Skin Notation (SK) Profile

Tetraethyl Lead (TEL)

[CAS No. 78-00-2]

Department of Health and Human Services

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
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Suggested Citation

NIOSH [20XX]. NIOSH skin notation profile: Tetraethyl lead. By Hudson NL, Dotson GS. 

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

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

Publication No. XXX

DHHS (NIOSH) Publication No. XXX
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information quality guidelines. It has not been formally disseminated by the National Institute for 

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

agency determination or policy.

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 tetraethyl lead 

(TEL). 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 riskmanagement 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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information quality guidelines. It has not been formally disseminated by the National Institute for 

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

agency determination or policy.

Contents

FOREWORD ............................................................................................................................................................III

ABBREVIATIONS.....................................................................................................................................................V

GLOSSARY .............................................................................................................................................................VII

ACKNOWLEDGMENTS..................................................................................................................................... VIII

1.0 INTRODUCTION .................................................................................................................................................1

1.1 GENERAL SUBSTANCE INFORMATION:.................................................................................................................1

1.2 PURPOSE..............................................................................................................................................................1

1.3 OVERVIEW OF SK ASSIGNMENT ..........................................................................................................................2

2.0 SYSTEMIC TOXICITY FROM SKIN EXPOSURE (SK: SYS) ......................................................................2

3.0 DIRECT EFFECTS ON SKIN (SK: DIR)...........................................................................................................4

4.0 IMMUNE-MEDIATED RESPONSES (SK: SEN) .............................................................................................4

5.0 SUMMARY............................................................................................................................................................4

REFERENCES ............................................................................................................................................................5

APPENDIX: CALCULATION OF THE SI RATIO FOR TEL .............................................................................7

OVERVIEW.................................................................................................................................................................7

CALCULATION ...........................................................................................................................................................9

APPENDIX REFERENCES...........................................................................................................................................10
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information quality guidelines. It has not been formally disseminated by the National Institute for 

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agency determination or policy.

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

CIB Current Intelligence Bulletin

cm2squared 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 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

kaq coefficient in the watery epidermal layer

kp skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

kpsc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LLNA local lymph node assay

LOAEL lowest-observed-adverse-effect level 

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

M molarity

m

3

cubic meter(s)

mg milligram(s)

mg/kg milligram(s) per kilogram body weight

mg/m3 milligram(s) per cubic meter

mL milliliter(s)

MLD minimum lethal dose 

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

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

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

agency determination or policy.

SK skin notation

SW solubility in water

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

the skin

TEL tetraethyl lead

USEPA United States Environmental Protection Agency 
vii

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

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

agency determination or policy.

Glossary 

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

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

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

Approximate Lethal Dose—The lowest dose which causes mortality.

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

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

agency determination or policy.

Acknowledgments

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

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

by Naomi Hudson, Dr.P.H. MPH, Heinz Ahlers, M.Sc., and Aaron Sussell, 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 Maier, Ph.D. 

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

acknowledgment is given to the following NIOSH personnel:

Denver Field Office

Eric Esswein, M.Sc.

Division of Applied Research and Technology 

Clayton B’Hymer, Ph.D. 

John Snawder, Ph.D.

Mark Toraason, Ph.D.

Division of Respiratory Disease Studies 

Gregory A. Day, Ph.D. 

Aleksander Stefaniak, Ph.D. 

Division of Surveillance, Hazard Evaluations, and Field Studies

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. 

Vic Johnson, Ph.D. 

Michael Luster, Ph.D. 

Paul Siegel, Ph.D.

Berran Yucesoy, Ph.D. 
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information quality guidelines. It has not been formally disseminated by the National Institute for 

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

agency determination or policy.

National Personal Protection Technology Laboratory

Heinz Ahlers, M.Sc.

Angie Shephard

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

acknowledgment is given to the following CDC personnel:

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

Program Office 

Barbara Landreth, M.A.

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

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

improvement of this document:

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

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

Environmental Health Sciences, Research Triangle, NC

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

Nashville, TN 

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

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

1.0 Introduction 

1.1 General Substance Information: 

Chemical: Tetraethyl Lead

CAS No: 78-00-2

Molecular weight (MW): 323.5

Molecular formula: Pb(C2H5)4

Structural formula:

Synonyms: Lead tetraethyl; TEL; Tetraethylplumbane

Uses: Tetraethyl lead (TEL) was historically used as an additive to fuel as an antiknock agent; currently, 

the substance is used during the manufacturing of other metals [HSDB 2008]. 

1.2 Purpose 

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

associated with skin contact with TEL and (2) the rationale behind the hazard-specific skin notation 

(SK) assignment for TEL. 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 TEL. A literature search was conducted through 

January 2013 to identify information on TEL, 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 

TEL. 
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policy.

1.3 Overview of SK Assignment

TEL 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 TEL: SK: SYS. Table 1 

provides an overview of the critical effects and data used to develop the SK assignment for TEL. 

Table 1. Summary of the SK Assignment for TEL

Skin Notation Critical Effect Available Data

SK: SYS Hepatotoxicity; Hemotoxicity Limited animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

No studies were identified that provided quantitative estimates of dermal absorption of TEL in humans 

or animals following dermal exposure. However, evidence of dermal absorption after topical application 

was provided by Kehoe and Thamann [1931] who uniformly spread 0.75 milliliter (mL) of TEL over an 

area of 25 square centimeters (cm2) on the abdominal skin of rabbits. The authors reported an

accumulation of 1.06 to 4.41 milligrams (mg) of lead in the carcass of the test animals, corresponding to 

exposure durations of 0.5 to 6 hours, respectively. Laug and Kunze [1948] noted that 90 to 95% of 

tetraethyl lead evaporated before it could be absorbed by the skin; however, using lead content of the 

kidney as an index for dermal absorption, the authors reported a hundredfold increase in the kidney lead 

concentration following application of TEL to shaved skin of rats. These authors also noted that 

scarifying the skin enhanced absorption [Laug and Kunze 1948]. The potential of TEL 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 0.01 was calculated for TEL. An SI ratio of ≥0.1 

indicates that skin absorption may significantly contribute to the overall body burden of a substance 

[NIOSH 2009]; therefore, TEL is not considered to be absorbed through the skin following dermal 

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

the appendix. 

No dermal lethal dose (LDLo) of TEL in humans has been identified. However, approximate lethal dose 

(ALD) (i.e., the lowest dose which causes mortality) and minimum lethal dose (MLD) values were 

identified. E.I. du Pont de Nemours and Company [1959, 1991] reported an ALD of 1500 and 2250 

milligrams per kilogram body weight (mg/kg) when TML was applied to the skin of male albino rabbits 

in a mixture of toluene and ethylene dibromide (EDB). However, the authors reported the clinical signs 

preceding death were indicative of EDB poisoning. MLD values of 1.5 milliliters per kilogram of 

bodyweight (mL/kg) (corresponding to 2475 mg/kg [Akatsura 1973] and 0.7 mL/kg (corresponding to 

1157 mg/kg) in adult rabbits [Kehoe 1927] have been reported. Akatsura [1973] reported 
3

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hyperglycemia, marked reduction in body weight, porphyrinuria, and marked reduction in liver function 

following dermal application of TEL to the rabbits. Although no dermal LD50 values (the dose resulting 

in 50% mortality in the exposed animals) were identified in animals, the ALD and MLD values for 

rabbits indicate that TEL was absorbed through the skin following dermal exposure. However, the data 

are insufficient to determine if TEL is lethal in concentrations less 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]. 

No epidemiological studies, case reports or occupational exposure studies or repeat-dose, subchronic or 

chronic toxicity studies in animals were identified following dermal exposure to TEL. No standard 

toxicity or specialty studies evaluating biological system/function specific effects (including 

reproductive and developmental effects and immunotoxicity) following dermal exposure to TEL were 

identified. No epidemiological studies or animal bioassays were identified that evaluated the 

carcinogenic potential of TEL following dermal exposure. No other organizations or agencies have 

classified TEL as a carcinogen by other routes of exposure. Table 2 summarizes carcinogenic 

designations of multiple governmental and nongovernmental organizations for TEL. 

Table 2. Summary of the carcinogenic designations* for TEL by numerous governmental and 

nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] No designation

NTP [2014] No designation

USEPA [2014] No designation

European Parliament [2008] No GHS designation

IARC [2012] Group 3: Not classifiable as to carcinogenicity to 

humans 

EC [2013]† 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; GHS = Globally Harmonized System for Classification and Labelling of 

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

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

*The listed cancer designations were based on data from nondermal (such as oral or inhalation) exposure since studies using 

the dermal route of exposure were unavailable.

†Date accessed.

Although the predictive mathematical model (see Appendix) did not indicate that the chemical can be 

absorbed through the skin, sufficient data exist from toxicokinetic [Kehoe and Thamann 1931; Laug 

and Kunze 1948]1and acute toxicity [Kehoe 1927; Akatsura 1973] data that demonstrate that the 

chemical is absorbed through the skin and is systemically available. Although limited, evidence suggests 

that TEL was absorbed by the skin and may cause hyperglycemia, marked reduction in body weight, 

porphyrinuria, and marked reduction in liver function was observed at high doses. Therefore, on the 

basis of the data for this assessment, TEL is assigned the SK: SYS notation. 

 

1References in bold text indicate studies that serve as the basis of the SK assignments.
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3.0 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies on corrosivity or in vitro tests for corrosivity using human or animal 

skin models or in vitro tests of skin integrity using cadaver skin were identified. No reliable studies that 

specifically evaluated the potential of TEL to cause skin irritation were identified. In an acute toxicity 

study, E.I. du Pont de Nemours and Company [1959, 1991] reported skin irritation at every dose of TEL 

tested; however it is unknown if the irritation was due to TEL or EDB since clinical signs preceding 

death were indicative of EDB poisoning There are insufficient data to determine skin irritation; 

therefore, on the basis of the data for this assessment, TEL is not assigned the SK: DIR notation. 

4.0 Immune-mediated Responses (SK: SEN)

No occupational exposure studies or predictive tests in animals (for example, guinea pig maximization 

tests, Buehler tests, murine local lymph nose assays, or mouse ear swelling tests) that evaluated the skin 

sensitization potential of TEL were identified. Therefore, on the basis of the data for this assessment, 

TEL is not assigned the SK: SEN notation. 

5.0 Summary

Although the predictive mathematical model (see Appendix) did not indicate that the chemical can be 

absorbed through the skin, toxicokinetic [Kehoe and Thamann 1931; Laug and Kunze 1948] and 

acute toxicity [Kehoe 1927] data indicate tetraethyl lead demonstrated the ability to be absorbed through 

the skin and has the potential to cause hyperglycemia, marked reduction in body weight, porphyrinuria, 

and marked reduction in liver function at high doses. No reliable information was identified upon which 

to evaluate the potential of TEL to cause skin irritation/corrosion or skin sensitization. Therefore, on the 

basis of these assessments, TEL is assigned a composite skin notation of SK: SYS. 

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

organizations. No dermal designation based on the Globally Harmonized System (GHS) of 

Classification and Labelling of Chemicals was identified for TEL [European Parliament 2008]. 

Table 3. Summary of previous skin hazard designations for TEL

Organization Skin hazard designation 

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

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

ACGIH [2001] [skin]: Based on systemic toxicity following percutaneous 

absorption.

EC [2013]* No designation

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.
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References

ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. Tetraethyl lead. In: 

Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 3. Cincinnati, OH: 

American Conference of Governmental Industrial Hygienists.

Akatsuka K [1973]. Tetraalkyl lead poisoning. Sangyo Igaku (Japanese Journal of Industrial Health) 

15:366. 

EC (European Commission) [ND]. Tetraethyllead. In: EINICS (European Inventory of Existing 

Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 01-24-13.

E.I. du Pont de Nemours and Company [1959]. Preliminary comparative toxicity studies with 

tetramethyl lead and tetraethyl lead. Newark, DE: E.I. du Pont de Nemours and Company, Haskell 

Laboratory for Toxicology and Industrial Medicine, Medical Research Project #MR-476, Report #20-59. 

On file with the U.S. Environmental Protection Agency under TSCA Section 8D. OTS #0555601. 

Document # 88-920010199. 

E.I. du Pont de Nemours and Company [1991]. Follow-up information: Concerning the enclosed 

summary from Haskell Laboratory on tetraethyl lead and tetramethyl lead with attachments. Newark, 

DE: E.I. du Pont de Nemours and Company. On file with the U.S. Environmental Protection Agency 

under TSCA Section 8D. OTS #0533656-1. Document # 89-92000023.

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://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF . 

Accessed: 01-23-15.

HSDB (Hazardous Substances Data Bank) [2008]. Tetraethyl lead. In: HSDB (Hazardous Substances 

Data Bank), http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~NjKI4B:1. Accessed: 01-23-15.

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

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

http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed: 01-23-15.

Kehoe RA [1927]. On the toxicity of tetraethyl lead and inorganic lead salts. J. Lab. Clin. Med. 7: 554-

560.

Kehoe RA, Thamann F [1931]. The behavior of lead in the animal organism. II. Tetraethyl lead. Am. J. 

Hyg. 13: 478-498.

Laug EP, Kunze FM [1948]. The penetration of lead through the skin. J. Ind. Hyg. Toxicol. 30: 256-259.
6

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

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

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

policy.

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

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

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

Accessed: 01-23-15.

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

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

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

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-23-15.

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

Services, Public Health Service. National Toxicology Program, 

http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01-23-15.

OSHA [ND]. Tetraethyl lead, as Pb. In: OSHA/EPA occupational chemical database, 

http://www.osha.gov/chemicaldata/chemResult.html?recNo=666. Accessed: 01-24-13.

USEPA [2014]. Integrated Risk Information System: tetraethyl lead. In: Integrated Risk Information 

System, http://www.epa.gov/ncea/iris/subst/0109.htm. Accessed: 01-23-15.
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Appendix: Calculation of the SI Ratio for TEL

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

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

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

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

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

Notations [NIOSH 2009]. 

Overview 

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

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

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

proposed strategy for assigning SYS notation are as follows:

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

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

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

hazard and should be labeled with the SYS notation.

The algorithm evaluation includes three steps:

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

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

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

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

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

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

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

appropriate for use.

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

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

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

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

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

of units must be used, such as outlined in Table A1. Other model-based estimates of kp may also be used 

[NIOSH 2009].
8

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

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

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

policy.

Equation 1: Calculation of Skin Permeation Coefficient (kp)

psc pol aq

p

k k k

k

1 1

1







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

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

These components are individually estimated by

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

kpol = 0.0001519 × MW−0.5

kaq = 2.5 × MW−0.5

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

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

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

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

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

centimeters [cm2]). 

Equation 2: Determination of Skin Dose

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

 = kp(cm/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.
9

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

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

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

policy.

Calculation 

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

TEL. The calculated SI ratio was 0.01. On the basis of these results, TEL is not predicted to represent a 

skin absorption hazard.

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

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hour 9.8 × 10-3

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hour 8.446 × 10-6

Permeation coefficient of the watery epidermal layer (kaq) cm/hour 1.39 × 10-2

Molecular weight (MW)

*

amu 323.44

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

* None 4.15

Calculated skin permeation coefficient (kp) cm/hour 9.2 × 10-3

Skin dose

Water solubility (Sw)

* mg/cm3

2.9 × 10-4

Calculated skin permeation coefficient (kp) cm/hour 9.2 × 10-3

Estimated skin surface area (palms of hand) cm2360

Exposure time hour 8

Calculated skin dose mg 1.36 × 10-2

Inhalation Dose

Occupational exposure limit (OEL)† mg/m30.075

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 0.5625

Skin dose–to–inhalation dose (SI) ratio None 0.01

*

Variables identified from SRC [ND].

†

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

2005].
10

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

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

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

policy.

Appendix References 

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

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

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

Accessed: 01-23-15.

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

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

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

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-23-15.

SRC [2009]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.asp?CAS=78002. Accessed: 01-23-15.