# 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 Healthii

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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. XXXiii

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## 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 potentiall y 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 con tact 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, t he 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 respo nses 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 deter mination 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 sup portive 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 ob jective, 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 Preventioniv

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- 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. 

## Contents

FOREWORD

................................ ................................ ................................ ................................ .............. III

ABBREVIATIONS

................................ ................................ ................................ ................................ ...... V

GLOSSARY

................................ ................................ ................................ ................................ .............. VII

ACKNOWLEDGMENTS

................................ ................................ ................................ ....................... VIII

1.0 INTRODUCTION

................................ ................................ ................................ ................................ .. 1

1.1 G ENERAL S UBSTANCE I NFORMATION :

................................ ................................ ................................ .. 1
1.2 P URPOSE

................................ ................................ ................................ ................................ ............... 1
1.3 O VERVIEW OF SK A SSIGNMENT

................................ ................................ ................................ ........... 2

2.0 SYSTEMIC TOXICIT Y FROM SKIN EXPOSURE (SK: SYS)

................................ ....................... 2

3.0 DIRECT EFFECTS O N SKIN (SK: DIR)

................................ ................................ ............................ 4

4.0 IMMUNE

- MEDIATED RESPONSES ( SK: SEN)

................................ ................................ .............. 4

5.0 SUMMARY

................................ ................................ ................................ ................................ ............. 4

REFERENCES

................................ ................................ ................................ ................................ ............. 6

APPENDIX: CALCULATION OF THE S I RATIO FOR HEPTACHL OR

................................ .......... 8

O VERVIEW

................................ ................................ ................................ ................................ .................. 8
C ALCULATION

................................ ................................ ................................ ................................ .......... 10

A PPENDIX R EFEREN CES

................................ ................................ ................................ ............................ 11v

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## Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists
ATSDR Agency for Toxic Substances and Disease Registry
CIB Current Intelligence Bulletin

cm 2 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
EC European Commission
GHS G lobally 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
k aq coefficient in the watery epidermal layer
k p skin permeation coefficient
k pol coefficient in the protein fraction of the stratum corneum
k ps c permeation coefficient in the lipid fraction of the stratum corneum

LD 50 d ose resulting in 50% mortality in the exposed population

LD Lo dermal lethal dose
LOAEL lowest

- observed

- adverse

- effect level log K OW base

- 10 logarithm of a substance’s octanol

– water partition

M molarity

m 3 cubic meter(s)

mg milligram(s) mg/cm 3 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 Oc cupational 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 notationvi

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. S W solubility in water
SYS skin notation indicating the potential for systemic toxicity follo wing exposure of

the skin
USEPA United States Environmental Protection Agencyvii

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## 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.

Cance r

— 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 carcino gen 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, oc curring at or near the point of contact with chemicals.

Immune

- mediated responses

— Responses mediated by the immune system, in cluding allergic

responses.

Sensitization

— A specific immune

- mediated response that develops following ex posure to a chemical, which, upon re

- exposure, can lead to allergic contact derma titis (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.viii

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- 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. 

## 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 con tribution 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.ix

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. 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 g iven 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, OH1

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- 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. 

## 1.0 Introduction

1.1 General Substance Information:

Chemical: Heptachlor
CAS No: 76

- 44

- 8 Molecular weight (

MW ): 373.4
Molecular formula: C 10 H 5 Cl 7 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
conduct ed 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 repro ductive 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.2

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. 

### 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 heptach lor 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 f

or 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 th e 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 appen dix

.

No estimate of the lethal dermal dose (LD Lo ) for humans has been identified. However, in rats, the reported dermal LD 50 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 LD 50 was greater than 2,000 mg/kg [Lehmann 1952]. However, Lehmann [1952] also reported an LD 50 of less than 20 mg/kg when
rabbits we re 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 LD 50 values reported for rats are at or
above the critical LD 50 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 repeat

dose (21

- day, 28

- day), subchronic (90

- day) or chronic (at least 12

- month) toxicity studies were3

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. 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 af ter 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 effec ts 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 carcinogenic ity 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 * fo r 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 = Intern ational 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 nonderm al (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 like ly to be absorbed through the skin, acute dermal toxicity studies in rats [Gaines 1960, 1969] 1 show that heptachlor can be absorbed through the skin and can be acutely toxic. Because the reported LD 50 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.

1 References in bold text indicate studies that serve as the basis of the SK assignments.4

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- 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. 

## 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, Deducti ve 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 t he 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, m urine 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 suf ficient 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 der mal 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 abs orbed 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 relatio nship 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 assess ments, 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 Chemi cals, is Acute Toxicity Category 3 (Hazard statement: Toxic in contact with the skin) [European Parliament 2008].5

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. 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 = Occupationa l Safety and Health Administration.
*Date accessed.6

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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 [Avail able 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, labelli ng 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

- 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. Acce ssed: 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 and7

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. Prevention, National Institute for Occupational Safety a nd 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. Na tional 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

- 15.8

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- 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: 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 dur ing 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 dat a 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 ( k p ) for the substance of interest, (2) estimating substance uptake by the skin and respiratory absorption routes, and (3) evaluating whether the substance poses a skin exposure hazard.

The algorithm is flexible in the data requirem ent 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 k p for the substance to describe the transdermal penetration rate of the substan ce [NIOSH 2009]. The k p , 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 par tition coefficient ( log K

OW ). In this example, k p is determined for a substance with use of Equation 1. A self

- consistent set of units must be used, such as outlined in Table A1. Other model

- based estimates of k p may also be used [NIOSH 2009].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 ( k p )

where k

psc is the permeation coefficient in the lipid fraction of the stratum corneum, k pol is the coefficient in the protein fraction of the stratum corneum, and k aq is the coefficient in the watery epidermal layer. These components are individually estimated by

log k psc = −1.326 + 0.6097 × log K
ow − 0.1786 × MW 0.5

k pol = 0.0001519 × MW −0.5

k aq = 2.5 × MW

−0.5

The second step is to calculate the biologic mass uptake of the substance from skin absorption (skin dose) and inhalation (inhalation dose) during the same period of exposure. The skin dose is calculated as a mathematical product of the k p , the water solub ility ( S

W ) 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
centi meters [cm 2 ]).

Equation 2: Determination of Skin Dose

Skin dose = k

p × S
w × Exposed skin surface area × Exposure time

= k p (cm/hour) × S
w (mg/cm 3 ) × 360 cm 2 × 8 hours

The inhalation dose (in mg) is derived on the basis of the occupational exposure limit (OEL) of the
substance

— if the OEL is 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 (m 3 ) 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/m 3 ) × 10 m 3 × 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates ( 1 ) the significanc e 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( k psc ) cm/hour 0.0876 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hour 7.8617 × 10 - 6
Permeation coefficient of the watery epidermal layer ( k aq ) cm/hour 0.1239 Molecular weight ( MW

) * amu 373.32
Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None 6.1 Calculated skin permeation coefficient ( k p ) cm/hour 0.0523
Skin dose
Water solubility ( S w ) * mg/cm 3 1.8 × 10 - 3
Calculated skin permeation coefficient ( k p ) cm/hour 0.0523

Estimated skin surface area (palms of hand) cm 2 360 Exposure time hour 8
Calculated skin dose mg 0.0271
Inhalation Dose Occupational exposure limit (OEL) † mg/m 3 0.5

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 Insti tute 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.