Skin Notation (SK) Profile

Ethyl p-nitrophenyl phenylphosphorothioate 

(EPN)

[CAS No. 2104-64-5]

Department of Health and Human Services

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
ii

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Suggested Citation

NIOSH [20XX]. NIOSH skin notation profile: Ethyl p-nitrophenyl phenylphosphorothioate 

(EPN). By Hudson NL, Dotson GS. Cincinnati, OH: U.S. Department of Health and Human 

Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety 

and Health, DHHS (NIOSH) Publication No. XXX

DHHS (NIOSH) Publication No. XXX
iii

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Foreword

As the largest organ of the body, the skin performs multiple critical functions, such as serving as 

the primary barrier to the external environment. For this reason, the skin is often exposed to 

potentially hazardous agents, including chemicals, which may contribute to the onset of a 

spectrum of adverse health effects ranging from localized damage (e.g., irritant contact 

dermatitis and corrosion) to induction of immune-mediated responses (e.g., allergic contact 

dermatitis and pulmonary responses), or systemic toxicity (e.g., neurotoxicity and hepatoxicity). 

Understanding the hazards related to skin contact with chemicals is a critical component of 

modern occupational safety and health programs. 

In 2009, the National Institute for Occupational Safety and Health (NIOSH) published 

Current Intelligence Bulletin (CIB) 61 – A Strategy for Assigning New NIOSH Skin Notations

[NIOSH 2009-147]. This document provides the scientific rationale and framework for the 

assignment of multiple hazard-specific skin notations (SK) that clearly distinguish between the 

systemic effects, direct (localized) effects, and immune-mediated responses caused by skin 

contact with chemicals. The key step within assignment of the hazard-specific SK is the 

determination of the hazard potential of the substance, or its potential for causing adverse health 

effects as a result of skin exposure. This determination entails a health hazard identification 

process that involves use of the following:

 Scientific data on the physicochemical properties of a chemical

 Data on human exposures and health effects

 Empirical data from in vivo and in vitro laboratory testing

 Computational techniques, including predictive algorithms and mathematical models that 

describe a selected process (e.g., skin permeation) by means of analytical or numerical 

methods. 

This Skin Notation Profile provides the SK assignments and supportive data for EPN. In 

particular, this document evaluates and summarizes the literature describing the hazard potential 

of the substance and its assessment according to the scientific rationale and framework outlined 

in CIB 61. In meeting this objective, this Skin Notation Profile intends to inform the audience—

mostly occupational health practitioners, researchers, policy- and decision-makers, employers, 

and workers in potentially hazardous workplaces—so that improved risk-management practices 

may be developed to better protect workers from the risks of skin contact with the chemicals of 

interest.

John Howard, M.D.

Director

National Institute for Occupational Safety and Health

Centers for Disease Control and Prevention
iv

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Contents

Foreword................................................................................................................................................ iii

Abbreviations.......................................................................................................................................... v

Glossary..................................................................................................................................................vii

Acknowledgments.................................................................................................................................viii

1.0 Introduction....................................................................................................................................... 1

1.1 General Substance Information ........................................................................................................... 1

1.2 Purpose ................................................................................................................................................ 1

1.3 Overview of SK Assignment.................................................................................................................. 2

2.0 Systemic Toxicity from Skin Exposure (SK: SYS).................................................................................. 2

3.0 Direct Effects on Skin (SK: DIR)........................................................................................................... 4

4.0 Immune-mediated Responses (SK: SEN)............................................................................................. 5

5.0 Summary............................................................................................................................................ 5

References............................................................................................................................................... 6

Appendix: Calculation of the SI Ratio for EPN .......................................................................................... 8

Overview .................................................................................................................................................... 8

Calculation ............................................................................................................................................... 10

Appendix References................................................................................................................................ 11
v

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2squared centimeter(s)

cm/hr centimeter(s) per hour

cm/s centimeter(s) per second

DEREK Deductive Estimation of Risk from Existing Knowledge

DIR skin notation indicating the potential for direct effects to the skin following 

contact with a chemical

EC European Commission 

g gram(s)

g/L gram(s)/liter

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

hr hour(s)

IARC International Agency for Research on Cancer

IPCS International Program for Chemical Safety 

(IRR) subnotation of SK: DIR indicating the potential for a chemical to be a skin irritant 

following exposure to the skin

kaq coefficient in the watery epidermal layer

kp skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

kpsc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LLNA local lymph node assay

LOAEL lowest-observed-adverse-effect level 

log KOW base-10 logarithm of a substance’s octanol–water partition

M molarity

m

3

cubic meter(s)

mg milligram(s)

mg/cm2/hr milligram(s) per square centimeter per hour

mg/kg milligram(s) per kilogram body weight

mg/m3 milligram(s) per cubic meter

mL milliliter(s)

mL/kg milliliter(s) per kilogram body weight

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level
vi

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information quality guidelines. It has not been formally disseminated by the National Institute for 

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agency determination or policy.

NTP National Toxicology Program

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

ppm parts per million

REL recommended exposure limit

RF retention factor 

SEN skin notation indicating the potential for immune-mediated reactions following 

exposure of the skin

SI ratio ratio of skin dose to inhalation dose

SK skin notation

SW solubility in water

SYS skin notation indicating the potential for systemic toxicity following exposure of 

the skin

USEPA United States Environmental Protection Agency

μg microgram(s)

μg/cm2 microgram(s) per square centimeter

μg/cm2/hr microgram(s) per square centimeter per hour

μL microliter(s)

μmol micromole(s)
vii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Glossary 

Absorption—The transport of a chemical from the outer surface of the skin into both the skin 

and systemic circulation (including penetration, permeation, and resorption). 

Acute exposure—Contact with a chemical that occurs once or for only a short period of time. 

Cancer—Any one of a group of diseases that occurs when cells in the body become abnormal 

and grow or multiply out of control. 

Contaminant—A chemical that is (1) unintentionally present within a neat substance or mixture 

at a concentration less than 1.0% or (2) recognized as a potential carcinogen and present within a 

neat substance or mixture at a concentration less than 0.1%. 

Cutaneous (or percutaneous)—Referring to the skin (or through the skin). 

Dermal—Referring to the skin. 

Dermal contact—Contact with (touching) the skin. 

Direct effects—Localized, non-immune-mediated adverse health effects on the skin, including 

corrosion, primary irritation, changes in skin pigmentation, and reduction/disruption of the skin 

barrier integrity, occurring at or near the point of contact with chemicals. 

Immune-mediated responses—Responses mediated by the immune system, including allergic 

responses. 

Sensitization—A specific immune-mediated response that develops following exposure to a 

chemical, which, upon re-exposure, can lead to allergic contact dermatitis (ACD) or other 

immune-mediated diseases such as asthma, depending on the site and route of re-exposure. 

Substance—A chemical. 

Systemic effects—Systemic toxicity associated with skin absorption of chemicals after exposure 

of the skin.
viii

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Acknowledgments

This document was developed by the Education and Information Division (Paul Schulte, Ph.D., 

Director). G. Scott Dotson, Ph.D., was the project officer for this document, assisted in great part 

by Naomi Hudson, Dr.P.H., MPH, Todd Niemeier, M.Sc., and Matt Dahm, M.Sc. The basis for 

this document was a report (Toxicology Excellence for Risk Assessment [TERA]) contracted by 

NIOSH and prepared by Bernard Gadagbui, Ph.D., and Andrew Maier, Ph.D. 

For their contribution to the technical content and review of this document, special 

acknowledgment is given to the following NIOSH personnel:

Denver Field Office

Eric Esswein, M.Sc.

Division of Applied Research and Technology 

Clayton B’Hymer, Ph.D. 

John Snawder, Ph.D.

Mark Toraason, Ph.D.

Division of Respiratory Disease Studies 

Gregory A. Day, Ph.D. 

Aleksander Stefaniak, Ph.D. 

Division of Surveillance, Hazard Evaluations, and Field Studies

Aaron Sussell, Ph.D.

Loren Tapp, M.D. 

Education and Information Division 

Devin Baker, M.Ed.

Charles L. Geraci, Ph.D.

Thomas J. Lentz, Ph.D.

Richard Niemier, Ph.D.

Ralph Zumwalde, M.Sc.
ix

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information quality guidelines. It has not been formally disseminated by the National Institute for 

Occupational Safety and Health. It does not represent and should not be construed to represent any 

agency determination or policy.

Health Effects Laboratory Division

Stacy Anderson, Ph.D.

H. Fredrick Frasch, Ph.D.

Vic Johnson, Ph.D. 

Michael Luster, Ph.D. 

Anna Shvedova, Ph.D.

Paul Siegel, Ph.D.

Berran Yucesoy, Ph.D.

National Personal Protective Technology Laboratory

Heinz Ahlers, J.D., M.Sc.

Angie Shepherd

For their contribution to the technical content and review of this document, special 

acknowledgment is given to the following CDC personnel:

Office of Surveillance, Epidemiology and Laboratory Services/Epidemiology and Analysis 

Program Office 

Barbara Landreth, M.A.

In addition, special appreciation is expressed to the following individuals for serving as

independent, external reviewers and providing comments that contributed to the development or 

improvement of this document:

 G. Frank Gerberick, Ph.D., The Procter and Gamble Company, Cincinnati, OH

 Dori Germolec, Ph.D., National Toxicology Program, National Institute for 

Environmental Health Sciences, Research Triangle, NC

 Ben Hayes, M.D., Ph.D., Division of Dermatology, Vanderbilt School of Medicine, 

Nashville, TN 

 Jennifer Sahmel, M.Sc., CIH, ChemRisk, Boulder, CO

 James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH
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1.0 Introduction 

1.1 General Substance Information 

Chemical: Ethyl p-nitrophenyl phenylphosphorothioate (EPN)

CAS No: 2104-64-5

Molecular weight (MW): 323.3

Molecular formula: C14H14O4NSP

Structural formula:

Synonyms: o-Ethyl-o-p-nitrophenyl phenylphosphonothioate, Ethyl p-nitrophenyl 

benzenethiophosphonate

Uses: EPN is an insecticide and acaricide no longer registered for use in the United States [Storm 2001]. 

1.2 Purpose 

This skin notation profile presents (1) a brief summary of epidemiological and toxicological data 

associated with skin contact with ethyl p-nitrophenyl phenylphosphorothioate (EPN) and (2) the 

rationale behind the hazard-specific skin notation (SK) assignment for EPN. The SK assignment is 

based on the scientific rationale and logic outlined in the Current Intelligence Bulletin (CIB) 61: A 

Strategy for Assigning New NIOSH Skin Notations [NIOSH 2009]. The summarized information and 

health hazard assessment are limited to an evaluation of the potential health effects of dermal exposure 

to EPN. A literature search was conducted through February 2013 to identify information on EPN, 

including but not limited to data relating to its toxicokinetics, acute toxicity, repeated-dose systemic

toxicity, carcinogenicity, biological system/function–specific effects (including reproductive and 

developmental effects and immunotoxicity), irritation, and sensitization. Information was considered 

from studies of humans, animals, or appropriate modeling systems that are relevant to assessing the 

effects of dermal exposure to EPN. 
2

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policy.

1.3 Overview of SK Assignment

EPN may potentially be capable of causing numerous adverse health effects following skin contact. A 

critical review of available data has resulted in the following SK assignment for EPN: SK: SYS 

(FATAL). Table 1 provides an overview of the critical effects and data used to develop the SK 

assignment for EPN. 

Table 1. Summary of the SK Assignment for EPN

Skin Notation Critical Effect Available Data

SK: SYS (FATAL) Neurotoxicity Sufficient animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

Limited toxicokinetic data following dermal exposure to EPN were identified. Although no data were 

identified for humans, a series of studies conducted by Abou-Donia et al. [1983a; 1983d, 1983e] 

evaluated absorption of EPN in cats and hens. After a single non-occluded dermal application of 20 

milligrams per kilogram of body weight (mg/kg) of uniformly phenyl-labeled [14C] EPN in 0.1 milliliter 

(mL) acetone to the clipped skin of cats, most of the radioactivity was excreted in the urine (29.9%), 

only 3.2% was recovered in the feces, and no radioactivity was detected in expired air [Abou-Donia 

1983d]. When cats were administered 0.5 mg/kg [14C] EPN dermally for 10 consecutive days, 62% of 

the cumulative dose was recovered in the urine, 10% in the feces, and no radioactivity was detected in 

the expired air [Abou-Donia et al 1983e]. In hens administered 0.5 mg/kg [0.56 micro Curie per dose 

(μCi/dose)] of [14C] EPN dermally for 10 consecutive days, a total of 65% of the cumulative dose was 

excreted in the combined urinary and fetal excrement 15 days after the last dose, an no radioactivity was 

detected in the expired air [Abou-Donia et al. 1983a]. These toxicokinetic studies indicate that EPN is 

absorbed through the skin following dermal exposure of cats and hens. The potential of EPN to pose a 

skin absorption hazard was also evaluated, with use of a predictive algorithm for estimating and 

evaluating the health hazards of dermal exposure to substances [NIOSH 2009]. The evaluation method 

compares an estimated dose accumulated in the body from skin absorption and an estimated dose from 

respiratory absorption associated with a reference occupational exposure limit. On the basis of this 

algorithm, a ratio of the skin dose to the inhalation dose (SI ratio) of 0.049 was calculated for EPN. An 

SI ratio of ≥0.1 indicates that skin absorption may significantly contribute to the overall body burden of 

a substance [NIOSH 2009]; therefore, EPN is not considered to be absorbed through the skin following 

dermal exposure. Additional information on the SI ratio and the variables used in its calculation are 

included in the appendix. 

No estimated dermal lethal dose (LDLo) for humans was identified. Dermal LD50 values (lethal doses in 

50% of exposed animals) of 230 and 25 mg/kg have been reported for male and female rats, respectively 

[Gaines 1969]. In cats, Abou-Donia et al. [1983b] reported an LD50 of 45 mg/kg. In rabbits, Hodge et al. 

[1954] reported a dermal lethal range of 30 to 50 mg/kg in males and of 90 to 150 mg/kg in females and 

Dupont Chemical [1980] and Dupont de Nemours [1980c] reported an LD50 of 296 to 312 mg/kg for 

intact skin and 218 to 467 mg/kg for abraded skin in rabbit,. Because the reported acute dermal LD50

values for cats, rabbits and female rats are lower than the critical dermal LD50 value of 200 mg/kg body 
3

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weight that identifies chemical substances that are fatal at relatively low doses following acute dermal 

exposure [NIOSH 2009], EPN is considered fatal after acute dermal exposure. 

No epidemiological or occupational exposure studies or chronic toxicity studies in animals were 

identified following dermal exposure to EPN. However, two subchronic (90-day) studies that evaluated 

the potential of EPN to induce neurotoxicity in animals following dermal exposure were identified 

[Abou-Donia et al. 1983b, c]. Cats administered 0.5 to 2.0 mg/kg-day EPN topically for 90 days 

exhibited significant weight loss during treatment, cats receiving 0.5 mg/kg-day exhibited mild ataxia, 

while cats that received 1.0 mg/kg-day exhibited severe ataxia [Abou-Donia et al 1983b]. Abou-Donia et 

al. [1983c] also administered dermal doses of 0.01 to 10.0 mg/kg of EPN (85%) on the back of the neck 

of hens for 90 days. Spinal cord lesions were observed at 0.5 mg/kg-day and above in cats [Abou-Donia 

et al. 1983b], and similar neurotoxic effects at doses of 2.5 mg/kg and above were observed in hens 

[Abou-Donia et al. 1983c]. Significant weight loss was observed at 1.0 to 10.0 mg/kg EPN at the onset 

of ataxia, with the loss increasing after development of paralysis [Abou-Donia et al. 1983c]. All hens 

treated with 0.01 to 10 mg/kg EPN exhibited signs of delayed neurotoxicity, with the onset and severity 

of neurologic dysfunction being dose-dependent [Abou-Donia et al. 1983c]. Brain cholinesterase 

activity at 2.5 mg/kg and above and plasma butylcholinesterase activity at 0.01 mg/kg and above were 

significantly inhibited compared to controls when these activities were measured 30 days after the 

dermal application [Abou-Donia et al. 1983c]. Hens’ exposure to 0.01 to 10 mg/kg showed histological 

changes in the spinal cord, such as degeneration of axons and myelin, which were more severe and 

frequent in hens that survived longer [Abou-Donia et al. 1983c]. However, it is important to note that 

although the investigators noted neurotoxicity in animals dermally exposed to EPN, Abou-Donia et al. 

[1983c] reported different concentrations in the abstract than in the methods. Francis et al [1985] 

reported ataxia in one egg-laying hen after daily dermal dosing of as little as 1.3 mg/kg for up to 90 

days. Higher doses caused similar effects that progressed to death [Francis et al. 1985]. The reported 

dermal subchronic LOAEL of 0.01 mg/kg-day based on histological changes in the spinal cord of hens 

[Abou-Donia et al. 1983c], of which similar effects were seen in subchronic studies in cats [Abou-Donia 

et al. 1983b], is lower than the critical dermal subchronic NOAEL of 1,000 mg/kg-day that identifies 

chemical substances with the potential for subchronic dermal toxicity [NIOSH 2009]. Based on these 

findings, EPN is considered systemically toxic following dermal exposure with dose-dependent effects 

on the nervous system that vary in severity, including lethality. 

No additional specialty studies evaluating biological systemic/function (including 

reproductive/developmental toxicity or immunotoxicity) were identified following dermal exposure. No 

studies were identified that evaluated the potential of EPN to be a carcinogen in humans or animals 

following exposure by the dermal route. Table 2 summarizes carcinogenic designations of multiple 

governmental and nongovernmental organizations for EPN. 
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Table 2. Summary of the carcinogenic designations for EPN by numerous governmental and 

nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] No designation

NTP [2011] No designation

USEPA [2015] No designation 

European Parliament [2008] No GHS designation 

IARC [2012] No designation

EC [2013]* No designation

ACGIH [2001] Not classifiable as a human carcinogen

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, 

Institute for Health and Consumer Protection; GHS = Globally Harmonized System for Classification and Labelling of 

Chemicals; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety and 

Health; NTP = National Toxicology Program; USEPA = United States Environmental Protection Agency.

Although the mathematical model did not predict EPN to be absorbed through the skin following dermal 

exposure, toxicokinetic data in cats [Abou-Donia et al. 1983a; 1983d, 1983e]1, acute toxicity studies in 

rats [Gaines 1969], rabbits [Hodge et al 1954], and cats [Abou-Donia et al. 1983b] and sub-chronic 

toxicity studies in hens and cats [Abou-Donia et al. 1983b, 1983c] indicate EPN is absorbed through 

skin, is systemically available and has the potential to cause systemic effects, including fatality, 

following dermal exposure. Therefore, on the basis of the data for this assessment, EPN is assigned the 

SK: SYS (FATAL) notation. 

3.0 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies that evaluated the corrosivity of EPN or in vitro tests for corrosivity 

using human or animal skin models or in vitro tests of skin integrity using cadaver skin were identified. 

No case reports or clinical studies evaluating the potential of EPN to cause skin irritation were 

identified. E.I. Du Pont de Nemours [1980a] reported mild irritation when rabbits were exposed to 500 

mg/kg of a mixture of EPN and 0,0-dimethyl 0-(4-nitrophenyl) phosphorothioate on clipped intact and 

abraded skin using the Draize procedure. Similar results were seen when E.I. Du Pont de Nemours 

[1980b] applied 0.5 ml a mixture of EPN and penyl-0-ethyl, 0-(4-nitrophenyl) ester on clipped intact and 

abraded skin using the Draize procedure. Exposure to these mixtures containing EPN caused fatalities in 

some of the rabbits [E.I. Du Pont de Nemours 1980a, b]. 

Although the E.I. Dupont de Nemours [1980a, b] studies indicate that EPN is a mild skin irritant, the 

animals were exposed to mixtures of EPN, and there is insufficient data that EPN alone can cause skin 

irritation Therefore, this assessment does not assign a SK: DIR notation for EPN. 

 

1References in bold text indicate studies that serve as the basis of the SK assignments.
5

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policy.

4.0 Immune-mediated Responses (SK: SEN)

No studies were identified that evaluated skin sensitization following dermal exposure to EPN. No 

reports of sensitization in humans, or predictive tests (for example, guinea pig maximization tests, 

Buehler tests, murine local lymph node assays, mouse ear swelling tests) or other tests that evaluated the 

potential of EPN to cause skin sensitization in animals were identified. Lack of data precludes adequate 

evaluation of the sensitization potential of EPN. Therefore, on the basis of the data for this assessment, 

EPN is not assigned the SK: SEN notation.

5.0 Summary

Although the mathematical model did not predict EPN to be absorpbed through the skin following 

dermal exposure, toxicokinetic data in cats [Abou-Donia et al. 1983a; 1983d, 1983e], acute toxicity

studies in rats [Gaines 1969], rabbits [Hodge et al 1954], and cats [Abou-Donia et al. 1983b], and subchronic studies identified in hens and cats [Abou-Donia et al. 1983b, 1983c] indicate EPN is absorbed 

through skin, is systemically available and has the potential to cause systemic effects, including fatality 

following dermal exposure. No in vivo or in vitro studies in humans or animals that evaluated the 

potential of EPN to cause direct skin effects or skin sensitization were identified. Therefore, on the basis 

of these assessments, EPN is assigned a composite skin notation of SK: SYS (FATAL). 

Table 3 summarizes the skin hazard designations for EPN previously issued by NIOSH and other 

organizations. The equivalent dermal designation for EPN, according to the Global Harmonization 

System (GHS) of Classification and Labelling of Chemicals, is Acute Toxicity Category 1 (Hazard 

statement: Fatal in contact with the skin) [European Parliament 2008]. 

Table 3. Summary of previous skin hazard designations for EPN

Organization Skin hazard designation 

NIOSH [2005] [skin]: potential for dermal absorption

OSHA [2015]*[skin]: potential for dermal absorption

ACGIH [2003] [skin]: Based on low doses applied to rabbit skin that produced 

lethality

EC [2013]* R27: Very toxic in contact with skin

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, 

Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = 

Occupational Safety and Health Administration.
6

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policy.

References

Abou-Donia MB, Abdel-Kader HM, Abou-Donia SA [1983a]. Tissue distribution, elimination, and 

metabolism of o-ethyl o-nitrophenyl phenylphosphonothionate in hens following daily dermal doses. J 

Amer Coll Toxicol 2(6): 391-404.

Abou-Donia MB, Graham DG, Kinnes CG. [1983b]. Sensitivity of the Cat to Delayed Neurotoxicity 

Induced by o-Ethyl o-4-Nitrophenyl Phenylphosphonothioate.

Toxicol Appl Pharmacol 68: 54-65.

Abou-Donia MB, Graham DG, Makkawy H, Abdo KM. [1983c]. Effect of Subchronic Dermal 

Application of o-Ethyl o-4-Nitrophenyl Phenylphosphonothioate on Producing Neurotoxicity in Hens. 

Neurotoxicolgy 4(2): 247-260.

Abou-Donia MB, Kinnes CG, Abdo KM, and Bjornsson D. [1983d]. Physiological Disposition and 

Metabolism of o-Ethyl-o-4-Nitrophenyl Phenylphosphonothiothate in Male Cats Following a Single 

Dermal Adminsitration. Drug Metabolism and Disposition 11(1): 31-36.

Abou-Donia MB, Sivarajah K, Abou-Donia A. [1983e]. Disposition, elimination and metabolism of oethyl o-4-nitrophenyl phenylphosphonothioate after subchronic dermal application in male cats. 

Toxicology 26: 93-111

ACGIH (American Conference of Governmental Industrial Hygienists) [2003]. EPN Documentation of 

Threshold Limit Values and Biological Exposure Indices. 7th Ed. Cincinnati, OH.

Dupont Chemical [1980]. Initial submission: Acute dermal toxicity of phosphonothioic acid, phenyl-,oethyl o-(nitorphenyl)ester with o,o-dimethyl o-(4-nitrophenyl)*with cover letter dated 082092. OTS No. 

0570800.

EC (European Commission) [2011]. O-ethyl O-4-nitrophenyl phenylphosphonothioate. In: EINICS 

(European Inventory of Exisiting Commerical Chemical Substances), 

http://ecb.jrc.ec.europa.eu/esis/index.php?GENRE=CASNO&ENTREE=2104-64-5. Accessed: 08-14-

13.

E.I. Dupont de Nemours [1980a]. Initial submission: Skin irritation test with EPN4-E in rabbits for EPA 

pesticide registratiaon with cover letter dated 061592 and attachments. OTS No. 0540536.

E.I. Dupont de Nemours [1980b]. Initial submission: Skin irritation test with EPN-MP3-3 in rabbits for 

EPA pesticide registration with cover letter dated 061592 and attachments. OTS No. 0540516.

E.I. Dupont de Nemours [1980c]. Initial submission: An acute skin absorption LD50 test with EPN in 

rabbits with cover sheets and letter dated 082092. OTS No. 0543804.
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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

European Parliament, Council of the European Union [2008]. Regulation (EC) No 1272/2008 of the 

European Parliament and of the Council of 16 December 2008 on classification, labeling and packaging 

of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and 

amending Regulation (EC) No 1907/2006. OJEU, Off J Eur Union L353:1–1355, 

http://eurex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF. Accessed: 

01-28-15.

Francis BM, Metcalf RL, Hansen LG. [1985]. Toxicity of Organophosphorus Esters to Laying Hens 

After Oral and Dermal Administration. J. Environ Sci. Health B20(1), 73-95.

Gaines TB. [1969]. Acute Toxicity of Pesticides. Toxicology and Applied Pharmacology 14: 513-534.

Hodge HC, Maynard EA, Hurwitz L, DiStefano V, Downs WI, Jones CK, Blanchet HJ. [1954]. Studies 

of the Toxicity and of the enzyme kinetics of ethyl p-nitrophenyl thionobenzene phosphate (EPN). J 

Pharmacol Exp Ther 112: 29-39.

IARC (International Agency for Research on Cancer) [2012]. Agents reviewed by the IARC 

monographs. In: IARC monographs on the evaluation of carcinogenic risks to humans, 

http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed: 01-28-15.

NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of Health 

and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational 

Safety and Health, DHHS (NIOSH) Publication No. 2005-149, 

http://www.cdc.gov/niosh/npg/npgd0211.html. Accessed: 01-28-15.

NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-28-15.

NTP [2014]. Report on Carcinogens. Thirteenth Edition; U.S. Department of Health and Human 

Services, Public Health Service. National Toxicology Program, 

http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01-28-15.

OSHA [ND]. EPN. In: OSHA Occupational chemical database, 

https://www.osha.gov/chemicaldata/chemResult.html?recNo=309. Accessed: 01-28-15.

Storm JE [2001]. EPN. In: Bingham E, Cohrssen B, Powell CH (Eds.), Patty's toxicology and industrial 

hygiene 5th ed., Vol. 7. New York: John Wiley and Sons pp. 836-842.

USEPA [2015]. Intergrated Risk Information System: ethyl p-nitrophenyl phenylphosphorothioate 

(EPN). In: Intergrated Risk Information System, http://www.epa.gov/iris/. Accessed: 01-28-15.
8

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Appendix: Calculation of the SI Ratio for EPN

This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for 

EPN. Although the SI ratio is considered in the determination of a substance’s hazard potential 

following skin contact, it is intended only to serve as supportive data during the assignment of the 

NIOSH SK. An in-depth discussion on the rationale and calculation of the SI ratio can be found in 

Appendix B of the Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin 

Notations [NIOSH 2009]. 

Overview 

The SI ratio is a predictive algorithm for estimating and evaluating the health hazards of skin exposure 

to substances. The algorithm is designed to evaluate the potential for a substance to penetrate the skin 

and induce systemic toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the 

proposed strategy for assigning SYS notation are as follows:

(1) Provide an alternative method to evaluate substances for which no clinical reports or animal 

toxicity studies exist or for which empirical data are insufficient to determine systemic effects.

(2) Use the algorithm evaluation results to determine whether a substance poses a skin absorption 

hazard and should be labeled with the SYS notation.

The algorithm evaluation includes three steps:

(1) determining a skin permeation coefficient (kp) for the substance of interest,

(2) estimating substance uptake by the skin and respiratory absorption routes, and 

(3) evaluating whether the substance poses a skin exposure hazard.

The algorithm is flexible in the data requirement and can operate entirely on the basis of the 

physicochemical properties of a substance and the relevant exposure parameters. Thus, the algorithm is 

independent of the need for biologic data. Alternatively, it can function with both the physicochemical 

properties and the experimentally determined permeation coefficient when such data are available and 

appropriate for use.

The first step in the evaluation is to determine the kp for the substance to describe the transdermal 

penetration rate of the substance [NIOSH 2009]. The kp, which represents the overall diffusion of the 

substance through the stratum corneum and into the blood capillaries of the dermis, is estimated from 

the compound’s molecular weight (MW) and base-10 logarithm of its octanol–water partition coefficient 

(log KOW). In this example, kp is determined for a substance with use of Equation 1. A self-consistent set 

of units must be used, such as centimeters per hour (cm/hr), outlined in Table A1. Other model-based 

estimates of kp may also be used [NIOSH 2009].
9

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Equation 1: Calculation of Skin Permeation Coefficient (kp)

psc pol aq

p

k k k

k

1 1

1







where kpsc is the permeation coefficient in the lipid fraction of the stratum corneum, kpol is the coefficient 

in the protein fraction of the stratum corneum, and kaq is the coefficient in the watery epidermal layer.

These components are individually estimated by

log kpsc = −1.326 + 0.6097 × log Kow − 0.1786 × MW0.5

kpol = 0.0001519 × MW−0.5

kaq = 2.5 × MW−0.5

The second step is to calculate the biologic mass uptake of the substance from skin absorption (skin 

dose) and inhalation (inhalation dose) during the same period of exposure. The skin dose is calculated as 

a mathematical product of the kp, the water solubility (SW) of the substance, the exposed skin surface 

area, and the duration of exposure. Its units are milligrams (mg). Assume that the skin exposure 

continues for 8 hours to unprotected skin on the palms of both hands (a surface area of 360 squared 

centimeters [cm2]). 

Equation 2: Determination of Skin Dose

Skin dose = kp × Sw × Exposed skin surface area × Exposure time

 = kp(cm/hr) × Sw (mg/cm3) × 360 cm2× 8 hr

The inhalation dose (in mg) is derived on the basis of the occupational exposure limit (OEL) of the 

substance—if the OEL is developed to prevent the occurrence of systemic effects rather than 

sensory/irritant effects or direct effects on the respiratory tract. Assume a continuous exposure of 8 

hours, an inhalation volume of 10 cubic meters (m3) inhaled air in 8 hours, and a factor of 75% for 

retention of the airborne substance in the lungs during respiration (retention factor, or RF).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation volume × RF

 = OEL (mg/m3) × 10 m3× 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of 

skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates (1) the significance of 

dermal absorption as a route of occupational exposure to the substance and (2) the contribution of 

dermal uptake to systemic toxicity. If a substance has an SI ratio greater than or equal to 0.1, it is 

considered a skin absorption hazard.
10

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Calculation 

Table A1 summarizes the data applied in the previously described equations to determine the SI ratio for 

EPN. The calculated SI ratio was 0.049. On the basis of these results, EPN is not predicted to represent a 

skin absorption hazard.

Table A1. Summary of Data used to Calculate the SI Ratio for EPN 

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr 0.0238

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hr 8.445 × 10-6

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.139

Molecular weight (MW)

*

amu 323.31

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

* None 4.78

Calculated skin permeation coefficient (kp) cm/hr 0.0203

Skin dose

Water solubility (Sw)

* mg/cm3

0.0031

Calculated skin permeation coefficient (kp) cm/hr 0.0203

Estimated skin surface area (palms of hand) cm2360

Exposure time hr 8

Calculated skin dose mg 0.1822

Inhalation Dose

Occupational exposure limit (OEL)† mg/m30.5

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 3.75

Skin dose–to–inhalation dose (SI) ratio None 0.0486

*

Variables identified from SRC [ND].

†

The OEL used in calculation of the SI ratio for EPN was the NIOSH recommended exposure limit (REL) [NIOSH 

2005].
11

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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Appendix References 

NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of Health 

and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational 

Safety and Health, DHHS (NIOSH) Publication No. 2005–149, http://www.cdc.gov/niosh/npg/. 

Accessed: 01-28-15. 

NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-28-15.

SRC [2009]. Interactive PhysProp database demo

http://esc.syrres.com/fatepointer/webprop.asp?CAS=2104645. Accessed: 01-28-15.