NIOSH Skin Notation Profile

IDSK

[SK]

SYS

DIR

DIR (IRR)

SYS (FATAL)

DIR (COR)

SEN

Cyclohexanone

Centers for Disease Control

and Prevention

National Institute for Occupational 

Safety and Health
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NIOSH Skin Notation Profile

Cyclohexanone

Naomi L. Hudson

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
ii Skin Notation Profile | Cyclohexanone

This document is in the public domain and may be freely 

copied or reprinted.

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Suggested Citation

NIOSH [2020]. NIOSH skin notation profile: cyclohexanone. By Hudson NL. 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. 

2021-103.

DHHS (NIOSH) Publication No. 2021-103

DOI: https://doi.org/10.26616/NIOSHPUB2021103

October 2020
Skin Notation Profile | Cyclohexanone iii

Foreword

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

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

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

spectrum of adverse health effects ranging from localized damage (such as irritant contact dermatitis and corrosion) to induction of immune-mediated responses (such as allergic contact 

dermatitis and pulmonary responses) or systemic toxicity (such as neurotoxicity and hepatotoxicity). Understanding the hazards related to skin contact with chemicals is a critical component 

of modern occupational safety and health programs.

In 2009, the National Institute for Occupational Safety and Health (NIOSH) published Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations [NIOSH 

2009-147]. This document provides the scientific rationale and framework for the assignment 

of multiple hazard-specific skin notations (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 (such as skin permeation) by means of analytical or 

numerical methods.

This Skin Notation Profile provides the SK assignments and supportive data for cyclohexanone. 

In particular, this document evaluates and summarizes the literature describing the hazard 

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

outlined in CIB 61. In meeting this objective, this Skin Notation Profile intends to inform the 

audience—mostly occupational health practitioners, researchers, policy- and decision-makers, 

employers, and workers in potentially hazardous workplaces—so that improved risk-management practices may be developed to better protect workers from the risks of skin contact with 

the chemicals of interest.

John Howard, M.D.

Director, National Institute for

Occupational Safety and Health

Centers for Disease Control and Prevention
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Skin Notation Profile | Cyclohexanone v

Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.1 General Substance Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.2 Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.3 Overview of SK Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

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

3 Direct Effects on Skin (SK: DIR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

4 Immune-mediated Responses (SK: SEN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Appendix: Calculation of the SI Ratio for Cyclohexanone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Appendix References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
vi Skin Notation Profile | Cyclohexanone

Abbreviations

ACGIH® American Conference of Governmental Industrial Hygienists 

AMU atomic mass unit

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm2 square centimeter(s)

cm/hr centimeter(s) per hour

cm/s centimeter(s) per second

COR subnotation of SK: COR indicating the potential for a chemical to be corrosive 

to the skin following exposure 

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

FATAL subnotation of SK: SYS, indicating the potential for the chemical to be fatal 

during dermal absorption

g gram(s)

g/L gram(s)/liter

GHS Globally Harmonized System of Classification and Labelling of Chemicals

GPMT guinea pig maximization test

hr hour(s)

IARC International Agency for Research on Cancer

ID(SK) skin notation indicating that a chemical has been evaluated, but insufficient 

data exist to accurately assess the hazards of skin exposure

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

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

LLNA local lymph node assay

LOAEL lowest-observed-adverse-effect level 

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

M molarity

m3 cubic meter(s)

MEST mouse ear swelling test

mg milligram(s)

mg/cm2/hr milligram(s) per square centimeter per hour

mg/kg milligram(s) per kilogram body weight
Skin Notation Profile | Cyclohexanone vii

mg/m3 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 limit

OSHA Occupational Safety and Health Administration

ppm parts per million

PVC polyvinyl chloride

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

SK skin notation indicating that the reviewed data did not identify a health risk 

associated with skin exposure

SW solubility in water

SYS skin notation indicating the potential for systemic toxicity following exposure 

of the skin

US EPA United States Environmental Protection Agency 

μg microgram(s)

μg/cm2 microgram(s) per square centimeter

μg/cm2/hr microgram(s) per square centimeter per hour

μL microliter(s)

μmol micromole(s)

w/v weight/volume
viii Skin Notation Profile | Cyclohexanone

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 occur when cells in the body become abnormal 

and grow or multiply out of control.

Contaminant—A chemical that is (1) unintentionally present within a neat substance or mixture at a concentration less than 1.0% or (2) recognized as a potential carcinogen and present 

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

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

Dermal—Referring to the skin.

Dermal contact—Contact with (touching) the skin.

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

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

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

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

responses.

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

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

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

Substance—A chemical.

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

of the skin.
Skin Notation Profile | Cyclohexanone ix

Acknowledgments

This document was developed by the Division of Science Integration (Paul Schulte, Ph.D., 

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

Special appreciation is expressed to the following individuals for serving as independent, 

external reviewers:

• Shane Que Hee, Ph.D., Professor, Environmental Health Sciences Director, UCLA Industrial Hygiene Program Director, UCLA Fielding School of Public Health, Los Angeles, CA

• M. Cecilia Aguila, D.V.M., Division of Human Food Safety, FDA, Center for Veterinary 

Medicine, Rockville, MD

Special appreciation is expressed to the following individuals for serving as internal reviewers 

by use of an Intergovernmental Personnel Agreement:

• Youcheng Liu, M.D., Sc.D., M.P.H., M.S., University of North Texas Health Science Center, 

Fort Worth, TX

• Ronald E. Baynes, D.V.M., Ph.D., College of Veterinary Medicine, North Carolina State 

University, Raleigh, NC

The following individuals contributed to the development or improvement of the skin notation 

profiles: 

• 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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Skin Notation Profile | Cyclohexanone 1

Cyclohexanone

1 Introduction

1.1 General Substance Information

Chemical: Cyclohexanone

CAS No: 108-94-1

Molecular weight (MW): 98.2

Molecular formula: C6H10O

Structural formula:

O

Image: National Center for Biotechnology Information [2020]

Synonyms: Anone; Cyclohexyl ketone; Pimelic 

ketone.

Uses: Cyclohexanone is an organic compound 

used as a solvent in multiple applications 

including metal degreasing; an estimated 1.1 

billion pounds (500 million kilograms) of the 

compound was used in 1994 [Bingham et al. 

2001].

1.2 Purpose

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological data associated with skin contact with 

cyclohexanone and (2) the rationale behind 

the hazard-specific skin notation (SK) assignment for cyclohexanone. 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 cyclohexanone. 

A search of all available relevant literature 

was conducted through January 2018 to identify information on cyclohexanone dermal 

absorption, 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 in 

humans, animals, or appropriate modeling 

systems that are relevant to assessing the 

effects of dermal exposure to cyclohexanone. 

The criteria for the search strategy, evaluation, and selection of data are described in 

Appendix E in the aforementioned CIB 61 

[NIOSH 2009].

1.3 Overview of SK Assignment

Cyclohexanone is potentially capable of causing 

numerous adverse health effects following skin 

contact. A critical review of available data has 

Table 1. Summary of the SK assignment for cyclohexanone

Skin notation Critical effect Available data

SK: DIR (COR) Skin irritation Sufficient animal data
2 Skin Notation Profile | Cyclohexanone

Cyclohexanone

resulted in the following SK assignment for 

cyclohexanone: SK: DIR (COR). Table 1 provides an overview of the critical effects and 

data used to develop the SK assignment for 

cyclohexanone.

2 Systemic Toxicity from Skin 

Exposure (SK: SYS)

Limited toxicokinetic data following dermal 

exposure to cyclohexanone were identified. 

Mraz et al. [1994] assessed the percutaneous 

absorption of cyclohexanone in an experiment 

in which three human volunteers immersed 

one hand in pure solvent for 30 minutes. 

These authors calculated the permeation rate 

of cyclohexanone through the skin to be 0.037 

to 0.069 (mean, 0.056) milligrams per square 

centimeter per hour (mg/cm2

/hr) [Mraz et al. 

1994]. Dennerlein et al. [2013] reported a mean 

penetration rate of 257.2-375.6 micrograms per 

square centimeter per hour (μg/cm2

/hr) (corresponding to 0.26-0.38 mg/cm2/hr) in excised 

abdominal human skin in exposure chambers 

treated with 50 microliters (μl) cyclohexanone 

for 4 hours. The potential of cyclohexanone to 

pose a skin absorption hazard was also evaluated 

using the NIOSH [2009] predictive algorithm 

for estimating and evaluating the health hazards 

of dermal exposure to chemical substances. 

Based on this algorithm, a ratio of the skin dose 

to the inhalation dose (SI ratio) of 0.24 was calculated for cyclohexanone. An SI ratio of ≥0.1 

indicates that skin absorption may significantly 

contribute to the overall body burden of a substance [NIOSH 2009]; therefore, cyclohexanone 

is considered to be absorbed through the skin 

following dermal exposure. Additional information on the SI ratio and the variables used in 

its calculation are included in the appendix.

No estimated dermal lethal dose (LDLo) for 

humans was identified. A dermal LD50 value 

(lethal doses in 50% of exposed animals) of 1 

milliliter per kilogram [mL/kg] (corresponding 

to 950 milligrams per kilogram [mg/kg]) has 

been reported in rabbits [Smyth et al. 1969; 

Union Carbide Corporation 1967]. Eastman 

Kodak Company [1978] and EI du Pont de 

Nemours and Company (DuPont) [1983a] 

reported dermal LD50 values of 10 to 20 mL/

kg (corresponding to 9,500 to 19,000 mg/

kg) in rabbits and guinea pigs. Because the 

reported acute dermal LD50 values for rabbits 

were conflicting and the LD50 value in guinea 

pigs was higher than the critical dermal LD50

value of 2,000 mg/kg body weight that identifies chemical substances with the potential for 

acute toxicity [NIOSH 2009], cyclohexanone is 

not considered acutely toxic following dermal 

exposure.

No epidemiological studies or human case 

reports were identified that evaluated the potential of cyclohexanone to cause systemic effects 

following dermal exposure. No chronic dermal 

toxicity studies for cyclohexanone were identified in animals. 

Repeat-dose studies have been conducted in 

guinea pigs and rats [Industrial Health Foundation, Inc. 1983; Rengstorff et al. 1972] that 

indicate dermal exposure to cyclohexanone 

may lead to formation of cataracts and lens vacuoles in the eye. Rengstorff et al. [1972] reported 

formation of cataracts/lens vacuoles in the 

eyes of guinea pigs when dermally exposed to 

cyclohexanone 3 times a week for 3 weeks. The 

guinea pigs were examined every 30 days for 6 

months [Rengstorff et al. 1972]. Union Health 

Foundation, Inc. [1983] exposed guinea pigs to 

0.5 mL of vehicle (saline) control, a 2% solution 

of cyclohexanone in saline (volume/volume), 

neat liquid cyclohexanone, or neat dimethyl 

sulfoxide (DMSO) (as positive control) to the 

shaven backs three times a week for 3 weeks 

(corresponding to 0, 17.4, or 872 mg cyclohexonone/kg-day in males, and 0, 19.16, or 971 mg 

cyclohexonone/kg-day in females, based on the 

individual body weights provided). All of the 

animals and positive controls were observed for 

6 months. Clinical observations and mortality 

checks were conducted twice daily during the 

treated and untreated phases of the study, body 

weights were measured weekly on all animals, 

and ophthalmoscopic examinations were 

conducted monthly on all animals throughout 

the study [Industrial Health Foundation, 

Inc. 1983]. Only the eyes were processed for 
Skin Notation Profile | Cyclohexanone 3

Cyclohexanone

Table 2. Summary of the carcinogenic designations for cyclohexanone 

by governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] No designation

NTP [2014] No designation

US EPA [2014] No designation

European Parliament [2008] No GHS designation

IARC [2012] Category 3: Not classifiable as to its carcinogenicity 

in humans

ACGIH® [2003] A3: Confirmed animal carcinogen with unknown 

relevance to humans

ACGIH® = American Conference of Governmental Industrial Hygienists; GHS = Globally Harmonized System for Classification and 

Labelling of Chemicals; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety 

and Health; NTP = National Toxicology Program; US EPA = United States Environmental Protection Agency.

histopathological evaluation. Industrial Health 

Foundation, Inc. [1983] reported that dermal 

exposure to cyclohexanone did not affect body 

weights or hematology parameters but caused 

ophthalmoscopic changes (vacuoles, which 

varied from subtle to marked involvement 

of the lens) as well as histopathologic changes 

(formation of vacuoles in the cells of the lens) 

in all treated groups, including the saline controls. From these findings, the Industrial Health 

Foundation, Inc. [1983] concluded that the 

vacuolar changes were spontaneous in guinea 

pigs and that they were not related to dermal 

exposure to (neat) cyclohexanone or the positive control material, DMSO. A limited number 

of systemic endpoints evaluated in these studies 

preclude determination of the potential of 

cyclohexanone to affect systemic toxicity following dermal exposure. 

No standard toxicity or specialty studies were 

identified that evaluated biological system/

function specific effects (including reproductive 

and developmental effects and immunotoxicity) 

following dermal exposure to cyclohexanone.

No studies were identified that evaluated the 

potential of cyclohexanone to be a carcinogen following exposure by the dermal route. 

Table 2 summarizes the carcinogenic designation of governmental and nongovernmental 

organizations. 

The mathematical model predicted that 

cyclohexanone is considered to be absorbed 

through the skin following dermal exposure. 

However, acute toxicity studies in rabbits and 

guinea pigs [Union Carbide Corporation 1967; 

Smyth et al. 1969; Eastman Kodak Company 

1978; EI du Pont de Nemours and Company 

(DuPont) 1983a] indicate that cyclohexanone 

is not acutely toxic. While no epidemiological 

studies, human case reports, or animal chronic 

dermal toxicity studies were identified, repeatdose studies [Rengstorff et al. 1972; Industrial 

Health Foundation, Inc. 1983] evaluated limited systemic endpoints and ophthalmologic 

and histopathologic changes in the eye, and 

these studies indicated no treatment-related 

systemic effects or other effects on the eye. 

Based on the limited information available in 

this assessment, a skin notation of SK: SYS is 

not assigned for cyclohexanone.

3 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies on corrosivity or in vitro tests for corrosivity using 

human or animal skin models or in vitro 

tests of skin integrity using cadaver skin 

were identified. Gupta et al. [1979] reported 

*

References in bold text indicate studies that serve 

as the basis of the SK assignments.
4 Skin Notation Profile | Cyclohexanone

Cyclohexanone

concentration-dependent irritation in occlusive 

conditions in rabbits, in which 12.4% to 99% of 

cyclohexanone in cottonseed oil was applied to 

the skin. Concentrations of 99% cyclohexanone 

were severely irritating, 49.5% was moderately 

irritating, 24.5% was mildly irritating, and 12.4% 

was very slightly/questionably irritating [Gupta 

et al. 1979]. Union Carbide [1982] applied two 

samples of 0.5 mL (471 mg) cyclohexanone 

under a 1.0 to 1.5 square inch (in2

) patch to the 

clipped skin of rabbits for 4 hours and observed 

for 72 hours post-application. The first sample 

caused necrosis in 5 of 6 rabbits, moderate erythema in 2 rabbits, and minor to moderate edema 

in 4 rabbits [Union Carbide 1982]. However, 

the second sample of cyclohexanone produced 

minor to moderate erythema in 3 rabbits and 

minor edema in 1 rabbit [Union Carbide 1982]. 

Eastman Kodak Company [1978] reported that 

cyclohexanone was moderately irritating to the 

skin of guinea pigs, but details of the study were 

not available for evaluation. In the repeat-dose 

dermal toxicity studies in which guinea pigs 

were exposed to 0.5 mL of neat cyclohexanone 

three times per week for 3 weeks, the Industrial 

Health Foundation Inc. [1983] reported skin 

irritation at the application site when guinea 

pigs and rats received 2% cyclohexanone or neat 

cyclohexanone for 3-13 weeks. The structure 

activity relationship model, DEREK®, predicted 

cyclohexanone to be negative for skin irritation.

Irritation tests in rabbits and guinea pigs [Gupta 

et al. 1979; Union Carbide 1982; Industrial Health Foundation Inc. 1983; Eastman 

Kodak Company 1978] indicate that high 

concentrations of cyclohexanone or repeated 

dermal exposures are mildly to severely irritating 

to the skin, with the potential to cause necrosis. 

Therefore, this assessment assigns a skin notation of SK: DIR (COR) for cyclohexanone.

4 Immune-mediated 

Responses (SK: SEN)

The potential of cyclohexanone to cause skin 

sensitization has been evaluated in a number of 

studies. In humans, a diagnostic patch test by Pazzaglia et al. [2003] revealed that concentrations 

as low as 1% cyclohexanone elicited irritation in 

a woman with frequent occupational interaction 

with neat cyclohexanone in a factory making 

polyvinyl chloride (PVC) fluid therapy bags. 

Sanmartin and de la Cuadra [1992] reported 

a case in which a woman manufacturing PVC 

fluidotherapy bags presented with pruriginous 

allergic contact dermatitis (a chronic, inflammatory skin disease characterized by pale-red 

papules and intense itching). Patch testing with 

1% cyclohexanone resin in petrolatum was 

negative, but 10% aqueous cyclohexanone produced a slight erythamatous reaction, which was 

confined to the patch test application zone after 

2 days, indicating the potential to cause skin 

irritation and not skin sensitization [Sanmartin 

and de la Cuadra 1992]. Bruze et al. [1988] 

reported five cases of allergic contact dermatitis 

in individuals handling various paints, and patch 

testing revealed the individuals were allergic 

to cyclohexanone resin present in the paints. 

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

cyclohexanone from NIOSH and other organizations

Organization Skin hazard designation

NIOSH [2005] [skin]: based on the potential for dermal absorption

OSHA [2018]* No designation

ACGIH® [2003] [skin]: based on the dermal LD50 data

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

Health; OSHA = Occupational Safety and Health Administration.

*Year accessed
Skin Notation Profile | Cyclohexanone 5

Cyclohexanone

Allergic responses were observed at doses as low 

as 0.001% (weight/volume, or w/v), and negative results were noted in 20 control patients 

who were tested with the cyclohexanone resin in 

petrolatum at 1% w/v [Bruze et al. 1988]. However, when Bruze et al. [1988] conducted Guinea 

Pig Maximization Tests (GPMTs), following 

identification of people with contact allergies 

to cyclohexanone resin, none of the guinea 

pigs had a positive response to cyclohexanone 

alone. These results indicate that the sensitizers 

responsible for the contact allergy to cyclohexanone resin may be the monomers and dimers 

formed when cyclohexanone is condensed in 

the production of the resin [Bruze et al. 1988]. 

Gad et al. [1986] evaluated the potential of cyclohexanone to cause delayed-type hypersensitivity 

by the dermal route in humans (details of the 

test not reported) and conducted the Mouse 

Ear Swelling Test (MEST) and GPMT, but no 

evidence of skin sensitization was found. In 

the MEST, induction and challenge with 100% 

cyclohexanone produced no sensitization in 

the animals, but a swelling of 102% suggested 

that the test material was irritating [Gad et al. 

1986]. The structure activity relationship model, 

DEREK®, predicted cyclohexanone to be negative for skin sensitization.

The available data indicate that cyclohexanone 

resin formulation may cause allergic contact 

dermatitis in humans [Bruze et al. 1988; Pazzaglia et al. 2003]; however, results from predictive 

tests in animals (GPMTs and MESTs) indicated 

that cyclohexanone alone is not a skin sensitizer 

[Gad et al. 1986; Bruze et al. 1988]. On the basis 

of the available data, a skin notation of SK: SEN 

is not assigned for cyclohexanone.

5 Summary

The mathematical model predicted that 

cyclohexanone is considered to be absorbed 

through the skin following dermal exposure. 

However, acute toxicity studies in rabbits and 

guinea pigs [Union Carbide Corporation 1967; 

Smyth et al. 1969; Eastman Kodak Company 

1978; EI du Pont de Nemours and Company 

(DuPont) 1983a] indicate that cyclohexanone 

is not acutely toxic. While no epidemiological 

studies, human case reports, or animal chronic 

dermal toxicity studies were identified, repeatdose studies [Rengstorff et al. 1972; Industrial 

Health Foundation, Inc. 1983] evaluated limited 

systemic endpoints and ophthalmologic and histopathologic changes in the eye, and these studies 

indicated no treatment-related systemic effects 

or other effects on the eye. Irritation tests in rabbits and guinea pigs [Gupta et al. 1979; Union 

Carbide 1982; Industrial Health Foundation 

Inc. 1983; Eastman Kodak Company 1978]

indicate that high concentrations of cyclohexanone or repeated dermal exposures are mildly to 

severely irritating to the skin with the potential 

to cause necrosis. The available data indicate that 

cyclohexanone resin may cause allergic contact 

dermatitis in humans [Bruze et al. 1988; Pazzaglia et al. 2003]; however, results from predictive 

tests in animals (GPMTs and MESTs) indicated 

that cyclohexanone itself is not a skin sensitizer 

[Gad et al. 1986; Bruze et al. 1988]. Based on the 

available information, this assessment assigns a 

composite skin notation of SK: DIR (COR) for 

cyclohexanone. 

Table 3 summarizes the skin hazard designations 

for cyclohexanone issued by NIOSH and other 

organizations. There were no equivalent dermal 

designations for cyclohexanone according to the 

Globally Harmonized System (GHS) of classification and labeling of chemicals [European 

Parliament 2008].

References

Note: Asterisks (*) denote sources cited in text; 

daggers (†) denote additional resources.

*ACGIH® [2003]. Documentation of threshold limit 

values and biological exposure indices. 7th Ed. 

Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*Bingham E, Cohrssen B, Powell CH [2001]. Patty’s 

toxicology, 5th ed. New York: Wiley.

†BIBRA [1996]. Toxicity profile of cyclohexanone. 

Carshalton, England: British Industrial Biological 

Research Association. Govt Reports Announcements; Index 19.

†Bjorkner B E [1994]. Industrial airborne dermatoses. Occup Dermatoses 12:501–509.
6 Skin Notation Profile | Cyclohexanone

Cyclohexanone

*Bruze M, Bowman A, Bergqvist-Karlsson B, Bjorkner J, Wahlberg E, Voog, E [1988]. Contact 

allergy to a cyclohexanone resin in humans and 

guinea pigs. Contact Dermatitis 18:46–49. 

†Chemical Hygiene Fellowship [1983]. Range finding for cyclohexanone. OTS # 84003A.

*Dennerlein K, Schneider D, Göen T, Schaller 

KH, Drexler H, Korinth G [2013]. Studies on 

percutaneous penetration of chemicals: impact 

of storage conditions for excised human skin. 

Toxicol In Vitro 27(2):708–713.

*EI DuPont De Nemours & Co [1983a]. Cyclohexanone toxicity sheet with cover letter. TSCATS, 

Doc. I.D. 878211745, 8DS OTS #84003A.

†EI DuPont De Nemours & Co [1983]. Ongoing 

health and safety studies conducted or initiated 

by DuPont. TSCATS, Doc. I.D. 878211718, 8DS, 

OTS #84003A.

*ECHA [2020]. Classification and labelling inventory: table of harmonised entries in Annex VI 

to CLP. European Chemicals Agency, https://

echa.europa.eu/information-on-chemicals/

annex-vi-to-clp. Accessed 01-21-2020. 

†Exxon Chemical Company [1982]. Aspiration hazard 

and toxicity of a series of ketones. TSCATS, Doc. 

I.D. 878210457, OTS #84003A.

†Exxon Chemical Company [1975]. Acute oral toxicity study with attached cover letter. TSCATS, 

Doc. I.D. 878210457, OTS #84003A.

*Gad SC, Dunn BJ, Dobbs DW, Reilly C, Walsh RD 

[1986]. Development and validation of an alternative dermal sensitization test: the mouse ear 

swelling test. Toxicol Appl Pharmacol 84:93–114.

*Gupta PK, Lawrence WH, Turner JE, Autian J 

[1979]. Toxicological aspects of cyclohexanone. 

Toxicol Appl Pharmacol 49:525–533.

*IARC [2012]. Agents reviewed by the IARC monographs. In: IARC monographs on the evaluation 

of carcinogenic risks to humans. Lyon, France: 

World Health Organization, International Agency 

for Research on Cancer, https://monographs.iarc.

fr/monographs-available/. Accessed 01-20-15.

*Industrial Health Foundation [1983]. Cataractogenic potential of cyclohexanone dosed dermally 

to guinea pigs and rats. WIL Research Laboratories Inc. Project No. WIL-81154, WIL-81155. 

*Eastman Kodak Company [1978]. Toxicity and 

health hazard summary with cover letters. Docket 

I.D. 878214382, OTS #0206538.

*Mraz J, Galova E, Nohova H, Vitkova D [1994] 

Uptake, metabolism and elimination of cyclohexanone in humans. Intl Arch Occup Environ 

Health 66:3. 

*NCBI [2020]. PubChem Database. Cyclohexanol, 

CID=7966. Bethesda, MD: National Center for 

Biotechnology Information, https://pubchem.

ncbi.nlm.nih.gov/compound/Cyclohexanol. 

Accessed 01-22-2020.

†NIH [1979]. Cyclohexanone. Final report. Bethesda, 

MD: National Institutes of Health, National 

Cancer Institute. 

*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, https://

www.cdc.gov/niosh/npg/. Accessed 01-28-2020. 

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, https://www.

cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. 

Accessed 01-28-2020.

*NTP [2014]. Report on carcinogens, 13th ed. 

Research Triangle, NC: 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 01-20-15.

*OSHA [2018]. OSHA Occupational chemical 

database. Washington, DC: Occupational Safety 

and Health Administration, https://www.osha.

gov/chemicaldata/chemResult.html?recNo=93. 

Accessed 01-22-2020.

*Pazzaglia M, Tullo S, Voudouris S, Tosti A [2003]. 

Contact dermatitis due to cyclohexanone: a further case. Contact Dermatitis 49:313.

†Rauma M, Johanson G [2007]. A computer-controlled system for generation of chemical vapours 

in in vitro dermal uptake studies. Skin Res Technol 13(1):79.

*Rengstorff RH, Petrali JP, Sim VM [1972]. Cataracts 

induced in guinea pigs by acetone, cyclohexanone, and dimethyl sulfoxide. Am J Optom Arch 

Am Acad Optom 49(4):308–319.

*Sanmartin O, De La Cuadra J [1992]. Occupational 

contact dermatitis from cyclohexanone as a PVC 

adhesive. Contact Dermatitis 27:189–190.

*Smyth HF, Carpenter CP, Weil CS, Pozzani UC, 

Striegel JA, Nycum JS [1969]. Range finding 

toxicity data: List VII. Am Ind Hyg Assoc J 

30:470–476. 
Skin Notation Profile | Cyclohexanone 7

Cyclohexanone

*Union Carbide Corporation [1967]. Range finding toxicity studies with cover letter. TSCATS, 

Doc. I.D. 878210816, 8DS, OTS #84003A. 

*Union Carbide Corporation [1982]. Skin corrosivity study in rabbits. Bushy Run Research Center, 

TSCATS, Doc. I.D. 878210819, 8DS, OTS #84003A.

†U.S. EPA [1988]. Recommendations for and documentation of biological values for use in risk 

assessment. EPA/600/6-87/008. Washington, 

DC: United States Environmental Protection 

Agency.

*U.S. EPA [2014]. Integrated Risk Information 

System (IRIS). Washington, DC: United States 

Environmental Protection Agency, https://www.

epa.gov/iris. Accessed 01-20-15.

†Walker JD, Rodford R, et al. [2003]. Quantitative 

structure-activity relationships for predicting 

percutaneous absorption rates. Environ Toxicol 

Chem 22(8):1870–1884. 
8 Skin Notation Profile | Cyclohexanone

Cyclohexanone

Appendix: Calculation of the SI Ratio for Cyclohexanone

This appendix presents an overview of the 

SI ratio and a summary of the calculation of 

the SI ratio for cyclohexanone. 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 centimeters per hour (cm/

hr), outlined in Table A1. Other model-based 

estimates of kp may also be used [NIOSH 2009].

 = 1

1

kpsc + kpol aq k

1 +

kp

Equation 1: Calculation of Skin Permeation 

 Coecient (kaq)

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 
Skin Notation Profile | Cyclohexanone 9

Cyclohexanone

continues for 8 hours to unprotected skin on 

the palms of both hands (a surface area of 360 

square centimeters [cm2

]).

Skin dose = kp × Sw × Exposed skin surface

area × Exposure time

= kp (cm/hr) × Sw (mg/cm3) × 

360 cm2 × 8 hr

Equation 2: Determination of Skin Dose

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).

Inhalation dose = OEL × Inhalation

volume × RF

= OEL (mg/m3

) × 10 m3 × 0.75

Equation 3: Determination of Inhalation Dose

The final step is to compare the calculated skin 

and inhalation doses and to present the result 

as a ratio of skin dose to inhalation dose (the 

SI ratio). This ratio quantitatively indicates 

(1) the significance of dermal absorption as 

a route of occupational exposure to the substance and (2) the contribution of dermal 

uptake to systemic toxicity. If a substance has 

an SI ratio greater than or equal to 0.1, it is 

considered a skin absorption hazard.

Calculation

Table A1 summarizes the data applied in the 

previously described equations to determine 

the SI ratio for cyclohexanone. The calculated 

SI ratio was 0.24. On the basis of these results, 

cyclohexanone is predicted to represent a skin 

absorption hazard.

Appendix References

Hayes WA [2008]. Principles and methods of toxicology. 5th ed. New York: Informa Healthcare USA.

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, https://www.cdc.gov/

niosh/npg/. Accessed 01-28-2020. 

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, https://www.

cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. 

Accessed 01-28-2020.

NLM [ND]. Toxnet, ChemIDplus: Cyclohexanone. 

Bethesda, MD: National Institutes of Health, 

National Library of Medicine, https://chem.

nlm.nih.gov/chemidplus/rn/108-94-1. Accessed 

01-28-2020.
10 Skin Notation Profile | Cyclohexanone

Cyclohexanone

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

Variables used in calculation Units Value

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path (kpsc) cm/hr 0.0025

Permeation coefficient of the protein fraction of the 

stratum corneum (kpol)

cm/hr 1.5329 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.2523

Molecular weight (MW)† amu 98.2

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

*

None 0.81

Calculated skin permeation coefficient (kp) cm/hr 0.00249

Skin dose

Water solubility (Sw)

* mg/cm3 25

Calculated skin permeation coefficient (kp) cm/hr 0.00249

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

Exposure time hr 8

Calculated skin dose mg 179.3418

Inhalation dose

Occupational exposure limit (OEL)δ mg/m3 100

Inhalation volume m3 10

Retention factor (RF) None 0.75

Inhalation dose mg 750

Skin dose–to–inhalation dose (SI) ratio None 0.2391

*

Variables identified from NLM [ND].

†

Variables identified from the NPG [2005].

δ

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

§

Hayes WA [2008]. Principles and methods of toxicology. 5th ed. New York: Informa Healthcare USA.
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Promoting productive workplaces through safety and health research

DHHS (NIOSH) Publication No. 2021-103

DOI: https://doi.org/10.26616/NIOSHPUB2021103