Skin Notation (SK) Profile

Heptachlor

[CAS No. 76-44-8]

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:Heptachlor. 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 heptachlor. 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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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 ............................................................................................................................................. 6

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

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

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

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

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

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 

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/cm3 milligram(s) per cubic centimeter

mg/kg milligram(s) per kilogram body weight

mL/kg milliliter(s) per kilogram body weight

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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agency determination or policy.

SW solubility in water

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

the skin

USEPA United States Environmental Protection Agency 
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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.

Glossary 

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

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

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

Cancer—Any one of a group of diseases that occurs when cells in the body become abnormal 

and grow or multiply out of control. 

Contaminant—A chemical that is (1) unintentionally present within a neat substance or mixture 

at a concentration less than 1.0% or (2) recognized as a potential carcinogen and present within a 

neat substance or mixture at a concentration less than 0.1%. 

Cutaneous (or percutaneous)—Referring to the skin (or through the skin). 

Dermal—Referring to the skin. 

Dermal contact—Contact with (touching) the skin. 

Direct effects—Localized, non-immune-mediated adverse health effects on the skin, including 

corrosion, primary irritation, changes in skin pigmentation, and reduction/disruption of the skin 

barrier integrity, occurring at or near the point of contact with chemicals. 

Immune-mediated responses—Responses mediated by the immune system, including allergic 

responses. 

Sensitization—A specific immune-mediated response that develops following exposure to a 

chemical, which, upon re-exposure, can lead to allergic contact dermatitis (ACD) or other 

immune-mediated diseases such as asthma, depending on the site and route of re-exposure. 

Substance—A chemical. 

Systemic effects—Systemic toxicity associated with skin absorption of chemicals after exposure 

of the skin.
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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, H. Fredrick Frasch, Ph.D., and Vic Johnson, 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.

Aaron Sussell, Ph.D.

Loren Tapp, M.D. 

Education and Information Division 

Devin Baker, M.Ed.

Charles L. Geraci, Ph.D.

Thomas J. Lentz, Ph.D.

Richard Niemeier, Ph.D.

Sudha Pandalai. M.D., Ph.D. 
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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.

Health Effects Laboratory Division

Stacey Anderson, Ph.D. 

Michael Luster, Ph.D. 

Paul Siegel, Ph.D.

Anna Shvedova, Ph.D.

Berran Yucesoy, Ph.D. 

National Personal Protection Technology Laboratory

Heinz Ahlers, M.Sc.

Angie Shepherd

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

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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1.0 Introduction 

1.1 General Substance Information: 

Chemical: Heptachlor

CAS No: 76-44-8

Molecular weight (MW): 373.4

Molecular formula: C10H5Cl7

Structural formula:

Synonyms: 1,4,5,6,7,8,8-Heptachloro-3a,4,7,7a-tetrahydro-4,7-methanoindene, 

Dicyclopentadiene, 3,4,5,6,7,8,8a-heptachloro-, Heptachlorotetrahydro-4,7-methanoindene, 

heptachlorodicyclopentadiene, 3-chloro-chlordene

Uses: Heptachlor is an organochlorine pesticide that was used for killing insects in homes, in buildings, 

and on food crops, but was banned from this use in 1988 [ATSDR 2007]. However, heptachlor is still 

approved by EPA for killing fire ants that are in buried power transformers [ATSDR 2007].

1.2 Purpose 

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

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

notation (SK) assignment for heptachlor. 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 heptachlor. A literature search was 

conducted through February 2013 to identify information on heptachlor, 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 

heptachlor. 
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1.3 Overview of SK Assignment

Heptachlor 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 heptachlor: SK: SYS.

Table 1 provides an overview of the critical effects and data used to develop the SK assignment for 

heptachlor. 

Table 1. Summary of the SK Assignment for Heptachlor

Skin Notation Critical Effect Available Data

SK: SYS Acute toxicity Limited animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

No specific animal or human toxicokinetic data were identified that estimated the degree of absorption 

of heptachlor following dermal exposure. A human study was identified where dermal exposure of 29 

applicators was evaluated by attaching gauze pads to outer and inner clothing at selected body regions 

[Kamble et al. 1992]. Hands had the highest amounts of heptachlor that was recovered, followed by 

ankles and the forearms [Kamble et al. 1992]. Total exposure to heptachlor during subterranean termite 

treatments was 1.8 micrograms per kilograms per hour (μg/kg/hr). In the absence of quantitative 

absorption data, the potential of heptachlor 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 

0.007 was calculated for heptachlor. An SI ratio of ≥0.1 indicates that skin absorption may significantly 

contribute to the overall body burden of a substance [NIOSH 2009]; therefore, heptachlor 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 estimate of the lethal dermal dose (LDLo) for humans has been identified. However, in rats, the 

reported dermal LD50 value (the dose resulting in 50% mortality in the exposed animals) ranged from 

195 to 250 milligrams per kilogram body weight (mg/kg) in male and female rats, respectively [Gaines 

1960, 1969]. When rabbits were exposed to heptachlor in powder form, the LD50 was greater than 2,000 

mg/kg [Lehmann 1952]. However, Lehmann [1952] also reported an LD50 of less than 20 mg/kg when 

rabbits were exposed to heptachlor in a solution of dimethyl phthalate, indicating that heptachlor may be 

more toxic in solution than in powder form. Because the dermal LD50 values reported for rats are at or 

above the critical LD50 value of 200 mg/kg body weight that identifies chemical substances with 

potential to be acutely fatal [NIOSH 2009], heptachlor is considered systemically available and acutely 

toxic by the dermal route.

No epidemiological studies, clinical case histories, or occupational exposure studies or animal repeatdose (21-day, 28-day), subchronic (90-day) or chronic (at least 12-month) toxicity studies were 
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identified for heptachlor following dermal exposure. Absence of these studies precludes detailed 

evaluation of the potential of heptachlor to cause systemic effects and the dermal dose levels at which 

these effects can be observed. A study was identified where rabbits received daily application to 

heptachlor for 14 days [Lehmann 1952]. There were no survivors after 14 doses when rabbits were 

given 20 mg/kg of heptachlor in a solution of dimethyl phthalate [Lehmann 1952]. No standard toxicity 

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

developmental effects and immunotoxicity) were identified for heptachlor following dermal exposure.

No epidemiological studies or standard bioassays that evaluated the carcinogenic potential of heptachlor 

following dermal exposure were identified. However, the carcinogenicity of the chemical has been 

evaluated following exposure via non-dermal routes. Table 2 summarizes carcinogenic designations of 

multiple governmental and nongovernmental organizations for heptachlor. 

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

and nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] Potential occupational carcinogen

NTP [2014] No designation

USEPA [2014] B2; probable human carcinogen 

European Parliament [2008] GHS Carcinogenicity Category 2: Suspected of causing 

cancer

IARC [2012] Group 2B: Possibly carcinogenic to humans

EC [2013]† R40: Limited evidence of a carcinogenic effect

ACGIH [2001] A3: Confirmed animal carcinogen with unknown 

relevance to humans

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.

Dermal absorption studies were not identified for heptachlor. Although a mathematical model predicted 

that the chemical is not likely to be absorbed through the skin, acute dermal toxicity studies in rats 

[Gaines 1960, 1969]1show that heptachlor can be absorbed through the skin and can be acutely toxic. 

Because the reported LD50 values were at or below the cutoff value of 200 mg/kg body weight that 

indicates a substance is acutely fatal, heptachlor 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 the corrosivity of heptachlor 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 

primary skin irritation tests were identified. The structure-activity relationship model, Deductive 

Estimation of Risk from Existing Knowledge (DEREK), predicted heptachlor to be negative for skin 

irritation. Absence of these studies precludes detailed evaluation of the potential of heptachlor to be 

corrosive or irritating to the skin. Therefore, on the basis of the data for this assessment, heptachlor is 

not assigned the SK: DIR (IRR) notation.

4.0 Immune-mediated Responses (SK: SEN)

No human diagnostic patch tests or predictive tests in animals (i.e., guinea pig maximization tests, 

Buehler tests, murine local lymph node assays, or mouse ear swelling tests) were identified that 

evaluated the potential of heptachlor to be a skin sensitizer. DEREK predicted heptachlor to be a 

plausible skin sensitizer. Although, model predictions are not considered sufficient to assign a SK: SEN 

notation, they highlight testing for this endpoint as an important data gap. Therefore, on the basis of the 

data for this assessment, heptachlor is not assigned the SK: SEN notation. 

5.0 Summary

No quantitative data on the dermal absorption kinetics of heptachlor were identified. A mathematical 

model predicted heptachlor is not likely to be absorbed through the skin. However, acute toxicity studies 

in rats [Gaines 1960, 1969] showed that the chemical has the potential to be absorbed through the skin, 

systemically available, and toxic following acute dermal exposure. No studies were identified that 

evaluated the potential of heptachlor to be corrosive or irritating to the skin or be a skin sensitizer. A 

structure-activity relationship model predicted heptachlor to be negative for skin irritation, but a 

plausible skin sensitizer. Skin sensitization potential predicted by the model highlights testing for this 

endpoint as an important data gap. Therefore, on the basis of these assessments, heptachlor is assigned a 

composite skin notation of SK: SYS. 

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

organizations. The equivalent dermal designation for heptachlor, according to the Global Harmonization 

System (GHS) of Classification and Labelling of Chemicals, is Acute Toxicity Category 3 (Hazard 

statement: Toxic in contact with the skin) [European Parliament 2008]. 
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Table 3. Summary of the previously issued skin hazard designations for heptachlor

Organization Skin hazard designation 

NIOSH [2005] [skin]: Potential for dermal absorption; prevent skin contact

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

ACGIH [2001] [skin]: based on systemic toxicity and mortality in animals following 

dermal application

EC [2013]* R24 - Toxic in contact with skin

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, 

Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = 

Occupational Safety and Health Administration.

*Date accessed.
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References

Note: Asterisks (*) denote sources cited in text; daggers (†) denote additional resources.

*ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. Heptachlor and 

heptachlor epoxide. In: Documentation of threshold limit values and biological exposure indices 7th ed., 

Vol. 2. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*ATSDR [2007]. ToxFAQs for Heptachlor and Heptachlor Epoxide [Available at: 

http://www.atsdr.cdc.gov/toxfaqs/tf.asp?id=744&tid=135]. Accessed: 05-04-13.

*EC (European Commission) [ND]. Heptachlor. In: EINICS (European Inventory of Exisiting 

Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 05-08-13.

*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, labelling 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://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF. Accessed: 01-28-15. 

*Gaines TB [1960]. Acute toxicity to rats. Toxicol Appl Pharmacol 2: 88-99.

*Gaines TB [1969]. Acute toxicity of pesticides. Toxicol Appl Pharmacol 14:515–534. 

*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: 01-28-15.

*Kamble ST, Ogg CL, Gold RE, Vance AD [1992]. Exposure of applicators and residents to chlordane 

and heptachlor when used for subterranean termite control. Arch Enviorn Contam Toxicol. 22(3): 253-

259.

*Lehmann AJ [1952]. Chemicals in foods: A report to the Association of Food and Drug Officials on 

current developments, Part II, Pesticides, Sec. II, Dermal Toxicity. Assoc. Food Drug Off U.S. Q. Bull. 

16:3-9.

*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: 01-28-15.

*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 
7

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

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policy.

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: 01-28-15.

*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: 01-28-15.

*OSHA [ND]. Heptachlor. IN: OSHA Occupational Chemical Database, 

https://www.osha.gov/chemicaldata/chemResult.html?recNo=618. Accessed: 01-28-15.

†USEPA (United States Environmental Protection Agency) [1992]. Reregistration Eligibility Decision 

(RED) for Heptachlor. Case: 0175. Office of Pesticides and Toxic Substances (7508P), 

http://www.epa.gov/pesticides/reregistration/REDs/old_reds/heptachlor.pdf. Accessed: 01-28-15.

*USEPA [2014]. Integrated Risk Information System. In: Integrated Risk Information System, 

http://www.epa.gov/iris/subst/0243.htm. Accessed: 01-28-15.
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Appendix: Calculation of the SI Ratio for Heptachlor

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

heptachlor. 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 

heptachlor. The calculated SI ratio was 0.0007. On the basis of these results, heptachlor is not predicted 

to represent a skin absorption hazard.

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

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hour 0.0876

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hour 7.8617 × 10-6

Permeation coefficient of the watery epidermal layer (kaq) cm/hour 0.1239

Molecular weight (MW)

*

amu 373.32

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

* None 6.1

Calculated skin permeation coefficient (kp) cm/hour 0.0523

Skin dose

Water solubility (Sw)

* mg/cm3

1.8 × 10-3

Calculated skin permeation coefficient (kp) cm/hour 0.0523

Estimated skin surface area (palms of hand) cm2360

Exposure time hour 8

Calculated skin dose mg 0.0271

Inhalation Dose

Occupational exposure limit (OEL)† mg/m30.5

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 375

Skin dose–to–inhalation dose (SI) ratio None 0.0007

*

Variables identified from SRC [ND].

†

The OEL used in calculation of the SI ratio for heptachlor 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: 01-28-15.

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: 01-28-15.

SRC [2009]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.asp?CAS=76448. Accessed: 01-28-15.