SK

NIOSH Skin Notation Profiles

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health

IDSK

[SK]

SYS

DIR

DIR (IRR)

SYS (FATAL)

DIR (COR)

SEN

Tetramethyl Lead (TML)
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Naomi L. Hudson and G. Scott Dotson

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 

NIOSH Skin Notation (SK) Profile

Tetramethyl Lead (TML)

[CAS No. 75-74-1]
ii Skin Notation Profiles | Tetramethyl Lead (TML)

This document is in the public domain and may be freely 

copied or reprinted.

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Suggested Citation

NIOSH [2017]. NIOSH skin notation profile: Tetramethyl 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. 2017-191.

DHHS (NIOSH) Publication No. 2017-191

August 2017
Skin Notation Profiles | Tetramethyl Lead (TML) iii

Foreword

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

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

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

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

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

dermatitis and pulmonary responses), or systemic toxicity (e.g., neurotoxicity and hepatotoxicity). 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 (SKs) 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 for tetramethyl 

lead (TML). In particular, this document evaluates and summarizes the literature describing 

the hazard potential of the substance and its assessment according to the scientific rationale 

and framework outlined in CIB 61. In meeting this objective, this Skin Notation Profile intends 

to inform the audience—mostly occupational health practitioners, researchers, policy- and 

decision-makers, employers, and workers in potentially hazardous workplaces—so that 

improved risk-management practices may be developed to better protect workers from the 

risks of skin contact with the chemicals of interest.

John Howard, M.D.

Director, National Institute for

Occupational Safety and Health

Centers for Disease Control and Prevention
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Skin Notation Profiles | Tetramethyl Lead (TML) v

Contents

Foreword . .

Abbreviations . 

Glossary . . 

Acknowledgments . 

1 Introduction .

1.1 General Substance Information: .

1.2 Purpose .

1.3 Overview of SK Assignment .

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

3 Direct Effects on Skin (SK: DIR) .

4 Immune-mediated Responses (SK: SEN) .

5 Summary .

References .

Appendix: Calculation of the SI Ratio for TML .

Overview .

Calculation .

Appendix References .
vi Skin Notation Profiles | Tetramethyl Lead (TML)

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ALD approximate lethal dose 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2 squared 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

EDB ethylene dibromide

GHS Globally Harmonized System for Classification and Labelling of Chemicals

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

LOAEL lowest-observed-adverse-effect level 

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

M molarity

m3 cubic meter(s)

mg milligram(s)

mg/kg milligram(s) per kilogram body weight

mg/m3 milligram(s) per cubic meter

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

SK skin notation
Skin Notation Profiles | Tetramethyl Lead (TML) vii

SW solubility in water

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

the skin

TML tetramethyl lead

USEPA United States Environmental Protection Agency
viii Skin Notation Profiles | Tetramethyl Lead (TML)

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 occur 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 | Tetramethyl Lead (TML) ix

Acknowledgments

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

Director). Naomi Hudson, Dr.P.H., MPH, was the project officer for this document, assisted in 

great part by G. Scott Dotson, Ph.D., Heinz Ahlers, 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. 

National Personal Protective Technology Laboratory

Heinz Ahlers, JD, M.Sc.

Angie Shepherd
x Skin Notation Profiles | Tetramethyl Lead (TML)

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:

Frank A. Barile, Ph.D., R.Ph. Full professor, Pharmaceutical Sciences, St. John’s University 

College of Pharmacy and Allied Health Professionals, Queens, NY

Larry Kenneth Lowry, Ph.D., Professor, Department of Occupational and Environmental 

Medicine, The University of Texas Health Science Center at Tyler, Tyler, TX

Sean Semple, Ph.D., Senior lecturer, Scottish Centre for Indoor Air Division of Applied 

Health Sciences, University of Aberdeen, Aberdeen, Scotland

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

Dori Germolec, Ph.D., National Toxicology Program, National Institute for Environmental Health Sciences, Research Triangle, NC

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

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

James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH
Skin Notation Profiles | Tetramethyl Lead (TML) 1

Tetramethyl Lead (TML)

1 Introduction

1.1 General Substance Information:

Chemical: Tetramethyl lead (TML) 

CAS No: 75-74-1

Molecular weight (MW): 267.3

Molecular formula: Pb(CH3)4

Structural formula:

Synonyms: Lead tetramethyl; Tetramethylplumbane; TML; Alkyllead; Organolead 

Uses: TML is an organic lead compound 

historically used as a octane booster (i.e., 

antiknock additive) for gasoline of premium 

and aviation grades [ACGIH 2001]. This 

substance is no longer used in large volumes 

commercially. 

1.2 Purpose

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological 

data associated with skin contact with TML 

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

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 TML. A literature search 

was conducted through June 2017 to identify information on TML, 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 TML. The criteria for the search strategy, evaluation, and selection of data are described in 

Appendix E in CIB 61: A Strategy for Assigning 

New NIOSH Skin Notations [NIOSH 2009].

1.3 Overview of SK Assignment

TML is potentially capable of causing numerous 

adverse health effects following skin contact. A 

critical review of available data has resulted in 

the following SK assignment for TML: SK: SYS. 

Table 1 provides an overview of the critical 

effects and data used to develop the SK assignment for TML.

2 Systemic Toxicity from

Skin Exposure (SK: SYS)

No toxicokinetic studies following dermal exposure to TML have been identified in humans or 

animals. The potential of TML to pose a skin 

absorption hazard was evaluated, with use of a 

predictive algorithm for estimating and evaluating the health hazards of dermal exposure 
2 Skin Notation Profiles | Tetramethyl Lead (TML)

Tetramethyl Lead (TML)

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 2.76 was calculated for TML. An SI ratio of 

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

a substance [NIOSH 2009]; therefore, TML has 

the potential to be absorbed through the skin 

and to become available systemically following 

dermal exposure. Additional information on the 

SI ratio and the variables used in its calculation 

are included in the appendix. 

No estimate of human dermal lethal dose (LDLo) 

or dermal LD50 values (the dose resulting in 50% 

mortality in the exposed animals) were identified for TML. E.I. du Pont de Nemours and 

Company [1959, 1991] reported an approximate lethal dose (ALD) (i.e., the lowest dose 

which causes mortality) of 6,203 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. A minimum lethal dose (MLD) 

value of 2.0 milliliters per kilogram (mL/kg) 

of bodyweight (mL/kg) (corresponding to 4,000 

milligrams per kilogram of bodyweight (mg/kg)) 

for rabbits was identified [Akatsura K 1973]. The 

ALD and MLD values for rabbits indicate that 

TML was absorbed through the skin following 

dermal exposure and is lethal in concentrations 

greater than the critical dermal LD50 value of 

2000 mg/kg body weight that identifies chemical 

substances with the potential for acute dermal 

toxicity [NIOSH 2009].

No epidemiological or occupational studies or 

case reports, nor repeat-dose, subchronic or 

chronic toxicity studies in animals were identified that evaluated the potential for TML 

to cause systemic effects following dermal 

exposure. Schepers [1964] has indicated that 

virtually identical effects could be induced by 

the oral, cutaneous, and inhalation routes of 

exposure to TML, based on studies that compared the severity and distribution of lesions 

cumulatively induced by separate but comparable repeated dosage studies, following 

each route of exposure. Based on this finding 

and the results of the model prediction that 

TML can be absorbed through the skin, the 

potential of the substance to induce systemic 

toxicity was evaluated following repeated 

or prolonged exposure via other routes. In 

a 20-week study conducted by Schepers 

[1964], tetramethyl lead administered to rats 

in peanut oil by gavage at 0.001 or 1.08 milligrams per kilogram body weight (mg/kg) 5 

days/week, caused cytoplasmic degeneration 

and vacuolation of the liver and neuronal 

damage at the low dose while animals exposed 

to the higher dose exhibited similar but more 

severe histopathologies. A Lowest Observed 

Adverse Effect Level (LOAEL) of 0.001 mg/

kg-day, the lowest dose tested, can be determined from this study. Because this LOAEL 

observed in this study is very low, this assessment concludes that TML has the potential to 

be systemically available and may cause similar effects (liver and neuronal damage), with 

a NOAEL that is likely to be lower or equal 

to the critical dermal NOAEL value of 1000 

mg/kg-day that identifies chemical substances 

with the potential for repeated-dose dermal 

toxicity [NIOSH 2009].

No standard toxicity or specialty studies 

were identified that evaluated biological 

Table 1. Summary of the SK assignment for TML

Skin notation Critical effect Available data

SK: SYS Hepatotoxicity; Neurotoxicity Animal data from studies of alternative 

exposure routes
Skin Notation Profiles | Tetramethyl Lead (TML) 3

Tetramethyl Lead (TML)

system/function specific effects (including 

reproductive and developmental effects and 

immunotoxicity) following dermal exposure 

to TML. No epidemiological studies or animal 

bioassays were identified that evaluated the 

carcinogenic potential of TML following 

dermal exposure. No other organizations or 

agencies have classified TML as a carcinogen 

by other routes of exposure. Table 2 summarizes carcinogenic designations of multiple 

governmental and nongovernmental organizations for TML.

No toxicokinetic data were identified that 

estimated the degree of absorption of TML 

following dermal exposure, although a model 

predicted TML to be absorbed following skin 

contact. No acute toxicity studies were identified that reported LD50 values for TML, 

however an ALD of 6,203 mg/kg [E.I. du Pont 

de Nemours and Company 1959, 1991] and a 

MLD of 4,000 mg/kg were identified [Akatsura 

1973]. No epidemiological or occupational 

exposure studies or case reports and no repeatdose, subchronic, or chronic studies in animals 

were identified that evaluated the potential of 

TML to cause systemic effects following dermal 

exposure. Given the results of the model prediction and because virtually identical effects 

could be induced by the oral, cutaneous, and 

inhalation routes of exposure to TML [Schepers 

1964], the potency of the substance was evaluated following repeated or prolonged exposure 

via alternative exposure routes (i.e., oral) in animals. TML caused liver and neuronal damage in 

rats in an oral exposure study [Schepers 1964]*

at low doses, indicating that the potential exists 

for dermal exposure to result in similar effects 

observed in this study. Therefore, on the basis 

of the data for this assessment, TML is assigned 

the SK: SYS notation.

3 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies on corrosivity of TML 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 occupational studies or case 

reports and no standard skin irritation tests 

in animals were identified that evaluated the 

potential of TML to cause direct skin effects. 

Lack of these studies precludes adequate evaluation of the potential of TML to cause skin 

*

References in bold text indicate studies that serve 

as the basis of the SK assignments.

Table 2. Summary of the carcinogenic designations* for TML by 

numerous governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] No designation

NTP [2014] No designation

European Parliament [2008] No GHS designation

USEPA [2015] No designation

IARC [2012] No designation

ACGIH [2001] No designation

ACGIH = American Conference of Governmental Industrial Hygienists; 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 non-dermal (such as oral or inhalation) exposure since studies using the 

dermal route of exposure were unavailable.
4 Skin Notation Profiles | Tetramethyl Lead (TML)

Tetramethyl Lead (TML)

irritation in humans or animals. Therefore, on 

the basis of the data for this assessment, TML 

is not assigned the SK: DIR notation. 

4 Immune-mediated

Responses (SK: SEN)

No occupational exposure studies or diagnostic 

(human patch) patch tests or predictive tests 

in animals (for example, guinea pig maximization tests, Buehler tests, murine local lymph 

node assays, or mouse ear swelling tests) or any 

other studies were identified that evaluated the 

potential of the substance to cause skin sensitization. Lack of these studies precludes adequate 

evaluation of TML as a potential skin sensitizer. 

Therefore, on the basis of the data for this assessment, TML is not assigned the SK: SEN notation. 

5 Summary

No toxicokinetic data were identified that 

estimated the degree of absorption of TML 

following dermal exposure; however, a 

model predicted TML to be absorbed following skin contact. An ALD of 6,203 mg/

kg [E.I. du Pont de Nemours and Company 

1959, 1991] and a MLD of 4,000 were identified, indicating that TML can be absorbed by 

the skin but were above the critical dermal LD50

value of 2000 mg/kg body weight that identifies chemical substances with the potential for 

acute dermal toxicity. Based on the results of 

the model prediction, and because virtually 

identical effects were produced by the oral, 

cutaneous, and inhalation routes of exposure 

to TML [Schepers 1964], the potency of the 

substance was evaluated following repeated 

or prolonged exposure via other exposure 

routes (i.e., oral) in animals. TML at very 

low doses caused liver and neuronal damage 

in rats in an oral exposure study [Schepers 

1964], indicating that the potential exists 

for dermal exposure to cause similar effects 

as observed in the oral study. No epidemiological investigations or experimental animal 

studies were identified that evaluated the 

potential for TML to cause direct skin effects 

or skin sensitization. Therefore, on the basis 

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

Table 3 summarizes the skin hazard designations for TML previously issued by NIOSH 

and other organizations. No Globally Harmonized System (GHS) of classification and 

labeling of chemicals dermal classification 

for TML was located [European Parliament 

2008].

References

Note: Asterisks (*) denote sources cited in 

text; daggers (†) denote additional resources.

*ACGIH (American Conference of Governmental 

Industrial Hygienists) [2001]. Tetramethyl lead. 

In: Documentation of threshold limit values and 

biological exposure indices 7th ed., Vol. 3. Cincinnati, OH: American Conference of Governmental 

Industrial Hygienists.

*Akatsura K [1973]. Tetraalkyl lead poisoning. 

Sangyo Igaku (Japanese Journal of Industrial 

Health) 15:366. 

†ATSDR [2007]. Toxicological profile for lead. 

Atlanta, GA: U.S. Department of Health and 

Human Services, Public Health Service, Agency 

for Toxic Substance and Disease Registry 

(ATSDR), http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=96&tid=22. Accessed: 06-07-17.

†Davis RK, Horton AW, Larson EE, Stemmer KL 

[1963]. Inhalation of tetramethyl lead and tetraethyl lead: a comparison of the effects in rats and 

dogs. Arch Environ Health 6:473–479.

*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 
Skin Notation Profiles | Tetramethyl Lead (TML) 5

Tetramethyl Lead (TML)

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: 06-07-17.

*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: 06-07-17.

*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: 06-07-17.

*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: 06-07-17.

*NTP [2014]. Report on Carcinogens. Thirteenth 

Edition; U.S. Department of Health and Human 

Services, Public Health Service. National Toxicology Program, https://ntp.niehs.nih.gov/

annualreport/2015/glance/roc/index.html. 

Accessed: 06-07-17.

*OSHA [ND]. Tetramethyl lead (as Pb). In: OSHA 

Occupational Chemical Database, http://

www.osha.gov/chemicaldata/chemResult.

html?recNo=597. Accessed: 06-07-17.

*Schepers GWH [1964]. Comparative Experimental 

Pathology: Part I. Lead Absorption and Pathology. 

Arch Environ Health 8:277–295.

*USEPA (United States Environmental Protection 

Agency) [2015]. Integrated Risk Information System (IRIS), https://www.epa.gov/iris. 

Accessed: 06-07-17. 

Table 3. Summary of previous skin hazard designations for TML

Organization Skin hazard designation

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

OSHA [2017]* [skin]: Potential for dermal absorption

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

ACGIH = American Conference of Governmental Industrial Hygienists; NIOSH = National Institute for Occupational Safety and 

Health; OSHA = Occupational Safety and Health Administration.

*

Date accessed.
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Skin Notation Profiles | Tetramethyl Lead (TML) 7

Tetramethyl Lead (TML)

Appendix: Calculation of the SI Ratio for TML

This appendix presents an overview of the SI 

ratio and a summary of the calculation of the 

SI ratio for TML. 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].

Equation 1: Calculation of Skin Permeation 

Coefficient (kp)

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 
8 Skin Notation Profiles | Tetramethyl Lead (TML)

Tetramethyl Lead (TML)

product of the kp, the water solubility (SW) of 

the substance, the exposed skin surface area, 

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

continues for 8 hours to unprotected skin on 

the palms of both hands (a surface area of 360 

square centimeters [cm2]). 

Equation 2: Determination of Skin Dose 

Skin dose = 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.

Calculation

Table A1 summarizes the data applied in the 

previously described equations to determine 

the SI ratio for TML. The calculated SI ratio 

was 2.76. On the basis of these results, TML 

is predicted to represent a skin absorption 

hazard.

Appendix References

Hayes, Wallace A [2008]. Principles and methods 

of toxicology. Fifth Edition. Informa Healthcare 

USA, Inc. New York, NY. 

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: 06-07-17.

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: 06-07-17.

SRC [2009]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.

asp?CAS=75741. Accessed: 06-07-17.
Skin Notation Profiles | Tetramethyl Lead (TML) 9

Tetramethyl Lead (TML)

Table A1. Summary of data used to calculate the SI ratio for TML

Variables used in calculation Units Value

Skin permeation coefficient

Permeation coefficient of stratum corneum 

lipid path(kpsc)

cm/hour 3.6713 × 10-3

Permeation coefficient of the protein fraction of 

the stratum corneum (kpol)

cm/hour 9.2909 × 10-6

Permeation coefficient of the watery epidermal 

layer (kaq)

cm/hour 0.1529

Molecular weight (MW)* amu 267.3

Base-10 logarithm of its octanol–water partition 

coefficient (Log Kow)*

None 297

Calculated skin permeation coefficient (kp) cm/hour

Skin dose

Water solubility (Sw)* mg/cm3 0.15

Calculated skin permeation coefficient (kp) cm/hour 3.5941 × 10-3

Estimated skin surface area (palms of hand)§ cm2 360

Exposure time hour 8

Calculated skin dose mg 1.5527

Inhalation Dose

Occupational exposure limit (OEL)† mg/m3 0.075

Inhalation volume m3 100

Retention factor (RF) None 0.75

Inhalation dose mg 0.5625

Skin dose–to–inhalation dose (SI) ratio None 2.76

*

Variables identified from SRC [ND].

†

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

§

Hayes, Wallace A [2008]. Principles and Methods of Toxicology. Fifth Edition. Informa Healthcare USA, Inc. New York, NY.
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