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 Healthii

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## 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) P ublication No. XXX

DHHS (NIOSH) Publication No. XXXiii

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## Foreword

As the largest organ of the body, the skin performs multiple critical functions, such as serving as the primary barrier to the external environment. For this reason, the skin is often exposed to potentially hazardous agents, including chemicals, which may contribute to the onset of a spectrum of adverse health effects ranging from localized damage (e.g., irritant contact dermatitis and corrosion) to induction of immune

- mediated responses (e.g. , allergic contact dermatitis and pulmonary responses), or 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 respo nses caused by skin contact with chemicals. The key step within assignment of the hazard

- specific SK is the determination of the hazard potential of the substance , or its potential for causing adverse health effects as a result of skin exposure. This deter mination entails a health hazard identification process that involves use of the following:

 Scientific data on the physicochemical properties of a chemical

 Data on human exposures and health effects

 Empirical data from in vivo and in vitro laboratory test ing

 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 workplac es

— so that improved risk

management 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 Co ntrol and Preventioniv

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupatio nal 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 G ENERAL S UBSTANCE I NFORMATION

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

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

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

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

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

3.0 DIRECT EFFECTS O N SKIN (SK: DIR)

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

4.0 IMMUNE

- MEDIATED RESPONSES ( SK: SEN)

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

5.0 SUMMARY

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

REFERENCES

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

APPENDIX: CALCULATIO N OF THE SI RATIO FO R TCE

................................ ................................ ........... 15

O VERVIEW

................................ ................................ ................................ ................................ ............................... 15
A PPENDIX R EFERENCES

................................ ................................ ................................ ................................ ........... 18v

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

cm 2 squared centimeter(s)
cm/hour centimeter(s) per hour

DEREK Deductive Estimation of Risk from Existing Knowledge

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

contact with a chemical
EC European Commission
GHS G lobally Harmonized System for Classification and Labelling of Chemicals
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
k aq coefficient in the watery epidermal layer
k p skin permeation coefficient
k pol coefficient in the protein fraction of the stratum corneum
k ps c permeation coefficient in the lipid fraction of the stratum corneum

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

LD Lo dermal lethal dose
LLNA local lymph node assay
LOAEL lowest

- observed

- adverse

- effect level log K OW base

- 10 logarithm of a substance’s octanol

– water partition

M molarity

m 3 cubic meter(s)

mg milligram(s) mg/kg milligram(s) per kilogram body weight mg/m 3 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 skinvi

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 Occupatio nal 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
S W solubility in water
SYS skin notation indicating the potential for systemic toxicity foll owing exposure of
the skin
USEPA United States Environmental Protection Agency
w/w weight by weight percentagevii

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

Cance r

— Any one of a group of diseases that occurs when cells in the body become abnormal and grow or multiply out of control.

Contaminant

— A chemical that is ( 1 ) unintentionally present within a neat substance or mixture at a concentration less than 1.0% or ( 2 ) recognized as a potential carcino gen and present within a
neat substance or mixture at a concentration less than 0.1%.

Cutaneous (or percutaneous)

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

Dermal

— Referring to the skin.

Dermal contact

— Contact with ( touching) the skin.

Direct effects

— Localized, non

- immune

- mediated adverse health effects on the skin, including corrosion, primary irritation, changes in skin pigmentation, and reduction/disruption of the skin barrier integrity, oc curring at or near the point of contact with chemicals.

Immune

- mediated responses

— Responses mediated by the immune system, in cluding allergic

responses.

Sensitization

— A specific immune

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

- exposure, can lead to allergic contact derma titis (ACD) or other
immune

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

- exposure.

Substance

— A chemical.

Systemic effects

— Systemic toxicity associated with skin absorption of chemicals after exposure of the skin.viii

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

Divi sion 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 Laboratoryix

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 Occupatio nal 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 Surv eillance, 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 comme nts that contributed to the development or improvement of this document:

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

 Dori Germolec, Ph.D., National Toxicology Program, National Institute for Environmental Health Sciences, Research Triangle, NC

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

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

 James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH1

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupatio nal 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: C 2 HCl 3 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 clea ning 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 Strateg y 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 t o 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

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupatio nal 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 der mally 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 Na kajima [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 co ncentration 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

exp osure 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 ( k

p ) values for TCE were 0.019 and 0.015 centimeters per hour (cm/hr) following water

patch 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 vola r forearm over an area of 27 square centimeters (cm 2 ) for 1 minute [Kezic et al. 2001]. Kezic et3

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 Occupatio nal 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/cm 2 per minute (nmol/cm 2 /min).

Several experimental studies of the dermal absor ption 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. T he 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/cm 2 /min [Tsuruta 1978]. Jakobsen et al. [1982] used guinea pigs to investigate the der mal 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 3 0 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 k p 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 alu minum dermal absorption block method reported by Moody et al. [1992], Nakai et al. [1999] reported a k p 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 predic tive 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
contrib ute 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 app endix. 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].

Altho ugh no estimate of the dermal lethal dose (LDLo) for humans has been identified, dermal LD 50 (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 e t al.1969]. Because the reported
acute dermal LD 50 value is greater than the critical dermal LD 50 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 pai rs 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 renal4

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupatio nal 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 t o 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 wa s 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 ha d 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 hospitali zed 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 clean ing 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. [20 08] 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 over time, 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 midbr ain 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 publi shed 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 non

Hodgkin’s lymphoma (relative risk=1.93; CI: 1.14 to 1.54) for all cohort and case

- control studies5

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 Occupatio nal 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; U SEPA = 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 t oxicokinetic 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 substan ce , 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 dat a, 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 inv olved 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 Occupatio nal Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. and dermatitis [Stewart and Dodd 196 4; 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 fo r 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 varyin g 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 wit h 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 [Smy th 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 cm 2 shaved 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 concent rations 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 inf lammation [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 ther e 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 applicati on); 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 p romotion 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 Occupatio nal 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]
report ed 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 TCE

induced 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 metabo lic 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 wor ker 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 a nd 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 c hallenged 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). T hree 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 ide ntified. 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 followed8

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 Occupatio nal 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 ca used 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 expose d 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 injuri es 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 li ver 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 m g/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 delayed

type hypersensitivity in guinea pigs. Predictions from structure

- activity relationship models provide
some inform ation 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 sensitizin g 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 occu pational 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 undilu ted 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 in9

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 Occupatio nal 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
mathe matical 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 f rom 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 pre vious 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 Occupatio nal 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.

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*Anderson C, Sundberg K, Groth O [1986]. Animal model for assessment of ski n irritancy. Contact
Dermatitis 15 (3):143

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*ATSDR [ 2014 ]. Draft t oxicological 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 . Acc essed: 01

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*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

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*Bauer M, Rabens SF [1974]. Cutaneous manifestations of trichloroethylene toxicity. Arch Dermatol
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†Bauer M, Rabens SF [1977]. Trichloroethylene toxicity. Int J Dermatol 16 :113

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*Bogen KT, Colston BW Jr, Machicao LK [1992]. Dermal absorption of dilute aqueous chloroform, trichloroethylene, and tetrachloroethylene in hairl ess guinea pigs. Fund Appl Toxicol 18 (1):30

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*Conde

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*Dow Chemical Company [1956]. Re sults 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
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*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

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*Karami S, Bassig B, Stewart PA, Lee KM, Rothman N, Moore LE, Lan Q [2013]. Occupational
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*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 Hea lth, DHHS (NIOSH) Publication No.
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## 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. A n 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 ( k p ) for the substance of interest, (2) estimating substance uptake by the skin and respiratory absorption routes, and (3) evaluating whether the substance poses a skin exposure hazard.

The algorithm is flexible in the data requirement and can operate entirely on the basis of the physicochemical 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 experimentall y determined permeation coefficient when such data are available and appropriate for use.

The first step in the evaluation is to determine the k p for the substance to describe the transdermal penetration rate of the substance [NIOSH 2009]. The k p , which represents the overall diffusion of the substance through the stratum corneum and into the blood capillaries of the dermis, is estimated from the compound’s molecular weight ( MW ) and base

- 10 logarithm of its octanol

– water partition coefficient (log K

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

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

- based estimates of k p may also be used [NIOSH 2009].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 Occupatio nal Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. Equation 1: Calculation of Skin Permeation Coefficient ( k p )

where k

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

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

k pol = 0.0001519 × MW −0.5

k aq = 2.5 × MW

−0.5

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

W ) of the substance, the exposed skin surface area, and the duration of exposure. Its units are milligrams (mg). Assume that the skin exposure continues for 8 hours to unprotected skin on the palms of both hands (a surface area of 360 squared
centi meters [cm 2 ]).

Equation 2: Determination of Skin Dose

Skin dose = k

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

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

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

— if the OEL is developed to prevent the occurrence of systemic effects rather than sensory/irritant effects or direct effects on the respiratory tract. Assume a continuous exposure of 8 hours, an inhalation volume of 10 cubic me ters (m 3 ) inhaled air in 8 hours, and a factor of 75% for retention of the airborne substance in the lungs during respiration (retention factor, or RF).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation volume × RF

= OEL (mg/m 3 ) × 10 m 3 × 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates ( 1 ) the significance of
dermal absorption as a route of occupational exposure to the substance and ( 2 ) the contribution of17

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 Occupatio nal 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 use d to Calculate the SI Ratio for Trichloroethylene

Variables Used in Calculation Units Value Skin permeation coefficient Permeation coefficient of stratum corneum lipid path( k psc ) cm/hr 0.01266 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hr 1.32519 x 10 - 5
Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.21810 Molecular weight ( MW

) a amu 131
Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) a None 2.42 Calculated skin permeation coefficient ( k p ) cm/hr 0.01197
Skin dose
Water solubility ( S w ) a mg/cm 3 1.28 Calculated skin permeation coefficient ( k p ) cm/hr 0.01197 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8
Calculated skin dose mg 44.14
Inhalation Dose Occupational exposure limit (OEL) b mg/m 3 268

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

a Variables 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 Occupatio nal 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 (NIO SH) 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

.