NIOSH Skin Notation Profile

Cyclonite

Centers for Disease Control

and Prevention

National Institute for Occupational 

Safety and Health
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NIOSH Skin Notation Profile

Cyclonite

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 | Cyclonite

This document is in the public domain and may be freely 

copied or reprinted.

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Suggested Citation

NIOSH [2020]. NIOSH skin notation profile: cyclonite. 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. 

2021-104.

DHHS (NIOSH) Publication No. 2021-104

DOI: https://doi.org/10.26616/NIOSHPUB2021104

October 2020
Skin Notation Profile | Cyclonite iii

Foreword

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

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

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

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

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

of modern occupational safety and health programs.

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

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

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

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

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

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

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

use of the following:

• Scientific data on the physicochemical properties of a chemical

• Data on human exposures and health effects

• Empirical data from in vivo and in vitro laboratory testing

• Computational techniques, including predictive algorithms and mathematical models 

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

numerical methods.

This Skin Notation Profile provides the SK assignments and supportive data for cyclonite. 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 | Cyclonite v

Contents

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

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

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

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

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

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

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

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

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

3 Direct Effects on Skin (SK: DIR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

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

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

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

Appendix: Calculation of the SI Ratio for Cyclonite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Calculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Appendix References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
vi Skin Notation Profile | Cyclonite

Abbreviations

ACGIH® American Conference of Governmental Industrial Hygienists 

AMU atomic mass unit

ATSDR Agency for Toxic Substances and Disease Registry

CIB Current Intelligence Bulletin

ChE cholinesterase

cm2 square centimeter(s)

cm/hr centimeter(s) per hour

CNS central nervous system

COR subnotation of SK: COR 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

DMSO Dimethyl sulfoxide

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

during dermal absorption

GHS Globally Harmonized System of Classification and Labelling of Chemicals

GPMT guinea pig maximization test

hr hour(s)

IARC International Agency for Research on Cancer

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

data exist to accurately assess the hazards of skin exposure

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

irritant following exposure to the skin

kaq coefficient in the watery epidermal layer 

kp skin permeation coefficient 

kpol coefficient in the protein fraction of the stratum corneum

kpsc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

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
Skin Notation Profile | Cyclonite vii

NTP National Toxicology Program

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

REL recommended exposure limit

RF retention factor 

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

exposure of the skin

SI ratio ratio of skin dose to inhalation dose

SK skin notation

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

associated with skin exposure

SW solubility in water

SYS skin notation indicating the potential for systemic toxicity following exposure 

of the skin

US EPA United States Environmental Protection Agency 

w/v weight/volume

μg/cm2 micrograms per square centimeter 

μL microliter
viii Skin Notation Profile | Cyclonite

Glossary

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

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

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

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

and grow or multiply out of control.

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

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

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

Dermal—Referring to the skin.

Dermal contact—Contact with (touching) the skin.

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

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

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

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

responses.

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

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

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

Substance—A chemical.

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

of the skin.
Skin Notation Profile | Cyclonite ix

Acknowledgments

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

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

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

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

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

external reviewers:

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

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

Medicine, Rockville, MD

The following reviewers provided comments through Intergovernmental Personnel Agreements:

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

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

Fort Worth, TX

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 | Cyclonite 1

Cyclonite

1 Introduction

1.1 General Substance Information

Chemical: Cyclonite

CAS No: 121-82-4

Molecular weight (MW): 222.2

Molecular formula: C3H6N6O6

Structural formula:

O

N O

N

N

O

N+

N+

N+

O–

–O

O–

Image by National Center for Biotechnology Information [2020]

Synonyms: Cyclotrimethylene-

 trinitramine; Hexogen; Hexahydro1,3,5-trinitro-1,3,5-triazine; RDX; 

1,3,5-Trinitro-1,3,5-triazacyclohexane.

Uses: Cyclonite is used primarily as a component of highly explosive materials and as a 

rodenticide [ATSDR 1995]. It is a white powder 

of melting point 205.5o

C [National Center for 

Biotechnology Information 2020]. An estimated 

16 million pounds (7.3 million kilograms) of 

cyclonite were produced in 1984.

1.2 Purpose

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological data associated with skin contact with 

cyclonite and (2) the rationale behind the 

hazard-specific skin notation (SK) assignment 

for cyclonite. 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 cyclonite. 

A search of all available relevant literature was 

conducted through January 2018 to identify 

information on cyclonite dermal absorption, 

acute toxicity, repeated-dose systemic toxicity, 

carcinogenicity, biological system/function 

specific effects (including reproductive and 

developmental effects and immunotoxicity), 

irritation, and sensitization. Information 

was considered from studies in humans, animals, or appropriate modeling systems that 

are relevant to assessing the effects of dermal 

exposure to cyclonite. 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

Cyclonite is potentially capable of causing adverse 

effects following skin contact. A critical review 

of available data has resulted in the following 

SK assignment for cyclonite: SK: DIR(IRR). 

Table 1. Summary of the SK assignment for cyclonite

Skin notation Critical effect Available data

SK: DIR(IRR) Skin irritation Limited animal data
2 Skin Notation Profile | Cyclonite

Cyclonite

Table 1 provides an overview of the critical effects 

and data used to develop the SK assignment for 

cyclonite.

2 Systemic Toxicity from Skin 

Exposure (SK: SYS)

In vitro studies were identified in which percutaneous absorption of cyclonite was determined 

from acetone or soil. Reifenrath et al. [2002] 

applied approximately 10 micrograms per 

square centimeter (μg/cm2

) of 14C-radiolabeled 

cyclonite in 5 microliters (μL) of acetone or in 

10 milligrams per square centimeter (mg/cm2

) 

of soil to excised pigskin for 24 hours. Percutaneous absorptions of 1.8%, 1.2%, and 8% of the 

applied dose were reported for the high-carbon 

soil, low-carbon soil, and acetone, respectively. 

Reddy et al. [2008] measured dermal absorption in acetone (10 μL) or in soils (10 mg) using 

excised human skin in Teflon flow-through 

diffusion cells. Cyclonite was applied to the epidermal surface and was allowed to transverse 

the skin and dissolved in a reservoir of receptor 

fluid that maintained contact with the dermal 

surface. Reddy et al. [2008] reported that only 

2.5 ± 1.8% of cyclonite in acetone was recovered 

in receptor fluid and 2.6 ± 1.1% and 1.4 ± 0.41% 

from high and low carbon soil, respectively. The 

potential of cyclonite to pose a skin absorption 

hazard was also evaluated using the NIOSH 

[2009] predictive algorithm for estimating and 

evaluating the health hazards of dermal exposure to chemical substances. 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 (OEL). Based on this algorithm, 

the ratio of skin dose to inhalation dose (the 

SI ratio) of 0.002 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, cyclonite 

is not 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 cyclonite. The dermal 

LD50 (the dose resulting in 50% mortality in the 

exposed animals) for guinea pigs was above 

2000 mg/kg [McNamara et al. 1974]. MacNamara et al. [1974] reported no death in guinea 

pigs following a single dermal exposure to 316 

to 2000 milligrams per kilogram body weight 

(mg/kg); 2000 mg/kg is the critical dermal LD50

value that identifies chemical substances with 

the potential for acute dermal toxicity [NIOSH 

2009]. 

No animal chronic or subchronic toxicity 

studies were identified that reported adverse 

systemic effects following dermal exposure to cyclonite. However, a repeated-dose 

toxicity study was identified in rabbits and 

beagles [McNamara et al. 1974]. In rabbits, 0.1 

or 1.0 milliliter (mL) of 33% RDX (cyclonite) 

in dimethyl sulfoxide (DMSO) [corresponding 

to 16.5 and 165 milligrams per kilogram body 

weight per day (mg/kg-day) of cyclonite, respectively], 7.5% cyclonite in cyclohexanone (3.75 

and 37.5 mg/kg-day of cyclonite, respectively), 

or 5.4% cyclonite in acetone (2.7 and 27 mg/

kg-day of cyclonite) was applied to the shaved 

skin under a polyethylene sleeve, 5 days/week 

for 4 weeks [McNamara et al. 1974]. Control 

animals received applications of 0.1 or 1.0 mL of 

the solvents alone [McNamara et al. 1974]. Two 

rabbits from each dose group and one control 

rabbit from each solvent group were sacrificed 

for pathological examination at 7 days (2 days 

after the 5th dose), 14 days (2 days after the 10th 

dose), and 28 days (2 days after the 20th dose). 

Signs of posterior leg weakness or posterior leg 

paralysis (possibly attributed to broken backs) 

were observed in three animals [McNamara et 

al. 1974]. No gross defects, lesions, microscopic 

abnormalities in organs, or changes in blood 

component values were noted in rabbits that 

died or were killed following repeated topical 

applications of cyclonite either in the three solvent groups or the solvents alone [McNamara 

et al. 1974]. For dogs, topical application of 480 

mg/kg for 3 consecutive days to the clipped 

back did not produce consistent noticeable 

changes in physiological parameters [electroencephalograph (EEG), respiratory and heart 
Skin Notation Profile | Cyclonite 3

Cyclonite

Table 2. Summary of the carcinogenic designations for cyclonite by 

governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] No designation

NTP [2014] No designation

US EPA [2018] Suggestive evidence of carcinogenic potential 

ECHA [2020] No GHS designation

IARC [2012] No designation

ACGIH® [2001] A4: Not classifiable as a human carcinogen

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.

rates, electrocardiograph (EKG), and gross 

hyperreflexia (overactive or over-responsive 

reflexes)] [McNamara et al. 1974]. Neither a 

No Observed Adverse Effect Level (NOAEL) or 

Lowest Observed Adverse Effect Level (LOAEL) 

could be identified. McNamara et al. [1974] 

indicated that cyclonite was not dermally 

absorbed in rabbits, guinea pigs, or dogs, as 

evidenced by lack of systemic effects in guinea 

pigs, unchanged blood component values in 

rabbits, and lack of physiological responses in 

dogs following a single or repeated topical 

exposure. 

No epidemiological studies were identified 

that evaluated the potential for cyclonite to 

cause systemic effects following dermal exposure. However, Kaplan et al. [1965] reported 

five cases of illness in workers handling RDX 

(i.e., cyclonite) in its finely powdered form in 

an explosives plant. The workers were reported 

to be exposed via inhalation, ingestion, and 

dermal routes, but the relative contribution 

by each route was unknown. Exposure to 

cyclonite resulted in loss of consciousness 

with, without, or followed by convulsions, and 

in some cases, stupor, nausea and vomiting, 

dizziness, and weakness, were also reported 

[Kaplan et al. 1965]. These results indicate 

the potential for cyclonite to cause central 

nervous system (CNS) effects; however, the 

dermal contribution is unknown. 

No standard toxicity or specialty studies evaluating biological system function–specific effects 

(including reproductive and developmental 

effects and immunotoxicity) following dermal 

exposure to cyclonite were identified. No epidemiological studies or animal bioassays were 

identified that evaluated the potential for 

cyclonite to be carcinogenic following dermal 

exposure. Table 2 summarizes the carcinogenic 

designations for cyclonite from governmental 

and non-governmental organizations.

No in vivo toxicokinetic data were identified 

that estimated the degree of absorption of 

cyclonite through human or animal skin following dermal exposure. In vitro toxicokinetic 

data identified from animals [Reifenrath et al. 

2002; Reddy et al. 2008], with support from a 

model prediction, indicate that cyclonite has a 

limited potential for skin absorption (absorption of less than 10% of the applied dose) 

whether applied in acetone or in soil. Five case 

reports identified health effects such as stupor, 

nausea and vomiting, dizziness, and weakness 

in workers exposed to powdered cyclonite 

[Kaplan et al. 1965]; however, the route of 

exposure is unknown and could have occurred 

via inhalation and ingestion in addition to the 

dermal route. Acute toxicity studies indicated 

that the LD50 for cyclonite was greater than 

*

References in bold text indicate studies that serve 

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

Cyclonite

2000 mg/kg for guinea pigs [McNamara et al. 

1974], which is above the critical value that 

identifies chemicals with the potential for acute 

dermal toxicity. Single- and repeat-dose toxicity studies in rabbits and dogs found no gross 

or microscopic abnormalities [McNamara et 

al. 1974]. Based on the acute toxicity data, this 

assessment does not assign an SK: SYS notation 

for cyclonite.

3 Direct Effects on Skin (SK: DIR)

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

using human or animal skin models or in vitro 

tests of skin integrity using cadaver skin were 

identified. No occupational exposure studies 

were identified that evaluated the potential of 

cyclonite to cause skin irritation. In a study that 

tested the irritant action of cyclonite on human 

skin, von Oettingen et al. [1949] reported no 

signs of irritation when 1 square centimeter 

(cm2

) of the forearm of a man was covered with 

an unspecified amount of dry cyclonite under 

cellophane and adhesive tape for 48 hours. 

McNamara et al. [1974] conducted a study 

where cyclonite was topically applied at a single 

dose or at multiple doses (5 days/week for 4 

weeks) of 33% [weight/volume, (w/v)] cyclonite 

dissolved in DMSO (165 mg/kg-day), 7.5% 

cyclonite in cyclohexanone (37.5 mg/kg-day), 

or 5.4% of cyclonite in acetone (27 mg/kg-day) 

to the skin of rabbits under a polyethylene 

sleeve for 24 h/day [McNamara et al. 1974]. 

Microscopic examination of the dosed area of 

animals after exposure revealed that cyclonite, 

al. 1974]. Therefore, based on the data, this 

assessment assigns an SK: DIR (IRR) notation 

for cyclonite.

4 Immune-mediated 

Responses (SK: SEN)

No occupational exposure studies or diagnostic (human patch) tests were identified 

that investigated the skin sensitization potential of cyclonite. The sensitization potential 

of cyclonite in DMSO, acetone, or cyclohexanone has been investigated in guinea pigs. 

McNamara et al. [1974] applied intradermal 

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

cyclonite from NIOSH and other organizations

in all three solvents, caused dermatitis that persisted for as long as 30 days, with 33% cyclonite 

in DMSO causing the most pronounced effect. 

McNamara et al. [1974] also reported that application of 316 to 2,000 mg/kg cyclonite (33% w/v) 

in DMSO to the clipped skin of guinea pigs produced no skin irritation at 316 to 510 mg/kg, but 

slight erythema was observed at higher doses of 

1,000 mg/kg and 2,000 mg/kg. In dogs, repeated 

applications of cyclonite in DMSO caused slight 

erythema and desquamation during the second 

and third week of application of DMSO alone or 

in combination with cyclonite. 

One study involving humans indicated that 

dry cyclonite was not a skin irritant [von 

Oettingen et al. 1949]. However, in animals, 

evidence from single and repeat-dose studies 

using different solvents indicate that cyclonite 

is irritating to the skin following repeated 

exposures in rabbits and at doses of 1000 mg/

kg or greater in guinea pigs [McNamara et 

Organization Skin hazard designation

NIOSH [2005] [skin]: Potential for dermal absorption

OSHA [2018] [skin]: Potential for dermal absorption

ACGIH® [2001] [skin]: Based on a report that skin absorption was a possible route of 

entry that led to CNS effects in cyclonite-exposed munitions workers

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

Health; OSHA = Occupational Safety and Health Administration.
Skin Notation Profile | Cyclonite 5

Cyclonite

injection/topical application, intradermal/ 

intradermal injections, topical/topical applications or topical application/intradermal 

injection of cyclonite for sensitization and challenge. In the sensitization phase, animals were 

topically or intradermally exposed to 0.5 mL of 

33% cyclonite in pure or technical grade DMSO, 

7.5% in cyclohexanone, or 5.4% in acetone, 3 

times a week for 3 weeks, followed by 2 weeks 

of rest [McNamara et al. 1974]. The guinea pigs 

were then challenged topically or intradermally 

with a predetermined maximum sub-effective 

level of cyclonite [1:1 (volume/volume)] solventsaline mixtures (intradermal) and polyethylene 

glycol (topical) [McNamara et al. 1974]. No 

evidence of skin sensitization was reported 

[McNamara et al 1974]. 

No diagnostic (human patch) tests were identified that evaluated the potential of cyclonite to 

cause skin sensitization. A skin sensitization 

study in guinea pigs [McNamara et al. 1974] 

found no evidence of the potential of cyclonite to 

cause skin sensitization. Therefore, the SK: SEN 

notation is not assigned to cyclonite.

5 Summary

No in vivo toxicokinetic data were identified that 

estimated the degree of absorption of cyclonite 

through human or animal skin following dermal 

exposure. In vitro toxicokinetic data identified 

from animals [Reifenrath et al. 2002; Reddy et 

al. 2008], with support from a model prediction, 

indicate that cyclonite has a limited potential for 

skin absorption (absorption of less than 10% of 

the applied dose) whether applied in acetone or 

in soil. Five case reports identified CNS effects in 

workers exposed to powdered cyclonite [Kaplan 

et al. 1965]; however, the route of exposure is 

unknown and could have occurred via inhalation and ingestion in addition to the dermal 

route of exposure. Acute toxicity studies indicated that the LD50 for cyclonite was greater 

than 2000 mg/kg for guinea pigs [McNamara 

et al. 1974], and single and repeat-dose toxicity 

studies in rabbits and dogs found no gross or 

microscopic abnormalities [McNamara et al. 

1974]. One study involving humans indicated 

that dry cyclonite was not a skin irritant [von 

Oettingen et al. 1949]. However, in animals, evidence from single and repeat-dose studies using 

different solvents indicate that cyclonite is irritating to the skin following repeated exposures 

in rabbits and at doses of 1000 mg/kg or greater 

in guinea pigs [McNamara et al. 1974]. No 

diagnostic (human patch) tests were identified 

that evaluated the potential of cyclonite to cause 

skin sensitization. A skin sensitization study in 

guinea pigs [McNamara et al. 1974] found no 

evidence of the potential of cyclonite to cause 

skin sensitization. Based on the available data, 

this assessment assigns a composite skin notation of SK: DIR(IRR) for cyclonite. 

Table 3 summarizes the skin hazard designations for cyclonite previously issued by NIOSH 

and other organizations. There were no equivalent dermal designations for cyclonite, according 

to the Globally Harmonized System (GHS) of 

Classification and Labelling of Chemicals [European Parliament 2008].

References

Note: Asterisks (*) denote sources cited in 

text; daggers (†) denote additional resources.

*ACGIH® [2001]. Cyclonite. In: 2014 TLVs and 

BEIs, based on the documentation of threshold 

limit values and physical agents and biological exposure indices. 7th Ed. Cincinnati, OH: 

American Conference of Governmental Industrial Hygienists.

*ATSDR [1995]. Toxicological profile for RDX. 

Atlanta, GA: Agency for Toxic Substances and 

Disease Registry, https://www.atsdr.cdc.gov/toxprofiles/tp78.pdf. 

*ECHA [2020]. Classification and labelling inventory: 

table of harmonised entries in Annex VI to CLP, 

https://echa.europa.eu/information-on-chemicals/annex-vi-to-clp. Accessed 01-21-2020. 

*IARC [2012]. Cumulative cross index to IARC 

monographs Volumes 1 to 125. European 

Chemicals Agency, https://monographs.iarc.

fr/wp-content/uploads/2018/07/cumulativecross-index.pdf. Accessed 01-21-2020.

 *McNamara BP, Averill HP, Owens EJ, et al. [1974]. 

The toxicology of cyclotrimethylenetrinitramine 

(RDX) and cyclotetramethylenetetranitramine 
6 Skin Notation Profile | Cyclonite

Cyclonite

(HMX) solutions in dimethylsulfoxide (DMSO), 

cyclohexanone, and acetone. Edgewood Arsenal, 

MD: U.S. Army Technical Report EB-TR-73040

*NCBI [2020]. PubChem Database. Cyclohexanol, 

CID=7966. Bethesda, MD: National Center for 

Biotechnology Information, https://pubchem.

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

Accessed 1-22-2020.

*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.

*NIOSH [2009]. Current intelligence bulletin 61: a 

strategy for assigning new NIOSH skin notations. 

Cincinnati, OH: U.S. Department of Health and 

Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational 

Safety and Health, DHHS (NIOSH) Publication No. 2009-147, https://www.cdc.gov/niosh/

docs/2009-147/pdfs/2009-147.pdf. Accessed 

01-28-2020

*NTP [2014]. Report on carcinogens, 14th ed. Research 

Triangle, NC: U.S. Department of Health and 

Human Services, Public Health Service, National 

Toxicology Program, https://ntp.niehs.nih.gov/

whatwestudy/assessments/cancer/roc/index.html.

*OSHA [ND]. Cyclonite. In: OSHA occupational 

chemical database. Washington, DC: Occupational Safety and Health Administration, 

https://www.osha.gov/chemicaldata/chemResult.html?recNo=171. Accessed 01-21-2020. 

*Reddy G, Allen NA, Major MA [2008]. Absorption of (14)C-Cyclotrimethylenetrinitramine 

(RDX) from soils through excised human skin. 

Toxicol Mech Methods 18(7):575–579.

*Reifenrath WG, Kammen HO, Palmer WG, Major 

MM, Leach GJ [2002]. Percutaneous absorption of explosives and related compounds: an 

empirical model of bioavailability of organic 

nitro compounds in soil. Toxicol Appl Pharmacol 182:160–168.

*UNECE [2007]. Globally harmonized system of 

classification and labeling of chemicals (GHS). 

Second revised edition. ST/SG/AC 10/30. New 

York, Geneva: United Nations Economic Commission for Europe. 

*U.S. EPA [2008]. Cyclonite. Integrated Risk Information System. Washington, DC: United States 

Environmental Protection Agency, https://

cfpub.epa.gov/ncea/iris2/chemicalLanding.

cfm?substance_nmbr=313. Accessed 01-21-2020.

*von Oettingen WF, Donahue DD, Yagoda H, et 

al. [1949]. Toxicity and potential dangers of 

cyclotrimethylenetrinitramine (RDX). J Indust 

Hyg Toxicol 3(1):21–23.

†Weeks MH [1982]. Preliminary Assessment of 

relative toxicity of 1-Nitroso-3,5-dinitro-1,3,5-

triazacyclohexane (mononitrose-RDX). Report 

Number 75-51-0345-82.

†Woody RC, Kearns GL, Brewster MA, Turley CP, 

Sharp GB [1986]. The neurotoxicity of cyclotrimethylenetrinitramine (RDX) in a child: a 

clinical and pharmacokinetic evaluation. Clin 

Toxicol 24(4):305–31
Skin Notation Profile | Cyclonite 7

Cyclonite

Appendix: Calculation of the SI Ratio for Cyclonite

This appendix presents an overview of the 

SI ratio and a summary of the calculation 

of the SI ratio for cyclonite. Although the SI 

ratio is considered in the determination of a 

substance’s hazard potential following skin 

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

NIOSH SK. An in-depth discussion on the 

rationale and calculation of the SI ratio can be 

found in Appendix B of the Current Intelligence 

Bulletin (CIB) 61: A Strategy for Assigning New 

NIOSH Skin Notations [NIOSH 2009].

Overview

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

skin exposure to substances. The algorithm is 

designed to evaluate the potential for a substance to penetrate the skin and induce systemic 

toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the proposed strategy 

for assigning SYS notation are as follows:

1. Provide an alternative method to evaluate 

substances for which no clinical reports or 

animal toxicity studies exist or for which 

empirical data are insufficient to determine systemic effects.

2. Use the algorithm evaluation results to 

determine whether a substance poses a 

skin absorption hazard and should be labeled with the SYS notation.

The algorithm evaluation includes three steps:

1. determining a skin permeation coefficient 

(kp) for the substance of interest,

2. estimating substance uptake by the skin 

and respiratory absorption routes, and

3. evaluating whether the substance poses a 

skin exposure hazard.

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

the physicochemical properties of a substance 

and the relevant exposure parameters. Thus, the 

algorithm is independent of the need for biologic 

data. Alternatively, it can function with both the 

physicochemical properties and the experimentally determined permeation coefficient when 

such data are available and appropriate for use.

The first step in the evaluation is to determine the 

kp for the substance to describe the transdermal 

penetration rate of the substance [NIOSH 2009]. 

The kp, which represents the overall diffusion of 

the substance through the stratum corneum and 

into the blood capillaries of the dermis, is estimated from the compound’s molecular weight 

(MW) and base-10 logarithm of its octanol–

water partition coefficient (log KOW). In this 

example, kp is determined for a substance with 

use of Equation 1. A self-consistent set of units 

must be used, such as centimeters per hour (cm/

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

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

 = 1

1

kpsc + kpol kaq

1 +

kp

Equation 1: Calculation of Skin Permeation 

 Coecient (kaq)

where kpsc is the permeation coefficient in the 

lipid fraction of the stratum corneum, kpol is 

the coefficient in the protein fraction of the 

stratum corneum, and kaq is the coefficient in 

the watery epidermal layer. These components 

are individually estimated by

log kpsc = -1.326 + (0.6097 × log Kow ) − 

(0.1786 × MW0.5)

kpol = 0.0001519 × MW-0.5

kaq = 2.5 × MW-0.5

The second step is to calculate the biologic 

mass uptake of the substance from skin 

absorption (skin dose) and inhalation (inhalation dose) during the same period of exposure. 

The skin dose is calculated as a mathematical 

product of the kp, the water solubility (SW) of 

the substance, the exposed skin surface area, 

and the duration of exposure. Its units are milligrams (mg). Assume that the skin exposure 
8 Skin Notation Profile | Cyclonite

Cyclonite

continues for 8 hours to unprotected skin on 

the palms of both hands (a surface area of 360 

square centimeters [cm2

]).

Skin dose = kp × Sw × Exposed skin surface

area × Exposure time

= kp (cm/hr) × Sw (mg/cm3) × 

360 cm2 × 8 hr

Equation 2: Determination of Skin Dose

The inhalation dose (in mg) is derived on 

the basis of the occupational exposure limit 

(OEL) of the substance—if the OEL is developed to prevent the occurrence of systemic 

effects rather than sensory/irritant effects or 

direct effects on the respiratory tract. Assume 

a continuous exposure of 8 hours, an inhalation volume of 10 cubic meters (m3

) inhaled 

air in 8 hours, and a factor of 75% for retention of the airborne substance in the lungs 

during respiration (retention factor, or RF).

Inhalation dose = OEL × Inhalation

volume × RF

= OEL (mg/m3

) × 10 m3 × 0.75

Equation 3: Determination of Inhalation Dose

The final step is to compare the calculated skin 

and inhalation doses and to present the result 

as a ratio of skin dose to inhalation dose (the 

SI ratio). This ratio quantitatively indicates 

(1) the significance of dermal absorption as 

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

uptake to systemic toxicity. If a substance has 

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

considered a skin absorption hazard.

Calculation

Table A1 summarizes the data applied in the 

previously described equations to determine 

the SI ratio for cyclonite. The calculated SI ratio 

was 0.002. On the basis of these results, cyclonite 

is predicted not 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: Cyclonite. 

Bethesda, MD: National Institutes of Health, 

National Library of Medicine, https://chem.nlm.

nih.gov/chemidplus/rn/121-82-4. Accessed 

01-28-2020.
Skin Notation Profile | Cyclonite 9

Cyclonite

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

Variables used in calculation Units Value

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path (kpsc) cm/hr 0.000349

Permeation coefficient of the protein fraction of the 

stratum corneum (kpol)

cm/hr 1.01921 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.167744

Molecular weight (MW) amu 222.12

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

*

None 0.87

Calculated skin permeation coefficient (kp) cm/hr 0.000358276

Skin dose

Water solubility (Sw)

* mg/cm3 0.03008

Calculated skin permeation coefficient (kp) cm/hr 0.000358276

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

Exposure time hr 8

Calculated skin dose mg 0.902752639

Inhalation dose

Occupational exposure limit (OEL)† mg/m3 1.5

Inhalation volume m3 10

Retention factor (RF) None 0.75

Inhalation dose mg 11.25

Skin dose–to–inhalation dose (SI) ratio None 0.002758898

*

Variables identified from NLM [ND].

†

The OEL used in calculation of the SI ratio for cyclonite 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. 2021-104

DOI: https://doi.org/10.26616/NIOSHPUB2021104