NIOSH Skin Notation Profile

Chlorodiphenyl (42% Chlorine)

Centers for Disease Control

and Prevention

National Institute for Occupational 

Safety and Health
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NIOSH Skin Notation Profile

Chlorodiphenyl (42% Chlorine)

Naomi L. Hudson

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health 
ii Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

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Suggested Citation

NIOSH [2020]. NIOSH skin notation profile: chlorodiphenyl (42% chlorine). By Hudson NL. 

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

and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2021-100.

DHHS (NIOSH) Publication No. 2021-100

DOI: https://doi.org/10.26616/NIOSHPUB2021100

October 2020
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) iii

Foreword

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

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

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

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

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

of modern occupational safety and health programs. 

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

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

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

of multiple hazard-specific skin notations (SKs) that clearly distinguish between the systemic 

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

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

hazard potential of the substance, or its potential for causing adverse health effects as a result 

of skin exposure. This determination entails a health hazard identification process that involves 

use of the following:

• Scientific data on the physicochemical properties of a chemical

• Data on human exposures and health effects

• Empirical data from in vivo and in vitro laboratory testing

• Computational techniques, including predictive algorithms and mathematical models 

that describe a selected process (such as skin permeation) by means of analytical or 

numerical methods.

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

(42% chlorine). In particular, this document evaluates and summarizes the literature describing 

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

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

inform the audience—mostly occupational health practitioners, researchers, policy- and decision-makers, employers, and workers in potentially hazardous workplaces—so that improved 

risk-management practices may be developed to better protect workers from the risks of skin 

contact with the chemicals of interest.

John Howard, M.D.

Director, National Institute for

Occupational Safety and Health

Centers for Disease Control and Prevention
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Skin Notation Profile | Chlorodiphenyl (42% Chlorine) v

Contents

Foreword . .

Abbreviations . 

Glossary . . 

Acknowledgments . 

1 Introduction .

1.1 General Substance Information .

1.2 Purpose .

1.3 Overview of SK Assignment .

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

3 Direct Effects on Skin (SK: DIR) .

4 Immune-mediated Responses (SK: SEN) .

5 Summary .

References .

Appendix: Calculation of the SI Ratio for Chlorodiphenyl (42% Chlorine) .

Overview .

Calculation . 

Appendix References . 
vi Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

Abbreviations

ACGIH® American Conference of Governmental Industrial Hygienists 

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

ChE cholinesterase

cm2 square centimeter(s)

cm/hr centimeter(s) per hour

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

the skin following exposure 

DIR skin notation indicating the potential for direct effects to the skin following contact with a chemical

DMBA 7,12-dimethylbenz(a)antracene

ECHA European Chemicals Agency

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

hr hour(s)

IARC International Agency for Research on Cancer

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

exist to accurately assess the hazards of skin exposure 

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 

k

p skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

k

psc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LOAEL lowest-observed-adverse-effect level 

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

M molarity

m3 cubic meter(s)

mg milligram(s)

mg/cm3 milligram(s) per cubic centimeter

mg/kg milligram(s) per kilogram body weight

mg/min milligram(s) per minute

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level

NTP National Toxicology Program

ODC ornithine decarboxylase

OEL occupational exposure limit
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) vii

OSHA Occupational Safety and Health Administration

PCB polychlorinated biphenyl

ppb parts per billion

REL recommended exposure limit

RF retention factor 

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

exposure of the skin

SI ratio ratio of skin dose to inhalation dose

SK skin notation

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

SW solubility in water

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

the skin

TPA 12-O-tetradecanoylphorbol-13-acetate

US EPA United States Environmental Protection Agency 

μg microgram(s)

μL microliter(s)
viii Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

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 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 or other immunemediated diseases such as asthma, depending on the site and route of re-exposure.

Substance—A chemical.

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

of the skin.
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) ix

Acknowledgments

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

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

document was a report (Toxicology Excellence for Risk Assessment [TERA]) contracted by 

NIOSH and prepared by Bernard Gadagbui, Ph.D., and Andrew Maier, Ph.D.

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

reviewers:

• Howard Maibach, M.D., Dermatologist, University of California San Francisco, San Francisco, CA

• Emily N. Reinke, Ph.D., DABT, Biologist, Health Effects Division, Toxicology Directorate, 

U.S. Army Public Health Center, Gunpowder, MD

The following reviewers provided comments through an Intergovernmental Personnel 

Agreement:

• Annette L. Bunge, Ph.D., Colorado School of Mines, Golden, CO

• Leena A. Nylander-French, Ph.D., CIH, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC

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

notation profiles: 

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

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

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

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

• James Taylor, M.D., Industrial Dermatology, The Cleveland Clinic, Cleveland, OH 
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Skin Notation Profile | Chlorodiphenyl (42% Chlorine) 1

Chlorodiphenyl

1 Introduction

1.1 General Substance Information

Chemical: Chlorodiphenyl (42% chlorine)

CAS No: 53469-21-9

Molecular weight (MW):

258 (approximate)

Molecular formula: 

C6H4ClC6H3Cl2

Structural formula:

Image by National Center for Biotechnology Information [2020]

Synonyms: Aroclor® 1242, PCB, Polychlorinated biphenyl

Uses: Chlorodiphenyl (42% chlorine) has 

historically been used as a dielectric fluid, 

hydraulic fluid, and rubber plasticizer. Since 

1977, the substance has not been produced 

or used in the United States [National Center 

for Biotechnology Information 2020]. It should 

be noted that chlorodiphenyl (42% chlorine) 

may still be present in transformers and capacitors now in use.

1.2 Purpose

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological 

data associated with skin contact with chlorodiphenyl (42% chlorine) — a commercial 

mixture of polychlorinated biphenyl (PCB) 

compounds—and (2) the rationale behind the 

hazard-specific skin notation (SK) assignment 

for chlorodiphenyl (42% chlorine). 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 

chlorodiphenyl (42% chlorine). A search of 

all available relevant literature was conducted 

through January 2020 to identify information 

on chlorodiphenyl (42% chlorine) dermal 

absorption, acute toxicity, repeated-dose 

systemic toxicity, carcinogenicity, biological 

system/function–specific effects (including 

reproductive and developmental effects and 

immunotoxicity), irritation, and sensitization. 

Information was considered from studies of 

humans, animals, or appropriate modeling 

systems that are relevant to assessing the 

effects of dermal exposure to chlorodiphenyl 

(42% chlorine). The criteria for the search 

strategy, evaluation, and selection of data are 

described in Appendix E in the aforementioned CIB 61 [NIOSH 2009].

1.3 Overview of SK Assignment

Chlorodiphenyl (42% chlorine) is potentially 

capable of causing adverse health effects following skin contact. A critical review of 

available data has resulted in the following 

SK assignment for chlorodiphenyl (42% chlorine): SK: SYS-DIR (IRR). Table 1 provides an 

overview of the critical effects and data used 

to develop the SK assignment for chlorodiphenyl (42% chlorine).
2 Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

Chlorodiphenyl

Table 1. Summary of the SK assignments and supporting 

data for chlorodiphenyl (42% chlorine)

Skin notation Critical effect Available data

SK: SYS Hepatotoxicity; central nervous 

system effects 

Limited human and animal data

SK: DIR(IRR) Skin irritancy, chloracne, and 

pigmentation of nails and skin

Limited human and animal data

2 Systemic Toxicity from Skin 

Exposure (SK: SYS)

No in vivo human studies were identified that 

estimated the degree of absorption of chlorodiphenyl (42% chlorine) following dermal 

exposure. However, in vivo dermal absorption 

studies in monkeys and guinea pigs and in vitro 

dermal absorption studies in human skin were 

identified [Wester et al. 1983, 1990, 1993]. In 

a previous study, Wester and Maibach [1975] 

reported that percutaneous absorption in the 

Rhesus monkey showed the same absorption 

in humans for selected compounds, hydrocortisone, testosterone, and benzoic acid. Wester et 

al. [1983] applied 50 microliters (μL) of a chlorodiphenyl (42% chlorine) in 1:1 benzene/hexane 

solution to a 13-square-centimeter (cm2

) area 

of abdominal skin of Rhesus monkeys [corresponding to either 4.1 micrograms (μg) of 

chlorodiphenyl (42% chlorine) per square centimeter (μg/cm2

) or 19.3 μg/cm2], which was 

washed from the skin surface with soap and 

water after 24 hours. The authors reported the 

average total absorption into the skin of two 

animals that received 4.1 μg of applied chlorodiphenyl (42% chlorine) was 25.6% and the 

average for the two animals that received 19.3 

μg/cm2

 of applied chlorodiphenyl (42% chlorine) was 17.3%. The average mass of applied 

chlorodiphenyl (42% chlorine) absorbed was 

1.0 and 3.3 μg/cm2

, respectively. The average 

absorption into the skin of three guinea pigs 

was 33.2% after exposure to 4.6 μg/cm2

 of chlorodiphenyl (42% chlorine) applied in 50 μL of 

acetone to 11.4 cm2

 of skin on the back of the 

ears, which were washed with acetone and water 

after 24 hours [Wester et al. 1983]. However, less 

than 1% of the applied dose was recovered in 

the skin wash used by Wester et al. [1983] to 

clean chlorodiphenyl (42% chlorine) from the 

guinea pig skin.

Wester et al. [1990] applied 10 μL of a chlorodiphenyl (42% chlorine) solution to a 10 cm2 

area of abdominal skin of four Rhesus monkeys 

[corresponding to 4.1 μg/cm2

 of chlorodiphenyl 

(42% chlorine)] delivered in mineral oil or 4.0 

μg/cm2

 delivered in trichlorobenzene. The 

authors reported absorption into the skin over 

24 hours of 20.4% in the mineral oil solution and 

18.0% in the trichlorobenzene solution [Wester 

et al. 1990], which corresponds to 0.84 μg/cm2

and 0.72 μg/cm2

, respectively. In an in vitro study, 

1–2 μg/cm2

 of chlorodiphenyl (42% chlorine) in 

a mineral oil or trichlorobenzene solution was 

applied to human cadaver skin for 17 hours, 

and the reported absorption out of the skin was 

less than 1% [Wester et al. 1990]; the amount 

in the skin at the end of the skin exposure was 

not reported. Wester et al. [1993] also reported 

in vitro absorption of chlorodiphenyl (42% 

chlorine) after 24 hours on human cadaver 

skin from 4 μL/cm2

 of mineral oil and water at 

unspecified concentrations. The total amount of 

chlorodiphenyl (42% chlorine) that absorbed 

into the skin over 24 hours was reported to be 

10.1% from mineral oil [10.0 ± 16.5% (mean ± 

standard deviation) and 0.12 ± 0.07% were in 

the skin and receptor solution, respectively] and 

44.4% from water [42.9 ± 24.1% and 1.5 ± 1.3% 
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) 3

Chlorodiphenyl

were in the skin and receptor solution, respectively]. Some of the differences between vehicles 

probably is related to differences in evaporation 

of the solvent. Results from the in vivo dermal 

absorption studies show that chlorodiphenyl 

(42% chlorine) in the skin at the end of the exposure does absorb systemically. Given this, both 

the in vitro and in vivo results indicate that chlorodiphenyl (42% chlorine) is absorbed (more 

than 10% of the applied dose) through the skin 

following dermal exposure.

The potential for chlorodiphenyl (42% chlorine) to pose a skin absorption hazard was also 

evaluated with the NIOSH [2009] predictive 

algorithm for estimating and evaluating the 

health hazards of dermal exposure to chemical 

substances. The evaluation method compares 

an estimated chemical dose accumulated in the 

body from skin absorption to an estimated dose 

from respiratory absorption associated with a 

reference occupational exposure limit. Based 

on this algorithm, a ratio of skin dose to inhalation dose (the SI ratio) of 12.43 was estimated. 

An SI ratio of ≥0.1 indicates that skin absorption may significantly contribute to the overall 

body burden of a substance [NIOSH 2009]; 

therefore, chlorodiphenyl (42% chlorine) is 

considered to be a skin absorption hazard 

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

in its calculation are included in the appendix.

No estimate of the human dermal lethal dose 

(LDLo) was identified for chlorodiphenyl (42% 

chlorine). In animals, dermal LD50 (lethal dose 

in 50% of exposed animals) values ranged 

from 794 to 1269 milligrams per kilogram 

(mg/kg) for the undiluted chlorodiphenyl 

(42% chlorine) for rabbits [Fishbein 1974]. 

Because the reported dermal LD50 values for 

rabbits are lower than the critical dermal LD50

value of 2000 mg/kg that identifies chemical 

substances with the potential to be acutely 

toxic following dermal exposure [NIOSH 

2009], chlorodiphenyl (42% chlorine) is considered systemically available and acutely toxic 

following dermal exposure. 

Several epidemiological studies and clinical 

surveys of PCB-exposed workers have revealed 

hepatic effects including increased serum levels 

of liver related enzymes [Agency for Toxic Substances and Disease Registry (ATSDR) 2000]. 

Several occupational studies were also identified 

that examined workers who had occupational 

exposure to chlorodiphenyl (42% chlorine), 

where sequential or concurrent exposure to 

other chlorodiphenyl mixtures nearly always 

occurred [ATSDR 2000]. For example, Ouw et 

al. [1976] reported that 34 workers exposed to 

0.32 to 2.22 milligrams per cubic meter (mg/m3

) 

of chlorodiphenyl (42% chlorine), had a mean 

blood chlorodiphenyl (42% chlorine) level of 394 

parts per billion (ppb); no chlorodiphenyl (42% 

chlorine) was detected in the blood of 30 individuals that served as a control group. A subgroup 

of the exposed workers, consisting of workers in 

the handling process, had excessive skin absorption due to the exposure to hot chlorodiphenyl 

(42% chlorine); however, while 4 of 7 of these 

workers had abnormal hepatic function in tests 

(there was no history of drug or alcohol use or 

hepatitis in these workers), the mean value for 

the whole group was within normal limits [Ouw 

et al. 1976]. Maroni et al. [1981] evaluated the 

health of 80 workers with long occupational 

exposure (an average of 12 years) to PCB 

mixtures, with 42% mean chlorine content, in 

electric capacitor manufacturing and testing 

plants. Absorption of PCBs in these workers 

had occurred mainly through the skin, but the 

relative contribution of the dermal route to the 

total exposure in the workers was unknown. The 

workers had blood PCB concentrations ranging 

from 41 to 1319 micrograms per kilogram body 

weight (μg/kg). The authors reported that 16 of 

the 80 workers had signs of pronounced hepatic 

involvement, consisting most often of hepatomegaly (abnormal enlargement of the liver) with 

an increase in several serum enzymes including 

gamma-glutamyl transferase, aspartate transaminase, alanine transaminase, and ornithine 

carbamyl transferase. Fischbein et al. [1979] 

also reported central nervous system effects as 

one of the most prevalent symptoms among 

326 capacitor workers employed at two capacitor manufacturing facilities where dielectric 

fluids containing various mixtures of PCBs (i.e., 

Aroclor 1254, 1242, and others) had been extensively used for approximately 30 years. About 
4 Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

Chlorodiphenyl

Table 2. Summary of the carcinogenic designations for chlorodiphenyl 

(42% chlorine) by governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] Potential occupational carcinogen

NTP [2011] Reasonably anticipated to be a human carcinogen

US EPA [2020] No designation

ECHA [2020] No GHS designation

IARC [2016] 1: Carcinogenic to humans

ACGIH® [2001] No designation

ACGIH® = American Conference of Governmental Industrial Hygienists; ECHA = European Chemicals Agency; GHS = Globally 

Harmonized System for Classification and Labelling of Chemicals; IARC = International Agency for Research on Cancer; NIOSH = 

National Institute for Occupational Safety and Health; NTP = National Toxicology Program; US EPA = United States Environmental 

Protection Agency.

40% of the workers were employed for 20 years 

or longer, and the prevalence of abnormal liver 

findings in these workers was low [Fischbein 

et al. 1979]. These epidemiological and occupational exposure studies involved inhalation 

and dermal routes, but the relative contribution 

by each route was unknown. However, PCBs 

are known to be absorbed by humans through 

ingestion, inhalation, and dermal routes, after 

which they are transported similarly through the 

systemic circulation [ATSDR 2000]. Similarity 

in the mode of transport indicates that different 

routes of exposure to chlorodiphenyl (42% 

chlorine) and other PCB mixtures can produce 

similar systemic effects. 

No repeat-dose, subchronic, or chronic toxicity studies involving animals were identified 

that specifically investigated the potential for 

chlorodiphenyl (42% chlorine) alone to cause 

systemic effects following dermal exposure. 

No standard toxicity or specialty studies 

were identified that evaluated the biological 

system/function–specific effects (including 

reproductive and developmental effects and 

immunotoxicity) following dermal exposure to 

chlorodiphenyl (42% chlorine).

No epidemiological studies or animal bioassays were identified that evaluated the 

potential for chlorodiphenyl (42% chlorine) 

to be carcinogenic in humans or animals. Table 

2 summarizes the carcinogenic designations for 

chlorodiphenyl (42% chlorine) from governmental and nongovernmental agencies.

Although no in vivo studies were identified for humans that estimated the degree of 

absorption for chlorodiphenyl (42% chlorine) 

following dermal exposure, in vivo dermal 

absorption studies in monkeys and guinea pigs 

[Wester et al. 1983, 1990] and in vitro dermal 

absorption studies in human skin [Wester et al. 

1993], supported by results of a mathematical 

model prediction, indicate that chlorodiphenyl 

(42% chlorine) is readily absorbed through 

the skin. An acute dermal toxicity study [Fishbein 1974] and several epidemiological and 

occupational exposure studies that involved 

both inhalation and dermal exposures to PCB 

mixtures or chlorodiphenyl (42% chlorine) 

with sequential or concurrent exposure to 

other chlorodiphenyl compounds [Ouw et 

al. 1976; Fischbein et al. 1979; Maroni et al. 

1981] indicate that PCBs have the potential 

to be acutely toxic and may cause systemic 

toxicity including liver and central nervous 

system effects. On the basis of available data, 

chlorodiphenyl (42% chlorine) is assigned the 

SK: SYS notation.

*

References in bold text indicate studies that serve 

as the basis of the SK assignments.
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) 5

Chlorodiphenyl

3 Direct Effects on Skin (SK: DIR)

No human or animal in vivo studies on corrosivity of chlorodiphenyl (42% chlorine) 

or in vitro tests for corrosivity using human 

skin models or in vitro tests of skin integrity 

using cadaver skin were identified. There is 

limited information on humans that indicates 

that chlorodiphenyl (42% chlorine) is irritating to the skin. Ouw et al. [1976] reported 

that 34 employees exposed to air concentrations of 0.32–2.22 mg/m3

 of chlorodiphenyl 

(42% chlorine) for 5–23 years experienced 

sensations of burning skin. Of these workers, 

one developed chloracne (an acne-like skin 

eruption of blackheads, cysts, and pustules 

associated with over-exposure to certain 

halogenated aromatic compounds, including 

PCBs and dioxins) but did not exhibit systemic symptoms such as anorexia, nausea, 

edema of the face and hands, or abdominal 

pain [Ouw et al. 1976]. Fischbein et al. [1979] 

examined the dermatological effects among 

326 capacitor-manufacturing workers handling various mixtures of PCBs [including 

chlorodiphenyl (42% chlorine)] at two facilities. The overall prevalence of dermatological 

symptoms was high, with 76 (45%) of the male 

workers and 87 (55%) of the female workers 

reporting a history of dermatologic symptoms. Skin rash, the most prevalent symptom, 

was reported by 128 workers (39%), acne by 

35 workers (11%), thickening of the skin by 12 

workers (3%), and pigmentation disturbances 

(darkening) and discoloration of the nails by 

8 workers each (3%). Although a mixture of 

chlorodiphenyls was used in these facilities, 

it is not specified whether these effects were 

caused by direct dermal contact with chlorodiphenyl (42% chlorine) or if they were a 

systemic effect resulting from dermal contact 

and inhalation of chlorodiphenyl (42% chlorine). Smith et al. [1982] investigated direct 

skin effects in cross-sectional surveys of 228 

workers occupationally exposed to PCBs in an 

electrical equipment plant. The greatest exposure to chlorodiphenyl (42% chlorine) was 

presumed to occur during the manufacture 

of electrical power capacitors. Skin wipes of 

selected workers indicated work-related skin 

contamination by PCBs. Although none of 

the participants was found to have acneform 

lesions suggestive of chloracne, rash or dermatitis was reported by some workers [Smith 

et al. 1982]. Direct skin effects including skin 

irritation, chloracne, and pigmentation of 

nails and skin have also been observed in 

humans following occupational exposure to 

PCBs [ATSDR 2000].

A study in mice has shown that chlorodiphenyl 

(42% chlorine) may be a tumor co-promoter 

in the skin. Dwivedi and Sitzman [1998] 

applied a mixture of 600 μg chlorodiphenyl 

(42% chlorine) alone or in combination with 

2.5 nanomoles (nmol) of 12-O-tetradecanoylphorbol-13-acetate (TPA) in acetone to 

the shaved skin of mice for 5 hours. Epidermal 

ornithine decarboxylase (ODC) activity—a 

prominent feature among the various biochemical changes observed during tumor 

promotion—was slightly but significantly 

increased in the skin following exposure to 

chlorodiphenyl (42% chlorine) alone [Dwivedi 

and Sitzman 1998]. When applied with TPA, 

chlorodiphenyl (42% chlorine) caused a synergistic effect on the induction of ODC activity 

in the skin, indicating the potential for the test 

substance to act as a tumor co-promoter with 

TPA [Dwivedi and Sitzman 1998]. To test the 

tumor promotion qualities of chlorodiphenyl 

(42% chlorine), the authors applied 200 nmol 

of the tumor initiator, 7,12-dimethylbenz(a)

antracene (DMBA), to the shaved backs of 

mice [Dwivedi and Sitzman 1998]. One 

week after DMBA treatment, either TPA 

(2.5 or 5 nmoles) in acetone, 600 μg of chlorodiphenyl (42% chlorine) in acetone, or a 

combination of chlorodiphenyl (42% chlorine) and TPA (2.5 nmols) was applied to the 

shaved backs of the mice twice a week for 24 

weeks. Chlorodiphenyl (42% chlorine) alone 

did not significantly increase skin papilloma 

development in any of the mice; however, a 

combination of chlorodiphenyl (42% chlorine) 

and TPA caused a significant decrease in the 

incidence (number of papillomas per mouse) 

or multiplicity (mean number) of papillomas 

per mouse when compared with TPA alone 

[Dwivedi and Sitzman 1998].
6 Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

Chlorodiphenyl

Limited data were identified from occupational exposure studies that likely involved 

both dermal and inhalation routes [Ouw 

1976; Fischbein et al. 1979, 1982; Smith et al. 

1982] that indicate that chlorodiphenyl (42% 

chlorine) has the potential to cause direct 

skin effects including irritation, chloracne, 

and pigmentation of nails and skin. In mice, 

chlorodiphenyl (42% chlorine) alone slightly 

increased mouse epidermal ODC activity, but 

in combination with TPA there was a synergistic 

effect on ODC activity [Dwivedi and Sitzman 

1998]. Because PCBs are mixtures of chlorodiphenyls and chloracne has been observed 

to be associated with PCBs, it is concluded 

that chlorodiphenyl (42% chlorine) has the 

potential to cause direct skin effects including 

skin irritation, chloracne, and pigmentation 

of nails and skin following dermal exposure. 

Therefore, chlorodiphenyl (42% chlorine) is 

assigned an SK: DIR(IRR) notation.

4 Immune-mediated 

Responses (SK: SEN)

No occupational exposure studies, diagnostic 

(human patch) tests or predictive tests in animals (for example, guinea pig maximization 

tests, Buehler tests, murine local lymph node 

assays, or mouse ear swelling tests), or any other 

studies were identified that evaluated the potential of chlorodiphenyl (42% chlorine) to cause 

skin sensitization. In the absence of relevant data, 

chlorodiphenyl (42% chlorine) is not assigned a 

SK: SEN notation.

5 Summary

No in vivo toxicokinetic studies were identified 

for humans that estimated the degree of absorption for chlorodiphenyl (42% chlorine) following 

dermal exposure in humans. In vivo toxicokinetic studies in monkeys [Wester et al. 1990], 

supported by results of a mathematical model 

prediction, indicate that chlorodiphenyl (42% 

chlorine) is readily absorbed through the skin. 

An acute animal study [Fishbein 1974] indicates 

that following dermal exposure, chlorodiphenyl 

(42% chlorine) has the potential to be absorbed 

through the skin, become systemically available, 

and cause acute toxicity. No epidemiological or 

occupational exposure studies and no repeatdose, subchronic or chronic toxicity studies in 

animals were identified that specifically evaluated 

the potential for chlorodiphenyl (42% chlorine) alone to cause systemic effects following 

dermal exposure. Several studies in humans that 

involved both inhalation and dermal exposures 

to PCB mixtures or chlorodiphenyl (42% chlorine) with sequential or concurrent exposure to 

other chlorodiphenyls [Ouw et al. 1976; Fischbein et al. 1979; Maroni et al. 1981] indicate 

that PCBs can cause systemic toxicity including 

hepatotoxicity. Although no standard irritation tests were identified in animals, limited 

data from occupational exposure studies [Ouw 

1976; Fischbein et al. 1979; Maroni et al. 1981; 

Smith et al. 1982] indicate that chlorodiphenyl 

(42% chlorine) has the potential to cause direct 

skin effects including irritation, chloracne, and 

pigmentation of nails and skin. Chlorodiphenyl 

(42% chlorine) alone induced ODC activity in 

mouse epidermis or, in combination with TPA, 

produced a synergistic effect on this activity 

[Dwivedi and Sitzman 1998]. No diagnostic 

(human patch) tests or predictive tests in 

animals were identified that evaluated the 

potential of the substance to cause skin sensitization. On the basis of the available data, 

chlorodiphenyl (42% chlorine) is assigned a 

composite SK: SYS-DIR(IRR) notation.

Table 3 summarizes the skin hazard designations for chlorodiphenyl (42% chlorine) 

previously issued by NIOSH and other organizations. There were no equivalent dermal 

designations for chlorodiphenyl (42% chlorine) according to the Globally Harmonized 

System (GHS) for Classification and Labelling 

of Chemicals [ECHA 2020].

References

Note: Asterisks (*) denote sources cited in 

text; daggers (†) denote additional resources.

*ACGIH [2001]. Chlorodiphenyl: documentation 

of threshold limit values and biological exposure 

indices. 7th Ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) 7

Chlorodiphenyl

Table 3. Summary of previous skin hazard designations for 

chlorodiphenyl (42% chlorine) from NIOSH and other organizations

Organization Skin hazard designation

NIOSH [2005] No designation

OSHA [2019] [skin]: Potential for dermal absorption

ACGIH® [2001] [skin]: Potential for dermal absorption

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

Health; OSHA = Occupational Safety and Health Administration.

*ATSDR [2000]. Toxicological profile for chlorodiphenyl (42% chlorine). Atlanta, GA: Agency for 

Toxic Substances and Disease Registry. 

†Bertazzi PA, Riboldi L, Pesatori A, Radice L, 

Zocchetti C [1987]. Cancer mortality of capacitor manufacturing workers. Am J Ind Med 

11:165–176.

†Cook JW [1970]. Status report on the chemistry 

and toxicology of PCBs, June 1. Washington, 

DC: U.S. Food & Drug Administration. 

*Dwivedi C, Sitzman J [1998]. Effects of polychlorinated biphenyls on skin tumor development 

and epidermal ornithine decarboxylase activity. 

Res Comm Pharm Tox 3(1–2):65–75.

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

to CLP. European Chemicals Agency, https://

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

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

*Fischbein A, Wolff MS, Lilis R, Thomton J, 

Selifoff IJ [1979]. Clinical findings among PCBexposed capacitor manufacturing workers. Ann 

NY Acad Sci 320:703–715.

†Fischbein A, Thornton J, Wolff MS, Bernstein J, Selifoff IJ [1985]. Dermatological findings in capacitor 

manufacturing workers exposed to dielectric fluids 

containing polychlorinated biphenyls (PCBs). 

Arch Environ Health 37:69–74.

*Fishbein L [1974]. Toxicity of chlorinated biphenyls. Ann Rev Pharmacol 14:139–156.

*IARC [2012]. Polychlorinated biphenyls and 

polybrominated biphenyls. In: IARC monographs on the evaluation of carcinogenic 

risks to human, Vol 107. Lyon, France: 

World Health Organization, International 

Agency for Research on Cancer, https://publications.iarc.fr/Book-And-Report-Series/

Iarc-Monographs-On-The-IdentificationOf-Carcinogenic-Hazards-To-Humans/

Polychlorinated-Biphenyls-And-Polybrominated-Biphenyls-2015. Accessed 01-21-2020.

*Maroni M, Columbi A, Arobsti G, Cantoni S, Foa 

V [1981]. Occupational exposure to polychlorinated biphenyls in electrical workers. II. Health 

effects. Br J Ind Med 38:55–60.

†Mayes BA, McConnell EE, Neal BH, Burnner MJ, 

Hamilton SB, Sullivan TM, Peters AC, Ryan MJ, 

Toft JD, Singer AW, Brown JF Jr, Menton RG, 

Moore JA [1998]. Comparative carcinogenicity 

in Sprague-Dawley rats of the polychlorinated 

biphenyl mixtures Aroclors 1016, 1242, 1254, 

and 1260. Toxicol Sci 41(1):62–76.

*NCBI [2020]. PubChem Database. 2,2',3,4'-Tetrachlorobiphenyl, CID=63103. Bethesda, MD: 

National Center for Biotechnology Information, https://pubchem.ncbi.nlm.nih.gov/

compound/1_2-dichloro-3-_2_4-dichlorophenyl_benzene. Accessed 01-21-2020.

*NIOSH [2005]. NIOSH pocket guide to chemical 

hazards. Cincinnati, OH: U.S. Department of 

Health and Human Services, Centers for Disease Control and Prevention, National Institute 

for Occupational Safety and Health, DHHS 

(NIOSH) Publication No. 2005–149, https://

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

*NIOSH [2009]. Current intelligence bulletin 61: 

a strategy for assigning new NIOSH skin notations. Cincinnati, OH: U.S. Department of 

Health and Human Services, Centers for Disease Control and Prevention, National Institute 

for Occupational Safety and Health, DHHS 

(NIOSH) Publication No. 2009-147, https://

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

147.pdf. Accessed 01-28-2020.

*NTP [2016]. Report on carcinogens, 14th ed. 

Research Triangle, NC: U.S. Department of 

Health and Human Services, Public Health 

Service, National Toxicology Program, https://
8 Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

Chlorodiphenyl

ntp.niehs.nih.gov/whatwestudy/assessments/

cancer/roc/index.html. Accessed 01-21-2020.

*OSHA [2019]. Chlorodiphenyl (42% Cl). In: 

OSHA occupational chemical database. Washington, DC: Occupational Safety and Health 

Administration, https://www.osha.gov/chemicaldata/chemResult.html?recNo=392. Accessed 

01-21-2020.

*Ouw HK, Simpson GR, Siyali DS [1976]. Use and 

health effects of aroclor 1242, a polychlorinated 

biphenyl in an electrical industry. Arch Environ 

Health 31:189–194.

†Panel on Hazardous Substances [1972]. Polychlorinated biphenyls environmental impact. 

Environ Res 5:249.

*Smith AB, Schloemer J, Lowry LK, Smallwood 

AW, Ligo RN, Tanaka S, Stringer W, Jones M, 

Hervin R, Glueck CJ [1982]. Metabolic and 

health consequences of occupational exposure 

to polychlorinated biphenyls. Br J Ind Med 

39:361–369.

*U.S. EPA [2020]. Integrated Risk Information 

System (IRIS). Washington, DC: United States 

Environmental Protection Agency, https://

www.epa.gov/iris. Accessed 01-21-2020.

*Wester RC, Bucks DA, Maibach HI, Anderson J 

[1983]. Polychlorinated biphenyls (PCBs): 

dermal absorption, systemic elimination, 

and dermal wash efficiency. J Toxicol Health 

12(4–6):511–519.

*Wester RC, Maibach HI [1975]. Percutaneous 

absorption in the rhesus monkey compared to 

man. Toxicol Appl Pharmacol 32(2):394–398.

*Wester RC, Maibach HI, Bucks DW McMaster 

J, Mobayen M, Sarason R, Moore A [1990]. 

Percutaneous absorption and skin decontamination of PCBs: in vitro studies with human 

skin and in vivo studies in the rhesus monkey. J 

Toxicol Environ Health 31:235–246.

*Wester RC, Maibach HI, Sedik L, Melendres J, 

Wade M [1993]. Percutaneous absorption of 

PCBs from soil: in vivo rhesus monkey, in vitro 

human skin, and binding to powdered human 

stratum corneum. J Toxicol Environ Health 

39(3):375–382.
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) 9

Chlorodiphenyl

Appendix: Calculation of the SI Ratio for Chlorodiphenyl 

(42% Chlorine)

This appendix presents an overview of the 

SI ratio and a summary of the calculation of 

the SI ratio for chlorodiphenyl (42% chlorine). Although the SI ratio is considered in 

the determination of a substance's hazard 

potential following skin contact, it is intended 

to serve only 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 

(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 experimentally determined permeation coefficient when 

such data are available and appropriate for use.

The first step in the evaluation is to determine 

the k

p

 for the substance to describe its transdermal penetration rate [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 KOW). 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].

 = 1

1

kpsc + kpol aq k

1 +

kp

Equation 1: Calculation of Skin Permeation 

 Coecient (kaq)

where k

psc 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. 
10 Skin Notation Profile | Chlorodiphenyl (42% Chlorine)

Chlorodiphenyl

The skin dose is calculated as a mathematical 

product of the k

p

, 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 

square centimeters [cm2

]).

Skin dose = kp × Sw × Exposed skin surface

area × Exposure time

= kp (cm/hr) × Sw (mg/cm3) × 

360 cm2 × 8 hr

Equation 2: Determination of Skin Dose

Inhalation dose = OEL × Inhalation

volume × RF

= OEL (mg/m3

) × 10 m3 × 0.75

Equation 3: Determination of Inhalation Dose

The final step is to compare the calculated skin 

and inhalation doses and to present the result 

as a ratio of skin dose to inhalation dose (the 

SI ratio). This ratio quantitatively indicates 

(1) the significance of dermal absorption as 

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

uptake to systemic toxicity. If a substance has 

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

considered a skin absorption hazard.

Calculation 

Table A1 summarizes the data applied in the 

previously described equations to determine 

the SI ratio for chlorodiphenyl (42% chlorine). 

The calculated SI ratio was 12.43. On the basis 

of these results, chlorodiphenyl (42% chlorine) is 

predicted to represent a skin absorption hazard.

Appendix References

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

NIOSH [2005]. NIOSH pocket guide to chemical 

hazards. Cincinnati, OH: U.S. Department of 

Health and Human Services, Centers for Disease Control and Prevention, National Institute 

for Occupational Safety and Health, DHHS 

(NIOSH) Publication No. 2005–149, https://

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

NIOSH [2009]. Current intelligence bulletin 61: a 

strategy for assigning new NIOSH skin notations. Cincinnati, OH: U.S. Department of 

Health and Human Services, Centers for Disease Control and Prevention, National Institute 

for Occupational Safety and Health, DHHS 

(NIOSH) Publication No. 2009-147, https://

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

147.pdf. Accessed 01-28-2020.

NLM [ND]. Toxnet, ChemIDplus: aroclor 1242. 

Bethesda, MD: National Institutes of Health, 

National Library of Medicine, https://chem.

nlm.nih.gov/chemidplus/rn/53469-21-9. 

Accessed 09-16-2020.
Skin Notation Profile | Chlorodiphenyl (42% Chlorine) 11

Chlorodiphenyl

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

chlorodiphenyl (42% chlorine) 

Variables Used in Calculation Units Value 

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(kpsc) cm/hr -0.32924

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol)

cm/hr 9.4569 × 10-6

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.15564

Molecular weight (MW)† amu 258

Base-10 logarithm of its octanol–water partition coefficient (Log 

Kow)*

None 6.34

Calculated skin permeation coefficient (kp

) cm/hr 0.11683409

Skin dose

Water solubility (Sw)* mg/cm3 2.77 × 10-4

Calculated skin permeation coefficient (kp) cm/hr 0.11683409

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

Exposure time hr 8

Calculated skin dose mg 0.93205561

Inhalation Dose

Occupational exposure limit (OEL)† mg/m3 0.001

Inhalation volume m3 10

Retention Factor (RF) None 0.75

Inhalation dose mg 0.0075

Skin dose–to–inhalation dose (SI) ratio None 12.4275

*Variables identified from NLM [ND].

†

The OEL used in calculation of the SI ratio for chlorodiphenyl (42% chlorine) was the NIOSH recommended exposure limit (REL) 

[NIOSH 2005]. §

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

DHHS (NIOSH) Publication No. 2021-100

DOI: https://doi.org/10.26616/NIOSHPUB2021100