table A.1.2.1 BMD results of single dose studies.

Coumaphos/Study Sex/age Compartment

BMD Results

BMD10 (mg/kg) BMDL10(mg/kg)

MRID 46258301

CCA Acute Study in 

Rats – Single Dose 

(gavage)

Male 

PND11 RBC 0.36 0.25

Female

PND11 RBC 0.38 0.25

Male 

PND11 Brain 0.55 0.46

Female

PND11 Brain 0.59 0.49

MRID 46258301

CCA Acute Study in 

Rats– Single Dose 

(gavage)

Adult Male 

PND 56-70 RBC 0.31 0.19

Adult Female

PND 56-70 RBC 0.57 0.34

Adult Male 

PND 56-70 Brain

No inhibition at highest dose tested of 4 

mg/kg/day; 

No reliable fit (g)

Adult Female

PND 56-70 Brain

No inhibition at highest dose tested of 4 

mg/kg/day; 

No reliable fit (g) 

Table A.1.2.2: BMD results of repeated dosing studies ranging in duration from 11 days to 1 year.

Coumaphos/Study Sex/age Compartment BMD Results

BMD10 (mg/kg) BMDL10(mg/kg)

MRID 46502201

CCA Repeat Study in 

Rats– 11 days 

(gavage)

Pup Male 

PND11 RBC 0.057 0.041

Pup Female

PND11 RBC 0.052 0.042

Pup Male 

PND11 Brain 0.337 0.237

Pup Female

PND11 Brain 0.528 0.278

Adult Male 

PND 56-70 RBC 0.127 0.089

Adult Female

PND 56-70 RBC 0.106 0.085

Adult Male 

PND 56-70 Brain

No inhibition at highest dose tested of 0.98 

mg/kg/day; 

No reliable fit (g) 

Adult Female

PND 56-70 Brain

No inhibition at highest dose tested of 0.98 

mg/kg/day; 

No reliable fit (g)
Coumaphos Human Health Risk Assessment DP#409347

Page 60 of 77

Table A.1.2.2: BMD results of repeated dosing studies ranging in duration from 11 days to 1 year.

Coumaphos/Study Sex/age Compartment BMD Results

BMD10 (mg/kg) BMDL10(mg/kg)

MRID 43055301 –

Subchronic (91 day) 

Dog (diet)

Male RBC 0.17 0.104

Female RBC 0.17 0.15

MRID 43055301 –

Chronic (1 yr) Dog 

(diet)

Male Brain 1.36 0.77

Female Brain 1.30a 0.52a

MRID 45912101 –

Developmental 

Neurotoxicity in Rats 

(Diet)

Male Pup PND21 RBC 1.50 0.11

Female Pup PND21 RBC 0.61 0.28

Male Pup PND21 Brain 6.70 2.86

Female Pup PND21 Brain 3.18 1.86

Maternal lactational 

day 21 (gestation 

and lactation) 

(~42D of dosing)

RBC 0.08b 0.03b

Maternal lactational 

day 21 (gestation 

and lactation) 

(~42D of dosing)

Brain 0.68 0.53

MRID 44775901 –

Subchronic 

Neurotoxicity Study 

in Rats (diet)

Male

4 weeks of dosing RBC 0.096 0.085

Female

4 weeks of dosing RBC 0.085 0.073

Male

14 weeks of dosing RBC 0.11 0.082

Female

14 weeks of dosing RBC 0.25 0.20

Male

14 weeks of dosing Brain Poor dose-response Poor dose-response

Female

14 weeks of dosing Brain 1.997 1.29

MRID - 00126526 

90 Day Rat Study 

(1983) (Diet)

Male

8 weeks of dosing RBC 0.16 0.1

Female

8 weeks of dosing RBC 0.17 0.14

Male

13 weeks of dosing RBC 0.15 0.12

Female

13 weeks of dosing RBC 0.1 (f) 0.08 (f)

Male

13 weeks of dosing Brain 1.05 0.58

Female

13 weeks of dosing Brain Poor dose-response Poor dose-response

MRID – 43061701 Male – F0 RBC No reliable fit No reliable fit
Coumaphos Human Health Risk Assessment DP#409347

Page 61 of 77

Table A.1.2.2: BMD results of repeated dosing studies ranging in duration from 11 days to 1 year.

Coumaphos/Study Sex/age Compartment BMD Results

BMD10 (mg/kg) BMDL10(mg/kg)

2 generation 

reproduction study in 

rats– 91 days (Diet)

Female – F0 RBC 0.07c 0.04c

Male – F0 Brain

Poor doseresponse(no brain 

AChEI in males at 

highest dose tested of 

1.79 mg/kg/day)

Poor dose-response 

Female – F0 Brain Poor dose-response Poor dose-response

Male – F1 RBC 0.048 0.036 (rounded to 

0.04)

Female – F1 RBC 0.050 0.036 (rounded to 

0.04)

Male – F1 Brain

7.55 (no brain 

AChEI in males at 

highest dose tested of 

1.79 mg/kg/day)

1.86

Female – F1 Brain 1.75 0.71

Table A.1.2.3 BMD results of repeated exposure studies via the dermal route for Coumaphos.

Coumaphos Study Sex/age Compartment BMD Results (mg/kg/day)

BMD10 BMDL10

MRID 42084901

21-Day Dermal 

Toxicity Study 

Male Brain 7.53 5.94

Female Brain 6.80 5.46

MRID 42084901

21-Day Dermal 

Toxicity Study 

Male RBC 1.24d 1.06d

Female RBC 0.82e 0.71e

MRID 42666401

21-Day Dermal 

Toxicity Study (h) 

Female RBC 0.72 0.50

Female Brain 

No inhibition 

observed at highest 

dose tested 

No inhibition 

observed at highest 

dose tested a

p=0.09 for model fit; based on visual inspection and supporting results from Chronic Dog Male Brain, this model fit is adequate. b p=0.03 for model fit; based on visual inspection and taking into account the observed dose spacing issues, this model fit is adequate and these 

results are reported for characterization purposes. 

c Based on visual inspection and taking into account the observed dose spacing issues, this model fit is adequate and these results are reported for 

characterization purposes. 

d p=0.07 for model fit; based on visual inspection, this model fit is adequate. 

e p=0.08 for model fit; based on visual inspection, this model fit is adequate. 

f p=0.09 for model fit; based on visual inspection and supporting RBC male 13 week results, this model fit is adequate and these results are 

reported for characterization purposes. g BMD10 outside dose range and therefore is unreliable.

h Only females evaluated in this dermal study.
Coumaphos Human Health Risk Assessment DP#409347

Page 62 of 77

A.2: Toxicology Profile and Executive Summaries

A.2.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for coumaphos are in Table 1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Table A.2.1.1 Toxicology Data Requirement for Coumaphos

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Acute Eye Irritation.......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents..................................

870.3150 90-Day Oral Toxicity in Non rodents............................

870.3200 21/28-Day Dermal Toxicity ..........................................

870.3250 90-Day Dermal Toxicity ...............................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

yes

yes

yes 

yes

yes

yes

no

870.3700a Prenatal Developmental Toxicity (rodent) ....................

870.3700b Prenatal Developmental Toxicity (Non rodents)...........

870.3800 Reproduction and Fertility Effects ................................

yes

yes

yes

Yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (Non rodents) ....................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse) ...............................................

870.4300 Combined Chronic Toxicity/Carcinogenicity ...............

yes

yes

yes

yes

yes

Yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test..

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Developmental Neurotoxicity .......................................

yes

yes

CR

yes

yes

yes

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

CR

yes

yes

yes

yes

CR- conditionally required 
Coumaphos Human Health Risk Assessment DP#409347

Page 63 of 77

A.2.2 Toxicity Profiles

Table A.2.2.1 Acute Toxicity Profile of Coumaphos

Guideline No. Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral [rat] 00110597

LD50 (M) >240 mg/kg

LD50 (F) = 17 mg/kg I

870.1200 Acute dermal [rabbit] 00110598 LD50: >2400 mg/kg III

870.1300 Acute inhalation [rat] 00110601

LC50 (M) = 1.081 mg/L

LC50 (F) = 0.341 mg/L

II

870.2400 Acute eye irritation 

[rabbit] 00110599 Mild Irritant, resolved by 

day 7 IV

870.2500 Acute dermal irritation 

[rabbit] 00110600 No Irritation IV

870.2600 Skin sensitization 

[guinea pig] 00110602 Non sensitizer N/A

Table A.2.2.2 . Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3100

90 day oral rat (Diet)

MRID 00126527 (1983)

guideline/acceptable

0, 2, 5 and 10 ppm 

equivalent to 0. 0.2, 0.5 

and 1 mg/kg/day

RBC AChEI:

BMD10 = 0.15/0.10 mg/kg/day for males/females

BMDL10 = 0.12/0.08* mg/kg/day for males/females (*=p=0.09 

for model fit for female data; based on visual inspection and 

supporting male RBC data this model fit is adequate and reported 

for characterization)

Brain AChEI:

BMD10 = 1.05 mg/kg/day for males; poor dose-response for 

females

BMDL10= 0.58 mg/kg/day for males; poor dose-response for 

females

NOAEL= not observed

LOAEL= 0.2 mg/kg/day (2 ppm) based on 18-32% RBC AChE 

inhibition 
Coumaphos Human Health Risk Assessment DP#409347

Page 64 of 77

Table A.2.2.2 . Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3250

21-Day Dermal Rat 

Toxicity

MRID 42084901

Acceptable guideline 

when considered with 

21 dermal study (MRID 

42666401, below)

0, 2, 4, 20 or 100 

mg/kg/day

RBC AChE inhibition:

BMD10=1.24(a)/0.82(b) mg/kg/day for males/females

BMDL10= 1.06(a)/0.71 (b) mg/kg/day for males/females

(a) P=0.07 for model fit; based on visual inspection this 

model fit is adequate

(b) P=0.08 for model fit; based on visual inspection this 

model fit is adequate

Brain AChE inhibition:

BMD10= 7.53/6.8 mg/kg/day for males/females

BMDL10= 5.94/5.46 mg/kg/day for males/females 

NOAEL= not identified (< 2 mg/kg/day)

LOAEL=< 2 mg/kg/day based on 14% and 20% RBC AChEI in 

females and males, respectively. 

870.3250

21-Day Dermal Rat 

Toxicity

MRID 42666401

Acceptable guideline 

when considered with 

21 day dermal study 

(MRID 42084901, 

above)

0, 0.1, 0.5, 1.1, or 2.1 

mg/kg/day in females 

only

RBC AChE inhibition:

BMD10=0.72 mg/kg/day for females

BMDL10= 0.5 mg/kg/day for females

Brain AChE inhibition:

No inhibition at the highest dose tested

NOAEL= 1.1 mg/kg/day

LOAEL = 2.1 mg/kg/day based on 28% RBC CheI. 

2- and 5-Day Dermal 

Toxicity in Rats

MRID 44749401 (1999)

Acceptable nonguideline

0, 2.5, 5, 10 , 20 and 50 

mg/kg in females only

5-Day

NOAEL= 5 mg/kg

LOAEL= 10 mg/kg based on 12% brain ChE inhibition

2-Day

NOAEL = 20 mg/kg

LOAEL= 50 mg/kg based on brain, plasma and RBC ChE 

inhibition

870.3700a

Prenatal 

developmental in 

(rodent)

MRID 00131684 (1983)

Acceptable guideline

0, 1, 5, or 25 mg/kg 

from GD 6 to 15

Maternal NOAEL = 5 mg/kg/day

LOAEL =25 mg/kg/day based on tremors.

Developmental NOAEL > 25 mg/kg/day

LOAEL = no effects noted 

AChE not measures in dams or fetuses. 

870.3700b

Prenatal 

developmental in 

(Non rodents)

MRID 00131683 (1983)

Acceptable guideline

0, 0.25, 2, or 18 mg/kg 

from GD 7 to 19

Maternal NOAEL = 2 mg/kg/day

LOAEL =18 mg/kg/day based on mortality (2/17) and 

cholinergic signs.

Developmental NOAEL > 18 mg/kg/day

LOAEL = no effects noted 

AChE not measures in dams or fetuses. 
Coumaphos Human Health Risk Assessment DP#409347

Page 65 of 77

Table A.2.2.2 . Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3800

Reproduction and 

Fertility Effects (Diet)

MRID 43061701 (1993)

Acceptable guideline 

0, 1, 5 and 25 ppm (F1 

females: 0, 0.08, 0.34, 

2.02 mg/kg/day; F1 

males: 0, 0.07, 0.3, 1.79 

mg/kg/day)

Parental/Systemic 

RBC AChEI BMD10 / BMDL10 = 0.07/0.04 (c ) for females; no 

reliable fit for males 

Brain ChEI BMD10 / BMDL10 = poor dose response 

(males/females) however, at 1.79/2.02 mg/kg/day brain AChEI 

was 30% in females. No brain AChEI in males at highest dose 

tested.

(c ) based on visual inspection and taking into account the 

observed dose spacing this model fit is adequate and reported for 

characterization.

Reproductive NOAEL =25 ppm (2.02/1.79 mg/kg/day) highest 

dose tested (HDT) mg/kg/day

LOAEL = not established 

Offspring

RBC AChEI:

BMD10 = 0.048/0.05 mg/kg/day (F1 males/females); BMDL10

0.036 mg/kg/day (F1 males and females at 91 days) 

Brain AChEI :

BMD10 = 7.55/1.75 mg/kg/day for males/females; 

BMDL10= 1.86/0.71 mg/kg/day for males/females. No brain 

AChEI in F1 or F2 males at highest dose tested

870.4100b

Chronic toxicity (dog) 

(Diet)

43055301 (1993) 

Acceptable guideline 

both studies together

0, 1, 30 or 90 ppm (0, 

0.025, 0.775 and 2.3 

mg/kg/day in males and 

0.024, 0.7 and 2.5 

mg/kg/day in females). 

RBC AChE inhibition:

BMD10 = 0.17 mg/kg/day for males and females

BMDL10 = 0.104/0.15 mg/kg/day for males/females (90 day 

measurement which reached steady state)

Brain AChE inhibition:

BMD10 =1.36/1.3 (d) mg/kg/day for males/females

BMDL10 = 0.77/0.52 (d) mg/kg/day for males/females 

(d) p=0.09 for model fit, based on visual inspection and 

supporting results from chronic male brain data, this model fit is 

adequate and reported for characterization.

NOAEL = 0.025 mg/kg/day

LOAEL = 0.7 mg/kg/day based on significant and biologically 

relevant depression of RBC and plasma ChE activity. (RBC 

AChEI was 53-63% for males, and 51-66% for females). 

870.4200b

Carcinogenicity 

(mouse) (Diet)

05009938 (1979) 

Acceptable guideline

0, 10 or 20 ppm

No clinical signs. No evidence of oncogenicity. No AChE 

measurements were made. 
Coumaphos Human Health Risk Assessment DP#409347

Page 66 of 77

Table A.2.2.2 . Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.4300

Combined Chronic 

Toxicity/Carcinogenic

ity in rat (Diet)

MRID 40836001 

(1988)

Acceptable guideline

0, 1, 5 or 25 ppm 

coumaphos (0, 0.07, 

0.36 or 1.7 mg/kg/day ) 

NOAEL = 0.36 mg/kg/day

LOAEL = 1.7 mg/kg/day based on decreased RBC activity in 

both males and females, and decreased body weight gain in 

females. 

Gene Mutation

870.5100

MRID 00131681

Acceptable guideline In a Pol A1 test on E. coli there was no evidence of mutagenicity.

Gene Mutation

870.5375

MRID 00131680 

Acceptable guideline

In salmonella/microsome assay coumaphos was inactive when 

tested either with or without liver microsomal enzyme 

preparations.

in vivo test for 

interaction with 

Gonadal DNA

chromosomal 

aberration 

MRID 41847501

Acceptable guideline No demonstration of mutagenic activity at 480 mg/kg. 

870.6200a

Acute Neurotoxicity 

Screening Battery

MRID 44544801 (1998)

Acceptable guideline

0, 2, 75 and 250 mg/kg

NOAEL = not identified

LOAEL =2 mg/kg/day based on significant RBC and plasma 

AChE inhibition.

870.6200b

Subchronic 

Neurotoxicity 

Screening Battery 

(Diet)

MRID 44775901 (1998)

Acceptable guideline

0, 1, 15 or 75 ppm 

coumaphos equivalent 

to 0, 0.07, 0.99 and 5 

mg/kg/day for males, 

and 0, 0.08, 1.15, and 6 

mg/kg/day for females

RBC AChE inhibition: 

BMD10 =0.11/0.25 mg/kg/day for males/females

BMDL10 = 0.082/0.2 mg/kg/day for males/females 

Brain AChE inhibition:

BMD10 =1.997 mg/kg/day for females 

BMDL10 = 1.29 mg/kg/day for females (poor dose response for 

males)

NOAEL = 0.07 mg/kg/day for males and 0.08 mg/kg/day for 

females

LOAEL =0.99/1.15 mg/kg/day for males and females, 

respectively based on 55-64% and 41-75% RBC inhibition, 

respectively.
Coumaphos Human Health Risk Assessment DP#409347

Page 67 of 77

Table A.2.2.2 . Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.6300

Developmental 

Neurotoxicity (Diet)

MRID 45912101 (2003)

Acceptable nonguideline pending 

review of positive 

control data

0, 1, 5 or 30 ppm in diet 

from gestation day 0 

through PND 21

equivalent to 

0, 0.09, 0.47. 2.77 

mg/kg during gestation 

and 0, 0.22, 1.06 and 7.4 

mg/kg/day during 

lactation

Maternal at LD21

RBC AChE inhibition:

BMD10 = 0.08 mg/kg/day (e)

BMDL10 = 0.03 mg/kg/day (e)

Brain AChE inhibition:

BMD10 = 0.68 mg/kg/day 

BMDL10 = 0.53 mg/kg/day 

(e) p=0.03 for model fit based on visual inspection and taking 

into account the observed dose spacing this model fit is adequate 

and reported for characterization

21% plasma and 78% RBC AChEI observed at 0.47 mg/kg/day 

Offspring

RBC AChE inhibition:

BMD10 = 1.5/0.61 mg/kg/day for males/female PND 21 pups

BMDL10= 0.11/0.28 mg/kg/day for males/female PND 21 pups

Brain AChE inhibition:

BMD10 = 6.7/3.18 mg/kg/day for male/female PND 21 pups

BMDL10 = 2.86/1.86 mg/kg/day for male/female PND 21 pups

NOAEL = 0.47 mg/kg/day

LOAEL = 2.77 mg/kg/day based on morphometric changes in the 

brain of PND21 males and inhibition of 27-30% plasma, 19-33% 

RBC and 4-8% brain cholinesterase activity. 

870.7485

Metabolism and 

Pharmacokinetics

MRID 00138596 (1983)

Coumaphos labeled on the leaving group was rapidly excreted as 

a conjugate n the urine. There were no dose-related changes in 

metabolism and no evidence of activation or bioaccumulation of 

the leaving group.

870.7800

Immunotoxicity

MRID 48325701 

Acceptable Guideline

Immunotoxicity NOAEL= 6.45/6.59 mg/kg/day (M/F) (Highest 

dose tested). LOAEL not established

Special studies 

Comparative 

Cholinesterase Assay 

(CCA)—Acute in Rat

MRID 46258301

Acceptable nonguideline

Adults: 1, 2, or 4 

mg/kg; PND 11 pups: 

0.25, 0.5, or 1 mg/kg

Adults: 

RBC AChE inhibition peak 8 hours

BMD10 = 0.31/ 0.57 mg/kg for males/females 

BMDL10 = 0.19 / 0.34 mg/kg for males/females

Brain AChE inhibition outside range of dosing and no reliable fit. 

No brain inhibition at highest dose tested.

PND 11 pups: 

RBC AChE inhibition peak 4 hours

BMD10 = 0.36/0.38 mg/kg for males/females 

BMDL10 = 0.25 mg/kg for both males/females

Brain AChE inhibition peak 4 hours:

BMD10 = 0.55/0.59 mg/kg for males/females 

BMDL10 = 0.46/0.49 mg/kg for males/females
Coumaphos Human Health Risk Assessment DP#409347

Page 68 of 77

Table A.2.2.2 . Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses Results

Special studies 

Comparative 

Cholinesterase Assay 

(CCA) in Rat

11-Day Repeat 

Dosing (Gavage)

MRID 46502201 (2005)

unacceptable nonguideline

Adults: 0, 0.2, 0.49, 

0.98

PND11 pups: 0, 0.19, 

0.46, 0.7 mg/kg/day

Adults: 

RBC AChE inhibition 

BMD10 = 0.127/0.106 mg/kg for males/females and 

BMDL10 = 0.089/0.0847 mg/kg for males/females

Brain ChE Inhibition: no reliable fit (BMD10 value outside dose 

range). No inhibition at 0.98 mg/kg/day (HDT)

Blood samples collected 4 hour post dosing.

PND 11 Pups:

RBC AChE inhibition: 

BMD10 = 0.057/0.052 mg/kg for males/females and 

BMDL10 = 0.041/0.042 mg/kg for males/females

Brain AChE Inhibition: 

BMD10 = 0.34/0.53 mg/kg for males/females and 

BMDL10 = 0.24/0.28 mg/kg for males/females

Blood samples collected 8 hours post-dosing

Special studies 

Comparative 

Cholinesterase Assay 

(CCA)

Gestational Dosing 

(Diet)

MRID 46295201 (2004)

unacceptable nonguideline

0, 1, 5, 30 ppm in diet 

to pregnant rats on GD 

0-20 

Equivalent to 0, 0.08, 

0.41, and 2.62

mg/kg/day

Dams at GD 20: 

NOAEL: 0.08 mg/kg/day

LOAEL: 0.41 mg/kg/day based on 19% RBC AChE inhibition 

BMD modeling not performed because DNT more sensitive with 

78% RBC AChE inhibition at 0.41 mg/kg/day

Fetus: 

NOAEL: 0.41 mg/kg/day

LOAEL: 2.62 mg/kg/day based on 22% RBC AChE inhibition

Acute Neurotoxicity 

in Hen

00115167

Acceptable guideline

22.7 mg/kg

Coumaphos-treated hens remained normal throughout the 

observation period and showed no histological signs of 

neurotoxicity. TOCP treated hens developed signs of 

neurotoxicity, and histopathological evidence of neurotoxicity. 
Coumaphos Human Health Risk Assessment DP#409347

Page 69 of 77

A.3: Hazard Identification and Toxicity Endpoint Selection 

Acute Reference Dose (aRfD) – All Populations 

Study Selected: Comparative cholinesterase (ChE) study in rats 

MRID Number: 46258301 

Dose and Endpoint for Establishing aRfD: 0.19 mg/kg (BMDL10), based on 10% RBC ChE 

inhibition in adult males. 

Uncertainty Factor(s): 100X (10X for interspecies variability, 10X for intraspecies variability) 

Comments about Study/Endpoint/Uncertainty Factor: 

The acute dietary endpoint for the general population is based on the BMDL10 for RBC AChE 

inhibition (measured at time of peak inhibition) in adult males following a single oral dose in the 

comparative AChE study. This endpoint is considered appropriate for all populations because the 

effects were observed following a single dose, and the route of administration (oral) is appropriate 

for dietary considerations. The BMDL10 is protective of RBC AChE inhibition in PND11 pups, as 

the BMDL10 for pups is 0.25 mg/kg. (See Table A.2.3).

Steady State Reference Dose (ssRfD) 

Study Selected: 2-Generation Reproductive Study in rats

MRID Number: 43061701

Dose and Endpoint for Establishing ssRfD: 0.04 mg/kg (BMDL10), based on 10% RBC ChE 

inhibition in both male and female F0 and F1 generations rats at 91 days. 

Uncertainty Factor(s): 100X (10X for interspecies variability, 10X for intraspecies variability) 

Comments about Study/Endpoint/Uncertainty Factor: 

The steady state dietary endpoint is based on RBC ChE inhibition in F0 and F1 generation males and 

females in the 2 generation reproductive study in rats. This endpoint is considered appropriate for 

steady state dietary exposure due to the oral route of administration and the chronic duration of 

exposure. The study and endpoint were selected because they are protective of effects observed in all 

the other available studies for all lifestages, including offspring effects seen in the DNT study, and 

RBC ChE inhibition in the pups of the CCA study. 

Dermal Absorption 

Since a dermal toxicity study is the basis of dermal points of departure (PoD), a dermal absorption 

factor is not required. 

Dermal Exposure (Steady State) 

Study Selected: 21 Day Dermal study in rats 

MRID Number: 42666401 

Dose and Endpoint for Establishing dermal PoD: 0.5 mg/kg (BMDL10), based on 10% RBC ChE 

inhibition in adult females (BMD10 = 0.72 mg/kg/day). 

Uncertainty Factor(s): 100X (10X for interspecies variability, 10X for intraspecies variability) 

Comments about Study/Endpoint/Uncertainty Factor: 

The steady state dermal endpoint is based on RBC ChE inhibition in female rats in at 21 day dermal 

toxicity study. 
Coumaphos Human Health Risk Assessment DP#409347

Page 70 of 77

Inhalation Exposure (Steady state) 

Study Selected: 2-Generation Reproductive Study in rats

MRID Number: 43061701

Dose and Endpoint for Establishing ssPoD: 0.04 mg/kg (BMDL10), based on 10% RBC ChE 

inhibition in both male and female F0 and F1 generation rats at 91 days. 

Uncertainty Factor(s): 1000X (10X for interspecies variability, 10X for intraspecies variability, 10X 

database factor for missing inhalation study) 

Comments about Study/Endpoint/Uncertainty Factor: 

The steady state inhalation endpoint is based on RBC ChE inhibition in F0 and F1 generation males 

and females in the 2 generation reproductive study in rats. The study and endpoint were selected 

because they are protective of effects observed in all the other available studies for all lifestages, 

including offspring effects seen in the DNT study, and RBC ChE inhibition in the pups of the CCA 

study. In the absence of absorption data, it is assumed that inhalation absorption is 100% 

(equivalent) to oral absorption.
Coumaphos Human Health Risk Assessment DP#409347

Page 71 of 77

A.4: Executive Summaries for Studies Selected as Basis of PoDs 

a. Acute Comparative Cholinesterase Assay (CCA)

The relative sensitivities to ChE inhibition at peak inhibition by coumaphos were measured in 

neonatal and young adult Wistar rats (MRID 46258301). In these studies, coumaphos was 

administered in a single gavage dose of 0, 0.25, 0.50, or 1.0 mg/kg/day to neonatal (postnatal day 

11) rats and of 0, 1.0, 2.0 or 4.0 mg/kg/day to young adult (postnatal day 58-63) rats. Peak ChE 

inhibition was measured 8 or 4 hours following dosing to young adult or neonatal rats, 

respectively. In young adults, doses of 1.0/2.0 mg/kg resulted in plasma 

(male/females=33%/38%) and erythrocyte (males/females=34%30%) ChE inhibition. Brain ChE 

activities were not inhibited at any dose level in males or females. In neonates, the 

NOAEL/LOAEL was 0.25/0.5 mg/kg based on plasma (males/females 19%/22%), erythrocyte 

(males /females 20%/19%), and brain (8%/7%) ChE inhibition. The study shows that 

coumaphos treatment of PND 11 male and female pups by a single gavage dose results in ChE 

inhibition at a lower dose than similar treatment of PND 58-63 male and female young adults. In 

addition, brain ChE was inhibited at the same LOAEL as plasma and erythrocyte ChE in male 

and female neonatal pups, whereas young adults showed no brain ChE inhibition at any dose 

level in males or females. Therefore, this comparative ChE study does demonstrate increased 

quantitative susceptibility of the offspring. 

For adults, the RBC ChE inhibition BMD10 = 0.31/ 0.57 mg/kg for males/females, and the 

BMDL10 = 0.19 / 0.34 mg/kg for males/females. Brain ChE inhibition outside range of dosing 

and no reliable fit of these data. For PND 11 pups RBC ChE inhibition BMD10 = 0.36/0.38 

mg/kg for males/females, and the BMDL10 = 0.25 mg/kg for both males/females. For brain ChE 

inhibition the BMD10 = 0.55/0.59 mg/kg for males/females, while the BMDL10 = 0.46/0.49 

mg/kg for males/females

b. Reproductive Toxicity

In a two-generation reproduction study, Sprague-Dawley rats were fed diets containing 

Coumaphos at 0, 1, 5 or 25 ppm (0, 0.07, 0.3, or 1.79 mg/kg/day in males and 0, 0.08, 0.34 or 

2.02 mg/kg/day in females, respectively). There was no increased sensitivity to pups over the 

adults. For parental/systemic toxicity, the NOEL was 25 ppm (1.79 mg/kg/day, (HDT); a LOEL 

was not established. For reproductive toxicity, the NOEL was 25 ppm (1.79 mg/kg/day); a 

LOEL was not established (MRID No. 430611701).

In the reproduction study, ChE activity was measured in adults and pups. There was doserelated decreases in plasma and red blood cell cholinesterase activity in dams at 5 and 25 ppm. 

Generally, no differences were seen on day 47 and day 91 measurements. Brain levels were 

biologically significantly inhibited (30%) in Fo and F1 adult females at 25 ppm, and in Fo adult 

males at 25 ppm. In pups, no significant changes in red blood cell or brain cholinesterase 

activity were seen on day 4, but on day 21 changes were seen at 25 ppm. In F1 pups, plasma and 

red blood cell ChE inhibition of 38-44% was seen, while in F2 pups, only plasma was affected 

(31-44%). The only significant brain inhibition in pups was an 8% decrease in F1 females on 
Coumaphos Human Health Risk Assessment DP#409347

Page 72 of 77

day 21. The NOEL was 5 ppm for cholinesterase inhibition in dams and in pups on day 21 

(MRID No. 430611701).

For parental F0 animals, the RBC ChEI BMD10 / BMDL10 are 0.07/0.04 mg/kg/day, and there 

was no reliable fit for males. For female RBC data, the BMDs did not provide statistically 

acceptable results with a P-value of 0.05 using a log-likelihood ratio test for RBC AChE 

inhibition; however, visual observation of the data show good fit and similar findings to the F1 

generation data in the study. The brain AChE data could not be modeled for BMDs due to poor 

dose response in both males and females. 

For F1 offspring, the RBC ChEI BMD10 = 0.048/0.05 mg/kg/day (F1 males/females); BMDL10

0.036 mg/kg/day (F1 males and females at 91 days). The Brain ChEI BMD10 = 7.55/1.75 

mg/kg/day for males/females; BMDL10= 1.86/0.71 mg/kg/day for males/females. 

c. 21-day dermal study in the rat (83-2); two studies 

1. MRID 42084901

Executive Summary: In a 21-day dermal study coumaphos was administered to 6 male and 

female Sprague-Dawley [Sas: CD (SD) BR] rats per group at doses of 0, 2, 4, 20 or 100 

mg/kg/day for 21 days.

At 2 mg/kg/day (LDT) there was erythrocyte cholinesterase (RBC ChE) inhibition in males (20, 

24, 84 and 96 % from low to high dose) and females (14, 42, 89 and 95 % from low to high 

dose) and plasma ChE inhibition in females (38, 38, 65 and 91 % from low to high dose). At 20 

and 200 mg/kg/day plasma (males - 44, 78 % for the 2 high doses) and brain ChE were 

decreased in males (22 and 59 % for 2 highest doses) and females (26 and 67 % for 2 highest 

doses). 

The BMD10= for RBC AChE inhibition is 1.24/0.82 mg/kg/day for males/females, 

respectively while the BMDL10 is 1.06/0.71 mg/kg/day for males/females. Although the 

BMD model fit is p=0.07, the Agency determined this model fit is adequate based on visual 

inspection of the data and consideration of BMDs from MRID 42666401 (see below). The 

BMD10= for brain AChE inhibition is 7.53/6.8 mg/kg/day for males/females, respectively 

while the BMDL10 is 5.94/5.46 mg/kg/day for males/females. 

Signs of systemic toxicity occurred at 20 mg/kg/day and above and included muscle 

fasciculation in males (17 and 67 % for 2 high doses) and females (17 and 100 % for 2 high 

doses) sporadically throughout the study. Tremors occurred in females (17 and 83 %) after the 

first week and there were anal stains in males. At 100 mg/kg/day there was increased incidence 

of hypothermia and activity in females and decreased body weight gains in males and females. 

The systemic LOAEL is 20 mg/kg/day based on muscle fasciculation and tremors. The systemic 

NOAEL is 4 mg/kg/day.

This study is classified as core-supplementary data (a NOEL for ChE was not determined) when 

considered alone and is not acceptable for regulatory purposes. However, the study is considered 
Coumaphos Human Health Risk Assessment DP#409347

Page 73 of 77

core-minimum when taken together with a second study conducted using lower doses in females 

(MRID 42666401).

2. MRID 42666401 

Executive Summary: In a 21-day dermal study coumaphos (was administered to 5 female 

Sprague-Dawley [Sas: CD (SD) BR] rats per group at doses of 0, 0.1, 0.5, 1.1 or 2.1 mg/kg/day 

for 21 days.

At 1.1 mg/kg/day RBC ChE was inhibited (24 and 28 % for 2 high doses). The BMD10= for 

RBC AChE inhibition is 0.72 mg/kg/day for females, while the BMDL10= 0.5 mg/kg/day for 

females. No brain ChE inhibition was noted at the highest dose tested of 2.1 mg/kg/day. 

There was no systemic toxicity observed at any dose. The systemic LOAEL is greater than 2.1 

mg/kg/day. The systemic NOAEL is 2.1 mg/kg/day (4 mg/kg/day based on a separate study).

This study (MRID 42666401) is considered core-minimum when taken together with study #1 
Coumaphos Human Health Risk Assessment DP#409347

Page 74 of 77

Appendix B: Physical/Chemical 

Appendix B.1: Physical/Chemical Properties.

Table B.1: Physicochemical Properties of Technical Grade Coumaphos.

Parameter Value Reference

Melting Point/Range 90-95oC DP #207352, Chris Olinger, 

pH Not available 12/12/1994

Specific Gravity 1.47 Occupational Health Services 

MSDS for Coumaphos, 2/12/1991

Water Solubility (20oC) 2.0 mg/100 mL

DP #207352, Chris Olinger, 

12/12/1994

Solvent Solubility (g/100 mL at 20oC)

Acetone 23.82

Diethyl phthalate 21.50

Ethanol 0.9

Xylene 0.9

Octanol 0.13

Mineral spirits 0.09

Hexane 0.07

Vapor Pressure (20oC) 0.013 mPa/9.7 x 10-8 mm Hg

Henry’s Law constant 3.1 x 10-8

Dissociation Constant (pKa) Not required

Octanol/Water Partition Coefficient 

(Log[KOW]) Not available

UV/Visible Absorption Spectrum Not available
Coumaphos Human Health Risk Assessment DP#409347

Page 75 of 77

Appendix B.2: International Residue Limits for Coumaphos

Table B.2: International Residue Limits for Coumaphos

US Canada Mexico2 Codex

Residue Definition:

40CFR180.189

Coumaphos ( O,O -diethyl O -3-

chloro-4-methyl-2-oxo-2H-1-

benzopyran-7-yl phosphorothioate 

and its oxygen analog ( O,O -

diethyl O -3-chloro-4-methyl-2-

oxo-2H-1-benzopyran-7-yl 

phosphate)

Livestock: O-(3-chloro-4-methyl-2-oxo2H-1-benzopyran-7-yl)

O,O-diethyl phosphorothioate, including 

the oxygen

analog O-(3-chloro-4-methyl-2-oxo-2H1-benzopyran7-yl) O,O-diethyl phosphate (calculated 

on the fat content)

Honey, honeycomb, beeswax: O-(3-

chloro-4-methyl-2-oxo-2H-1-

benzopyran-7-yl)

O,O-diethyl phosphorothioate, including 

the oxygen

analog O-(3-chloro-4-methyl-2-oxo-2H1-benzopyran7-yl) O,O-diethyl phosphate

None

(withdrawn 

1980)

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

Commodity US Canada Mexico Codex

Cattle, fat 1.0 0.51

Cattle, meat 1.0 0.51

Cattle, meat byproducts 1.0 0.51

Goat, fat 1.0 0.51

Goat, meat 1.0 0.51

Goat, meat byproducts 1.0 0.51

Hog, fat 1.0 0.51

Hog, meat 1.0 0.51

Hog, meat byproducts 1.0 0.51

Honey 0.15 0.02

Honeycomb 45.0 0.1

Horse, fat 1.0 0.51

Horse, meat 1.0 0.51

Horse, meat byproducts 1.0 0.51

Milk, fat (=n in whole milk) 0.5

Sheep, fat 1.0 0.51

Sheep, meat 1.0 0.51

Sheep, meat byproducts 1.0 0.51

MRLs with NO US Equivalent

Beeswax 1

Fat of poultry 0.51

Meat-by-products of poultry 0.51

Meat or poultry

Completed by M. Negussie; 05/21/14

1 Calculated on the fat content.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Coumaphos Human Health Risk Assessment DP#409347

Page 76 of 77

Appendix C: Summary of Occupational Non-Cancer Algorithms 

Potential daily exposures for occupational handlers are calculated using the following formulas:

E=UE * AR * A * 0.001 mg/ug

Where:

E = exposure (mg ai/day),

UE = unit exposure (μg ai/lbs ai),

AR = maximum application rate according to proposed label (lbs ai A or lbs ai/gal), and

A = area treated or amount handled (e.g., A/day, gal/day).

The daily doses are calculated using the following formula:

ADD= 

E * AF

BW

Where:

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day),

E = exposure (mg ai/day),

AF = absorption factor (dermal and/or inhalation), and

BW = body weight (kg).

Margin of Exposure: Non-cancer risk estimates for each application handler scenario are 

calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to 

the daily dose of concern. The daily dermal and inhalation dose received by occupational 

handlers are compared to the appropriate PoD (i.e., BMDL10) to assess the risk to occupational 

handlers for each exposure route. All MOE values are calculated using the following formula:

MOE= 

POD

ADD

Where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),

PoD = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).

BMDL10 = bench mark dose limit.

The aggregate risk index (ARI) was calculated as follows:

Aggregate Risk Index (ARI) = 1÷ (1 ÷ RIdermal) + (1 ÷ RIinhalation)

Where:

Risk Index (RI) = MOE ÷ LOC
Coumaphos Human Health Risk Assessment DP#409347

Page 77 of 77

Appendix D: Review of Human Research 

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

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the Pesticide Handlers Exposure Database (PHED) 1.1, and the Agricultural Handler Exposure 

Task Force (AHETF) database, 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 

website9. 

 9 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data

and http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-post-applicationexposure