# Skin Notation (SK) Profile

Chlorinated Camphene

[CAS No. 8001

- 35

- 2]

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: Chlorinated camphene. 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)

Pub lication No. XXX

DHHS (NIOSH) Publication No. XXXiii

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## Foreword

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

- mediated responses (e.g., allergic contact dermatitis and pulmonary responses), or system ic toxicity (e.g., neurotoxicity and hepatoxicity). Understanding the hazards related to skin contact with chemicals is a critical component of modern occupational safety and health programs.

In 2009, the National Institute for Occupational Safety and H ealth (NIOSH) published Current Intelligence Bulletin (CIB) 61

– A Strategy for Assigning New NIOSH Skin Notations [NIOSH 2009

- 147]. This document provides the scientific rationale and framework for the assignment of multiple hazard

- specific skin notation s (SK) that clearly distinguish between the systemic effects, direct (localized) effects, and immune

- mediated responses caused by skin contact with chemicals. The key step within assignment of the hazard

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

 Scientific data on the physicochemical propertie s of a chemical

 Data on human exposures and health effects

 Empirical data from in vivo and in vitro laboratory testing

 Computational techniques, including predictive algorithms and mathematical models that describe a selected process (e.g., skin permeation) by means of analytical or numerical

methods.

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

. 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 m ay 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 Preventioniv

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## Contents

Foreword

................................ ................................ ................................ ................................ ................ iii

Abbreviations

................................ ................................ ................................ ................................ .......... v Glossary

................................ ................................ ................................ ................................ .................. vii Acknowledgments

................................ ................................ ................................ ................................ . viii

1.0 Introd uction

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

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

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

................................ ................................ ................................ .................. 2 2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

................................ ................................ .................. 2 3.0 Direct Effects on Skin (SK: DIR)

................................ ................................ ................................ ........... 4

4.0 Immune

- mediated Responses (SK: SEN)

................................ ................................ ............................. 5
5.0 Summary

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

References

................................ ................................ ................................ ................................ ............... 7 Appendix: Calculation of the SI Ratio for Chlorinated camphene

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

Overview

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

Calculation

................................ ................................ ................................ ................................ ............... 12 Appendix References

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

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

cm 2 squared centimeter(s)

cm/hr centimeter(s) per hour

cm/s centimeter(s) per second

CNS central nervous system

DEREK Deductive Estimation of Risk from Existing Knowledge

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

contact with a chemical

EC European Commission

GHS G lobally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

hr hour(s)

IARC International Agency for Research on Cancer (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/cm 2 /hr milligram(s) per square centimeter per hour mg/kg milligram(s) per kilogram body weight mg/m 3 milligram(s) per cubic meter

mL milliliter(s)

mL /kg milliliter(s) per kilogram body weight

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no

- observed

- adverse

- effect level

NTP National Toxicology Program

OEL occupational exposure limit

OSHA Occupational Safety and Health Administrationvi

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 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

S W s olubility in water

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

the skin

USEPA United States Environmental Protection Agency

μg microgram(s) μg/cm 2 microgram(s) per square centimeter μg/cm 2 /hr microgram(s) per s quare centimeter per hour μL microliter(s) μmol micromole(s)vii

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## Glossary

Absorption

— The transport of a chemical from the outer surface of the skin into both the skin and systemic circulation (including penetration, permeation, and resorption).

Acute exposure

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

Cancer

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

Contaminant

— A chemical that is ( 1 ) uninten tionally 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 t he 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 pigm entation, 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 chemi cal.

Systemic effects

— Systemic toxicity associated with skin aborption 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 Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## Acknowledgments

This document was developed by the Education and Information Division (Paul Schulte, Ph.D., Director). G. Scott Dotson, Ph.D., was the project officer for this document, assisted in great part by Naomi Hudson, Dr.P.H., MPH, Todd Niemeier, M.Sc., and Berran Yucesoy, Ph.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. Mark Toraason, Ph.D.

Division of Respiratory Disease Studies Gregory A. Day, Ph.D. Aleksander Stefaniak, Ph.D.

Division of Surveillance, Hazard Evaluations, and Field Studies Matt Dahm, M.Sc. Todd Niemeier, M.Sc. Aaron Sussell, Ph.D. Loren Tapp, M.D.

Education and Inform ation Division Devin Baker, M.Ed. Charles L. Geraci, Ph.D. Thomas J. Lentz, Ph.D. Richard Niemeier, Ph.D. Ralph Zumwalde, M.Sc.ix

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. Health Effects Laboratory Division Stacey Anderson, Ph.D. H. Fredrick Frasch, Ph.D. Michael Luster, Ph.D.

Anna Shvedova, Ph.D. Paul Siegel, Ph.D. Berran Yucesoy, Ph.D.

National Personal Protective Technology Laboratory Heinz Ahlers, J.D., M.Sc. Angie Shepherd

For their contribution to the technical content and review of this document, special acknowledgment is gi ven to the following CDC personnel:

Office of Surveillance, Epidemiology and Laboratory Services/Epidemiology and Analysis Program Office Barbara Landreth, M.A.

In addition, special appreciation is expressed to the following individuals for serving as independent, external reviewers and providing comments that contributed to the development or improvement of this document:

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

 Dori Germolec, Ph.D., National Toxicology Program, Natio nal 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 Derma tology, The Cleveland Clinic, Cleveland, OH1

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## 1.0 Introduction

1.1 General Substance Information

Chemical: Chlorinated camphene
CAS No: 8001

- 35

- 2 Molecular weight (

MW ): 413.8
Molecular formula: C 10 H 10 Cl 8 Structural formula:

Synonyms: Chlorocamphene; Octachlorocamphene; Polychlorocamphene; Toxaphene

Uses: Chlorinated camphene was used primarily as an insecticide. The Agency for Toxic Substance and Disease Registry (ATSDR) reported that an estimated that 3.7 million pounds [less than 2 million kilograms (kg)] were produced in the United States in 1982 [ATSD R 1996]. The United States Environmental Protection Agency (USEPA) banned chlorinated camphene in 1990 [55 Fed. Reg. 31164 (1990); ATSDR 2014].



### 1.2 Purpose

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

- specific skin notation (SK) assignment for chlorinated camphene. The SK assignment is based on the scientific rationale and logic outlined in the Current Intelli gence 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 chlorinated camphene. A

lite rature search was conducted through February 2013 to identify information on chlorinated camphene, including but not limited to data relating to its toxicokinetics, acute toxicity, repeated

- dose systemic toxicity, carcinogenicity , biological system/functio n

– 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 chlorinated camphene.2

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

### 1.3 Overview of SK Assignment

Chlorinated camphene is potentially capable of causing numerous adverse health effects following skin contact. A critical review of available data has resulted in the following SK as signment for chlorinated camphene: SK: SYS

- DIR (IRR) . Table 1 provides an overview of the critical effects and data used to develop the SK assignment for chlorinated camphene.

Table 1. Summary of the SK Assignment for chlorinated camphene

Skin Notation Critical Effect Available Data

SK: SYS Central nervous system (CNS),

liver, kidney, spleen, thyroid Limited human and animal data

SK: DIR (IRR) Skin irritation Limited animal data



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

No quantitative toxicokinetic data following dermal exposure to chlorinated camphene were identified

for humans or animals. The potential of chlorinated camphene to pose a skin absorption hazard was also evaluated, with use of a predictive algorithm for estimating and eva luating the health hazards of dermal exposure to substances [NIOSH 2009]. The evaluation method compares an estimated dose accumulated in the body from skin absorption and an estimated dose from respiratory absorption associated with a reference occupation al exposure limit. On the basis of this algorithm, a ratio of the skin dose to the inhalation dose (SI ratio) of 0.01was calculated for chlorinated camphene. An SI ratio of ≥0.1 indicates that a chemical is capable of producing systemic toxicity from skin exposure [NIOSH 2009]; therefore, chlorinated camphene is not considered to be absorbed through the skin following dermal exposure.

Additional information on the SI ratio and the variables used in its calculation are included in the appendix

.

No estimate of the dermal lethal dose (LD LO ) of chlorinated camphene for humans was identified.

Dermal LD 50 (lethal dose in 50% of exposed animals) values of 780 milligrams per kilogram body weight (mg/kg) to 1,075 mg/kg were reported for rats [Gaines 1969]. For rabbits, a dermal LD 50 range of 1,025 mg/kg to 1,075 mg/kg was reported using a non

- standard acute dermal toxicity test that involved immersing the animals in water suspension of wettable chlorinated camphene powder for 2 minutes [Johnston and Eden 1953]. Dermal LD 50 values ranging from 3,725 mg/kg when applied to skin burned with ultraviolet light to 4,556 mg/kg for intact skin areas have been reported for rabbits after dermal exposure to chlorinated camphene (90% weight/volume in xylene) for 24 hours (hr) [Industrial BioTest Labs 1973]. Because the reported acute dermal LD 50 values for chlorinated camphene in rats and rabbits

are lower than the critical dermal LD 50 value of 2,000 mg/kg body weight that identifies chemical substances with the potential for systemic toxicity following dermal exposure [NIOSH 2009], chlorinated camphene has the potential to be absorbed through the skin and be systemically available. This is in contrast to the model prediction that indicated a low potential of chlorinated camphe ne for absorption through the skin.3

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. No epidemiological studies were identified that evaluated the potential of chlorinated camphene to cause systemic toxicity following dermal exposure. A case report by Pollock [1958] described severe systemic

effects inc luding generalized muscular aches and pain (particularly of the extremities) and stiffness,

semi

- consciousness, vomiting, and epigastric pain following a 2 hr contact with a lindane

– chlorinated camphene solution. The worker handled the material while mixin g the solution into the wool of sheep as a pesticide treatment; the contaminated skin was not washed and symptoms developed 10 hr after exposure. The doses of lindane or chlorinated camphene were not quantified, and it is unclear which chemical produced th e systemic effects. Both chlorinated camphene and lindane produce similar symptoms, with the usual sequence of events after ingestion being central nervous system (CNS) stimulation, high temperature, convulsions, gastric irritation, vomiting, diarrhea, res piratory failure, and death [Pollock 1958]. The systemic CNS effects observed, secondary to cutaneous absorption, are similar to those reported following oral ingestion or inhalation exposure in humans [McGee et al. 1952] and animals [DiPietro and Haliburt on 1979; Lawrence and Casida 1984], suggesting that chlorinated camphene has the potential to cause CNS effects following prolonged dermal exposure.

No repeated

- dose, sub

- chronic, or chronic toxicity studies were identified that evaluated dermal

exposure to chlorinated camphene in humans or animals. However, several oral exposure studies to chlorinated camphene identified the liver, kidney, spleen, and the immune system as target organs and systems [Agency for Toxic Substances and Disease Registry (ATSDR) 1996]. In a 13

- week feeding study rats were given 0, 4.0, 20, 100, or 500 ppm chlorinated camphene [corresponding to 0, 4.0, 20, 100, and 500 mg/kg] [Chu et al. 1986]. Chu et al. [1986] reported that rats receiving 20 mg/kg daily of chlorinated camphene o nly ingested approximately 1.8 milligrams per kilograms per day (mg/kg

- day), and that those rats receiving doses of 20 mg/kg

- day and greater had histological changes in liver, kidney and thyroid. Chu et al. [1986] also fed dogs 0.2 to 5.0 mg/kg

- day of chlo rinated camphene for 13 weeks, and reported increased relative liver weight and histological changes in the liver and thyroid. In a later study, Chu et al. [1988] reported that chlorinated camphene caused increased liver and kidney weights,

elevated serum cholesterol, and histological changes in the liver, thyroid and kidney of adult rats in a generation 2 reproductive toxicity study following dietary exposure. These studies indicate that chlorinated camphene, in addition to inducing CNS effects, has the po tential to be systemically available and may cause hepatic, liver, spleen and thyroid effects.

No specialty studies were identified that evaluated biological system/function specific effects (including reproductive and developmental effects and immunotox icity) following dermal exposure to chlorinated camphene. However, a reproductive toxicity study in which rats were administered chlorinated camphene in the diet observed no impairment in reproductive performance including the gestation index,

survival ind ices, and litter size at doses up to 500 ppm, of which approximately 37 to 49 mg/kg

- day was ingested [Chu et al. 1988].

No studies were identified that evaluated the carcinogenic potential of chlorinated camphene following dermal exposures. However, organizations and agencies have evaluated the carcinogenic potential of chlorinated camphene following other routes of exposur e. Table 2 summarizes carcinogenic designations of multiple governmental and nongovernmental organizations for chlorinated camphene.4

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. Table 2. Summary of the carcinogenic designations * for chlorinated camphene 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] B2: Probable human carcinogen IARC [2012] 2B: Possibly carcinogenic to humans European Parliament [2008] GHS Carcinogenicity Category 2: Suspected of causing

cancer EC [2013] † R40: Limited evidence of a carcinogenic effect ACGIH [2001] A3: Confirmed animal carcinogen with unknown

relevance to humans
ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, Institute for Health and Consumer Protection; GHS = Globally Harmonized System for Classificati on and Labelling of Chemicals; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; USEPA = United States Environmental Protection Agency.

* The listed cancer designations were based on data from nondermal (such as oral or inhalation) exposure since studies using the dermal route of exposure were unavailable. †Date accessed

No studies were identified that provided quantitative estimates of chlo rinated camphene absorption through the skin. Although the percent absorption following dermal exposure has not been estimated and no epidemiological studies or repeated

- dose, subchronic or chronic toxicity studies in animals were

identified that evaluated the potential of chlorinated camphene to cause systemic effects following dermal exposure, standard acute dermal toxicity study in rats [Gaines 1969] 1 and a non

- standard acute toxicity test in rabbits [ Johnston and Eden 1953] suggest that chlorinated camp hene is absorbed through the skin following dermal exposure and can be systemically toxic. The potential to cause CNS effects are supported by a human case study which was also exposed to the pesticide lindane [Pollock 1958] and by oral and inhalation toxi city studies [DiPietro and Haliburton 1979; Lawrence and Casida 1984], indicating the CNS effects are not route

- specific. In addition, subchronic oral toxicity studies [Chu et al. [1986, 1988] have identified the liver, kidney, spleen, and thyroid as targe t organs for chlorinated camphene at doses up to 2 mg/kg

- day. NIOSH [2005] has previously identified chlorinated camphene as a potential occupational carcinogen, but data are not available to assess the carcinogenic potential of dermal exposures. Therefore , on the basis of the data for this assessment, chlorinated camphene is assigned the SK: SYS notation.



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

No human or animal in vivo studies that evaluated the corrosivity of chlorinated camphene or in vitro
tests for corrosivity using human or animal skin models or in vitro tests of skin integrity using cadaver skin were identified. A human case report of an individual exposed to a lindane

- chlorinated camphene

mixture for 2 hr reported itchy skin that was not accompanied by a rash [Pollock 1958], although it is unknown if the irritation was caused by chlorinated camphene or lindane. Standard irritation and

1 References in bold text indicate studies that serve as the basis of the SK assignments.5

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. corrosivity tests were conducted on albino rabbits using 500 mg of techn ical grade chlorinated camphene, 0.5 milliliter (mL) of a 90% solution or a formulation of chlorinated camphene

– the diluents for the solution and the formulation were not reported

– was applied to an area of clipped and abraded

skin that was occluded for 4 h [International Research and Development Corporation (IRDC) 1973]. The technical grade chlorinated camphene caused slight to moderate erythema and edema at 24 and 72 hr
later on both intact and abraded skin. Similar effects were observed for the 90% sol ution and the formulated preparation at 4, 24 and 72 hr on both intact and abraded skin. IRDC [1973] defined a primary irritant as a substance which was not corrosive, but which resulted in a score of 5 or more. Because an irritation score of 2.1 was repor ted for the technical grade, 3.2 for the 90% solution, and 2.6 for the formulated preparation, IRDC [1973] concluded that the dosing regimens used did not result in

skin irritation and that the irritation noted was due to the test articles to the skin. How ever, this assessment concludes that observations at the specified time points (24 and 72 h) show the potential of chlorinated camphene to cause skin irritation. Industrial BioTest [1973] reported moderate to severe edema and erythema, followed by severe d esquamation in rabbits after dermal application of very high doses (3,038 mg/kg and greater) of chlorinated camphene (90% in xylene) under occlusion for 24 hr. It is possible that xylene may have contributed to the skin effects observed in the Industrial B io Test [1973] study, given that xylene causes mild irritation in guinea pigs and rats with a Draize score of 1.2 [Anderson et al. 1986; Chatterjee et al. 2005]. However, the dermal irritation score reported by Industrial Bio Test [1973] exceeds what we wo uld expect to see from xylene alone, suggesting that chlorinated camphene has irritant properties. This is further supported by IRDC [1973], which reports slight to moderate erythema and edema following dermal exposure to technical grade chlorinated camphe ne.

The standard skin irritation tests identified [IRDC 1973] and results from prolonged exposure [Industrial BioTest Labs 1973] indicate that chlorinated camphene has the potential to cause mild to moderate skin irritation, and prolonged dermal contact with very high doses may be irritating to the skin. Therefore, on the basis of the data for this assessment, chlorinated camphene is assigned the SK: DIR (IRR) notation.



## 4.0 Immune

- mediated Responses (SK: SEN)

No reports of sensitization in humans, or pr edictive tests (for example, guinea pig maximization tests, Buehler tests, murine local lymph node assays, mouse ear swelling tests) or other tests were identified that evaluated the potential of chlorinated camphene to cause skin sensitization in animals Lack of data precludes adequate evaluation of chlorinated camphene to cause skin sensitization . Therefore, on the basis of the data for this assessment, chlorinated camphene is not assigned the SK: SEN notation.



## 5.0 Summary

Although no studies were identi fied that provided quantitative estimates of absorption of chlorinated camphene through the skin, a standard acute toxicity study in rats [Gaines 1969] ] and a non

- standard acute toxicity test in rabbits [ Johnston and Eden 1953] indicate that chlorinated camphene has the potential to be absorbed and be systemically toxic. Because neurotoxic effects have also been reported6

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. by a human case study who was also exposed to the pesticide lindane [Pollock 1958] and by following

inhalation and ingestion exposure in humans [McGee et al. 1952] and animals [DiPietro and Haliburton 1979; Lawrence and Casida 1984] to chlorinated camphene, the limited dermal exposure data in animals [Chu et al. 1986; 1988] support the conclusion that chlorinated camphene causes CNS effects following exposure via skin contact. In addition, subchronic oral toxicity studies with chlorinated camphene have identified the liver, kidney, spleen, and thyroid as target organs at doses of chlorinated camphene up to 2 mg/kg

- day [Chu et al. 1986, 1988] . The standard irritation tests with a technical grade chlorinated camphene, a 90% solution of chlorinated camphene, and a commercially

- available product [IRDC 1973] and results from prolonged dermal contact with high doses [Indu strial BioTest Labs 1973] are sufficient to indicate that the chlorinated camphene has the potential to cause skin irritation. No diagnostic tests in humans or predictive tests in animals were identified to adequately evaluate the potential of chlorinated camphene to cause skin sensitization. Therefore, on the basis of these assessments, chlorinated camphene is assigned a composite skin notation of SK: SYS

- DIR (IRR)

.

Table 3 summarizes the skin hazard designations for chlorinated camphene previously issue d by NIOSH and other organizations. The equivalent dermal designations for chlorinated camphene, according to the Global Harmonization System (GHS) of Classification and Labelling of Chemicals, are Acute Toxicity Category 4 (Hazard statement: Harmful in co ntact with the skin), and Skin Irritation Category 2 (Hazard statement: Causes skin irritation) [ European Parliament 2008].

Table 3. Summary of previous skin hazard designations for chlorinated camphene

Organization Skin hazard designation

NIOSH [2005] [skin]: Potential for dermal absorption; prevent skin contact OSHA [2015] * [skin]: Potential for dermal absorption ACGIH [2001] [skin]: Based on the absorption of chlorinated camphene through

intact and abraded skin of treated rabbits leading to systemic effects and lethality EC [2013] * R21: Harmful if in contact with skin

R38: Irritating to skin

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research,

Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration.

*Date accessed7

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## References

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

*55 Fed. Reg. 31164 [1990]. Environmental Protection Agency: notice to intent to remove certain active ingredients from reregistration List B and to cancel pesticides containing those ingredients.

*ACGIH [2001]. Chlorinated camphene. In: Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 1. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

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

Dermatitis 1 5 :143

- 151.

*ATSDR [2014]. Toxicological profile for toxaphene, http://www.atsdr.cdc.gov/toxprofiles/tp94.pdf. Atlanta: U.S. Department of Health and Human Services, Public Health Serice, Agency for Toxic Substances and Disease Registry. Accessed: 01

- 29

- 15

.

*Chatterjee A, Babu RJ, Ahaghotu E, Singh M [2005]. The effect of occlusive and unocclusive exposure to xylene and benzene on skin irritation and molecular responses in hairless rats. Arch Toxicol 79 (5):

294

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*Chu I, Villeneuve DC, Sun CW, Secours V, Proctor B, Arnold EP, Clegg D, Reynolds L, Valli VE. [1986]. Toxicity of chlorinated camphene in the rat and beagle dog. Fund Appl Toxicol 7 :406

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*Chu I, Secours V, Villeneuve DC, Valli VE, Nakamura A, Colin D, Clegg DJ, Arnold EP. [1988]. Reproduc tion study of toxaphene in the rat. J Environ Sci Health (B) 23 :101

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*Dille JR, Smith PW [1964]. Central nervous system effects of chronic exposure to organophosphate insecticides. Aerospace Med 351475

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*DiPietro JA, Haliburton JC [1979]. Toxaphene toxicosis in swine. J Am Vet Med Assoc 175 :452

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*EC (European Commission) [ND]. Toxaphene. In: EINICS (European Inventory of Existing Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 08

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*European Parliament, Council of the European Union [2008]. Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548 /EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. OJEU, Off J Eur Union L353 :1

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

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*Gaines, TB. [1969]. Acute Toxicity of Pesticides . Toxicology and Applied Pharmacology 14 :515

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This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. *IARC (International Agency for Research on Cancer) [2012]. Agents reviewed by the IARC monographs. In: IARC monographs on the evaluation of carcinogenic risks to humans, http://monographs.iarc.fr/ENG/Mono graphs/PDFs/index.php. Accessed: 01

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*Industrial Biotest [1973]. Acute dermal toxicity studies with four samples in female albino rabbits. Northbrook, IL: Industrial Biotest Laboratories, Inc., Project No. 72

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*IRDC (International Research and D evelopment Corporation) [1973]. Primary skin irritation study in the albino rabbit. International Research and Development Corporation. Report to Hercules, Inc. Wilmington, Delaware. Mattawon, Michigan.

*Johnston BL, Eden WG [1953]. The toxicity of aldrin , dieldrin and toxaphene to rabbits by skin absorption. Journal of Economic Entomology 46(4):702

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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.

2009

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† Prasada Rao KS, Trottman CH, Morrow W, Desaiah D [1986]. Toxaphene inhibition of calmodulin

dependent ca lcium ATPase activity in rat brain synaptosomes. Fundam Appl Toxicol 6 (4): 648

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This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. †UNECE (United Nations Economic Commission for Europe) [2007]. Part 3: health hazards. In: Globally harmonized system of classification and labeling of chemical (GHS): thi rd revised edition, http://www.unece.org/trans/danger/publi/ghs/ghs_rev02/English/03e_part3.pdf. Accessed: November 20

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* USEPA [2014]. Chlorinated Camphene. In: Integrated risk information system, http://www.epa.gov/iris. Accessed: 01

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This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

## Appendix: Calculation of the SI Ratio for Chlorinated camphene

This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for chlorinated camphene. Although the SI ratio is considered in the determination of a subs tance’s hazard potential following skin contact, it is intended only to serve as supportive data during the assignment of

the NIOSH SK. An in

- depth discussion on the rationale and calculation of the SI ratio can be found in Appendix B of the Current Intell igence 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 eval uate 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 s hould 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

inde pendent 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 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, i s 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 centimeters per hour (cm/hr), outlined in Table A1. Other model

- based

estimates of k

p may also be used [NIOSH 2009].11

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. Equation 1: Calculation of Skin Permeation Coefficient ( k p )

where k

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

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

k pol = 0.0001519 × MW −0.5

k aq = 2.5 × MW

−0.5

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

W

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

centi meters [cm 2 ]).

Equation 2: Determination of Skin Dose

Skin dose = k

p × S

w × Exposed skin surface area × Exposure time

= k p (cm/hr) × S

w (mg/cm 3 ) × 360 cm 2 × 8 hr

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

substance

— if the OEL is developed to prevent the occurrence of systemic effects rather than sensory/irritant effects or direct effects on the respiratory tract. Assume a continuous exposure of 8 hr,

an inhalation volume of 10 cubic meters (m 3 ) inhaled air in 8 s, and a factor of 75% for retention of the airborne substance in the lungs during respiration (retention factor, or RF).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation volume × RF

= OEL (mg/m 3 ) × 10 m 3 × 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates ( 1 ) the significance of dermal absorption as a route of occupational exposure to the substance and ( 2 ) the contribution of dermal uptake to systemic toxicity. If a substance has an SI ratio greater than or equal to 0.1, it is considered a skin absorption hazard.12

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

### Calculation

Table A1 summarizes the data applied in the previously described equations to determine the SI ratio for chlorinated camphene. The calculated SI ratio was 0.01. On the basis of these results, chlorinated camphene is predicted not to represent a skin absorp tion hazard.

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

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

pol ) cm/hr 7.1745 × 10 - 6

Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.11808 Molecular weight ( MW

) * amu 448.26

Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None 5.9 Calculated skin permeation coefficient ( k p ) cm/hr 0.02449

Skin dose
Water solubility ( S w ) * mg/cm 3 5.5 × 10 - 4

Calculated skin permeation coefficient ( k p ) cm/hr 0.02449

Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8

Calculated skin dose mg 0.0388

Inhalation Dose
Occupational exposure limit (OEL) † mg/m 3 0.5

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

Inhalation dose mg 3.75

Skin dose

– to

– inhalation dose (SI) ratio None 0.01

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

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 

### Appendix References

NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2005

– 149, http://www.cdc. gov/niosh/npg/.

Accessed: 01

- 29

- 15.

NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Inst itute for Occupational Safety and Health, DHHS (NIOSH) Publication No.

2009

- 147, http://www.cdc.gov/niosh/docs/2009

- 147/pdfs/2009

- 147.pdf. Accessed: 01

- 29

- 15.

SRC [2009]. Interactive PhysProp database demo, http://esc.syrres.com/fatepointer/webprop.asp?CA S=8001352 . Accessed: 01

- 29

- 15.