### 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

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

Assessment

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

40 CFR: §180.189 MRIDNo.: NA

FROM:

# She~la Piper

, Risk

# A~sesso**~*~** _ Chns Schlosser

, Tox1cologi;t 

# r '%v**~­** Bridgett Bobowiec

, Biologist**~ ~**  

### Registration Action Branch VI

Health E ffects 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 She i la Piper ; the occupational and residential exposure assessmentCoumaphos Human Health Risk Assessment DP#409347

Page 2 of 77 

### w ere 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, & Excret ion (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 D eparture 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

................................ ..... 35Coumaphos 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

................................ ................................ ................ 77Coumaphos 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

a r thro pod 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 du st 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 a pplication 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, backpack s
, and ear tags. Us e 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 dus ting is prohibited and t here 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 applicati on rate. In addition, a pplicators are limited to dusting no more than 25 animals in one day and no more than 1

, 000 square f eet 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 t he 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. A fter repeated dosing at the same dose level, the degree of i nhibition comes into equilibrium with the production of new, uninhibited enzyme. Therefore, steady state exposure assessments of 21 days and longer w ere 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 PoD s are based on the results of benchmark dose (BMD) analyses

wh ere 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 (B MDL 10 

### ) 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, t his 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 2Coumaphos Human Health Risk Assessment DP#409347

Page 6 of 77 

### generation rat reproduction study . The BMDL 10 

### is 0.04 mg/kg/day for RBC ChE inhibition in both sexes of the F0 and F1 generations. The acute and steady state PoD s are based on the most

sensitive BMDL 10 

### s 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 o f 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 childbe aring 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 neuro developmental 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.

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

include s coumaphos and its oxygen analog, coumaphoxon. The residue of concern for risk assessment purposes in drinking water is coumaphos and coumaphoxon. The Env ironmental Fate and Effects Division (EFED) performed surface water and groundwater modeling using the highest application rate s. The highest estimated drinking water concentrations were from surface

wate r 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 lives tock 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 ( a PAD) ) 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 99.9 th


### percentile. Combined dietary exposure from food and drinking water at t he 99.9 th 

### 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

.

S teady

- 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 ofCoumaphos Human Health Risk Assessment DP#409347

Page 7 of 77 

### 21

- day (“steady

- state”) average daily exposures. S teady

- state assessments exposure estimates are

above HED’s LOC (>100% of the steady state population adjusted d ose ( ssPAD) ) for the U.S. population and all population subgroups , except adults 50

- 99 years old

. The food only dietary exposure estimate is 2 1 0 % of ssPAD for the U.S. population, and 38 0 % of the ssPAD for

children 1

- 2 years old, the most highly exposed po pulation subgroup at the 99.9 th 

### percentile. Combined dietary exposure from food and drinking water is 2 1 0 % of the ssPAD for the U.S. population and 39 0% 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 co umaphos in or around residences; therefore, risk assessments for residential (non

- occupational) exposure are not warranted at this time. A non

occupational bystander spray drift assessment was not performed for coumaphos at the time

because of the limite d use pattern on livestock.

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

exposures. Residential aggregate exposure assessments are not required since none of the currently registered uses result in residentia l exposure. Because coumaphos has been classified as a “not likely human carcin ogen ” , a cancer aggregate risk assessment is not required.

Occupational exposure is possible with use of p roducts containing coumaphos applied as both liqui d 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 ove r 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/applyin g liquids for backpack, mechanically pressurized handguns, and manually pressurized hand

- wands. Exposure to applying ear tags and bee hive control strips were not quantitatively asse ssed.

P ersonal 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 in dex (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 l abel 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 d ermal post

- application exposure was not conducted for coumaphos uses. T he amount of dermal exposure to post

- application workers is likely to be substantially lower than the exposure to handlers

, therefore, the handler assess ment 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

- app lication 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 website 1



### .

2.0 HED Recommendations

2.1 Data Deficiencie s

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 (c oumaphoxon , 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 t he methods are adequate for determining either couma phos 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

- application

exposureCoumaphos 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 tolerance s . T he GC

- NPD enforcement method 74310 adequately recover s 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 fa t 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 toleranc e 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 coumapho s , i ncluding 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 c oumaphos (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

- 2H

1

- ben zopyran

- 7

- yl phosphate , calculated as the stoichiometric equivalent of coumaphos

.

Honey

................................ ................................ ................................ . 0. 15 ppm Honeycomb

................................ ................................ ........................ 45 ppm Cattle, f at

................................ ................................ ............................ 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 ppmCoumaphos 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 F at

................................ ................................ .............................. 0. 5 ppm

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

No ne

2. 3

. 2 Recommendations from Occupational Assessment

A s ummary 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 re gistrants 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

a nd 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 C 14 H 16 ClO 5 PS Molecular Weight 362.78

IUPAC Name O

- 3

- chloro

- 4

- methyl

- 2

- oxo

- 2 H

- chromen

- 7

- yl O,O

- diethyl phosphorothioate

CAS Name O

- (3

- chloro

- 4

- methyl

- 2

- oxo

- 2 H

- 1

- benzopyran

- 7

- yl) O,O

- diethyl phosphorothioate CAS Registry Number 56

- 72

- 4

Chemical Class Organophosphate

Coumaphos

- oxon

Molecular Formula C 14 H 16 ClO 6 P 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 sta ble 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 e mbedded into cattl e 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 treat ed 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 mo re than 25 animals in one day and applying coumaphos to no more than 1

, 000 square f eet of swine bedding in one day. O O Cl

O P S

H 5 C 2 O O C 2 H 5 C H 3Coumaphos 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, backpack s , 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 lb s a

. i

. per animal for dust application, and 0.000042 lb s 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 ma ximum spra y 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

- APHIS 2



### 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 coumap hos for each of the formulated products sorted by livestock type.

2 APHIS

- Animal and Plant Health Inspection ServiceCoumaphos 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 Applic ation

Rate Max. No. Applic ation 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. RUP 1 and use is restricted to employees of the USDA APHIS 2 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 wa ter. 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],

A nd

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 o r 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],

A nd

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 S haker 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 bag s 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 Applic ation

Rate Max. No. Applic ation 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

- R al (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.

M echanical 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

OP s. 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/ft 2 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 ft 2

.

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 a n assessment of human health risk to support the registrati on 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 an d may be used

i n strips in hives resulting in residues in honey and honeycomb . Additionally, humans may be exposed to coumaphos in drinking water since c oumaphos wash

- off from treated cattle can come

into contact with and be adsorbed onto manure as well as transported a s 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 w hile handling the pesticide prior to application, as well as during application. Occupa tional p ost

- 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://ww w.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 subgrou ps 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 b y 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

consideration s 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 sub groups.

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 toCoumaphos 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 me tabolic 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 charact erization; 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 O P s

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 ri sk estimates using the current P o D 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 a vailable for coumaphos, EPA plans to move forward with the coumaphos human health risk assessment without t oxicity data for coum aphos’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 p otency 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 an d 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 acetylcholineCoumaphos 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 [ 14 

### C] 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 plasm a 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 r epeated dose group s ). Oral absorption

was estimated to be 80 % and 90% for the 1 mg/kg/day groups (single and repeat dosing, respectively), a nd 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 residu es 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 administe red 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 Toxicologica l 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 P o D s . Coumaphos has quality dose response data across multiple life stages, durations, an d 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 A 2, 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 . A ll of the oral studies

modeled for BMD analysis were based on dietary administration except for the acute and 11 dayCoumaphos 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) w ere 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 s tudies, pregnant animals were approximately 2

- fold more sensitive than non

- pregnant females in repeat exposure studies. N o

sex

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

, at higher

doses adult female rats appear to b e 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, neurobehavior al effects such as decreased open field activity in males and

decreased for elimb grip strength in females were observed. I n the developmental studies, tremors were observed in maternal rats, and c holinergic 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 co nsidered 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 assessm ents. 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, singl e 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 fr om 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 BMD 10 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

1 a 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

90 d 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 reprodu ctive 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 pur poses.

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



### As show n 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 t he same level , the degree of inhibition comes into equilibrium with the produ ction 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 subchr onic 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 2 1

- 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, t he 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 P o D 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 P o D s 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 P o D s 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 neurodevelopmenta l 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, t he agen cy 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, Ch ild Growth and Development Study or the “Mt. Sinai Child Growth and Development Study;” and 3) the Center for Health Assessment of Mothers and Children of Salinas Valley (CHAMACOS) conducted by researchers at University of California Berkeley. The agency has evaluated these studies and sought external peer review (FIFRA SAP reviews in 2008 and 2012; federal panel, 2013 3 

### ) and concludes they are of high quality. In the three US epidemiology cohort studies, mother

- infant pairs were recruited for the purpose o f 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 o n 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 assessmen t, in large part, based on the findings of these studies.

In the 2015 updated literature review (OPP/USEPA; D331251; 9/15/ 20 15), the agency conducted a systematic review expanding the scope of the 2012/2014 review focused on US cohort studies with particu lar 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 stud ies which were

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

- HQ

- OPP

- 2008

- 0850

- 0170Coumaphos 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 f rom 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 alon e 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.pdfCoumaphos 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 t o 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, bensuli de, 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, a nd 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 a n 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.

Wit h 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)] in vestigators 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 DE AP, 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 betwe en 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 behavioralCoumaphos Human Health Risk Assessment DP#409347

Page 23 of 77 

### problems may not have been as sen sitive 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 a utism 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 respons iveness 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, increase d 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 dif ferent 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 o f 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 i ntelligence 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 expos ure 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 20 00 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 u ncertainty 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/a dverse 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 pathwa y 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 significantl y 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/ 20 15). Neurobehavioral alterations in la boratory 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 demonstr ate, 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 uncerta inties 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 reviewe d 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 studie s 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

evi dence 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 f or 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 forCoumaphos Human Health Risk Assessment DP#409347

Page 25 of 77 

### neurodevelopmenta l 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 r evised 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 wit h 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 inh ibition. 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 child hood, 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 s tudy. Therefore, a total database uncertainty f actor 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 i nclude 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 50 X 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; neurotoxic ity is the most sensitive effect in all species, routes, and lifestages and is being used in deriving P o D s for risk assessment.

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

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### Comparative AChE studies are available and pro vide 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 P o D s 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 quantita tive 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 P o D 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 P o D s are based on the most sensitive BMDL 10 

### s 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 warr ants 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 uncertaintie s 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 Selectio ns

4.6.1 Dose

- Response Assessment

Table 4. 6

. 5 .1 summarizes the coumaphos toxicity endpoints and PoD s selected from an evaluation of the database. This endpoint selection was based on a weight of the evidence evaluation using the following consideratio ns:

• 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 P o D derivation as these

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

Page 27 of 77 

### many studies, and thus a majority of brain data w ere not suitable for BMD analysis, or had a poor dose response.

• Potentially susceptible popu lations (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 e xposure. However, there is no sensitivity at low doses near the P o D s 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 major ity 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 acro ss studies. The coumaphos database demonstrates a striking consistency across studies which allows

for P o D s to be derived from multiple critical studies, thereby, increasing the confidence

in such values.

Descriptions of the primary toxicity studies us ed 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 (Licci one & 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 BMD 10 

### s and BMDL 10 

### s. The

BMD 10 

### is the estimated dose where AChE is in hibited by 10% compared to background. The

BMDL 10 

### is the lower confidence bound on the BMD 10 

### . As a matter of science policy, the Agency uses the BMDL, not the BMD, for use as the P o D (USEPA, 2012). All BMD/BMDL modeling was completed using USEPA BMD Sof tware, 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

c omparable for RBC AChE data in pups ages post

- natal day (PND) 11 and adult male and

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

the results of a well

- conducted acute CCA rat study (MRID 46258301). A BMDL 1 0 

### of 0.19 mg/kg/day associated with RBC AChE inhibition in adult males was selected as a suitable P o D for the acute dietary (all populations) exposure scenario. The corresponding BMD 10 

### 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 t he 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 i nhibition (4 hours for adults and 8 hours for pups). RBC AChE inhibition was selected for

the P o D 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 fa ctor due to uncertainty

in the human dose

- response relationship for neurodevelopmental effects (see Section 4.4)) is applied to the BMDL 10 

### to obtain an aPAD of 0.00019 mg/kg/day for exposure scenarios with infants, children, youth , and women of childbearin g 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 P o D for the steady state dietary (all populations) exposure scenario was derived from the results of a 2 genera tion reproduction study (MRID 43061701). A BMDL 10 

### 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 P o D for the steady

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

### s 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 du ration 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 P o D of 0.04 mg/kg/day for RBC AChE inhibition is supported by several other studies including:

• BMDL 10 

### of 0.041/0.042 mg/kg/day (males/females) in PND 11 pups in repeat CCA study via gavage (11 days) (MRID 46502201)

• BMDL 10 

### 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 l og

- likelihood ratio test. However, visual observation of the data

show s a good fit and comparable findings to the F1 generation data

, which were selected as the

Po D

.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 BMDL 10 

### to obtain a ssPAD 6 

### of 0.00004 mg/kg/day for e xposure 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 Sta te

Based on the use pattern for coumaphos, only a repeated exposure dermal P o D is required

. Therefore, the two available 21

- day dermal studies were used for the steady state dermal

assessment.

A steady state dermal P o D was selected from a 21

- day derma l toxicity study (MRID 42666401) in rats based on RBC AChE inhibition (BMDL 10 

### = 0.5 mg/kg/day; BMD 10 

### = 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 m g/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 ( BMDL 10 

### 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 interspe cies 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 dose

response relationship for neurodevelopmental effects (see Se ction 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 P o D 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 or al 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 BMD 10 

### of 0.05 mg/kg/day associated with RBC AChE inhibition in both male and female adult rats of the F0 and F1 generations fro m the 2 generation reproductive study was selected as a suitable PoD for the steady

- state inhalation (all populations) exposure scenario. The corresponding BMDL 10 

### 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 durationCoumaphos 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 bec ause 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 conve rsion 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 t oxicity 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 Age ncy initially used upper bound oxon adjustment factors of 10X and 100X for estimating potential oxon poten cy. The 100X was used considering the highest relative toxicity difference observed (61X) for malathion/maloxon, based on the data available at the

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

malathion and mal aoxon. 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 es timate 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

C hlor pyrifos 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

P o D s 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, c oumaphos 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 Toxicologica l 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 Factors 5 RFD, PAD, & LOC

for Risk Assessment Study and Toxicological

Effects

Acute Dietary

(All Populations Except Adults 50

- 99 Years) BMDL 10 = 0.19 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 10x Acute RfD =0.0019 mg/kg

aPAD = 0.00019 mg/kg CCA St udy (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) BMDL 10 = 0.19 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD = 0.0019 mg/kg

aPAD = 0.0019 mg/kg CCA St udy (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) BMDL 10 = 0.04 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 10x ssRfD = 0.0004 mg/kg

ssPAD = 0.00004 mg/kg/day 2 generation repr oductive 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) BMDL 10 = 0.04 mg/kg/day UF A = 10x

UF H = 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. BMDL 10 = lower confidence interval on the benchmark dose for 10% response. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, 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) BMDL 10 = 0.5 mg/kg/day UF A =10x

UF H =10x

UF DB =

10x a Occupational LOC for

MOE = 1000 21

- day dermal toxicity study (MRID 42666401) in female rats

BMD 10 = 0.72 mg/kg/day for

inhibition of RBC AChE in adult

female rats.

Inhalation Steady State (21 days and longer) BMDL 10 = 0.04 mg/kg/day

Inhalation absorption 100% of

oral absorption UF A =10x

UF H =10x

UF DB = 30x b Occupational LOC for

MOE = 3000 2 generation reproductive study (MRID 43061701)

BMD 10 = 0.05 mg/kg/day for

Inhibition of RBC AChE in F 0 and F 1 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 ( P o D ) = 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. BMDL 10 = lower confidence interval on the

benchmark dose fo r 10% response. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = database uncertainty factor. MOE = margin of

exposu re. 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 UF DB for occupational dermal exposures = database uncertainty factor for uncertainty in the human dose

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

b UF DB for occupational inhalation exposures = database uncertainty factor incorporating uncertainty in the human dose

- response relationship for neurodevelopmental effects (see Section 4.4) and the UF L 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 inc lude 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 studi es 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 aCoumaphos 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 t hat 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 dat a. 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 pestic ide 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 screeni ng was published on June 14, 2013 6 

### 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 website 7

.



### 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 residue s 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

residue s of concern for risk assessment and for tolerance e nforcement are coumaphos and coumaph oxon

. The registrant has canceled uses on poult ry ; 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 t o 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 K d 

### values. A major degradate, the oxygen analog

, coumaphoxon, wa s 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

. Co umaphos 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 PathwaysCoumaphos 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 bioac cumulation and t he 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 Applicable 1

Rotational Crop Not Applicable 1 Not Applicable 1

Livestoc k Ruminant Parent and oxygen analog (coumapho xon ) 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 a r t hro pod pests on livestock and use d 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 wi th 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 f eeding study looked for the combined residue of parent and coumaphoxon in livestock and found

detec table resid u es 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 i s 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 ProfileCoumaphos 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. How ever
, 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 operation s and pasture/rangeland.

The estimat ed 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 Wat er Program) f or groundwater

. Pesticide Root Zone Model

- Ground Water model ( PRZM

- GW 

### ) was also used for ground water. The drinking water assessment assumed that d uring a rain event, coumaphos wash

- off from treated cattle can be potentially adsorbed into ma nure as well as transported as effluent from concentrated animal feeding ope rations and pasture/rangeland. U se of this product is restricted to employees of the USDA

- APHIS 7 

### 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 dip

vat 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 (3 62.76 g/mol) to coumaphoxon (3 46.7 g/mol).

Table 5.3 summarizes recommended EDWCs fo r 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 pr obabilistic 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 ServiceCoumaphos 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 D rinking Water Estimated Drinking Water concentration (μg/L)

Acute Chronic Average

chronic Coumaphos

Surface Water 1 0.10 0.05 0.03

Groundwater 2 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 1.9 2 x 10

- 03 1.9 2 x 10

- 03 1.9 2 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, Febr uary 4, 2016



### 5.4.1 Description of Residue Data Used in Dietary Assessment

P artially refined acute and steady state dietary exposure and risk assessment s for coumaphos

w ere 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 assessment s 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. Sme arman)

.

5.4.3 Acute Dietary Risk Assessment

The acute dietary exposure estimates are summarized in Table s 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

99.9 th 

### 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 99.9 th 

### percentile. Combined dietary

exp osure from food and drinking water at the 99.9 th 

### 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 exposedCoumaphos 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 99.9 th 

### percentile. Beef meat is the risk driver when combining food in the acute assessment for coumaphos, acc ounting 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) 95 th 

### Percentile 99 th 

### Percentile 99.9 th 

### 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 99.9 th 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) 95 th 

### Percentile 99 th 

### Percentile 99.9 th 

### 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 99.9 th 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) 95 th 

### Percentile 99 th 

### Percentile 99.9 th 

### 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 2.9Coumaphos 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) 95 th 

### Percentile 99 th 

### Percentile 99.9 th 

### 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 99.9 th percentile is in bold font

.



### 5.4.4 Steady State Dietary Risk Assessment

S teady

- 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. S teady

- 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 diet ary exposure estimate is 2 10 % of ssPAD for the U.S. population, and 38 0 % of the

ssPAD for children 1

- 2 years old, the most highly exposed population subgroup at the 99.9 th


### percentile. The drinking water only dietary exposure estimate is 36% of the ssPAD f or the U.S. population and 1 10 % of the ssPAD for all infants (<1 year old), the most highly

- exposed population subgroup, at the 99.9 th 

### percentile. Combined dietary exposure from food and drinking

water is 2 10 % of the ssPAD for the U.S. population and 39 0% 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) 95 th 

### Percentile 99 th 

### Percentile 99.9 th 

### 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 99.9 th 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) 95 th 

### Percentile 99 th 

### Percentile 99.9 th 

### 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 99.9 th 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) 95 th 

### Percentile 99 th 

### Percentile 99.9 th 

### 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 1 30 0.000067 190 0.000140 390

Children 3

- 5 years old 0.00004 0.000044 12 0 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 99.9 th percentile is in bold font



### 5.4.5 Cancer Dietary Risk AssessmentCoumaphos 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 method s (e.g., groundboom and airblast). The approach is outlined in the revised (2012) Standard Operating Procedures f or 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

assessmen t.

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., f lux 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 r esidential sources are added together and compared to quantitative estimates of hazard ( e.g. ,Coumaphos Human Health Risk Assessment DP#409347

Page 4 2 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 expo sure. 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
aggregat e exposure. See Section 5.4.3. The acute aggregate risks associated with the registered

use s of coumaphos do not exceed HED’s level of concern for the general U.S. populat ion 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 use s of coumaphos do exceed HED’s level of concern for the gene ral U.S. populat ion 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 b asis for the OP common mechanism grouping per

OPP’s Guidance f or 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 P o D s 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

sin ce 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 th e neurodevelopment

outcomes which precludes the agency from formally establishing a common mechanism group per the Guidance f or Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) based on that outcom e. 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 con tinue to evaluate the epidemiology studies associated with neurodevelopmental outcomes and OP exposure prior to the release of theCoumaphos 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 exposu res 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, t he 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

,

• mixi ng/loading/applying liquid sprays for mechanically pressurized handguns,

and

• mixing/loading/ applying l iquid sprays for manually pressurized hand

- wands.

A series of assumptions and exposure factors served as the basis for completing the occupational

hand ler 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

“u nit exposure s” a s well as their corresponding estimates for area treated or amount ofCoumaphos 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

- specif ic body weight of 69 kg was used to protect for pregnant women due to uncertainty in the human dose

- response relationship f or 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. T he inhalatio n 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 app lication rate with handheld equipment and 200 animals a day at one half the maximum application rate. Dust application s to livestock via a shaker can is restricted to 25 animals a day and 1000 ft 2 

### of bedding a day

. The amount treated or amount handled wa s 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 t he previous assessment memo (D267778, R. Sandvig, August 3, 1999)

. Amount handled is

summa rized below.

o S wim 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 h erd 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 M anually 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 ch olinesterase

inhibition. The “steady state” endpoint selection for coumaphos overlaps HED’s traditional

short

- term endpoint selection as well as being a ppropriately 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, t here is no quantitative data such as number of cattle dipped per day, number of days dipping takes place per y ear, etc

. H ED continues to request more quantitative data, such as the number of cattle dipped per day, number of days d ipping 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 equi pment, 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 presente d for “baseline,” defined as a single layer ofCoumaphos 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 R eg . 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 v arious 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 fa ce 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 P o D s for inputs can be found in the Section 4.6.4. A total aggregated risk index (ARI) approach was used since the toxico logical effects for the

dermal and inhalation exposure routes were similar (RBC cholinesterase inhibition), but the LOC values for dermal exposure (100 0 ) 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 formulat ion 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 Table s 9 .1.1.

– 9 .1.9 with the unit exposures for each formulation presented in a separate table s. The unit formulation tables are then followed by scenario specific inhalation and dermal exposure risk estimates and then lastly followed by the ARI estimate

tab les

. The following list provides a summary of the scenarios that resulted in risk estimates of

concern:

• T he 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

.

• T he liquid coumaphos products that require gloves but no r espirator also result in risk

estimates of concern. At label level of PPE ARI s 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 Rate 2 Amount Handled / Area Treated 3 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 res pirator; 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 Ris k 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

Rate 1 Amount

Handled

/ Area

Treated 2 Dermal Dose (mg/kg/day) 3 Dermal M OE 7 (LOC=1000) Inhalation Dose (mg/kg

- day) 5 Inhalation MOE 6 (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 0.05 5 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

Manually

pressurized

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

Mechanically

pressurized 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

Mechanically

pressurized 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 f or 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.) × Conve rsion 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. Stea dy S tate

- Term Duration Occupational ARI Handler Non

- Cancer Exposure and Risk Estimates for Co

- Ral Flowable Insecticide, REG # 11556

- 98 1

Application Equipment Application Rate 2 Amount Handled

/ Area Treated 3 ARI 4

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 glove s, 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 registe red 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 Opera tor 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 S tate

- Term Duration Unit Exposures for Liquid Formulations ( Reg #s. 11556

- 115, and 11556

- 23 )

Application Equipment Target Animal Application

Rate 2 Amount Handled /

Area Treated 3 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 Manually

pressurized

Handwand Cattle 0.01 lb ai/gallon 40 gallons 100000 430 365 ND 30 6 3 ND Manually

pressurized

Handwand Swine 0.005 lb ai/gallon

Mechanically

pressurized

Handgun Cattle 0.01 lb ai/gallon 100 gallons 1800 640 365 ND 79 15.8 7.9 ND

Mechanically

pressurized

Handgun Swine 0.005 lb ai/gallon 100 gallons 1800 640 365 ND 79 15.8 7.9 ND

Mechanically

pressurized

Handgun Cattle 0.01 lb ai/gallon 400 gallons 1800 640 365 ND 79 15.8 7.9 ND

Mechanically

pressurized

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 res pirator; PF5 = “Protection Factor 5”, indicatin g 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 cholinester ase monitoring program

3 Exposure Science Advisory Council Policy #9.1.and assumptions from Memo D262059. Reassessment of Operator Exposure and Risk f or 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

- 23 1 )

Application Equipment Target

Animal Application

Rate 2 Amount

Handled

/ Area

Treated 3 Dermal Dose (mg/kg/day) 4 Dermal MOE 5 (LOC=1000) Inhalation Dose (mg/kg

- day) 6 Inhalation MOE 7 (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 0.07617 lb ai/ gallon 14 gallons/

day 0.003 0.00 1 0.0005 0.0001 150 860 1100 3800 3.39E

- 06 6.77E

- 07 3.39E

- 07 1.28E

06 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

Manually

pressurized

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 Manually

pressurized

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

Mec hanical 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 baselin e 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 f or 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 Da ily (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) ÷ Inhal ation Dose (mg/kg/day).Coumaphos Human Health Risk Assessment DP#409347

Page 51 of 77 Table 9.1.6. Steady S tate

- Term Duration ARI Occupational Handler Non

- Cancer Exposure and Risk Estimates for Liquid Formulations ( Reg #s. 11556

- 115, and 11556

- 23 1 )

Application Equipment Application Type Target

Animal Application

Rate 2 Amount Handled

/ Area Treated 3 ARI 4

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 0.01 lb ai/gallon 40 gallons 0.00085 0.052 0.054 0.13 0.14 0.16 0.18 ND

Manually

- pressurized

Handwand Broadcast Swine 0.005 lb ai/gallon 40 gallons 0.0017 0.1 0.11 0.25 0.28 0.31 0.35 ND

Mechanically

pressurized 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

Mechanically

pressurized 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

Mechanically

pressurized 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

Mechanically

pressurized 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 res pirator; PF5 = “Protection Factor 5”, indicatin g 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 ÷ Inhalati on 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 Rate 2 Amount Handled /

Area Treated 3 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

C ows 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 Tag 9 Cattle 20% a.i./tag Negligible exposure

Bee Mite Strip 9 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 res pirator; PF5 = “Protection Factor 5”, indicatin g 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 Material 1

Application Equipment Crop / Target Category Application

Rate 2 Amount

Handled /

Area

Treated 3 Dermal Dose (mg/kg/day) 4 Dermal MOE 5 (LOC=1000) Inhalation Dose (mg/kg

- day) 6 Inhalation MOE 7
(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

C ows 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 Tag 9 Cattle 20% a.i./tag Negligible exposure

Bee Mite

Strip 9 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 re presented in table includes baseline inhalation and additional PPE

required gloves (G) and PF5 respirator

. It is noted that the la bels 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.an d assumptions from Memo D262059. June 10, 1997. Dust bag estimates are best judgments utilizing farm surveys from memo. EXPOS AC

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 S tate

- Term ARI Occupational Handler Non

- Cancer Exposure and Risk Estimates for Dust Based Formulations 1

Application Equipment Target Category Application

Rate 2 Amount Handled / Area

Treated 3 ARI 4

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

C ows 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 re presented 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 IndexCoumaphos 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 re

entry 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 natu re 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

- applicati on 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 sourc es 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 Rodenti cide 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 c oumaphos.

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, subseque ntly, 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 p attern 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) (4 0 CFR 170.103: Exceptions), there is an exception for pesticides applied “o n livestock or other animals, or in or about animal premises.” Therefore, coumaphos labels do not fall under WPS. Language onCoumaphos Human Health Risk Assessment DP#409347

Page 56 of 77 

### coumaphos end use product labels should retain statem ents 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 asse ssment 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. B ased 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

approac h 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 Assessmen ts to Support Registration Review. D412870, 0 2 / 04 / 2016, S. Piper.

Addendum to Revised Drinking Water Assessment for the Registration Review of Coumaphos . D420394, 06/02/2014, F. Khan.

Coumaphos: Registratio n Review Occupa tional 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.

D 3 47381, 02/28/2008, S. Recore.

Coumaphos: Human Health Risk Assessment for Registration Review. D 3 15769,

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, 2000 8 

### ) 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 ( P o D ) 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, b ut 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 (BuCh E). 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 inh ibition 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 PoD s for AChE inhibiting compo unds. Most often the decreasing exponential e mpirical 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

re presents a 10% reduction in AChE activity (i.e., inhibition) compared to background (i.e., controls). Specifically, the BMD 10 

### is the estimated dose where ChE is inhibited by 10% compared to background. The BMDL 10 

### is the lower confidence bound on the BMD 10



### .

The use of the 10% BMR is derived from a combination of statistical and biological considerations. A power analysis was conducted by 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 d ecrease 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 neuro toxic 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 U se 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 PoD s are protective for brain AChE inhibition, potential peripheral inhibition, and clinical signs of neurotoxicity.

A. 1.2: R esults for BMD/BMDL M odeling for Coumaphos

Table A. 1.2.1 BMD results of single dose studies.

Coumaphos/Study Sex/age Comp artment BMD Results

BMD 10 (mg/kg) BMDL 10 (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

BMD 10 (mg/kg) BMDL 10 (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

BMD 10 (mg/kg) BMDL 10 (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 1.30 a 0.52 a

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 0.08 b 0.03 b

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 fitCoumaphos 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

BMD 10 (mg/kg) BMDL 10 (mg/kg)
2 generation
reproduction study in

rats

– 91 days (Diet) Female

– F0 RBC 0.07 c 0.04 c

Male

– F0 Brain Poor dose

response(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)

BMD 10 BMDL 10
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 1.24 d 1.06 d

Female RBC 0.82 e 0.71 e

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 adequa te.

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 o bserved 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 thes e results are reported for characterization purpos es.

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

ye s

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 (N on rodent s )

................................ .... 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 requiredCoumaphos 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 LD 50 (M) >240 mg/kg

LD 50 (F) = 17 mg/kg I

870.1200 Acute dermal [rabbit] 00110598 LD 50 : >2400 mg/kg III

870.1300 Acute inhalation [rat] 00110601 LC 50 (M) = 1.081 mg/L

LC 50 (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:

BMD 10 = 0.15/0.10 mg/kg/day for males/females

BMDL 10 = 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:

BMD 10 = 1.05 mg/kg/day for males; poor dose

- response for

females

BMDL 10 = 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

inhibitionCoumaphos 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:

BMD 10 =1.24(a)/0.82(b) mg/kg/day for males/females

BMD L10 = 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:

BMD 10 = 7.53/6.8 mg/kg/day for males/females

BMDL 10 = 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:

BMD 10 =0.72 mg/kg/day for females

BMD L10 = 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 non

guideline

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

(N on rodent s ) MRID 00131683 (1983)
Acceptable guideline
0, 0.25, 2, or 18 mg/kg

from GD 7 to 19 Materna l NOAEL = 2 mg/kg/day
LOAEL =18 mg/kg/day based on mortality (2/17) and
cholinergic signs

. Developmenta l 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 BMD 10 / BMDL 10 = 0.07/0.04 (c ) for females; no

reliable fit for males

Brain ChEI BMD 10 / BMDL 10 = 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:

BMD 10 = 0.048/0.05 mg/kg/day (F1 males/females); B MDL 10 0.036 mg/kg/day (F1 males and females at 91 days)

Brain AChEI :

BMD 10 = 7.55/1.75 mg/kg/day for males/females;

BMDL 10 = 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:

BMD 10 = 0.17 mg/kg/day for males and females

BMDL 10 = 0.104/0.15 mg/kg/day for males/females (90 day
measurement which reached steady state)

Brain AChE inhibition:

BMD 10 =1.36/1.3 (d) mg/kg/day for males/females

BMDL 10 = 0.77/0.52 (d) mg/kg/day for males/females
(d) p=0.09 for model fit, based on vis ual 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:

BMD 10 = 0.11/0.25 mg/kg/day for males/females

BMDL 10 = 0.082/0.2 mg/kg/day for males/females

Brain AChE inhibition:

BMD 10 = 1.997 mg/kg/day for females

BMDL 10 = 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 non

guideline 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:

BMD 10 = 0.08 mg/kg/day (e)

BMDL 10 = 0.03 mg/kg/day (e)

Brain AChE inhibition:

BMD 10 = 0.68 mg/kg/day

BMDL 10 = 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:

BMD 10 = 1.5/0.61 mg/kg/day for males/female PND 21 pups

BMDL 10 = 0.11/0.28 mg/kg/day for males /female PND 21 pups

Brain AChE inhibition:

BMD 10 = 6.7/3.18 mg/kg/day for male/female PND 21 pups

BMDL 10 = 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 non

guideline

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

BMD 10 = 0.31/ 0.57 mg/kg for males/females

BMDL 10 = 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

BMD 10 = 0.36/0.38 mg/kg for males/females

BMDL 10 = 0.25 mg/kg for both males/females
Brain AChE inhibition peak 4 hours :

BMD 10 = 0.55/0.59 mg/kg for males/females

BMDL 10 = 0.46/0.49 mg/kg for males/fe malesCoumaphos 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 non

guideline

Adults: 0, 0.2, 0.49,

0.98
PND11 pups: 0, 0.19,
0.46, 0.7 mg/kg/day Adults:

RBC AChE inhibition

BMD 10 = 0.127/0.106 mg/kg for males/females and

BMDL 10 = 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 Pu ps:

RBC AChE inhibition:

BMD 10 = 0.057/0.052 mg/kg for males/females and

BMDL 10 = 0.041/0.042 mg/kg for males/females

Brain AChE Inhibition:

BMD 10 = 0.34/0.53 mg/kg for males/females and

BMDL 10 = 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 non

guideline

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 g eneral 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

effect s 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 Stat e 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/Uncertai nty 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 ora l 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, a nd 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 ( P o D ), a dermal absorption factor is not required.

Dermal Exposure (Steady State)

Study Selected: 21 Da y Dermal study in rats

MRID Number: 42666401 Dose and Endpoint for Establishing dermal P o D : 0.5 mg/kg (BMDL 10 

### ), based on 10% RBC ChE inhibition in adult females (BMD 10 

### = 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 E xposure (Steady state)

Study Selected: 2

- Generation Reproductive Study in rats

MRID Number: 43061701 Dose and Endpoint for Establishing ss P o D : 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,

incl uding 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 n eonatal (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 m g/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/fema les 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 5 8

- 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 a dults, the RBC ChE inhibition BMD 10 

### = 0.31/ 0.57 mg/kg for males/females, and the

BMDL 10 

### = 0.19 / 0.34 mg/kg for males/females. Brain ChE inhibitio n 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 BMDL 10 

### = 0.25 mg /kg for both males/females. For brain ChE

inhibition the BMD 10 

### = 0.55/0.59 mg/kg for males/ females, while the BMDL 10 

### = 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 NO EL 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 dose

related decreases in plasma and red blood cell cholinesterase activity in dams at 5 a nd 25 ppm. Generally, no differences were seen on day 47 and day 91 measurements. Brain levels were biologically significantly inhibited (30%) in F
o 

### and F 1 

### adult females at 25 ppm, and in F
o 

### 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 F 1 

### pups, plasma and

red blood cell ChE inhibition of 38

- 44% was seen, while in F 2 

### pups, only plasma was affected (31

- 44%). The only significant brain inhibition in pups was an 8% decrease in F 1 

### females onCoumaphos 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 BMD 10 / 

### BMDL 10 

### 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 BMD 10 = 

### 0.048/0.05 mg/kg/day (F 1 males/females); BMDL 10 

### 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; BMDL 10 

### = 1.86/0.71 mg/kg/day for males/females.

c. 21

- day dermal study in the rat (83

- 2); two studies

1. MRID 4208 4901

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 cholinestera se (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 BMD 10 

### = for RBC AChE inhibition is 1.24/0.82 mg/kg/day for males/females, respectively while the BMD L 10 

### 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

BMD 10 

### = for brain ACh E inhibition is 7.53/6.8 mg/kg/day for males/females, respectively

while the BMDL 10 

### 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 fas ciculation 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 consideredCoumaphos 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 grou p 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 BMD 10 

### = for RBC AChE inhibition is 0.72 mg/kg/day for females, while the BMD L10 

### = 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 #1Coumaphos 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,

12/12/1994 pH Not available

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 (pK
a ) Not required

Octanol/Water Partition Coefficient (Log[K OW ]) Not available

UV/Visible Absorption Spectrum Not availableCoumaphos 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 Mexico 2 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

- oxo

2H

- 1

- benzopyran

- 7

- yl) O,O

- diethyl phosphorothioate, including the oxygen analog O

- (3

- chloro

- 4

- methyl

- 2

- oxo

- 2H

1

- benzopyran

7

- yl) O,O

- diethyl phosphate (calculated on the fat content)

Honey, honeycomb, beeswax: O

- (3

- chloro

- 4

- methyl

- 2

- oxo

- 2 H

- 1

- benzopyran

- 7

- yl)

O

, O

- diethyl phosphorothioate, including the oxygen analog O

- (3

- chloro

- 4

- methyl

- 2

- oxo

- 2 H

1

- benzopyran

7

- 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 0.5 1
Cattle, meat 1.0 0.5 1
Cattle, meat byproducts 1.0 0.5 1

Goat, fat 1.0 0.5 1

Goat, meat 1.0 0.5 1
Goat, meat byproducts 1.0 0.5 1
Hog, fat 1.0 0.5 1
Hog, meat 1.0 0.5 1
Hog, meat byproducts 1.0 0.5 1
Honey 0.15 0.02 Honeycomb 45.0 0.1

Horse, fat 1.0 0.5 1

Horse, meat 1.0 0.5 1
Horse, meat byproducts 1.0 0.5 1
Milk, fat (=n in whole milk) 0.5 Sheep, fat 1.0 0.5 1
Sheep, meat 1.0 0.5 1
Sheep, meat byproducts 1.0 0.5 1
MRLs with NO US Equivalent

Beeswax 1 Fat of poultry 0.5 1

Meat

- by

- products of poultry 0.5 1

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 calcul ated 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

h andlers are compared to the appropriate P o D (i.e., BMDL 10 

### ) 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),

P o D = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).

BMDL 10 

### = bench mark dose limit.

The aggregate risk index (ARI) was calculated as follows:

Aggregate Risk Index (ARI) = 1÷ (1 ÷ RI dermal 

### ) + (1 ÷ RI inhalation 

### )

Where: Risk Index (RI) = MOE ÷ LOCCoumaphos 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 Agricul tural 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

website 9



### .

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

- application

exposure