DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 

NIOSH Skin Notation (SK) Profiles

2-Ethoxyethyl Acetate

[CAS No. 111-15-9]
ii Skin Notation Profiles | Ethoxyethyl Acetate

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Suggested Citation

NIOSH [2014]. NIOSH skin notation profiles: 2-ethoxyethyl acetate. 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. 2014-141.

DHHS (NIOSH) Publication No. 2014-141

August 2014

Safer • Healthier • PeopleTM
Skin Notation Profiles | Ethoxyethyl Acetate iii

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 2-Ethoxyethyl 

acetate (2-EEA). 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
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Skin Notation Profiles | Ethoxyethyl Acetate v

Contents

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

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

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

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

1.3 Overview of SK Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

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

3 Direct Effects on Skin (SK: DIR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

4 Immune-mediated Responses (SK: SEN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Appendix: Calculation of the SI Ratio for 2-EEA . . . . . . . . . . . . . . . . . . . . . . . . 7

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Appendix References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
vi Skin Notation Profiles | Ethoxyethyl Acetate

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2 square centimeter(s)

cm/hr centimeter(s) per hour

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 

2-EEA 2-ethoxyethyl acetate 

EEC European Economic Communities

GHS Globally Harmonized System for Classification and

 Labelling of Chemicals

GPMT guinea pig maximization test

IARC International Agency for Research on Cancer

(IRR) subnotation of SK: DIR indicating the potential for a chemical

 to be a skin irritant following exposure to the skin

k

aq coefficient in the watery epidermal layer 

k

p skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

k

psc permeation coefficient in the lipid fraction of the stratum corneum

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LOAEL lowest-observed-adverse-effect level 

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

M molarity

m3 cubic meter(s)

mg milligram(s)

mg/cm2-hr milligram(s) per square centimeters per hour

mg/cm3 milligram(s) per cubic centimeter

mg/kg milligram(s) per kilogram body weight

mL milliliter(s)

mL/kg milliliter(s) per kilogram body weight

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

nmole/cm2-min nanomoles per square centimeters per minute 

NOAEL no-observed-adverse-effect level

NTP National Toxicology Program

OEL occupational exposure limit
Skin Notation Profiles | Ethoxyethyl Acetate vii

OSHA Occupational Safety and Health Administration

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 

SYS skin notation indicating the potential for systemic toxicity following

 exposure of the skin

USEPA United States Environmental Protection Agency 
viii Skin Notation Profiles | Ethoxyethyl Acetate

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.
Skin Notation Profiles | Ethoxyethyl Acetate ix

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, Clayton B’Hymer, Ph.D., 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

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

Todd Niemeier, M.Sc.

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 Niemeier, Ph.D.

Sudha Pandalai, M.D., Ph.D. 

Health Effects Laboratory Division

Stacey Anderson, Ph.D. 

H. Fredrick Frasch, Ph.D. 

Vic Johnson, Ph.D.

Michael Luster, Ph.D. 

Paul Siegel, Ph.D.

Berran Yucesoy, Ph.D. 

National Personal Protection Technology Laboratory

Heinz Ahlers, 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.
x Skin Notation Profiles | Ethoxyethyl Acetate

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:

Glenn Sipes, Ph.D., University of Arizona, College of Medicine, Tucson, AZ

Phillip L. Williams, Ph.D., CIH, The University of Georgia, College of Public Health, 

Athens, GA

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
Skin Notation Profiles | Ethoxyethyl Acetate 1

Ethoxyethyl Acetate

1 Introduction

1.1 General Substance Information 

Chemical: 2-Ethoxyethyl acetate (2-EEA)

CAS No: 111-15-9

Molecular weight (MW): 132.2

Molecular formula:

CH3COOCH2CH2OC2H6

Structural formula:

Synonyms:

2-EEA; Cellosolve® acetate; EGMEA; Ethylene glycol monoethyl ether acetate; Glycol 

monoethyl ether acetate

Uses:

2-Ethoxyethyl acetate (2-EEA) is used as a 

solvent and chemical intermediate.

1.2 Purpose 

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological data associated with skin contact with 

2-EEA and (2) the rationale behind the hazard-specific skin notation (SK) assignment for 

2-EEA. 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 2-EEA. A literature search was conducted through April 

2014 to identify information on 2-EEA, 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 2-EEA. 

1.3 Overview of SK Assignment

2-EEA is potentially capable of causing adverse systemic health effects following skin 

contact. A critical review of available data has 

resulted in the following SK assignment for 

2-EEA: SK: SYS. Table 1 provides an overview of the critical effects and data used to develop the SK assignment for 2-EEA. 

Table 1. Summary of the SK assignment for 2-EEA

Skin notation Critical effect Available data

SK: SYS Maternal and developmental toxicity Limited animal data
2 Skin Notation Profiles | Ethoxyethyl Acetate

Ethoxyethyl Acetate

2 Systemic Toxicity from

Skin Exposure (SK: SYS)

Limited toxicokinetic data were identified 

that estimated the percent absorption of 

2-EEA following dermal exposure in humans 

or animals in vivo or in vitro. However, percutaneous absorption studies were identified 

that measured permeability constants and/

or rate of absorption of 2-EEA in animals in 

vivo and in vitro and in humans in vitro. For 

example, in an in vivo test Guest et al. [1984] 

applied 15 milliliters (mL) of undiluted, radiolabeled 2-EEA to the thorax of dogs for 30 or 

60 minutes and estimated the absorption rate 

to be 110 nanomoles per square centimeters 

per minute (nmole/cm2-min) [corresponding to 0.87 mg/cm2

-hr]. Dugard et al. [1984] 

measured the absorption of 2-EEA, after 

application of 1 mL for 8 hours (hr) to the 

isolated human abdominal epidermis. The authors reported a permeability constant of 8.07 

x 104 cm/hr and an absorption rate of 0.8 milligrams per square centimeters per hour (mg/

cm2-hr), with a lag time of less than 1 hr. Barber et al. [1992] reported an absorption rate of 

1.41 mg/cm2-hr and a permeability constant 

of 1.45 x 10-3 cm/hr when undiluted 2-EEA 

was applied to isolated human stratum corneum in vitro for 8 hr. Using full thickness rat 

skin in vitro, Barber et al. [1992] estimated an 

absorption rate of 2.41 mg/cm2-hr and permeability constant of 2.47 x 10-3 cm/hr following application of undiluted 2-EEA for 8 

hr using full thickness rat skin in vitro. Guest 

et al. [1984] also performed in vitro tests in 

which 0.3 mL of radiolabeled 2-EEA was applied to the skin from the thorax of necropsied 

beagles and absorption rates were measured 

hourly from 2 to 7 hr after application. The 

estimated percutaneous absorption rate was 

279.7 nmole/cm2-min [corresponding to 2.22 

mg/cm2-hr]. 

The potential of 2-EEA 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 0.003 was calculated for 2-EEA. 

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

body burden of a substance [NIOSH 2009]; 

therefore, 2-EEA is not considered to be absorbed through the skin following dermal exposure using only the SI ratio. However, Shih 

et al. [2009] found that 2-EEA on the skin 

was strongly associated with airborne 2-EEA, 

indicating that airborne 2-EEA needs to be 

considered when assessing dermal exposure. 

Additional information on the SI ratio and 

the variables used in its calculation are included in the appendix. 

No estimate of the dermal lethal doses (LDLo) 

of 2-EEA for humans was identified. Reported dermal LD50 (lethal dose in 50% of exposed 

animals) values ranged from 10300 milligrams 

per kilogram body weight (mg/kg) in rabbits 

to 18800 mg/kg in guinea pigs when applied 

under occlusion [Carpenter 1947]. The acute 

dermal LD50 values for 2-EEA in rabbits and 

guinea pigs are greater than the critical dermal 

LD50 value of 2000 mg/kg body weight that 

identifies chemical substances with the potential for acute dermal toxicity [NIOSH 2009], 

indicating that 2-EEA is not acutely toxic following dermal exposure. 

No epidemiological or occupational case reports or repeated-dose, subchronic, or chronic 

toxicity studies in animals were identified that 

evaluated the potential of 2-EEA to cause 

systemic effects following dermal exposure. 

Specialty studies were identified that evaluated biological system/function specific effects, such as reproduction and developmental 

effects following dermal exposure to 2-EEA. 

Hardin et al. [1984] applied 0.35 mL of pure, 

undiluted 2-EEA to adult rats 4 times per 

day, for a total daily dose of 1.4 mL [corresponding to 1365 mg/day], on days 7 to 16 of 

gestation. Based on the average body weight 
Skin Notation Profiles | Ethoxyethyl Acetate 3

Ethoxyethyl Acetate

provided on gestation days 5, 7, 12, 17, and 

21, an average daily body weight of approximately 234 grams was estimated, giving a dose 

of 5830 mg/kg-day of 2-EEA. Compared to 

water controls, treatment with 2-EEA caused 

maternal toxicity that manifested as significant reductions in maternal body weight gain, 

gravid uterus weights, and extragestational 

body weight gains. 2-EEA was also embryotoxic, as reflected in significantly higher 

frequencies of completely resolved litters, 

significantly increased number of dead implants per litter, significantly reduced number 

of live fetuses per litter, significantly reduced 

body weight of live fetuses, and significantly 

increased total cardiovascular malformations 

and skeletal variations (total ribs, vertebrae, 

and reduced ossification variations) [Hardin 

et al. 1984]. A Lowest Observed Adverse Effect Level (LOAEL) of 5830 mg/kg-day, the 

only dose tested, for maternal and developmental toxicity can be established from this 

study. 2-EEA is expected to be readily hydrolyzed in vivo to 2-ethoxyethanol and acetate [Hardin et al. 1984; ACGIH 2001b]. In 

the Hardin et al. [1984] study, at equimolar 

doses of 2-EEA and 2-ethoxyethanol, 2-EEA 

caused even more severe maternal, embryo, 

and fetal toxicity than did 2-ethoxyethanol. 

In an earlier study, Hardin et al. [1982] observed significant increase in resorptions, 

decreases in number of live fetuses per litter, 

decreases in fetal body weight, and an increase 

in the incidence of visceral malformations 

(predominantly of the cardiovascular system) and skeletal variations in rats dermally 

exposed 4 times/day to 0.25 mL/application 

of 2-ethoxyethanol [corresponding to 1 mL/

day] and intrauterine death in rats dermally 

exposed 4 times/day to 0.50 mL/application 

of 2-ethoxyethanol [corresponding to 2 mL/

day] during gestation days 7 to 16, followed 

by a 5-day post exposure period. A LOAEL of 

3445 mg/kg-day, derived from the group that 

received 1 mL/day, for developmental effects 

can be established in the absence of maternal 

toxicity from these studies [Hardin et al. 1982, 

1984]. 2-EEA is considered a potential reproductive and developmental toxicant following 

repeated dermal exposure.

Use of the developmental toxicity studies 

by Hardin et al. [1982, 1984] to determine 

whether dermal application of 2-EEA is a 

systemic toxicant is hindered by dosing regimen, since a LOAEL was identified at the 

only dose tested. Therefore, these studies do 

not indicate whether 2-EEA causes such effects at doses below 1000 mg/kg body weight 

that identifies chemicals with systemic toxicity potential following repeated dermal administration. 

No specialty studies evaluating immunotoxicity following dermal exposure were identified. No epidemiological studies or animal 

bioassays were identified that evaluated the 

potential of 2-EEA to be a carcinogen following dermal exposure. Table 2 summarizes 

carcinogenic designations of multiple governmental and nongovernmental organizations 

for 2-EEA. 

No epidemiological studies, occupational exposure studies or repeat-dose or long-term 

studies in animals were identified for dermal 

exposure to 2-EEA. However, in vitro evaluations of the skin permeability of 2-EEA [Dugard et al. 1984; Barber et al. 1992] *

 indicate 

that it is readily absorbed by the skin. Toxicity 

studies indicate 2-EEA is not acutely toxic 

following dermal exposure; however, developmental toxicity studies that utilized high 

dermal doses of 2-EEA showed the potential of the substance to cause maternal and 

developmental toxicity [Hardin et al. 1984]. 

Therefore, on the basis of the data for this 

assessment, 2-EEA is assigned the SK: SYS 

notation. 

3 Direct Effects on Skin

(SK: DIR)

No human or animal data on corrosivity of 

2-EAA or in vitro tests for corrosivity using human or animal skin models or in vitro

tests of skin integrity using cadaver skin were 

*References in bold text indicate studies that serve 

as the basis of the SK assignments.
4 Skin Notation Profiles | Ethoxyethyl Acetate

Ethoxyethyl Acetate

identified. Truhaut et al. [1979] tested the irritancy of 2-EEA using the Draize method and 

found very slight erythema in 2 of 6 rabbits at 

24 hours, but no irritation was observed after 

72 hours, even in previously affected animals. 

Zissu et al. [1995] tested 3 rabbits using the 

European Economic Communities (EEC) 

methods and 6 rabbits using the Draize protocol. The authors found 2-EEA to be a nonirritant using the EEC test and to be slightly 

irritating using the Draize protocol. Zissu 

[1995] suggested that the slight irritation observed using the Draize protocol was due to 

the extended exposure period of 24 hours in 

the Draize test compared to the shorter exposure of 4 hours in the EEC test. The authors 

placed greater weight on the EEC protocol 

than on the Draize test results, based on the 

consideration that 24 hours continuous exposure is not representative of a potential human 

occupational exposure scenario. 

The overall data indicate that at most, 2-EEA 

is a mild irritant. The effects are rapidly reversible and the appearance of irritation is 

dependent on the duration of exposure. This 

assessment is for occupational scenarios with 

daily exposures (typically 8 to 12 hours) intermediate between a duration that causes mild 

irritation (24 hours) and a duration that does 

not cause irritation (4 hours). Based on the 

minimal irritation observed even at 24 hours 

with constant contact, the weight of evidence 

from standard skin irritation tests suggests 

that 2-EEA is not likely to be a significant 

skin irritant in typical workplace scenarios. 

Therefore, on the basis of the data for this assessment, 2-EEA is not assigned the SK: DIR 

notation. 

4 Immune-mediated 

Responses (SK: SEN)

No occupational exposure studies or diagnostic (human patch) studies were identified that 

investigated the skin sensitization potential of 

2-EEA in humans. Zissu [1995] conducted 

a Magnusson Kligman [guinea pig maximization test (GPMT)] on 30 guinea pigs (10 

guinea pigs were controls and 20 guinea pigs 

were treated). Using a 10% concentration as 

the challenge, the authors found no evidence 

of skin sensitization. Based on the results 

of the single GPMT available that indicate 

that 2-EEA is not a potential skin sensitizer, 

2-EEA is not assigned the SK: SEN notation. 

Table 2. Summary of the carcinogenic designations* for 2-EEA by

numerous governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] No designation

NTP [2011] No designation

USEPA [2014] No designation

European Parliament [2008] No designation

IARC [2007] No designation

EC [2014]† No designation

ACGIH [2001a] No designation 

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

Health and Consumer Protection; 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.

*The listed cancer designations were based on data from nondermal (such as oral or inhalation) exposure rather than dermal exposure.

†

Date accessed.
Skin Notation Profiles | Ethoxyethyl Acetate 5

Ethoxyethyl Acetate

5 Summary

Toxicokinetic studies were identified for 

2-EEA, but percent absorption estimates 

were not available. In vitro evaluation of the 

skin permeability of 2-EEA [Dugard et al. 

1984; Barber et al. 1992] indicates the chemical is readily absorbed. No epidemiological 

or occupational exposure studies were identified that evaluated the potential of 2-EEA 

to cause systemic effects following dermal exposure. 2-EEA is not acutely toxic following 

dermal exposure; however, repeat-dose developmental toxicity studies identified in animals 

that employed high dermal doses resulted in 

maternal and developmental effects [Hardin et al. 1984]. The weight of evidence from 

standard irritation tests indicates that 2-EEA 

is not likely to be a skin irritant under typical 

workplace scenarios. Limited data from a predictive test (GPMT) indicate that 2-EEA is 

not a skin sensitizer. Therefore, on the basis of 

these assessments, 2-EEA is assigned a composite skin notation of SK: SYS.

Table 3 summarizes the skin hazard designations for 2-EEA previously issued by NIOSH 

and other organizations. The equivalent dermal designation for 2-EEA, according to the 

Global Harmonization System (GHS) of 

Classification and Labelling of Chemicals, is 

Acute Toxicity Category 4 (Hazard statement: 

Harmful in contact with the skin) [European 

Parliament 2008]. 2-EEA has also been classified as a Reproductive Toxicity Category 2 

(Hazard statement: Suspected of damaging 

fertility or the unborn child) [European Parliament 2008]. 

References

Note: Asterisks (*) denote sources cited in 

text; daggers (†) denote additional resources.

*ACGIH (American Conference of Governmental Industrial Hygienists) [2001a]. 2-ethoxyethyl acetate. In: Documentation of threshold 

limit values and biological exposure indices 7th 

ed., Vol. 2. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*ACGIH [2001b]. 2-EEA. Documentation of Biological Exposure Indices. 7th Ed. Cincinnati, 

OH: American Conference of Governmental 

Industrial Hygienists.

*Barber ED, Teetsel NM, Kolberg KF, Guest D 

[1992]. A comparative study of the rates of in 

vitro percutaneous absorption of eight chemicals using rat and human skin. Fundam Appl 

Toxicol 19:493-497.

*Boatman RJ, Knaak JB [2001]. Ethers of ethylene 

glycol and derivatives. In: Bingham E, Cohrssen B, Powell CH (Eds.), Patty’s toxicology 5th 

ed., Vol. 7. New York: John Wiley & Sons, Inc.

*Carpenter CP [1947]. Cellosolve acetate. JAMA 

135:880.

*Dugard PH, Walker M, Mawdsley SJ, Scott 

RC [1984]. Absorption of some glycol ethers 

through human skin in vitro. Environ Health 

Persp 57:193–197.

*EC (European Commission) [ND]. 2-Ethoxyethyl acetate. In: EINICS (European Inventory of Existing Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/index.

php?PGM=ein]. Accessed: 05-01-14.

Table 3. Summary of previous skin hazard designations for 2-EEA

Organization Skin hazard designation

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

OSHA [2006] [skin]: Potential for dermal absorption

ACGIH [2001a] [skin]: Potential for dermal absorption

EC [2014]* R21: Harmful if 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.

*Date accessed.
6 Skin Notation Profiles | Ethoxyethyl Acetate

Ethoxyethyl Acetate

*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:2008:3

53:0001:1355:EN:PDF]. Accessed: 05-01-14.

*Guest D, Hamilton ML, Deisinger PJ, DiVincenzo GD [1984]. Pulmonary and percutaneous absorption of 2-propoxyethyl acetate and 

2-ethoxyethyl acetate in beagle dogs. Environ 

Health Persp 57:177–183.

*Hardin BD, Goad PT, Burg JR [1984]. Developmental toxicity of four glycol ethers applied cutaneously to rats. Environ Healt Persp 57:69–74.

*Hardin BD, Niemeier RW, Smith RJ, Kuczuk 

MH, Mathinos PR, Weaver TF [1982]. Teratogenicity of 2-ethoxyethanol by dermal application. Drug Chem Toxicol 5(3):277–294.

*IARC (International Agency for Research on 

Cancer) [2007]. Agents reviewed by the IARC 

monographs. In: IARC monographs on the 

evaluation of carcinogenic risks to humans, 

http://monographs.iarc.fr/ENG/Classification/

Listagentsalphorder.pdf]. Accessed: 05-01-14.

*NIOSH [2005]. 2-Ethoxyethyl acetate. In: 

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: 05-01-14.

*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: 05-01-14.

†

NIOSH [1991]. Criteria for a recommended 

standard: occupational exposure to ethylene glycol monomethyl ether, ethylene glycol 

monoethyl ether, and their acetates. Cincinnati: U.S. Department of Health and Human 

Services, Centers for Disease Control, National 

Institute for Occupational Safety and Health, 

DHHS (NIOSH) Publication No. 91-119. 

*NTP [2011]. Report on Carcinogens. Twelfth 

Edition; U.S. Department of Health and Human Services, Public Health Service. National 

Toxicology Program, http://ntp.niehs.nih.gov/

ntp/roc/twelfth/roc12.pdf. Accessed 05-01-14.

*OSHA [2006]. 2-Ethoxyethyl acetate. In: Chemical sampling information, http://www.osha.

gov/dts/chemicalsampling/data/CH_239300.

html. Accessed: 05-01-14.

* Shih T, Kuo Y, Liang R, Liou S, Chang H, Chou 

T. [2009]. Assessment of airborne and dermal 

exposure to 2-Ethoxyehtyl acetate in an occupational environment. AJIM 52:654-661.

*Truhaut R, Dutertre-Catella H, Phu-Lich N, 

Huyen VN [1979]. Comparative toxicological 

study of ethylglycol acetate and butylglycol acetate.Toxicol Appl Pharm 51:117–127.

*USEPA (United States Environmental Protection Agency) [2014]. Integrated Risk Information System (IRIS), http://www.epa.gov/ncea/

iris/. Accessed: 05-01-14.

*Zissu D [1995]. Experimental study of cutaneous 

tolerance to glycol ethers. Contact Dermatitis 

32:74–77.
Skin Notation Profiles | Ethoxyethyl Acetate 7

Ethoxyethyl Acetate

Appendix: Calculation of the SI Ratio for 2-EEA

This appendix presents an overview of the SI 

ratio and a summary of the calculation of the 

SI ratio for 2-EEA. 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 (k

p

) 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 k

p

 for the substance to describe the 

transdermal penetration rate of the substance 

[NIOSH 2009]. The k

p

, 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, 

k

p

is determined for a substance with use of 

Equation 1. A self-consistent set of units must 

be used, such as outlined in Table A1. Other 

model-based estimates of k

p

 may also be used 

[NIOSH 2009].

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

k

aq

 = 2.5 × MW−0.5
8 Skin Notation Profiles | Ethoxyethyl Acetate

Ethoxyethyl Acetate

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 

square centimeters [cm2]). 

Equation 2: Determination of Skin Dose 

Skin dose = k

p

 × Sw × Exposed skin surface

 area × Exposure time

= k

p

(cm/hour) × Sw (mg/cm3) × 

 360 cm2 × 8 hours

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.

Calculation 

Table A1 summarizes the data applied in the 

previously described equations to determine 

the SI ratio for 2-EEA. The calculated SI ratio was 0.003. On the basis of these results, 

2-EEA is not predicted to represent a skin 

absorption hazard.

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: 05-01-14.

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: 05-01-14.

SRC [2009]. Interactive PhysProp database demo, 

http://www.srcinc.com/what-we-do/databaseforms.aspx?id=386. Accessed: 05-01-14.
Skin Notation Profiles | Ethoxyethyl Acetate 9

Ethoxyethyl Acetate

Table A1. Summary of data used to calculate the SI ratio for 2-EEA 

Variables used in calculation Units Value

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(k

psc) cm/hour 1.3432 × 10-3

Permeation coefficient of the protein fraction of

the stratum corneum (kpol)

cm/hour 1.3211 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hour 0.2174

Molecular weight (MW)* amu 132.2

Base-10 logarithm of its octanol–water partition

coefficient (Log Kow)*

None 0.83

Calculated skin permeation coefficient (k

p

) cm/hour 1.3383 × 10-3

Skin dose

Water solubility (Sw)* mg/cm3 0.13

Calculated skin permeation coefficient (k

p

) cm/hour 1.3383×10-3

Estimated skin surface area (palms of hand) cm2 360

Exposure time hour 8

Calculated skin dose mg 0.5029

Inhalation Dose

Occupational exposure limit (OEL)† mg/m3 24.17

Inhalation volume m3 10

Retention factor (RF) None 0.75

Inhalation dose mg 181.28

Skin dose–to–inhalation dose (SI) ratio None 0.003

*Variables identified from SRC [2009].

†

The OEL used in calculation of the SI ratio for 2-EEA was the NIOSH recommended exposure limit (REL) [NIOSH 2005].
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