# Skin Notation (SK) Profile

Catechol

[CAS No. 120

- 80

- 9]

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:Catechol. 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 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 system ic 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 H ealth (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 notation s (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 poten tial 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 propertie s 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 catechol

. 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, t his 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 develo ped 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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## 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 FOR C ATECHOL

................................ ................................ ................................ . 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)

................................ ................................ ............................. 5

5.0 SUMMARY

................................ ................................ ................................ ................................ ............................ 5

REFERENCES

................................ ................................ ................................ ................................ ............................ 7

APPENDIX: CALCULATIO N OF THE SI RATIO FO R CATECHOL

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

O VERVIEW

................................ ................................ ................................ ................................ ............................... 10
C ALCULATION

................................ ................................ ................................ ................................ ......................... 12
A PPENDIX R EFERENCES

................................ ................................ ................................ ................................ ........... 13v

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## Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists
ATSDR Agency for Toxic Substances and Disease Registry

BaP benzo[a]pyrene

BaP

- 7,8

- diol 7,8

- dihydroxy

- 7,8

- dihydrobenzo[a]pyrene
CIB Current Intelligence Bulletin

cm 2 square d centimeter(s)
cm/hr centimeter(s) per hour
cm/s centimeter(s) per second

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
GPMT guinea pig maximization test
hr hour(s)
IARC International Agency for Research on Cancer
IPCS International Program for Chemical Safety (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 psc 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
LLNA local lymph node assay
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 2 milligram(s) per square centimeter mg/kg milligram(s) per kilogram body weight mg/m 3 milligram(s) per cubic meter

mL milliliter(s) 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 limitvi

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ppm parts per million

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 s kin notation
S W solubility in water
SYS skin notation indicating the potential for systemic toxicity following exposure of

the skin
USEPA United States Environmental Protection Agency μg/cm 2 /hr microgram(s) per square centimeter per hourvii

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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 o f 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 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 contac t

— 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, u pon 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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## 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, Stacey Anderson, Ph.D., and Lore n Tapp, M.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 th is 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.

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.
Cha rles L. Geraci, Ph.D. Thomas J. Lentz, Ph.D. Richard Niemeier, Ph.D. Ralph Zumwalde, M.Sc.

Health Effects Laboratory Division H. Fredrick Frasch, Ph.D. Michael Luster, Ph.D. Anna Shvedova, Ph.D. Paul Siegel, Ph.D. Berran Yucesoy, 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 Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. National Personal Protective Technology Laboratory Heinz Ahlers, J.D., 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 Heal th 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, Clevel and, OH1

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional 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: Catechol
CAS No: 120

- 80

- 9 Molecular weight (

MW ): 110.1
Molecular formula: C 6 H 4 (OH) 2 Structural formula:

Synonyms: 1,2

- Benzenediol; o

- Benzenediol; 1,2

- Dihyroxybenzene; Pyrocatechol; Pyrocatechin; o

Dihydroxybenzene; 2

- Hydroxyphenol

Uses: Catechol is used primarily as an antioxidant in rubber, dye fa t, and oil industries and is used in pesticides, pharmaceutical ingredients, and aroma chemicals [ACGIH 2001].



### 1.2 Purpose

This skin notation profile presents ( 1 ) a brief summary of epidemiological and toxicological data
associated with skin contact with catechol and ( 2 ) the rationale behind the hazard

- specific skin notation (SK) assignment for catechol. 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 catechol and the potential for direct skin injuries
from catechol. A literature s earch was conducted through February 2013 to identify catechol toxicokinetics, acute toxicity, repeated

- dose systemic toxicity, carcinogenicity , biological system/function

– specific effects (including reproductive and developmental effects and
immunotoxicit y), 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
catechol.2

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional 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 for Catechol

Catechol 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 catechol : SK: SYS

DIR(IRR)

- SEN

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

Table 1. Summary of the SK assignment for catechol

Skin Notation Critical Effect Available Data
SK: SYS Acute toxicity Limited animal data SK: DIR(IRR) Skin irritancy; skin

depigmentation Sufficient animal data

SK:SEN Skin allergy Limited human data



## 2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

There were no in vivo toxicokinetic studies of humans or animals that evaluated the degree of skin absorption of catechol from dermal exposure that were identified. Rhodia Incorporated [2005] investigated the in vitro percutaneous penetration of [ 14 C]

- labeled catechol through human skin

mem branes. When an aqueous solution was applied at a concentration of 1 milligram per cubic centimeter (mg/cm 3 ), corresponding to an area concentration of 0.1 mg/cm 3 , the author reported that 0.04% and 0.22% of the applied dose penetrated through the skin mem brane within 10 and 60 minutes, respectively [Rhodia Incorporated 2005]. Within 24 hours, 26.65% of the applied dose penetrated through the membrane [Rhodia Incorporated 2005]. Rhodia Incorporated [2005] also reported a penetration rate of 1.425 micrograms per square centimeter per hour (μg/cm 2 /hr) after a lag time of 6 hours. In that study, the permeability constant, k p , was reported as 1.430 x 10 - 3 cm/hr [Rhodia Incorporated 2005]. This k p is greater than the value of 0.001 cm/hr that identifies a chemica l as readily absorbed by the skin [NIOSH 2009]; therefore, catechol is considered to be absorbed through the skin via dermal exposure. The potential of catechol to pose a skin absorption hazard was also evaluated, with use of a predictive algorithm for est imating 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 refer ence occupational exposure limit. On the basis of this algorithm, a ratio of the skin dose to the inhalation dose (SI ratio) of 17.9 was calculated for catechol. An SI ratio of ≥0.1 indicates that skin absorption may significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore catechol 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.3

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 Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. N o estimat e of the human dermal lethal dose (LD Lo ) of catechol has been reported in the literature. A
dermal LD 50 ( the dose resulting in 50% mortality in the exposed population) value of 800 milligrams per kilogram body weight (mg/kg) in rabbits was reported [ Flickinger 1976]. Because the reported acute dermal LD 50 value is lower than the critical dermal LD 50 value of 2,000 mg/kg that identifies chemicals with the potential for acute dermal toxicity [NIOSH 2009], catechol is considered acutely toxic following d ermal exposure.

No epidemiological or occupational exposure studies of humans and no repeated

- dose, subchronic, or chronic exposure studies in animals have evaluated the potential of catechol to cause systemic effects following dermal exposure. In additio n, no standard toxicity or specialty studies evaluating biological system/function

– specific effects (including reproductive and developmental effects and immunotoxicity) following dermal exposure to catechol were identified in the literature.

No epidemio logical studies or standard animal bioassays have evaluated the carcinogenic potential of
catechol. In two

- stage carcinogenicity studies in mice, topically applied catechol did not exhibit tumor

promoting activity with benzo[a]pyrene (BaP) as an initiator [Van Duuren and Goldschmidt 1976], but

co

- application of the substance with the racemic mixture or either of the enantiomers of 7,8

- dihydroxy

7,8

- dihydrobenzo[a]pyrene (BaP

- 7,8

- diol) increased the tumor

- initiating activity of racemic BaP

- 7,8

- diol [Melikian et al. 1989]. However, it had no statistically significant effect on the tumor

- initiating activity of the (+)

- or (

- )

- enantiomers in mouse skin [Melikian et al. 1989]. Catechol was a potent co

carcinogen when tested for co

- carcinogenic activity by dermal application at doses of 0.01 to 2 mg to mouse skin three times per week with a low dose of BaP (3 μg) for 48 to 59 weeks [Van Duuren and Goldschmidt 1976; Hecht et al. 1982; Melikian et al. 1989] or with racemic and enantiomeric BaP

- 7,8

- diols for 48 weeks [Melikian et al. 1989]. Co

- carcinogenesis is a process in which a co

- carcinogen, applied repeatedly (in this case, on mouse skin) with low doses of a known carcinogen such as benzo[a]pyrene (BaP), enhances considerably the carcinogenic activity of the carc inogen [Van Duuren and Goldschmidt 1976]. Although these studies indicate a co

- carcinogenetic effect of catechol, the lack of data precludes adequate evaluation of the underlying mode of action or of whether catechol itself has carcinogenic potential follo wing skin contact. Table 2 summarizes carcinogenic designations of multiple governmental and nongovernmental organizations for catechol.4

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 Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. Table 2. Summary of the carcinogenic designations * for catechol by governmental and nongovernmental organizations

Organization Carcinogenic Designation NIOSH [2005] No designation NTP [2014] No designation USEPA [2015] No designation European Parliament 2008] No GHS designation IARC [2012] Group 2B: Possibly carcinogenic to humans EC [2013] † No designation ACGIH [2001] Group A3: Confirmed animal carcinogen of
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.

Al though no in vivo toxicokinetic data have been reported reflecting the degree of skin absorption following dermal exposure, an in vitro study [Rhodia 2005] 1 , supported by a model prediction and acute toxicity data from rabbits [Flickinger 1976] , indicate t hat catechol has the potential to be absorbed through the skin and can cause acute toxicity following dermal exposure. No epidemiological or case studies of humans and no repeated

- dose, subchronic, or chronic exposure studies or specialty studies of
animal s have investigated the potential of catechol to cause systemic effects following dermal exposure. Therefore, on the basis of this assessment, catechol is assigned the SK:SYS notation.



## 3.0 Direct Effects on Skin (SK: DIR)

No human or animal in vivo data on the skin corrosivity of catechol and no data from in vitro tests for corrosivity in human or animal skin models or in vitro tests for skin integrity in cadaver skin were found in the literature. O’Malley et al. [1988] reported the finding of vitil igo (an acquired skin disease characterized by patches of unpigmented skin, often surrounded by a heavily pigmented border) in five of 200 workers who handled catecholic substances on a regular basis; however the authors did not find any evidence of para

- s ubstituted phenolic or catecholic derivatives in the rubber formulations and adhesive sprays, indicating that another substance caused the occupational cases of vitiligo. Gellin et al. [1979] noted moderate depigmentation following application of 5 and 10% of catechol to the clipped dorsal skin of guinea pigs. These authors also noted primary skin irritation following application of catechol [Gellin et al. 1979]. Bleehen et al. [1968] applied 1% to 10% catechol in creams once daily, five times a week, to wa x

- epilated skin of the back and the unepilated skin of the ear of black guinea pigs for up to 1 month. Catechol did not depigment or irritate rabbit skin at a concentration of 1.0%, but

at 3.0% it induced depigmentation, and very strong depigmentation was induced at 7% to 10%.

1 References in bold text indicate studies that served as the basis of the SK assignment.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 Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. Flickinger et al. [1976] reported moderate erythema and slight edema on intact skin and necrosis on abraded skin of rabbits after exposure to 500 mg/kg of catechol on the abdomen.

Sufficient data in animals [Bleehen et al. 1968; Flic kinger et al. 1976; Gellin et al. 1979] are available to indicate that repeated application of catechol is irritating to the skin and generates skin depigmentation. Therefore, the notation SK: DIR(IRR) is assigned to catechol.



## 4.0 Immune

- mediated Responses (SK: SEN)

A limited number of diagnostic patch tests have investigated the skin sensitization potential of catechol
in humans. Morelli et al. [1989] described a patient occupationally exposed to catechol as a radiographer, who presented with contact dermatitis of the hands. Patch tests showed strong positive reactions to 0.1%, 0.5%, and 2% catechol [Morelli et al. 1989]. In a nonoccupati onal exposure case, a patient presented with acute contact dermatitis around the eyes from treatment of the eyelashes and eyebrows with a permanent dye cream and had positive reactions when patch

- tested with 0.1% to 2% catechol [Andersen and Carlsen 1988]. Keil [1962] reported that persons sensitive to resorcinol have
mild cross

- reactions to catechol. No predictive tests in animals (for example, guinea pig maximization tests, murine local lymph node assays, or mouse ear swelling tests) or any other studies have evaluated the potential of the substance to cause skin sensitization.

A limited number of patch tests [ Keil 1962; Andersen and Carlsen 1988; Morelli et al. 1989 ] have indicated the potential of catechol to cause skin sensitization in humans. Althoug h no predictive tests in animals have been reported, the notation SK: SEN is assigned to catechol on the basis of the limited
number of human cases identified.



## 5.0 Summary

No in vivo toxicokinetic data have been reported on the degree of skin absorption o f catechol via dermal exposure. However, the findings of an in vitro study [Rhodia 2005] , supported by a model prediction and acute toxicity data in rabbits [Flickinger 1976] , indicate catechol has the potential to be absorbed through the skin and can caus e acute toxicity following dermal exposure. No epidemiological or case studies of humans or repeated

- dose, subchronic, or chronic exposure studies or specialty studies of animals have investigated the potential of catechol to cause systemic effects via der mal exposure.
Suffi cient data are available in animals [ Bleehen et al. 1968; Flickinger et al. 1976; Gellin et al. 1979] to indicate that catechol has the potential to irritate and depigment the skin following repeated contact. No predictive tests have inv estigated the potential of catechol to cause skin sensitization in animals, but a limited number of case reports [ Keil 1962; Andersen and Carlsen 1988; Morelli et al. 1989 ] have indicated that catechol has the potential to cause skin sensitization. On the basis of the available information, a composite skin notation of SK: SYS

- DIR(IRR)

- SEN is assigned to catechol.

Table 3 summarizes the skin hazard designations for catechol previously issued by NIOSH and other organizations. The equivalent dermal designati ons for catechol, according to the Global Harmonization System (GHS) of Classification and Labelling of Chemicals, are Acute Toxicity Category 4 (Hazard6

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. statement: Harmful in contact with the skin), and Skin Irritation Category 2 (Hazard statement: Causes skin irritation) [ European Parliament 2008].

Table 3. Summary of the previously issued skin hazard designations for catechol

Organization Skin hazard designation NIOSH [2005] [skin]: Potential for dermal absorption; prevent skin contact OSHA [2015] * None ACGIH [2001] [skin]: Based on dermal studies of mice and data on dermally

exposed workers with symptoms of illness resembling those associated with phenol as well as central nervous system effects EC [2013] * R21: Harmful if in contact with skin

R38: Irritating to 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.7

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## References

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

*ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. TLVs and BEIs Based on the Documentation of threshold limit values for chemical substances and physical agents and biological expsoure indices. Cincinnati, OH: American Conference o f Governmental and Industrial Hygienists.

*Andersen KE, Carlsen L [1988]. Pyrocatechol contact allergy from a permanent cream dye for eyelashes and eyebrows. Contact Dermatitis 18 (5):306

– 307.

†Baer H, Dawson CR, Byck JS, Kurtz AP [1970]. The immunochemis try of immune tolerance: II. The relationship of chemical structure to the induction of immune tolerance to catechols. J Immunol.
104 (1):178

– 184.

*Bleehen SS, Pathak MA, Hori Y, Fitzpatrick TB [1968]. Depigmentation of skin with 4

- isopropylcatechol mercap toamines, and other compounds. J Invest Dermatol 50 (2):103

– 117.

†Elder R [1986]. Final report on the safety assessment of hydroquinone and pyrocatechol. J Am Coll
Toxicol 15 :123

– 165.

* EC (European Commission) [ND]. EINECS (European INventory of Existing Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 09

- 03

- 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://eur

lex.europa.eu/LexUriServ/LexUriServ.do ?uri=OJ:L:2008:353:0001:1355:EN:PDF. Accessed: 01

- 29

- 15

.

*Flickinger CW [1976]. The benzenediols: catechol, resorcinol and hydroquinone. a review of the industrial toxicology and current industrial exposure limits. Am Ind Hyg Assoc J 37 :596

– 607.

†Forsyt h WGC, Quesnel VA [1957]. Intermediated in the enzymic oxidation of catechol. Biochem Biophys Acta 25 :155

– 160.

*Gellin GA, Maibach HI, Misiaszek MH, Ring M [1979]. Detection of environmental depigmenting
substances. Contact Dermatitis 5 (4): 201

- 213.

†Gel lin GA, Maibach HI [1983]. Detection of environmental depigmenting chemicals. In: Marzulli FN, Maibach HI, eds. Dermatotoxicology, 2nd Ed. New York, NY: Hemisphere Publishing, pp. 443

– 459.8

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. *Hecht SS, Carmella S, Furuya K, LaVoie EJ [1982]. Polynuclear aro matic hydrocarbons and catechol derivatives as potential factors in digestive tract carcinogenesis. In: Environmental mutagens and carcinogens. Proceedings of the 3rd International Conference on Environmental Mutagens. Tokyo: Mishima and Kyoto, pp. 545

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†Hirosawa I, Asaeda G, Arizono H, et al. [1976]. Effects of catechol on human subjects: a field study. Int Arch Occup Environ Health 37 :107

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*IARC (International Agency for Research on Cancer) [2012]. Agents reviewed by the IARC monographs. In: IAR C monographs on the evaluation of carcinogenic risks to humans, http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed: 01

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† Kavlock RJ [1990]. Structure

- activity relationships in the developmental toxicity of substituted phenols: in vivo effects. Teratology 41 (l):43

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*Keil H [1962]. Group reactions in contact dermatitis due to resorcinol. Arch Dermatol 86 :212

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†Melikian AA, Leszcynska JM, Hecht SS, Hoffman D [1986]. Effects of the co

- carcinogen catechol on benzo[a]pyrene metabolism and DNA adduct formation in mouse skin. Carcinogenesis 7 (1):9

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*Melikian AA, Jordan, KG, Braley J, Rigotty J, Meschter CL, Hecht SS, Hoffman D [1989]. Effects of catechol on the induction of tumors in mouse skin by 7,8

- dihydroxy

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†Melikian AA, Bagheri K, Goldin BF, Hoffman D [1989]. Catechol

- induced alterations in metabolic activation and binding of enantiometric and racemic 7,8

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- 7,8

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in mouse skin. Carcinogenesis 10 (10):1863

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†Melikian AA, Bagheri K, Hoffman D [1990]. Oxidation and DNA binding of (+)

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*Mo relli R, Piancastelli E, Lanzarini M, Restani S [1989]. Occupational contact dermatitis from pyrocatechol. Contact Dermatitis 21 :201

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†Nakamura S [1981]. The effects of oral administration of catechol in mice. Osaka

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*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

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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 Occupa tional Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. *NIOSH [2009]. Current intelligence bulletin 61: a strategy f or 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.
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†Yonemoto K, Gellin GA, Epstein WL, Fukuyama K [1983]. Glutathione reductase activity in skin exposed to 4

- tertiary butyl catechol. Int Arch Occup Environ Health 51 :341

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupa tional 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 Catechol

This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for catechol. Although the SI rat io 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 c an 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 foll ows:

(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 ( 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 requirement and can operate entirely on the basis of the physicochemical p roperties 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 coefficien t 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 substance [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 partition coefficient ( log K

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

- consistent set of units must be used, such as centimeters per hour (cm/hr), outlined in Table A1. Other model

- based
estimates of k

p may also be used [NIOSH 2009].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 Occupa tional 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 C oefficient ( 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/hr) × S
w (mg/cm 3 ) × 360 cm 2 × 8 hr

The inhalation dose (in mg) is derived on the basis of the occupational exposure li mit (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 mete rs (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 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.12

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 Occupa tional 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 catechol. The calculated SI ratio was 17.9. On the basis of these results, catechol is predicted to represent a skin absorption hazard.

Table A1. Summ ary of Data used to Calculate the SI Ratio for catechol

Variables Used in Calculation Units Value Skin permeation coefficient Permeation coefficient of stratum corneum lipid path( k psc ) cm/hr 0.0309 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hr 1.4477 × 10 - 5
Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.23826 Molecular weight ( MW

) * amu 110.1
Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None 0.88 Calculated skin permeation coefficient ( k p ) cm/hr 0.00216
Skin dose
Water solubility ( S w ) * mg/cm 3 430 Calculated skin permeation coefficient ( k p ) cm/hr 0.00216 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8
Calculated skin dose mg 2680
Inhalation Dose Occupational exposure limit (OEL) † mg/m 3 20

Inhalation volume m 3 10 Retention factor (RF) None 0.75

Inhalation dose mg 150
Skin dose

– to

– inhalation dose (SI) ratio None 17.9

* Variables identified from SRC [ND].
† The OEL used in calculation of the SI ratio for catechol was the NIOSH recommended exposure limit (REL) [NIOSH 2005].13

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 Occupa tional 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

- 29

- 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

- 29

- 15.

SRC [2009]. Interactive PhysProp database demo, http://esc.syrres.com/fatepointer/webprop.asp?CAS =120809 . Accessed: 01

- 29

- 15.