# NIOSH Skin Notation (SK) Profiles

DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health 

# Allyl Glycidyl Ether (AGE) [CAS No. 106-92-3]ii S kin Notation Profiles | Allyl glycidyl ether 

## 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: a llyl glycidyl ether (AGE). By Hudson NL, Dotson GS. Cincinnati, OH: U .S. Depar tment of Health and Human Services, Centers for Disease Control and Prevention, N ational Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014-143. DHHS (NIOSH) Publication No. 2014-143 August 2014



### Safer • Healthier • PeopleTMSkin Notation Profiles | Allyl glycidyl ether 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 ana

lytical or numerical methods. This Skin Notation Profile provides the SK assignments and supportive data for allyl glycidyl ether (AGE) . 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 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 | Allyl glycidyl ether 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)

. . . . . . . . . . . . . . . . . . . . . . . 1 3 Direct Effects on Skin (SK: DIR)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 4 Immune-mediated Responses (SK: SEN)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 5 Summary

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 References

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Appendix: Calculation of the SI Ratio for AGE

. . . . . . . . . . . . . . . . . . . . . . . . . . 6 Overview

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Calculation

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Appendix References

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7vi Skin Notation Profiles | Dichloropropene 

# Abbreviations
ACGIH American Conference of Governmental Industrial Hygienists AGE allyl glycidyl ether CIB Current Intelligence Bulletin

cm 2 square centimeter(s) cm/hour 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 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 LLNA local lymph node assay 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) MEST mouse ear swelling test mg milligram(s) mg/kg milligram(s) per kilogram body weight mg/m 3 milligram(s) per cubic meter mL milliliter(s) MW molecular weight NIOSH National Institute for Occupational Safety and Health NOAEL no-observed-adverse-effect level NTP National Toxicology Program OEL occupational exposure limit OSHA Occupational Safety and Health Administration pmol/g picomoles per gram REL recommended exposure limit RF retention factorSkin Notation Profiles | Allyl glycidyl ether vii 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 | Allyl glycidyl ether 

# 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 | Allyl glycidyl ether ix 

# Acknowledgments This document was developed by the NIOSH 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, Vic Johnson, Ph.D., and Aaron Sus

sell, Ph.D. 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 Ma

ier, 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 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 Matt Dahm, M.Sc. Todd Niemeier, M.Sc. 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. Michael Luster, Ph.D. Anna Shevedova, 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 | Allyl glycidyl ether 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: Frank A Barile, Ph.D., St. John’s University, College of Pharmacy, Queens, NY 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 | Allyl glycidyl ether 1 

# 1 Introduction
1.1 General Substance Information:

Chemical: Allyl glycidyl ether (AGE) CAS No: 106-92-3 Molecular weight ( MW ): 114.2 Molecular formula: C 6 H 10 O 2 Structural formula: Synonyms: AGE; 1-Allyloxy-2,3-epoxypro

pane; Glycidyl allyl ether; [(2-Propenyloxy) methyl] oxirane Uses: AGE is used primarily as a commercial chemical of as a resin intermediate, and is also used as a stabilizer of chlorinated compounds, vinyl resins, and rubber [Waechter et al. 2001].



### Table 1. Summary of the SK assignment for AGE
Skin notation Critical effect Data available SK: DIR (IRR) Skin irritation Limited human and animal data SK: SEN Skin allergy Sufficient human data 

## 1.2 Purpose This skin notation profile presents (1) a brief summary of epidemiological and toxicological data associated with skin contact with AGE and (2) the rationale behind the hazard-spe

cific skin notation (SK) assignment for AGE. The SK assignment is based on the scientific rationale and logic outlined in the Current In

telligence Bulletin (CIB) 61: A Strategy for As

signing 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 AGE. A literature search was conducted through April 2014 to iden

tify information on AGE, 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 rel

evant to assessing the effects of dermal expo

sure to AGE.


## 1.3 Overview of SK Assignment AGE is potentially capable of causing nu

merous adverse health effects following skin contact. A critical review of available data has resulted in the following SK assignment for AGE: SK: DIR (IRR)-SEN. Table 1 provides an overview of the critical effects and data used to develop the SK assignment for AGE. 

# 2 Systemic Toxicity from Skin Exposure (SK: SYS) There is paucity of data on the toxicokinetic studies of AGE following dermal exposure. A study that provided some evidence for dermal absorption was conducted by Perez and Os

terman-Golker [2000] in which application2 Skin Notation Profiles | Allyl glycidyl ether of 4 milligrams (mg) of AGE (99% pure) dis

solved in acetone to the skin of mice for 5 or 24 hours resulted in hemoglobin (AGE-Val) adduct levels of about 20 picomoles per gram (pmol/g) globin (median value) compared to undetected levels in control mice (detection limit 2 pmol/g globin). The potential of AGE to pose a skin absorption hazard was also eval

uated, 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 refer

ence occupational exposure limit. On the ba

sis of this algorithm, a ratio of the skin dose to the inhalation dose (SI ratio) of 0.84 was calculated for AGE. An SI ratio of ≥0.1 in

dicates that skin absorption may significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore, AGE is considered to be absorbed through the skin following dermal exposure. Additional infor

mation on the SI ratio and the variables used in its calculation are included in the appendix. No dermal lethal doses (LD Lo ) of AGE for humans have been identified. The reported dermal LD 50 value (the dose resulting in 50% mortality in the exposed animals) in rabbits was 2550 milligrams per kilogram (mg/kg) bodyweight [Hine et al. 1956]. Although no newer studies have been identified, the avail

able acute dermal LD 50 value for rabbits is higher than the critical dermal LD 50 value of 2000 mg/kg body weight that identifies chemical substances with the potential for acute dermal toxicity [NIOSH 2009]. There

fore, AGE is not considered acutely toxic fol

lowing dermal exposure. No epidemiological or occupational expo

sure studies in humans or standard repeatdose, subchronic, or chronic toxicity stud

ies in animals were identified that evaluated systemic effects following dermal exposure. No studies that evaluated standard biological system or function specific effects (including reproductive and developmental effects and immunotoxicity) in humans or animals fol

lowing dermal exposure to AGE were iden

tified. No epidemiological studies or animal bioassays were identified that evaluated the carcinogenic potential of AGE following dermal exposure. No other organizations or agencies have classified AGE as a carcinogen by other routes of exposure. Table 2 summa

rizes carcinogenic designations of multiple governmental and nongovernmental organi

zations for AGE. Although the detection of hemoglobin ad

ducts in mice dermally exposed to AGE indi

cates that the substance was absorbed through the skin, the available acute dermal toxicity study [Hine et al. 1956] indicated that the substance was not acutely toxic following der

mal exposure until the applied dose exceeded 2000 mg/kg. Lack of epidemiological studies in exposed workers or repeat-dose, subchron

ic, or chronic toxicity studies in humans or animals precludes adequate evaluation of the potential of the substance to cause systemic effects following dermal exposure. Therefore, on the basis of the available data for this as

sessment, AGE is not assigned the SK: SYS notation. 

# 3 Direct Effects on Skin (SK: DIR)
No human or animal in vivo studies on cor

rosivity of AGE or in vitro tests for corrosivity using human or animal skin models or in vitro tests of skin integrity using cadaver skin were identified. Limited occupational exposure data were identified. Dermatitis, consisting of tenderness, itching, swelling, and blister for

mation, and whitish macules, were observed in 10 of 20 workers dermally exposed to AGE vapor and/or liquid [Hine et al., 1956]. In rabbits, a single application of 0.5 milliliter (mL) of undiluted AGE to the clipped skin for 24 hours, according to the Draize proto

col, resulted in moderate skin irritation on in

tact skin and moderate to severe irritation on abraded skin [Hine et al. 1956; Dow Chemi

cal Company 1957]. The structure activitySkin Notation Profiles | Allyl glycidyl ether 3 

### Table 2. Summary of the carcinogenic designations* for AGE by governmental and nongovernmental organizations Organization Carcinogenic designation NIOSH [2005] No designation NTP [2011] No designation US EPA [2012] No designation European Parliament [2008] Carcinogenicity Category 2: Suspected of causing cancer IARC [2011] No designation EC [2014] † No designation ACGIH [2001] Group A4: not classifiable as a human carcinogen 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 non-dermal (such as oral or inhalation) exposure rather than dermal exposure. † Date accessed. relationship model, Deductive Estimation of Risk from Existing Knowledge ( DEREK ), predicted AGE to be a skin irritant. Results from a number of studies, including human experience [Hine et al. 1956] * and studies conducted using standard methods in animals [Hine et al. 1956; Dow Chemi

cal Company 1957] , with supporting infor

mation from a structure activity relationship model, demonstrate that AGE is a potential skin irritant. Therefore, on the basis of the data for this assessment, AGE is assigned the SK: DIR (IRR) notation. 

# 4 Immune-mediated Responses (SK: SEN)
A limited number of studies were identi

fied that evaluated the potential of AGE to cause skin sensitization in both humans and animals. Hine et al. [1956] provided data that indicated that occupational exposure to AGE resulted in skin sensitization. Occupational ex

posure to a resin composed of epoxy resin and ortho-cresyl glycidyl ether produced contact

*References in bold text indicate studies that serve

as the basis of the SK assignments. dermatitis and airborne contact dermatitis in 10 of 22 workers after 20 days to 2 months of exposure [Angelini et al. 1996]. All 10 re

acted to the diluent ortho-cresyl glycidyl ether (CGE), while only one of the 22 showed al

lergic reactions to AGE [Angelini et al. 1996]. Dooms-Goossens et al. [1995] also reported a case study in which a worker in the plastics industry who presented with dermatitis on his hands and forearms reacted positively to AGE after patch testing. Fregert and Rorsman [1964] conducted patch tests on people that presented with contact allergies to resins of di

glycidyl ethers of bisphenol A. In this study, 2 of 20 subjects were sensitized to AGE. No predictive tests [guinea pig maximization test (GPMT), Buehler test, local lymph node as

says (LLNA), mouse ear swelling test (MEST) etc.] were identified. DEREK predicted AGE to be a skin sensitizer. A number of occupational exposure stud

ies [Hine et al. 1956; Dooms-Goossens et al. 1995] and patch test studies [Fregert and Rorsman 1964; Angelini et al. 1996] demon

strate that AGE is a potential skin sensitizer. This conclusion is also supported by a struc

ture activity relationship model. Therefore, on the basis of the data for this assessment, AGE is assigned the SK: SEN notation.4 Skin Notation Profiles | Allyl glycidyl ether 

### Table 3. Summary of previous skin hazard designations for AGE

Organization Skin hazard designation NIOSH [2005] [skin]: Potential for dermal absorption; prevent skin contact OSHA [2014]* No designation ACGIH [2001] No designation EC [2014]* R38—Irritating to skin R43—May cause sensitization by skin contact 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. 

# 5 Summary No estimates of percent absorption of AGE following dermal exposure were identified. However, a mathematical model predicts that the chemical is poorly absorbed through the skin. Acute dermal toxicity data demonstrate that AGE has low systemic toxicity. No re

peat-dose, subchronic or chronic dermal tox

icity studies in animals or epidemiological or occupational exposure studies following der

mal exposure that estimated systemic effect levels were identified. Occupational exposure information and standard skin irritation tests [Hine et al., 1956; Dow Chemical Company 1957] provide sufficient evidence of the po

tential for AGE to cause skin irritation. Simi

larly, studies from occupational exposures and positive results from patch testing of individ

uals occupationally exposed to AGE [ Hine et al. 1956; Fregert and Rorsman 1964; Dooms-Goossens et al. 1995; Angelini et al. 1996 ] are sufficient to demonstrate that AGE is a potential skin sensitizer. Therefore, on the basis of these assessments, AGE is as

signed a composite skin notation of SK: DIR (IRR)-SEN

. Table 3 summarizes the skin hazard designa

tions for AGE previously issued by NIOSH and other organizations. The equivalent der

mal designations for AGE, according to the Global Harmonization System (GHS) of Classification and Labeling of Chemicals, are Skin Irritation Category 2 (Hazard statement: Causes skin irritation) and Skin Sensitization Category 1 (Hazard statement: May cause an allergic skin reaction) [ European Parlia

ment 2008]. In addition, AGE has been clas

sified as a Mutagenicity Category 2 (Hazard Statement: Suspected of causing genetic de

fects) and a Reproductive Toxicity Category 2 (Hazard Statement: Suspected of damaging fertility) [ European Parliament 2008]. 

# References

* ACGIH (American Conference of Governmen

tal Industrial Hygienists) [2001]. Allyl glycidyl ether. In: Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 1. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. *Angelini, G; Rigano, L; Foti, C; Grandolfo, M; Vena, GA;Bonamonte, D; Soleo; Scorpiniti, AA. [1996]. Occupational sensitization to ep

oxy resin and reactive diluents in marble work

ers. Contact Dermatitis. 35 (1):11–16. *Dooms-Goossens A, Bruze M, Buysse L, Fregert S, Gruvberger B, and Stals H [1995]. Contact allergy to allyl glycidyl ether present as an im

purity in 3-glycidyloxypropyltrimethoxysilane, a fixing additive in silicone and polyurethane resins. Contact Dermatitis 33 (1):17–19. *Dow Chemical Company [1957]. Results of range-finding toxicological tests on allyl glyc

idyl ether. Midland, MI: Dow Chemical Com

pany. On file with the US Environmental Pro

tection Agency under TSCA Section 8D. OTS #: 0206671.Document #: 878214852. *EC (European Commission) [ND]. Allyl 2,3-ep

oxypropyl ether. In: EINICS (European In

ventory of Existing Commercial ChemicalSkin Notation Profiles | Allyl glycidyl ether 5 Substances), http://esis.jrc.ec.europa.eu/. Ac

cessed: 04-29-14. *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:2008:35 3:0001:1355:EN:PDF. Accessed: 04-29-14. *Fregert S; Rorsman H [1964]. Allergens in epoxy resins. Acta Allegrol. 19 :296–299. *Hine CH, Kodama, JK, Kodama JK; Wellington JS, Dunlap MK, Anderson, HH [1956]. The toxicology of glycidol and some glycidyl ethers. Arch Ind Health 14 :250–264 *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: 04-29-14. *NIOSH [2005]. Allyl glycidyl ether. In: NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Pre

vention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publica

tion No. 2005-149, http://www.cdc.gov/niosh/ npg/. Accessed: 04-29-14. *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: 04-29-14. *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 05-29-13. *OSHA [ND]. Allyl glycidyl ether. In: OSHA occupational chemical database, https://www .osha.gov/chemicaldata/chemResult.html? recNo=47. Accessed: 04-29-14. *Perez HL, Osterman-Golkar S [2000]. Biotrans

formation of the double bond in allyl glycidyl ether to an epoxide ring. Evidence from hemo

globin adducts in mice. Chem-Biol. Interac

tions 125 :17–28. *USEPA (United States Environmental Protec

tion Agency) [2013]. Integrated Risk Informa

tion System (IRIS), http://www.epa.gov/ncea/ iris/. Accessed: 04-29-14.

* Waechter JM Jr., Pottenger LH, Veenstra GE [2001]. Epoxy compounds: olefin oxides, ali

phatic glycidyl ethers and aromatic monoglyc

idyl ethers. In: Bingham E, Cohrssen B, Powell CH (Eds.), Patty’s toxicology 5th ed., Vol. 6. New York: John Wiley & Sons, Inc.Skin Notation Profiles | Allyl glycidyl ether 7 

# Appendix: Calculation of the SI Ratio for AGE This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for allyl glycidyl ether. 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 support

ive 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 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 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 ( k p 

### )

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 −0.5 The second step is to calculate the biologic mass uptake of the substance from skin ab

sorption (skin dose) and inhalation (inhalation8 Skin Notation Profiles | Allyl glycidyl ether 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

= 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 AGE. The calculated SI ra

tio was 0.837. On the basis of these results, AGE is predicted to represent a skin absorp

tion 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: 04-29-14. 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: 04-29-14. SRC [2009]. Interactive PhysProp database demo http://www.srcinc.com/what-we-do/database forms.aspx?id=386 . Accessed: 04-29-14.Skin Notation Profiles | Allyl glycidyl ether 9 

### Table A1. Summary of data used to calculate the SI ratio for AGE
Variables used in calculation Units Value Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path( k ps c ) cm/hr 1.099 × 10 -3 Permeation coefficient of the protein fraction of the stratum

corneum ( k pol

) cm/hr 1.4223 × 10 -5 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.234089 Molecular weight ( MW ) * amu 114.06 Base-10 logarithm of its octanol–water partition coefficient

(Log K
ow ) * None 0.45 Calculated skin permeation coefficient (k p ) cm/hr 1.1078 × 10 -3 Skin dose

Water solubility ( S w ) * mg/cm 3 43.3 Calculated skin permeation coefficient ( k p ) cm/hr 1.1078 × 10 -3 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8 Calculated skin dose mg 138.15 Inhalation Dose

Occupational exposure limit (OEL) † mg/m 3 22 Inhalation volume m 3 10 Retention factor (RF) None 0.75 Inhalation dose mg 165 Skin dose–to–inhalation dose (SI) ratio None 0.837

* Variables identified from SRC [2009]. † The OEL used in calculation of the SI ratio for allyl glycidyl ether was the NIOSH recommended exposure limit (REL)

[NIOSH 2005].