Skin Notation (SK) Profile

Tetramethyl lead (TML)

[CAS No. 75-74-1]

Department of Health and Human Services

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 

Disclaimer
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Suggested Citation

NIOSH [20XX]. 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. 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 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 decisionmakers, 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 FOR TML ..........................................................................................................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 ............................................................................................................................................................6

APPENDIX: CALCULATION OF THE SI RATIO FOR TML ............................................................................8

OVERVIEW.................................................................................................................................................................8

CALCULATION .........................................................................................................................................................10

APPENDIX REFERENCES...........................................................................................................................................11
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agency determination or policy.

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ALD approximate lethal dose 

ATSDR Agency for Toxic Substances and Disease Registry

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 

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

m

3

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
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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.

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 
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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, 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: 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 

January 2013 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. 
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policy.

1.3 Overview of SK Assignment for TML

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. 

Table 1. Summary of the SK Assignment for TML

Skin Notation Critical Effect Available Data

SK: SYS Hepatotoxicity; Neurotoxicity Limited animal data

2.0 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 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 is 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 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 [Akatsuka 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 
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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 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. 

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

EC [2013]† No designation

ACGIH [2001] No designation

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.

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 4000 mg/kg were identified [Akatsuka 

1973]. No epidemiological or occupational exposure studies or case reports and no repeat-dose, 

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 
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TML [Schepers 1964] 1, 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. 

3.0 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 irritation in humans or animals. Therefore, on the basis 

of the data for this assessment, TML is not assigned the SK: DIR notation. 

4.0 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. 

5.0 Summary

No toxicokinetic data were identified that estimated the degree of absorption of TML following dermal 

exposure. A model predicted TML to be absorbed following skin contact. No acute toxicity studies that 

reported LD50 values for TML were identified. However, 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 ALD and MLD identified are above the critical dermal LD50 value of 2000 

mg/kg body weight that identifies chemical substances with the potential for acute dermal toxicity. 

Additionally, no epidemiological or occupational exposure studies or case reports nor repeated-dose, 

subchronic, or chronic studies in animals were identified that evaluated the potential of TML to cause 

systemic effects following dermal exposure. 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 

 

1References in bold text indicate studies that serve as the basis of the SK assignments.
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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]

Table 3. Summary of previous skin hazard designations for TML

Organization Skin hazard designation 

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

OSHA [2013]*[skin]: Potential for dermal absorption

ACGIH [2001] [skin]: Potential for dermal 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

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.

*Akatsuka 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: 01-23-15.

†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.

*EC (European Commission) [2010]. Tetramethyllead. In: EINICS (European Inventory of Existing 

Commercial Chemical Substances), http://ecb.jrc.it/esis/index.php?GENRE=CASNO&ENTREE=75-

74-1. 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.

*EC (European Commission) [ND]. Tetramethyl lead. In: EINICS (European Inventory of Existing 

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

*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.
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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.

*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.

*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]. Tetramethyl lead (as Pb). In: OSHA Occupational Chemical Database, 

http://www.osha.gov/chemicaldata/chemResult.html?recNo=597. Accessed: 01-25-13.

*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), http://www.epa.gov/ncea/iris/. Accessed: 01-23-15.
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information quality guidelines. It has not been formally disseminated by the National Institute for Occupational 

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policy.

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].
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.

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.
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.

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.

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) cm2360

Exposure time hour 8

Calculated skin dose mg 1.5527

Inhalation Dose

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

Inhalation volume m

3

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].
11

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=75741. Accessed: 01-23-15.