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 

## This document is in the public domain and may be freely copied or reprinted.



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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 Con

trol 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 • PeopleTMSkin 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 spec

trum 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). Under

standing 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 con

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

tion 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 numeri

cal 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 describ

ing 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 de

cision-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 PreventionSkin 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

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8vi 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

cm 2 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 G lobally 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 k

pol coefficient in the protein fraction of the stratum corneum k

psc permeation coefficient in the lipid fraction of the stratum corneum LD 50 dose resulting in 50% mortality in the exposed population LD Lo dermal lethal dose LOAEL lowest-observed-adverse-effect level log K OW base-10 logarithm of a substance’s octanol–water partition M molarity

m 3 cubic meter(s) mg milligram(s) mg/cm 2 -hr milligram(s) per square centimeters per hour mg/cm 3 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/cm 2 -min nanomoles per square centimeters per minute NOAEL no-observed-adverse-effect level NTP National Toxicology Program OEL occupational exposure limitSkin 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 S W solubility SYS skin notation indicating the potential for systemic toxicity following exposure of the skin USEPA United States Environmental Protection Agencyviii 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 acknowl

edgment 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 acknowl

edgment 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 inde

pendent, 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, OHSkin Notation Profiles | Ethoxyethyl Acetate 1 

# 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; Eth

ylene 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 toxicologi

cal data associated with skin contact with 2-EEA and (2) the rationale behind the haz

ard-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 Strat

egy for Assigning New NIOSH Skin Notations [NIOSH 2009]. The summarized informa

tion and health hazard assessment are lim

ited to an evaluation of the potential health effects of dermal exposure to 2-EEA. A lit

erature search was conducted through April 2014 to identify information on 2-EEA, in

cluding 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 ef

fects of dermal exposure to 2-EEA.


## 1.3 Overview of SK Assignment 2-EEA is potentially capable of causing ad

verse 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 over

view of the critical effects and data used to de

velop 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 data2 Skin Notation Profiles | 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, per

cutaneous 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, radio

labeled 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/cm 2 -min) [correspond

ing to 0.87 mg/cm 2 -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 au

thors reported a permeability constant of 8.07 x 10 4 cm/hr and an absorption rate of 0.8 mil

ligrams per square centimeters per hour (mg/
cm 2 -hr), with a lag time of less than 1 hr. Bar

ber et al. [1992] reported an absorption rate of 1.41 mg/cm 2 -hr and a permeability constant of 1.45 x 10 -3 cm/hr when undiluted 2-EEA was applied to isolated human stratum cor

neum in vitro for 8 hr. Using full thickness rat skin in vitro , Barber et al. [1992] estimated an absorption rate of 2.41 mg/cm 2 -hr and per

meability constant of 2.47 x 10 -3 cm/hr fol

lowing 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 ap

plied 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/cm 2 -min [corresponding to 2.22 mg/cm 2 -hr]. The potential of 2-EEA to pose a skin absorp

tion hazard was also evaluated, with use of a predictive algorithm for estimating and evalu

ating the health hazards of dermal exposure to substances [NIOSH 2009]. The evaluation method compares an estimated dose accumu

lated in the body from skin absorption and an estimated dose from respiratory absorption associated with a reference occupational ex

posure 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 absorp

tion may significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore, 2-EEA is not considered to be ab

sorbed through the skin following dermal ex

posure 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 includ

ed in the appendix. No estimate of the dermal lethal doses (LD Lo ) of 2-EEA for humans was identified. Report

ed dermal LD 50 (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 LD 50 values for 2-EEA in rabbits and guinea pigs are greater than the critical dermal LD 50 value of 2000 mg/kg body weight that identifies chemical substances with the poten

tial for acute dermal toxicity [NIOSH 2009], indicating that 2-EEA is not acutely toxic fol

lowing dermal exposure. No epidemiological or occupational case re

ports 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 evalu

ated biological system/function specific ef

fects, 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 [corre

sponding to 1365 mg/day], on days 7 to 16 of gestation. Based on the average body weightSkin Notation Profiles | Ethoxyethyl Acetate 3 provided on gestation days 5, 7, 12, 17, and 21, an average daily body weight of approxi

mately 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 signifi

cant reductions in maternal body weight gain, gravid uterus weights, and extragestational body weight gains. 2-EEA was also em

bryotoxic, as reflected in significantly higher frequencies of completely resolved litters, significantly increased number of dead im

plants 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 Ef

fect Level (LOAEL) of 5830 mg/kg-day, the only dose tested, for maternal and develop

mental toxicity can be established from this study. 2-EEA is expected to be readily hy

drolyzed in vivo to 2-ethoxyethanol and ac

etate [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] ob

served 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 sys

tem) 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 repro

ductive 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 regi

men, since a LOAEL was identified at the only dose tested. Therefore, these studies do not indicate whether 2-EEA causes such ef

fects at doses below 1000 mg/kg body weight that identifies chemicals with systemic toxic

ity potential following repeated dermal ad

ministration. No specialty studies evaluating immunotox

icity following dermal exposure were identi

fied. No epidemiological studies or animal bioassays were identified that evaluated the potential of 2-EEA to be a carcinogen fol

lowing dermal exposure. Table 2 summarizes carcinogenic designations of multiple govern

mental and nongovernmental organizations for 2-EEA. No epidemiological studies, occupational ex

posure studies or repeat-dose or long-term studies in animals were identified for dermal exposure to 2-EEA. However, i n vitro evalua

tions of the skin permeability of 2-EEA [Du

gard 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, devel

opmental toxicity studies that utilized high dermal doses of 2-EEA showed the poten

tial 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 us

ing 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 identified. Truhaut et al. [1979] tested the irri

tancy 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 pro

tocol. 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 ob

served using the Draize protocol was due to the extended exposure period of 24 hours in the Draize test compared to the shorter expo

sure 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 expo

sure 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 re

versible 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) inter

mediate 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 as

sessment, 2-EEA is not assigned the SK: DIR notation. 

# 4 Immune-mediated Responses (SK: SEN) No occupational exposure studies or diagnos

tic (human patch) studies were identified that investigated the skin sensitization potential of 2-EEA in humans. Zissu [1995] conducted a Magnusson Kligman [guinea pig maximi

zation 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 Occu

pational 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 

# 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 chemi

cal is readily absorbed. No epidemiological or occupational exposure studies were iden

tified that evaluated the potential of 2-EEA to cause systemic effects following dermal ex

posure. 2-EEA is not acutely toxic following dermal exposure; however, repeat-dose devel

opmental toxicity studies identified in animals that employed high dermal doses resulted in maternal and developmental effects [ Har

din 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 pre

dictive test (GPMT) indicate that 2-EEA is not a skin sensitizer. Therefore, on the basis of these assessments, 2-EEA is assigned a com

posite skin notation of SK: SYS. Table 3 summarizes the skin hazard designa

tions for 2-EEA previously issued by NIOSH and other organizations. The equivalent der

mal 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 clas

sified as a Reproductive Toxicity Category 2 (Hazard statement: Suspected of damaging fertility or the unborn child) [European Par

liament 2008]. 

# References
Note : Asterisks (*) denote sources cited in text; daggers (†) denote additional resources. *ACGIH (American Conference of Governmen

tal Industrial Hygienists) [2001a]. 2-ethoxy

ethyl acetate. In: Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 2. Cincinnati, OH: American Confer

ence of Governmental Industrial Hygienists. *ACGIH [2001b]. 2-EEA. Documentation of Bi

ological 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 chemi

cals 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, Cohrs

sen 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-Ethoxy

ethyl acetate. In: EINICS (European Inven

tory of Existing Commercial Chemical Sub

stances), 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 *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, label

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

lation (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, DiVin

cenzo GD [1984]. Pulmonary and percutane

ous 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]. Develop

mental toxicity of four glycol ethers applied cu

taneously to rats. Environ Healt Persp 57 :69

– 74. *Hardin BD, Niemeier RW, Smith RJ, Kuczuk MH, Mathinos PR, Weaver TF [1982]. Tera

togenicity of 2-ethoxyethanol by dermal appli

cation. 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 In

stitute 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 ethyl

ene glycol monomethyl ether, ethylene glycol monoethyl ether, and their acetates. Cincin

nati: 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 Hu

man 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: Chem

ical 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 occu

pational environment. AJIM 52 :654-661. *Truhaut R, Dutertre-Catella H, Phu-Lich N, Huyen VN [1979]. Comparative toxicological study of ethylglycol acetate and butylglycol ac

etate.Toxicol Appl Pharm 51 :117

– 127. *USEPA (United States Environmental Protec

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tion 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 

# 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 sub

stance’s hazard potential following skin con

tact, 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 Bul

letin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations [NIOSH 2009]. 

## Overview The SI ratio is a predictive algorithm for esti

mating and evaluating the health hazards of skin exposure to substances. The algorithm is designed to evaluate the potential for a sub

stance to penetrate the skin and induce sys

temic toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the pro

posed strategy for assigning SYS notation are as follows: 1. Provide an alternative method to evalu

ate substances for which no clinical re

ports 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 la

beled with the SYS notation. The algorithm evaluation includes three steps: 1. determining a skin permeation coeffi

cient ( 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 require

ment 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 deter

mine 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 capil

laries of the dermis, is estimated from the compound’s molecular weight ( MW ) and base-10 logarithm of its octanol–water par

tition coefficient ( log K OW

). 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)



### aq pol psc p 

# k k k k 1 1 1

+ + =

Where k psc is the permeation coefficient in the lipid fraction of the stratum corneum, k pol is the coefficient in the protein fraction of the stratum corneum, and k aq is the coefficient in the watery epidermal layer. These components are individually estimated by log k psc = −1.326 + 0.6097 × log K ow − 0.1786 × MW 0.5 k pol

= 0.0001519 × MW −0.5 k aq = 2.5 × MW −0.58 Skin Notation Profiles | Ethoxyethyl Acetate The second step is to calculate the biologic mass uptake of the substance from skin ab

sorption (skin dose) and inhalation (inhala

tion dose) during the same period of exposure. The skin dose is calculated as a mathematical product of the k p , the water solubility ( S W ) of the substance, the exposed skin surface area, and the duration of exposure. Its units are mil

ligrams (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 [cm 2 ]). 

### Equation 2: Determination of Skin Dose Skin dose = k p × S w × Exposed skin surface area × Exposure time

= k p (cm/hour) × S w (mg/cm 3 ) × 360 cm 2 × 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 de

veloped 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 inhala

tion volume of 10 cubic meters (m 3 ) inhaled air in 8 hours, and a factor of 75% for reten

tion 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/m 3 ) × 10 m 3 × 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 indi

cates (1) the significance of dermal absorp

tion 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 ra

tio 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 Dis

ease 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 In

stitute 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/databas

eforms.aspx?id=386 . Accessed: 05-01-14.Skin Notation Profiles | Ethoxyethyl Acetate 9 

### 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 ( k pol

) cm/hour 1.3211 × 10 -5 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hour 0.2174 Molecular weight ( MW )* amu 132.2 Base-10 logarithm of its octanol–water partition

coefficient (Log K ow )* None 0.83 Calculated skin permeation coefficient ( k p ) cm/hour 1.3383 × 10 -3
Skin dose Water solubility (S
w )* mg/cm 3 0.13 Calculated skin permeation coefficient ( k p ) cm/hour 1.3383×10 -3 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hour 8 Calculated skin dose mg 0.5029
Inhalation Dose Occupational exposure limit (OEL) † mg/m 3 24.17 Inhalation volume m 3 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].