i

Skin Notation (SK) Profile

Trichloroethylene (TCE)

[CAS No. 79-01-6]

Department of Health and Human Services

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
ii

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.

Disclaimer

Mention of any company or product does not constitute endorsement by the National Institute for 

Occupational Safety and Health (NIOSH). In addition, citations to Web sites external to NIOSH 

do not constitute NIOSH endorsement of the sponsoring organizations or their programs or 

products. Furthermore, NIOSH is not responsible for the content of these Web sites. 

Ordering Information

To receive this document or information about other occupational safety and health topics, 

contact NIOSH: 

Telephone: 1-800-CDC-INFO (1-800-232-4636)

TTY: 1-888-232-6348

E-mail: cdcinfo@cdc.gov

Or visit the NIOSH Web site: www.cdc.gov/niosh

For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting 

www.cdc.gov/niosh/eNews.

Suggested Citation

NIOSH [20XX]. NIOSH skin notation profile: Tricholoroethylene (TCE). By Hudson NL, Dotson GS. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. XXX

DHHS (NIOSH) Publication No. XXX
iii

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.

Foreword

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

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

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

spectrum of adverse health effects ranging from localized damage (e.g., irritant contact 

dermatitis and corrosion) to induction of immune-mediated responses (e.g., allergic contact 

dermatitis and pulmonary responses), or systemic toxicity (e.g., neurotoxicity and hepatoxicity). 

Understanding the hazards related to skin contact with chemicals is a critical component of 

modern occupational safety and health programs.

In 2009, the National Institute for Occupational Safety and Health (NIOSH) published 

Current Intelligence Bulletin (CIB) 61 – A Strategy for Assigning New NIOSH Skin Notations

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

assignment of multiple hazard-specific skin notations (SK) that clearly distinguish between the 

systemic effects, direct (localized) effects, and immune-mediated responses caused by skin 

contact with chemicals. The key step within assignment of the hazard-specific SK is the 

determination of the hazard potential of the substance, or its potential for causing adverse health 

effects as a result of skin exposure. This determination entails a health hazard identification 

process that involves use of the following:

 Scientific data on the physicochemical properties of a chemical

 Data on human exposures and health effects

 Empirical data from in vivo and in vitro laboratory testing

 Computational techniques, including predictive algorithms and mathematical models that 

describe a selected process (e.g., skin permeation) by means of analytical or numerical 

methods. 

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

(TCE). 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 riskmanagement practices may be developed to better protect workers from the risks of skin contact 

with the chemical of interest.

John Howard, M.D.

Director

National Institute for Occupational Safety and Health

Centers for Disease Control and Prevention
iv

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.

Contents

Contents

FOREWORD ............................................................................................................................................................III

ABBREVIATIONS.....................................................................................................................................................V

ACKNOWLEDGMENTS..................................................................................................................................... VIII

1.0 INTRODUCTION .................................................................................................................................................1

1.1 GENERAL SUBSTANCE INFORMATION ..................................................................................................................1

1.2 PURPOSE..............................................................................................................................................................1

1.3 OVERVIEW OF SK ASSIGNMENT ..........................................................................................................................2

2.0 SYSTEMIC TOXICITY FROM SKIN EXPOSURE (SK: SYS) ......................................................................2

3.0 DIRECT EFFECTS ON SKIN (SK: DIR)...........................................................................................................5

4.0 IMMUNE-MEDIATED RESPONSES (SK: SEN) .............................................................................................7

5.0 SUMMARY............................................................................................................................................................8

REFERENCES ..........................................................................................................................................................10

APPENDIX: CALCULATION OF THE SI RATIO FOR TCE ...........................................................................15

OVERVIEW...............................................................................................................................................................15

APPENDIX REFERENCES...........................................................................................................................................18
v

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.

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

CIB Current Intelligence Bulletin

cm2squared centimeter(s)

cm/hour centimeter(s) per hour

DEREK Deductive Estimation of Risk from Existing Knowledge

DIR skin notation indicating the potential for direct effects to the skin following 

contact with a chemical

EC European Commission 

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

HPA 2-hydropropyl acrylate 

IARC International Agency for Research on Cancer

(IRR) subnotation of SK: DIR indicating the potential for a chemical to be a skin irritant 

following exposure to the skin

kaq coefficient in the watery epidermal layer

kp skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

kpsc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

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

m

3

cubic meter(s)

mg milligram(s)

mg/kg milligram(s) per kilogram body weight

mg/m3 milligram(s) per cubic meter

mL milliliter(s)

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level

NTP National Toxicology Program

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

REL recommended exposure limit

RF retention factor 

SEN skin notation indicating the potential for immune-mediated reactions following 

exposure of the skin
vi

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.

SI ratio ratio of skin dose to inhalation dose

SK skin notation

SW solubility in water

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

the skin

USEPA United States Environmental Protection Agency

w/w weight by weight percentage
vii

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.

Glossary

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

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

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

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

and grow or multiply out of control. 

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

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

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

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

Dermal—Referring to the skin. 

Dermal contact—Contact with (touching) the skin. 

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

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

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

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

responses. 

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

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

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

Substance—A chemical. 

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

of the skin.
viii

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.

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, Michael Luster, Ph.D., and Loren 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 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.

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 

Education and Information Division 

Devin Baker, M.Ed.

Charles L. Geraci, Ph.D.

Thomas J. Lentz, Ph.D.

Richard Niemeier, Ph.D.

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

Health Effects Laboratory Division

Stacey Anderson, Ph.D. 

H. Fredrick Frasch, Ph.D. 

Vic Johnson, Ph.D.

Berran Yucesoy, Ph.D. 

National Personal Protection Technology Laboratory
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.

Heinz Ahlers, JD, M.Sc.

Gregory Day, Ph.D.

Angie Shepherd

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

acknowledgment is given to the following CDC personnel:

Office of Surveillance, Epidemiology and Laboratory Services/Epidemiology and Analysis 

Program Office 

Barbara Landreth, M.A.

In addition, special appreciation is expressed to the following individuals for serving as 

independent, external reviewers and providing comments that contributed to the development or 

improvement of this document:

 G. Frank Gerberick, Ph.D., The Procter and Gamble Company, Cincinnati, OH

 Dori Germolec, Ph.D., National Toxicology Program, National Institute for 

Environmental Health Sciences, Research Triangle, NC

 Ben Hayes, M.D., Ph.D., Division of Dermatology, Vanderbilt School of Medicine, 

Nashville, TN 

 Jennifer Sahmel, M.Sc., CIH, ChemRisk, Boulder, CO

 James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH
1

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.

1.0 Introduction 

1.1 General Substance Information

Chemical: Trichloroethylene (TCE)

CAS No: 79-01-6

Molecular weight (MW): 131.39

Molecular formula: C2HCl3

Structural formula:

Synonyms: Ethylene trichloride; TCE; Trichloroethene; Trilene; TRI

Uses: Trichloroethylene (TCE) is a chlorinated organic compound used primarily as a solvent in metal 

degreasing operations and as a component of the refrigerant HFC-134a [ATSDR 2014; Bakke et al. 

2007; EPA 2014]. TCE is also used as a spotting agent in dry cleaning operations [EPA 2014] and

historically has been used as a general anesthetic or analgesic [ATSDR 2014; Bakke et al. 2007; EPA 

2014].

1.2 Purpose 

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

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

(SK) assignment for TCE. 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 TCE. A literature search was conducted through 

February 2013 to identify information on TCE, including but not limited to data relating to its 

toxicokinetics, acute toxicity, repeated-dose systemic toxicity, carcinogenicity, biological 

system/function–specific effects (including reproductive and developmental effects and 

immunotoxicity), irritation, and sensitization. Information was considered from studies of humans, 

animals, or appropriate modeling systems that are relevant to assessing the effects of dermal exposure to 

TCE. 
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

TCE 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 TCE: SK: SYS-DIR(IRR)-

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

for TCE. 

Table 1. Summary of the SK Assignment for TCE

Skin Notation Critical

Effect

Available

Data

SK: SYS Hepatotoxicity; nephrotoxicity; 

neurotoxicity

Limited human data and animal 

data

SK: DIR (IRR) Skin irritation Limited human data; sufficient 

animal data

SK: SEN Skin sensitization; liver damage 

associated with delayed-type 

hypersensitivity reaction

Limited human and animal data

2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

Numerous studies of dermal absorption of TCE in humans have indicated that the substance can be 

absorbed following skin contact [Stewart and Dodd 1964; Sato and Nakajima 1978; Poet et al. 2000; 

Kezic et al. 2001]. In a study conducted by Stewart and Dodd [1964], volunteers immersed their thumbs 

in TCE for 30 minutes. Concentrations of TCE in exhaled air were determined during exposure and for 5 

hours post-exposure; the mean peak breath concentration was reported to be 0.5 parts per million (ppm) 

[corresponding to 0.5 milligrams per kilogram (mg/kg)] and occurred within 15 minutes post-exposure 

[Stewart and Dodd 1964]. The rate of dermal uptake of TCE was not determined, although the authors 

indicated that the amount dermally absorbed would be similar to the amount absorbed by the lung from 

inhalation [Stewart and Dodd 1964]. The authors noted that factors including integrity as well as 

thickness of the skin affected dermal penetration [Stewart and Dodd 1964]. Sato and Nakajima [1978] 

reported dermal absorption of in four male volunteers who immersed one hand up to the wrist for 30 

minutes in TCE in a covered jar to avoid inhalation exposure. For 10 hours post-exposure, 

concentrations of TCE in breath and blood, and the concentration of metabolites in urine were measured 

at regular intervals [Sato and Nakajima 1978]. Sato and Nakajima [1978] indicated that the levels found 

in the breath and blood from exposure to TCE were similar to those noted after a 4 hour inhalation 

exposure to TCE (100 ppm; corresponding to 100 mg/kg); however, the rate of dermal uptake of TCE 

was not determined. Poet et al. [2000] estimated that in volunteers, the average dermal permeability 

coefficient (kp) values for TCE were 0.019 and 0.015 centimeters per hour (cm/hr) following waterpatch and hand-immersion studies, respectively and 0.015 cm/hr of TCE through the skin of volunteers 

when a fully occluded patch system was used. In another study, volunteers were exposed to neat TCE on 

the volar forearm over an area of 27 square centimeters (cm2) for 1 minute [Kezic et al. 2001]. Kezic et 
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 Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

al. [2001] noted fast dermal permeation through skin: a flux of 430 nanomoles/cm2per minute 

(nmol/cm2/min). 

Several experimental studies of the dermal absorption of TCE in animals [Tsuruta 1978; Jakobson et al. 

1982, Bogen et al. 1992, Nakai et al. 1999; Poet et al. 2000] were identified. Tsuruta [1978] exposed 

mice to undiluted liquid TCE for 5, 10, or 15 minutes to determine the rate of dermal absorption. The 

reported results indicated that the amount of TCE absorbed increased linearly, and the rate of dermal 

absorption through mouse abdominal skin was estimated to be 8 μg/cm2/min [Tsuruta 1978]. Jakobsen 

et al. [1982] used guinea pigs to investigate the dermal absorption of undiluted TCE in occluded 

conditions. Blood samples were collected at intervals of 5 to 20 minutes during the 6-hour exposure 

period [Jacobsen et al. 1982]. The authors reported that peak blood levels of around 0.79 μg/mL 

occurred after 30 minutes [Jacobsen et al. 1982]. Bogen et al. [1992], dermally exposed guinea pigs to 

aqueous diluted solutions (approximately 10 to 100 parts per billion [ppb]; corresponding to .01 to 0.1 

mg/kg) of TCE, and reported kp values of 0.21 to 0.23 cm/hr. Poet et al. [2000] measured dermal 

absorption of TCE using physiologically based pharmacokinetic modeling in a water matrix in rats, and 

reported a kp of 0.31 cm/hr [Poet et al. 2000]. In vitro studies on dermal absorption of TCE were 

identified. Using the aluminum dermal absorption block method reported by Moody et al. [1992], Nakai 

et al. [1999] reported a kp of 0.12 cm/hr for human abdomen and breast skin samples. 

The potential of TCE to pose a skin absorption hazard was also evaluated with use of a predictive 

algorithm for estimating and evaluating the health hazards of dermal exposure to substances [NIOSH 

2009]. The evaluation method compares an estimated dose accumulated in the body from skin 

absorption with 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 

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

contribute to the overall body burden of a substance [NIOSH 2009]; therefore, TCE is not considered to 

be absorbed through the skin following dermal exposure. Additional information on the SI ratio and the 

variables used in its calculation are included in the appendix. Although the mathematical predictive 

model indicated that TCE is not readily absorbed by the skin, studies in humans and animals indicates

that TCE is absorbed by the skin and may be similar to uptake via inhalation [Sato and Nakajima 1978]. 

Although no estimate of the dermal lethal dose (LDLo) for humans has been identified, dermal LD50

(lethal dose for 50% of exposed population) values of >10,000 milligrams per kilogram (mg/kg) have 

been reported for the rabbit [Dow Chemical Company 1956; Smyth et al.1969]. Because the reported 

acute dermal LD50 value is greater than the critical dermal LD50 value of 2,000 mg/kg that identifies 

chemical substances with the potential for acute dermal toxicity [NIOSH 2009], TCE is not considered 

acutely toxic by the dermal route.

No health effects data were identified regarding dermal repeated-dose, subchronic, or chronic toxicity of 

TCE in humans or animals. Yu et al. [2012] evaluated renal impairment in TCE-sensitized guinea pigs. 

Animals were exposed to three pairs of 0.1 ml injections of 5% TCE solution in olive oil followed by an 

application of 0.5 ml of 40% TCE solution applied to the skin with non-irritant tape for 24 hours [Yu et 

al. 2012]. The investigators noted that metabolites of TCE caused the deposition of C3 and MAC renal 
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 Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

epithelial cells and indicated this mechanism may account for TCE induced kidney and liver dysfunction 

[Yu et al. 2012].

Occupational exposure to an unquantified amount of TCE that involved both dermal and inhalation 

exposure for up to 20 years has been reported to cause dizziness, headache, insomnia, lethargy, 

forgetfulness, and loss of feeling in the hands and feet, or enlarged liver [Bauer and Rabens 1974; 

Kohlmuller and Kochen 1994]. In a case series, Liu [2009] reported the onset of dermatitis and systemic 

toxicity in workers (six males, one female) who used TCE to clean metal surfaces. Although the report 

did not precisely describe the exposure conditions, it can be assumed that skin exposures were a primary 

pathway since there was onset of dermatitis in all cases, and the degree of liver and renal dysfunction 

was related to the degree of skin injury [Liu 2009]. Liu [2009] reported that liver or kidney damage in 

five of the seven workers was attributed to TCE exposures, in addition to effects on the central nervous 

system (i.e., dizziness) and changes in blood chemistry (i.e., elevated white blood cell count). All five of 

the workers who had liver dysfunction developed liver steatosis (fatty liver) within 2 months, and one 

worker had kidney dysfunction with inflammation and swelling [Liu 2009]. Liu [2009] concluded that 

TCE is capable of causing both systemic and localized adverse health effects. Watanabe et al. [2010] 

reported a patient that had been exposed to TCE and was hospitalized with severe liver dysfunction. Xu 

et al. [2009] conducted a study with 21 patients with TCE-induced skin disorders that worked at 3 

separate factories from 2003-2005 with an average exposure duration of 38 days. These patients were 

exposed during cleaning and degreasing operations and did not wear gloves, and were also possibly 

exposed via inhalation [Xu et al. 2009]. The patients reported neurological symptoms (headache, 

dizziness), skin effects, and liver dysfunction [Xu, et al. 2009]. Gash et al. [2008] reported 3 workers 

that were exposed to TCE both through chronic inhalation and dermal contact for 25 years or greater had 

Parkinson’s disease (PD). Of these workers, 2 had no family history of PD. The workers shared the same 

work hours, including overtime, and cleaned parts directly in a vat of TCE without use of gloves or other 

protective equipment [Gash et al. 2008]. Other workers in the same factory, more distant from the 

source of TCE who were exposed via inhalation, reported neurological symptoms, such as significant 

motor slowing [Gash et al. 2008]. The neurotoxicity of TCE was supported by animal studies conducted 

by Gash et al. [2008], which demonstrated that oral exposure to TCE was accompanied by complex 1 

mitochondrial impairment in the midbrain and loss of dopamine neurons, which is a hallmark of PD. 

No epidemiological investigations or experimental animal studies evaluating the potential for TCE to 

induce carcinogenicity were identified; however, evidence that TCE is carcinogenic to humans has been 

found in multiple studies but the exposure route (i.e. inhalation, dermal, oral) is unknown [Hansen et al. 

2013; Karami et al. 2013]. Hansen et al. [2013] found increased liver cancer 1.93 times more likely 

(confidence interval [CI] 1.19 to 2.95) and cervical cancer 2.31 times more likely (CI: 1.32 to 3.75) in 

workers exposed to TCE; however, exposure routes are unknown and were likely a combination of 

multiple routes (inhalation and dermal). Karami et al. [2013] conducted a meta-analysis of published 

cohort and case control studies that assessed occupational exposure to TCE and five different cancers: 

non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, multiple myeloma, leukemia, and chronic/small 

lymphocytic leukemia. Routes of exposure were unknown for these studies and cases were likely 

exposure from multiple routes. These authors reported a significantly raised summary estimate of nonHodgkin’s lymphoma (relative risk=1.93; CI: 1.14 to 1.54) for all cohort and case-control studies 
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.

[Karami et al. 2013]. Table 2 provides a summary of carcinogenic designations from multiple 

governmental and nongovernmental organizations for TCE.

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

nongovernmental organizations

Organization Carcinogenic designation 

NIOSH [2005] Potential occupational carcinogen

NTP [2014] Reasonably anticipated to be a human 

carcinogen

USEPA [2014] Carcinogenic to humans

European Parliament [2008] GHS Category 1B: May cause cancer

IARC [2014] Group 1: Carcinogenic to humans

EC [2013]

† R45: May cause cancer

ACGIH [2007] Group A2: Suspected human carcinogen

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.

Although the toxicokinetic studies indicate that TCE has limited dermal absorption potential, which is 

supported by the limited available animal data reporting low acute toxicity in rabbits [Dow Chemical 

Company 1956; Smyth et al.1969], case reports, case series and an occupational exposure study [Bauer 

and Rabens 1974; Kohlmuller and Kochen 1994; Liu 2009; Watanabe et al. 2010] and one animal 

study [Yu et al. 2012] provide evidence of TCE-induced liver and kidney dysfunction following 

subchronic exposures to the substance, and occupational studies [Gash et al. 2008; Liu 2009; Xu et al. 

2009] reported neurological effects. These limited human data provide evidence of its ability to cause 

systemic toxicity following subchronic exposure. Therefore, on the basis of these data, TCE is assigned 

the SK: SYS notation.

3.0 Direct Effects on Skin (SK: DIR)

No human in vivo studies on the corrosive potential of TCE in humans were identified. Evidence of 

corrosivity in animals is limited to findings from a single acute toxicity study. In that study, high doses 

of TCE, ranging from 2,520 to 20,000 mg/kg, were administered to the skin of 16 rabbits under an 

impervious covering, resulting in burning, scabbing, and scarring [Dow Chemical Company 1956]. 

In occupational exposures that involved inhalation of the vapor, percutaneous penetration, or both, TCE 

caused skin irritation and rashes, central nervous system effects, and/or eye effects after repeated 

exposure [El Ghawabi et al. 1973; Bauer and Rabens 1974; Xu et al. 2009]. Xu et al. [2009] reported 

skin irritation in 21 patients diagnosed with a TCE-induced skin disorder, and symptoms included skin 

erythema, rashes, and blistering. Study volunteers have reported burning sensations, erythema, rashes, 
6

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.

and dermatitis [Stewart and Dodd 1964; Sato and Nakajimi 1978]. Four volunteers who each immersed 

a single hand up to the wrist for 30 minutes in liquid TCE reported a burning sensation that increased 

with time and distinct pain toward the end of the exposure, as well as moderate erythema for over an 

hour post-exposure [Sato and Nakajima 1978]. Similar effects were seen in three volunteers who 

immersed their thumbs in TCE for 30 minutes [Stewart and Dodd 1964]. Kezic et al. [2001] noted 

intensive skin irritation, with burning sensation varying from “hardly noticed” to “unbearable pain” in 

six volunteers. Wahlberg [1984b] reported marked and persistent erythema in a healthy individual 

following excess application (1.5 mL) of neat TCE to the unoccluded volar forearm (3.1 cm2) for 5 

minutes, and application for 1 or 3 minutes caused transient whitening and then erythema. Wahlberg 

[1984b] reported stinging and/or burning sensations after exposure to TCE in human volunteers. Liu 

[2009] investigated seven workers exposed who all experienced erythema and were exposed to TCE 

when using it to clean metal surfaces. In six of the seven workers, dermatitis occurred within 1 month of 

exposure to TCE [Liu 2009]. Liu [2009] also reported that the workers experienced a variety of effects, 

including erythema with pruritus, rashes on the extremities, and systemic toxic effects attributed to 

exposures to TCE.

Several studies in rabbits and guinea pigs indicate that TCE caused severe irritation to the skin following 

occlusive and unocclusive dermal application [Smyth et al. 1969; Wahlberg 1984b]. Anderson et al. 

[1986] conducted a guinea pig irritant-contact reaction test in which 10 microliters (μL) TCE was 

applied under occlusion to 1 cm2shaved skin on the flank three times daily for 3 days. Macroscopic 

assessment of erythema and edema as well as microscopic assessments of epidermal thickness and 

dermal inflammatory cell infiltration (total and differential cell responses) indicated that TCE was 

irritating to the guinea pig skin [Anderson et al. 1986]. Shen et al. [2008] investigated the effects of TCE 

on skin irritation and oxidative stress, using hairless mice under acute and cumulative exposure 

conditions. Mice were administered concentrations of TCE (20%, 40%, 80%, or 100% v/v) dissolved in 

olive oil [Shen et al. 2008]. In an acute irritation test, TCE administration for 1 day resulted in mild to 

moderate irritation that was concentration dependent, and erythema and intracellular edema developed 

[Shen et al. 2008]. Epidermal necrosis occurred in a few mice treated with 100% TCE. In a cumulative 

irritation test, mice underwent daily topical applications of TCE for 14 days, resulting in epidermal 

hyperplasia, hyperkeratosis, edema, and inflammation [Shen et al. 2008]. Kronevi et al. [1981] noted 

degenerative changes in the epidermis, including karyopyknosis, oedema, junctional separation and 

cellular infiltration in the dermis. The structure-activity relationship model (Deductive Estimation of 

Risk from Existing Knowledge, or DEREK, for Windows) predicted TCE to be negative for skin 

irritation, indicating that the chemical does not have a structural alert for skin irritation.

An epidemiological study concerning the potential of TCE to cause cancer was identified. Axelson et al. 

[1994] assessed the exposure of workers from a plant in central Sweden that produced TCE. Although 

the routes of exposure were unknown, the authors noted a doubled incidence of nonmelanocytic skin 

cancer; however there was no correlation with exposure categories [Axelson et al. 1994]. One dermal 

carcinogenicity study in animals was identified. Van Duuren et al.[1979] found no tumors in mice at the 

site of topical application of TCE (1 mg in 0.1 mL acetone per application); in addition, there was no 

statistically significant difference in the incidence of distant tumors in this group versus no-treatment 

and vehicle control groups. The investigators also found no skin tumor–initiating activity in a mouse 

skin initiation promotion experiment [Van Duuren et al. 1970].
7

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.

Although results indicate that undiluted TCE is corrosive to the skin [Dow Chemical Company 1956], 

TCE is not expected to be corrosive to the skin under usual conditions of handling. Evidence of skin 

whitening, erythema, and dermatitis in humans [Stewart and Dodd 1964; Bauer and Rabens 1974; 

Sato and Nakajima 1978; Wahlberg 1984 a,b; Kezic et al. 2001; Liu 2009; Xu et al. 2009] and of 

erythema, edema, and changes in the epidermis in animals [Anderson et al.1986; Shen et al. 2008]

indicates that TCE is a skin irritant. Therefore, on the basis of the data for this assessment, TCE is 

assigned the SK: DIR (IRR) notation. 

4.0 Immune-mediated Responses (SK: SEN)

Few reports were identified that suggest that TCE may be a skin sensitizer in humans. An occupational 

study on 19 patients hospitalized for generalized skin disorders and their healthy colleagues by 

Kamijima et al. [2008], indicated that TCE caused the hypersensitivity disorders. Watanabe et al. [2010] 

reported a case with generalized rash and liver dysfunction that had been exposed to TCE at work. This 

patient was patch tested for TCE and its metabolites trichlorethanol and chloral hydrate; the patient had 

positive reactions to the metabolites but not to TCE [Kamijima et al. 2008]. Dai et al. [2009] compared 

111 workers with hypersensitivity dermatitis and 154 healthy workers, all of whom were exposed to 

TCE, to determine if there was a gene polymorphism that influenced individual susceptibility to TCEinduced hypersensitivity dermatitis. All of the cases diagnosed with occupational hypersensitivity 

dermatitis by an occupational disease physician developed skin damage within 3 months of exposure to 

TCE [Dai et al. 2009]. The authors concluded that a slow metabolic phenotype of N-acetyltransferases 

(NATs) and combined slow acetylator phenotypes of NAT1 and NAT2, two isoenzymes of NAT that 

are encoded by separate genes, may be risk factors for TCE-induced hypersensitivity [Dai et al. 2009], 

In a case report, a worker developed severe dermal effects, including skin lesions and erythroderma with 

edematous face and eyelids, a combined inhalation and dermal exposure to TCE [Nakayama et al. 1988]. 

This subject had positive reactions to 10% and 25% TCE in olive oil (and to 0.005%, 0.05%, and 5% 

trichloroethanol, a metabolite of TCE) [Nakayama et al. 1988]. Nakayama et al. [1988] regarded this 

result to be due to delayed hypersensitivity to TCE. The findings in that case indicate that the subject 

was allergic to both TCE and its metabolite, trichloroethanol. In another reported case, a female worker 

developed erythematous lesions and had a positive reaction when patch tested with TCE (5% in olive 

oil) [Conde-Salazar et al. 1983]. The worker developed the same lesions when challenged on many 

occasions, after exposure to TCE. Phoon et al. [1984] reported five cases in which individuals were 

occupationally exposed to TCE for periods ranging from 2 to 5 weeks presented with Stevens-Johnson 

syndrome (erythema multiforme major). Three of the cases had air exposure only, and the remaining 

two had air and direct skin contact [Phoon et al. 1984]. One individual exposed to fairly high levels of 

TCE vapor in the air and by direct skin contact was patch tested with TCE after the episode but tested 

negative. In spite of the negative reaction, Phoon et al. [1984] did not rule out the possibility of a 

hypersensitivity response.

Animal studies regarding the potential for TCE to induce immune-mediated responses following skin 

contact were identified. Yu et al. [2012 ] conducted modified guinea pig maximization tests (GPMT), 

where animals were exposed to three pairs of 0.1 ml injections of 5% TCE solution in olive oil followed 
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 Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

by application of 0.5ml of 40% TCE solution was applied to the skin with non-irritant tape for 24 hours 

[Yu et al. 2012]. The investigators reported a sensitization rate of 63.16% compared to 100% for the 

positive control [Yu et al. 2012]. In an earlier study, Tang et al. [2002], using a modified GPMT, 

reported that TCE caused skin sensitization (i.e., edema and erythema) in guinea pigs. The authors 

reported a sensitization rate of 71.4% (10/14) for TCE and of 58.3% trichloroacetic acid. 

Histopathological analysis revealed allergenic transformation in guinea pig skin exposed to TCE, and 

the authors concluded that TCE appeared to be a strong allergen following skin contact [Tang et al. 

2002]. In a subsequent investigation, Tang et al. [2008] attempted to characterize the liver injury 

associated with hypersensitive skin injuries in guinea pigs by using dermal patches containing TCE and 

performing a GPMT. The results of the study included sensitization rates of TCE-induced dermal allergy 

of 66%, accompanied by skin edema, and erythema [Tang et al. 2008]. In addition, elevated liver 

enzymes and the presence of lesions were reported [Tang et al. 2008]. The GPMT revealed 

histopathologic evidence of fatty degeneration in the liver, hepatic sinusoid dilation, and inflammatory 

cell infiltration with an acute intradermal dose of 4,500 mg/kg [Tang et al. 2008]. Tang et al. [2008] 

concluded that TCE may be capable of inducing dermatitis and liver damage, on the basis of delayedtype hypersensitivity in guinea pigs. Predictions from structure-activity relationship models provide 

some information regarding this endpoint. On the basis of its chemical structure, TCE is predicted by 

DEREK to be negative for sensitization, indicating that the chemical does not have a structural alert for 

skin sensitization.

Although the mathematical model predicted TCE to be negative for sensitization, isolated reports of 

cases involving humans [Conde-Salazar et al. 1983; Nakayama et al. 1988] and an epidemiological 

study [Dai et al. 2009] suggest that TCE may have sensitizing potential. Evidence of immune-mediated 

responses in workers is often confounded by exposures via both dermal and inhalation routes. Although 

animal data are limited, positive results from predictive tests (GPMTs) [Tang et al. 2002, 2008; Yu et 

al. 2012] demonstrate that TCE is capable of inducing dermatitis and liver damage via delayed-type 

hypersensitivity in guinea pigs. Therefore, on the basis of the data for this assessment, TCE is assigned 

the SK: SEN notation.

5.0 Summary

Although the toxicokinetic studies indicate that TCE has limited dermal absorption potential, which is 

supported by the limited available animal data reporting low acute toxicity in rabbits [Dow Chemical 

Company 1956; Smyth et al.1969], case reports, case series and an occupational exposure study [Bauer 

and Rabens 1974; Kohlmuller and Kochen 1994; Liu 2009; Watanabe et al. 2010] and one animal 

study [Yu et al. 2012] provide evidence of TCE-induced liver and kidney dysfunction following 

subchronic exposures to the substance, and occupational studies [Gash et al. 2008; Liu 2009; Xu et al. 

2009] reported neurological effects. These limited human and animal data provide evidence of its ability 

to cause systemic toxicity following subchronic exposure. Although results indicate that undiluted TCE 

is corrosive to the skin [Dow Chemical Company 1956], TCE is not expected to be corrosive to the skin 

under usual conditions of handling. Evidence of skin whitening, erythema, and dermatitis in humans 

[Stewart and Dodd 1964; Bauer and Rabens 1974; Sato and Nakajima 1978; Wahlberg 1984 a,b; 

Kezic et al. 2001; Liu 2009; Xu et al. 2009] and of erythema, edema, and changes in the epidermis in 
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.

animals [Anderson et al.1986; Shen et al. 2008] indicates that TCE is a skin irritant. Although the 

mathematical model predicted TCE to be negative for sensitization, isolated reports of cases involving 

humans [Conde-Salazar et al. 1983; Nakayama et al. 1988] suggest that TCE may have sensitizing 

potential. Although animal data are limited, positive results from predictive tests (GPMTs) [Tang et al. 

2002, 2008; Yu et al. 2012] demonstrate that TCE is capable of inducing dermatitis and liver damage 

via delayed-type hypersensitivity in guinea pigs. Therefore, on the basis of these assessments, TCE is 

assigned a composite skin notation of SK: SYS-DIR (IRR)-SEN.

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

organizations. The equivalent dermal designations for TCE, according to the Global Harmonization 

System (GHS) of Classification and Labelling of Chemicals, are Skin Irritation Category 2 (Hazard 

Statement: Causes skin irritation) and Mutagenicity Category 2 (Hazard Statement: Suspected of causing 

genetic defects) [European Parliament 2008]. 

Table 3. Summary of previous skin hazard designations for TCE

Organization Skin hazard designation 

NIOSH [2005] No designation

OSHA [2014]

* No designation

ACGIH [2007] No designation

EC [2013]* R38: Irritating to the 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.
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.

References

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

*ACGIH (American Conference of Governmental Industrial Hygienists) [2007]. Trichloroethylene. In: 

Threshold limit values for chemical substances and physical agents and biological exposure indices. 

Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*Anderson C, Sundberg K, Groth O [1986]. Animal model for assessment of skin irritancy. Contact 

Dermatitis 15(3):143–151.

*ATSDR [2014]. Draft toxicological profile for trichloroethylene. US Department of Health and Human 

Services (HHS), Public Health Service, ATSDR, 

http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=173&tid=30. Accessed: 01-22-15.

*Axelson O, Selden A, Andersson K, Hogstedt C [1994]. Updated and expanded Swedish cohort study 

on trichloroethylene and cancer risk [1994]. J Occup Med 36(5): 556-562.

*Bakke B, Stewart PA, Waters MA [2007]. Uses of and exposure to trichloroethylene in U.S. industry: a 

systematic literature review. J Occup Environ Hyg 4(5): 375-390.

*Bauer M, Rabens SF [1974]. Cutaneous manifestations of trichloroethylene toxicity. Arch Dermatol 

110(6):886–890.

†Bauer M, Rabens SF [1977]. Trichloroethylene toxicity. Int J Dermatol 16:113–116.

*Bogen KT, Colston BW Jr, Machicao LK [1992]. Dermal absorption of dilute aqueous chloroform, 

trichloroethylene, and tetrachloroethylene in hairless guinea pigs. Fund Appl Toxicol 18(1):30–39.

*Conde-Salazar L, Guimarciens D, Romero LV, Yus ES [1983]. Subcorneal pustular eruption and 

erythema from occupational exposure to trichloroethylene. Contact Dermatitis 19:235–237.

*Dai Y, Leng S, Li L, Niu Y, Huang H, Liu Q, Duan H, Cheng J, Liu Q, Zheng Y [2009]. Effects of 

genetic polymorphisms of N-Acetyltransferase on trichloroethylene-induced hypersensitivity dermatitis 

among exposed workers. Ind Health 47(5): 479-486.

*Dow Chemical Company [1956]. Results of skin absorption studies on carbon tetrachloride, ethylene 

dichloride, tetrachlorethylene, trichloroethylene, and chlorothene. Midland, MI: Dow Chemical 

Company. On file with the U.S. Environmental Protection Agency under TSCA Section 8D. OTS 

#0515981. Document #86-870002191.
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.

†ECB (European Chemical Bureau) [2004]. European Union risk assessment report: trichloroethylene. 

In: Existing chemicals risk assessment report, http://echa.europa.eu/documents/10162/83f0c99f-f687-

4cdf-a64b-514f1e26fdc0. Accessed: 01-22-15.

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

Commercial Chemical Substances), http://ecb.jrc.ec.europa.eu/esis/. Accessed: 08-14-13.

*European Parliament, Council of the European Union [2008]. Regulation (EC) No 1272/2008 of the 

European Parliament and of the Council of 16 December 2008 on classification, labeling and packaging 

of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and 

amending Regulation (EC) No 1907/2006. OJEU, Off J Eur Union L353:1–1355, 

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

01-22-15.

*El Ghawabi SM, Mansoor MB, El Gamel MS, El Saharti AA, El Enany FF [1973]. Chronic 

trichloroethylene exposure. J Egypt Med Assoc 56:715–724.

*Gash DM, Rutland K, Hudson NL, Sullivan PG, Bing G, Cass WA, Pandya JD, Liu M, Choi D, Hunter 

RL, Gerhardt GA, Smith CD, Slevin JT, Prince TS [2008]. Trichloroethylene: Parkinsonism and 

complex 1 mitochondrial neurotoxicity. Ann Neurol 63: 184-192.

*Hansen J, Sallmèn M, Seldèn AI, Anttila A, Pukkala E, Andersson K, Bryngelsson IL, RaaschouNielsen O, Olsen JH, McLaughlin JK [2013]. Risk of cancer among workers exposed to 

trichloroethylene: analysis of three Nordic cohort studies. J Natl Cancer Inst 105(12): 869-877.

*IARC (International Agency for Research on Cancer) [2014]. IARC monographs Trichloroethylene, 

Tetrachloroethylene, and some other chlorinated agents. Volume 106. In: IARC monographs on the 

evaluation of carcinogenic risks to humans, 

http://monographs.iarc.fr/ENG/Monographs/vol106/mono106.pdf. Accessed: 01-22-15.

*Jakobson I, Wahlberg JE, Holmberg B , Johanson G [1982]. Uptake via the blood and elimination of 

10 organic solvents following epicutaneous exposure of anesthetized guinea pigs. Toxicol Appl 

Pharmacol 63(2):18l–l87.

*Kamijima M, Wang H, Huang H, Li L, Shibata E, Lin B, Sakai K, Liu H, Tsuchiyama F, Chen J, 

Okamaura A, Huang X, Hisanaga N, Huang Z, Ito Y, Takeuchi Y, Nakajimi T [2008]. Trichloroethylene 

causes generalized hypersensitivity skin disorders complicated by hepatitis. J Occup Health 50: 328-

338.

*Karami S, Bassig B, Stewart PA, Lee KM, Rothman N, Moore LE, Lan Q [2013]. Occupational 

trichloroethylene exposure and risk lymphatic and haematopoietic cancers: a meta-analysis. Occup 

Environ Med 70(8): 591-599.
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 Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

*Kezic S, Monster AC, van de Gevel IA, Kruse J, Opdam JJ, Verberk MM [2001]. Dermal absorption 

of neat liquid solvents on brief exposures in volunteers. Am Ind Hyg Assoc J 62:2–18.

*Kinkead ER, Wolfe RE [1980]. Single oral toxicity of various organic compounds. J Am Coll Toxicol 

11(6):713.

*Kohlmuller D, Kochen W [1994]. Exhalation air analyzed in long-term postexposure investigations of 

acetonitrile and trichloroethylene exposures in two subjects. Clin Chem 40:1462–1464.

*Kronevi T, Wahlberg JE, Holmberg B [1981]. Skin pathology following epicutaneous exposure to 

seven organic solvents. Int J Tiss React 111(1): 21–30.

*Liu J [2009]. Clinical analysis of seven cases of trichloroethylene medicamentose-like dermatitis. 

Indust Health 47: 685–688.

*Nakai JS, Stathopulos PB, Campbell GL, Chu I, Li-Muller A, Aucoin R [1999]. Penetration of 

chloroform, trichloroethylene, and tetrachloroethylene through human skin. J Toxicol Environ Health 

58(3):157–170.

*Nakayama H, Kobayashi M, Takahashi M, Ageishi Y, Takano T [1988]. Generalized eruption with 

severe liver dysfunction associated with occupational exposure to trichloroethylene. Contact Dermatitis 

19(1):48–51.

†NIOSH (National Institute for Occupational Safety and Health) [1974]. Effects of trichloroethylene on 

behavioral performance capabilities. Behavioral toxicology: early detection of occupational hazards. 

Cincinnati, OH: U.S. Department of Health, Education, and Welfare, Public Health Service, Center for 

Disease Control, National Institute for Occupational Safety and Health, DHEW (NIOSH) Publication 

No. 74-126.

*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: 01-22-15.

*NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-22-15.

*NTP [2014]. Report on Carcinogens. Thirteenth Edition; U.S. Department of Health and Human 

Services, Public Health Service. National Toxicology Program, 

http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01-21-15.
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 Occupational 

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

*OSHA [ND]. Trichloroethylene. In: OSHA Occupational Chemical Database, 

https://www.osha.gov/chemicaldata/chemResult.html?recNo=684. Accessed: 01-22-15.

*Phoon WH, Chan MO, Rajan VS, Tan KJ, Thirumoorthy T, Goh CL [1984]. Stevens- Johnson 

syndrome associated with occupational exposure to trichloroethylene. Contact Dermatitis 10(5):270–

276.

*Poet TS, Corley RA, Thrall KD, Edwards JA, Tanojo H, Weitz KK, Hui X, Maibach HI, Wester RC 

[2000]. Assessment of the percutaneous absorption of trichloroethylene in rats and humans using 

MS/MS real time breath analysis and physiologically based pharmacokinetic modeling. Toxicol Sci 

56(1):61–72.

*Sato A, Nakajima T [1978]. Differences following skin or inhalation exposure in the absorption and 

excretion kinetics of trichloroethylene and toluene. Br J Ind Med 35(1):43–49.

*Shen T, Zhu QZ, Yang S, Wu CH, Zhang HF, Zhou CF, Zhang XJ [2008]. Trichloroethylene induced 

cutaneous irritation in BALB/c hairless mice: histopathological changes and oxidative damage. 

Toxicology 248:113–120.

*Smyth HF Jr, Carpenter CP, Weil CS, Pozzani UC, Striegel JA, Nycum JS [1969]. Range-finding 

toxicity data: list VII. Am Ind Hyg Assoc J 30(5):470-476.

*Stewart RD, Dodd HC [1964]. Absorption of carbon tetrachloride, trichloroethylene, 

tetrachloroethylene, methylene chloride, and 1,1,1-trichloroethane through the human skin. Am Ind Hyg 

Assoc J 25:439-446.

†Stewart RD, Dodd HC, Gay HH, Erley DS [1970]. Experimental human exposure to trichloroethylene. 

Arch Environ Health 20(1):64–71.

*Tang XJ, Li LY, Huang JX, Deng YY [2002]. Guinea pig maximization test for trichloroethylene and 

its metabolites. Biomed Environ Sci 15(2): 113–118.

*Tang XJ, Que B, Song X, Li S, Yang X, Wang H, Huang H, Kamuima M, Nakajima T, Lin Y, Li L 

[2008]. Characterization of liver injury associated with hypersensitive skin reactions induced by 

trichloroethylene in the guinea pig maximization test. J Occup Health 50:114–121.

*Tsuruta H [1978]. Percutaneous absorption of trichloroethylene in mice. Ind Health 16:145–148.

*UNECE (United Nations Economic Commission for Europe) [2007]. Part 3: health hazards. In: 

Globally harmonized system of classification and labelling of chemicals (GHS). 2nd Rev. Ed., 

http://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev02/English/03e_part3.pdf. 

Accessed: 01-22-15.
14

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.

*USEPA (United States Environmental Protection Agency) [2012]. Integrated Risk Information System 

(IRIS), http://www.epa.gov/iris/. Accessed: 08-14-13.

*USEPA [2014]. TSCA Work plan chemical risk assessment trichloroethylene: Degreasing, spot 

cleaning and arts and crafts uses. Washington, DC: US Environemntal Protection Agency, EPA 

Document # 740-R1-4002. 

*Van Duuren BL, Goldschmidt BM, Loewengart G, Smith AC, Melchionne S, Seldman I, Roth D 

[1979]. Carcinogenicity of halogenated olefinic and aliphatic hydrocarbons in mice. J Natl Cancer Inst 

63(6):1433–1439.

*Wahlberg JE [1984a]. Edema-inducing effects of solvents following topical administration. Derm 

Beruf Umwelt 32(3):91–94.

*Wahlberg JE [1984b]. Erythema-inducing effects of solvents following epicutaneous administration to 

man: studied by laser Doppler flowmetry. Scand J Work Environ Health 10(3):159–162.

*Watanabe H, Tohyama M, Kamijima M, Nakajima T, Yoshida T, Hashimoto K, Lijima M [2010]. 

Occupational tricholoroethylene hypersensitivity syndrome with human herpesvirus-6 and 

cytomegalovirus reactivation. Dermatology 221: 17-22.

*Xu X, Yang R, Wu N, Zhong P, Ke Y, Zhou L, Yuan J, Li G, Huang H, Wu B [2009]. Severe 

hypersensitivity dermatitis and liver dysfunction induced by occupational exposure to trichloroethylene. 

Industrial Health 47: 107-112.

*Yu J, Leng J, Shen T, Zhou C, Xu H, Jiang T, Xu S, Zhu Q [2012]. Possible role of complement 

activation in renal impairment in trichloroethylene-sensitized guinea pigs. Toxicology 302: 172-178.
15

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: Calculation of the SI Ratio for TCE

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

TCE. Although the SI ratio is considered in the determination of a substance’s hazard potential 

following skin contact, it is intended only to serve as supportive data during the assignment of the 

NIOSH SK. An in-depth discussion on the rationale and calculation of the SI ratio can be found in 

Appendix B of the Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin 

Notations [NIOSH 2009]. 

Overview 

The SI ratio is a predictive algorithm for estimating and evaluating the health hazards of skin exposure 

to substances. The algorithm is designed to evaluate the potential for a substance to penetrate the skin 

and induce systemic toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the 

proposed strategy for assigning SYS notation are as follows:

(1) Provide an alternative method to evaluate substances for which no clinical reports or animal 

toxicity studies exist or for which empirical data are insufficient to determine systemic effects.

(2) Use the algorithm evaluation results to determine whether a substance poses a skin absorption 

hazard and should be labeled with the SYS notation.

The algorithm evaluation includes three steps:

(1) determining a skin permeation coefficient (kp) for the substance of interest,

(2) estimating substance uptake by the skin and respiratory absorption routes, and 

(3) evaluating whether the substance poses a skin exposure hazard.

The algorithm is flexible in the data requirement and can operate entirely on the basis of the 

physicochemical properties of a substance and the relevant exposure parameters. Thus, the algorithm is 

independent of the need for biologic data. Alternatively, it can function with both the physicochemical 

properties and the experimentally determined permeation coefficient when such data are available and 

appropriate for use.

The first step in the evaluation is to determine the kp for the substance to describe the transdermal 

penetration rate of the substance [NIOSH 2009]. The kp, which represents the overall diffusion of the 

substance through the stratum corneum and into the blood capillaries of the dermis, is estimated from 

the compound’s molecular weight (MW) and base-10 logarithm of its octanol–water partition coefficient 

(log KOW). In this example, kp is determined for a substance with use of Equation 1. A self-consistent set 

of units must be used, such as outlined in Table A1. Other model-based estimates of kp may also be used 

[NIOSH 2009].
16

This information is distributed solely for the purpose of pre-dissemination peer review under applicable 

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

Safety and Health. It does not represent and should not be construed to represent any agency determination or 

policy.

Equation 1: Calculation of Skin Permeation Coefficient (kp)

psc pol aq

p

k k k

k

1 1

1







where kpsc is the permeation coefficient in the lipid fraction of the stratum corneum, kpol is the coefficient 

in the protein fraction of the stratum corneum, and kaq is the coefficient in the watery epidermal layer. 

These components are individually estimated by

log kpsc = −1.326 + 0.6097 × log Kow − 0.1786 × MW0.5

kpol = 0.0001519 × MW−0.5

kaq = 2.5 × MW−0.5

The second step is to calculate the biologic mass uptake of the substance from skin absorption (skin 

dose) and inhalation (inhalation dose) during the same period of exposure. The skin dose is calculated as 

a mathematical product of the kp, the water solubility (SW) of the substance, the exposed skin surface 

area, and the duration of exposure. Its units are milligrams (mg). Assume that the skin exposure 

continues for 8 hours to unprotected skin on the palms of both hands (a surface area of 360 squared 

centimeters [cm2]). 

Equation 2: Determination of Skin Dose

Skin dose = kp × Sw × Exposed skin surface area × Exposure time

 = kp(cm/hour) × Sw (mg/cm3) × 360 cm2× 8 hours

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

substance—if the OEL is developed to prevent the occurrence of systemic effects rather than 

sensory/irritant effects or direct effects on the respiratory tract. Assume a continuous exposure of 8 

hours, an inhalation volume of 10 cubic meters (m3) inhaled air in 8 hours, and a factor of 75% for 

retention of the airborne substance in the lungs during respiration (retention factor, or RF).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation volume × RF

 = OEL (mg/m3) × 10 m3× 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of 

skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates (1) the significance of 

dermal absorption as a route of occupational exposure to the substance and (2) the contribution of 
17

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.

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 TCE. The calculated SI ratio was 0.02. On the basis of these

results, TCE is not predicted to represent a skin absorption hazard.

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

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr 0.01266

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol) cm/hr 1.32519 x 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.21810

Molecular weight (MW)

a

amu 131

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

a None 2.42

Calculated skin permeation coefficient (kp) cm/hr 0.01197

Skin dose

Water solubility (Sw)

a mg/cm3

1.28

Calculated skin permeation coefficient (kp) cm/hr 0.01197

Estimated skin surface area (palms of hand) cm2360

Exposure time hr 8

Calculated skin dose mg 44.14

Inhalation Dose

Occupational exposure limit (OEL)b mg/m3268

Inhalation volume m

3

10

Retention factor (RF) None 0.75

Inhalation dose mg 2010

Skin dose–to–inhalation dose (SI) ratio None 0.02

aVariables identified from SRC [ND].

b

The OEL used in calculation of the SI ratio was the NIOSH-recommended exposure limit (REL) 

[NIOSH 2005].
18

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: 03-08-11.

NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 

2009-147, http://www.cdc.gov/niosh/docs/2009-147/pdfs/2009-147.pdf. Accessed: 01-22-15.

SRC [ND]. Interactive PhysProp database demo, 

http://esc.syrres.com/fatepointer/webprop.asp?CAS=79016. Accessed: 01-22-15.