# Skin Notation (SK) Profile

Morpholine

[CAS No. 110

- 91

- 8]

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: Morpholine. By Hudson NL, Dotson GS.
Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control
and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH)

Publication No. XXX

DHHS (NIOSH) Publication No. 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 morpholine

. 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 deve loped 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 Introduction

................................ ................................ ................................ ................................ ....... 1

1.1 General Substance Information

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

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

................................ ................................ ................................ .................. 1 2.0 Systemic Toxicity from Skin Exposure (SK: SYS)

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

................................ ................................ ................................ ........... 3

4.0 Immune

- mediated Responses (SK: SEN)

................................ ................................ ............................. 4
5.0 Summary

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

References

................................ ................................ ................................ ................................ ............... 6 Appendix: Calculation of the SI Ratio for Morpholine

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

Overview

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

Calculation

................................ ................................ ................................ ................................ ............... 10 Appendix Referen ces

................................ ................................ ................................ ................................ 11v

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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

DEREK Deductive Estimation of Risk from Existing Knowledge

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

con tact with a chemical

EC European Commission

g gram(s) g/L gram(s)/liter

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

IPCS International Program for Chemical Safety (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 psc 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 wei ght 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 levelvi

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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. NTP National Toxicology Program

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

ppm parts per million

REL recommended exposure limit

RF retention factor

SEN skin notation indicating the potential for immune

- mediated reactions following

exposure o f the skin

SI ratio ratio of skin dose to inhalation dose

SK skin notation

S W solubility in water

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

the skin

USEPA United States Environmental Protection Agency

μg m icrogram(s) μg/cm 2 microgram(s) per square centimeter μg/cm 2 /hr microgram(s) per square 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.

Cance r

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

Contaminant

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

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

Cutaneous (or percutaneous)

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

Dermal

— Referring to the skin.

Dermal contact

— Contact with ( touching) the skin.

Direct effects

— Localized, non

- immune

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

Immune

- mediated responses

— Responses mediated by the immune system, in cluding allergic

responses.

Sensitization

— A specific immune

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

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

immune

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

- exposure. Substance

— A chemical.

Systemic effects

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

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- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for 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 contr ibution 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. Aaron Sussell, Ph.D. Loren Tapp, M.D.

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

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.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. 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 given to the following CDC personnel:

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

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

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

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

Envi ronmental Health Sciences, Research Triangle, NC

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

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

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

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: Morpholine

CAS No: 110

- 91

- 8 Molecular weight (

MW ): 87.1

Molecular formula: C 4 H 9 ON

Structural formula:

Synonyms: Diethylene imidoxide; Diethylene oximide; Tetrahydro

- 1,4

- oxazine; Tetrahydro

- p

- oxazine

Uses: Morpholine is used primarily as a rubber accelerator, boiler water additive, and solvents; an estimated 44 million pounds of the chemical was used in 1992 [HSDB 2014].



### 1.2 Purpose

This skin notation profile presents ( 1 ) a brief summary of epidemiological and toxi cological data associated with skin contact with morpholine and ( 2 ) the rationale behind the hazard

- specific skin notation (SK) assignment for morpholine. 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 morpholine. A literature search w as conducted through February 2013 to identify information on morpholine, including but not limited to data relating to its toxicokinetics, acute toxicity, repeated

- dose systemic toxicity, carcinogenicity

, biological system/function

– specific effects (inclu ding 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

mor pholine.



### 1.3 Overview of SK Assignment

Morpholine is potentially capable of causing numerous adverse health effects following skin contact. A critical review of available data has resulted in the following SK assignment for morpholine: SK: SYS

DIR (COR) . Table 1 provides an overview of the critical effects and data used to develop the SK assignment for morpholine.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. Table 1. Summary of the SK Assignment for morpholine

Skin Notation Critical

Effect Available

Data

SK: SYS Liver, kidney, spleen Sufficient animal data SK: DIR (COR) Skin corrosivity Sufficient animal data



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

No toxicokinetic data following dermal exposure to morpholine were identified



## . The potential of morpholine to pose a skin absorption hazard was also evaluated, with use of a predictive algorithm for estimating and evaluating the health hazards of dermal exposure to substances [NIOSH 2009]. The evaluation method compares an estimated dose accumulated in the bod y from skin absorption and an estimated dose from respiratory absorption associated with a reference occupational exposure limit. On the basis of this algorithm, a ratio of the skin dose to the inhalation dose (SI ratio) of 1.76 was calculated for morpholi ne. An SI ratio of ≥0.1 indicates that skin absorption may significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore, morpholine is considered to be absorbed through the skin following dermal exposure. Additional informatio n on the SI ratio and the variables

used in its calculation are included in the appendix.

No human dermal lethal dose (LD Lo ) estimates were identified. A minimum lethal dose of 0.9 grams per kilogram body weight [g/kg; 900 milligrams per kilogram body wei ght (mg/kg)] was reported in guinea pigs [Shea 1939]. T he reported dermal LD 50 value ( the dose resulting in 50% mortality in the exposed

animals ) was 0.5 milliliters per kilogram (mL/kg) [corresponding to 503.5 mg/kg] in the rabbit [Smyth et al. 1954]. Because the reported acute dermal LD 50 value for rats and the minimum lethal dose for guinea pigs were lower than the critical dermal LD 50 value of 2,000 mg/kg that identifies chemical substances with the potential for acute toxicity [NIOSH 2009], morpholi ne is considered acutely toxic following dermal exposure.

No epidemiological studies or human case reports or repeated

- dose, sub

- chronic, or chronic dermal toxicity studies in animals were identified. However, Shea [1939] reported a dermal toxicity stud y in rabbits and guinea pigs exposed to morpholine for up to 2 weeks to 900 mg/kg

- day of diluted (aqueous) (rabbits) or undiluted (guinea pigs). In this study, all animals died before the eleventh (rabbits) or thirteenth (guinea pigs) dose. Morpholine at t his dose caused necrosis of the liver and kidney tubules (rabbits and guinea pigs) and congestion of the spleen (rabbits). Although prolonged dermal exposure studies were not identified, the Shea [1939] study suggests the potential for effects at doses low er than

the critical dermal No

- Observed

- Adverse

- Effect

- Level (NOAEL) value of 1000 mg/kg for repeat

- dose toxicity that identifies chemical substances with the potential for repeated

- dose dermal toxicity [NIOSH 2009]. Therefore, morpholine is considered to be systemically toxic, causing liver, kidney and spleen effects, following repeated dermal exposure.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 standard toxicity or specialty studies were identified that evaluated biological system/function specific effects (including reproductive and developm ental effects and immunotoxicity) following dermal exposure to morpholine. No studies were identified that evaluated the potential of morpholine to be a carcinogen in humans or animals following dermal exposure. Table 2 summarizes carcinogenic designations of multiple governmental and nongovernmental organizations for morpholine.

Table 2. Summary of the carcinogenic designations * for morpholine by numerous governmental and nongovernmental organizations

Organization Carcinogenic designation NIOSH [2005] No designation NTP [2014] No designation USEPA [2015] No designation European Parliament [2008] No GHS designation IARC [2012] Group 3: Not classifiable as to its carcinogenicity to

humans EC [2013] † No designation ACGIH [2001] A4: Not classifiable as carcinogenic 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 Classification and Label ling of Chemicals; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; USEPA = United States Environmental Protection Agency.

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

Although no toxicokinetic data were identified to evaluate the potential of morpholine to be absorbed through the skin, data from acute dermal toxicity study in rabbits [ Smyth et al. 1954 ] 1 and a short

- term dermal toxicity study in guinea pigs and rabbits [ Shea 1939] are sufficien t to suggest that that morpholine can be absorbed by the skin, systemically available, and toxic, with the potential to cause liver, kidney and spleen effects following repeated exposure. Therefore, on the basis of the data for this assessment, morpholine is assigned the SK: SYS notation.



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

Only one study was identified that reported the potential of morpholine to have direct effects on human skin. Shea [1939] reported that undiluted morpholine applied to the human finger tip caused cracking of the cuticle and epithelium of the nail bed and burning sensations. Evidence of skin corrosivity of morpholine is well

- documented in experimental animals. Occluded topical application of 900 mg/kg of

the undiluted or un

- neutralized mo rpholine as a single dose or same dose of diluted morpholine applied daily for up to two weeks caused necrosis of the skin, inflammation, edema, and severe burning in rabbits [Shea 1939]. Guinea pigs receiving occluded, daily topical application of 900 mg/ kg undiluted morpholine for up two weeks also exhibited edema and necrosis of the skin [Shea 1939]. Smyth [1954]

1 References in bold text indicate studies that serve as the basis of the SK assignments.4

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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. reported that topical application of 0.001 mL of undiluted morpholine [corresponding to 1 mg] resulted

in skin necrosis in rabbits within 24 ho urs. Wang and Suskind [1988] reported 0.1 g applications of 0.5, 2, 5 and 10% morpholine concentrations produced no irritation when applied to 1.5 squared centimeter (cm 2 ) of the shaved skin of guinea pigs under occlusive conditions.

Evidence of direct skin effects of morpholine in humans and animals are also provided by in vitro studies. Gay et al. [1992] applied morpholine to living skin equivalent (LSE), collagen

- fibroblast lattice from which human epidermal keratinocytes forms a st ratified epidermis. Concentrations greater than 1% morpholine (by weight) were required to produce inflammation, indicative of irritation in both rabbit and human LSE. In a similar study conducted by van de Sandt and Rutten [1995], rabbit cell cultures

adm inistered 5% morpholine solution exhibited no changes. The structure

- activity relationship model, Deductive Estimation of Risk from Existing Knowledge ( DEREK ) for Windows, predicted morpholine to be negative for skin irritation.

Based on the results of th e studies that evaluated the direct effects of undiluted morpholine in animals [Shea 1939; Smyth 1954] , there is sufficient information that suggests that morpholine is corrosive to the skin. Therefore, on the basis of the data for this assessment, morphol ine is assigned the SK: DIR (COR) notation.



## 4.0 Immune

- mediated Responses (SK: SEN)

No evidence was identified in human studies to suggest that morpholine has the potential to produce skin sensitization. Animal data was limited to a single study. In a mod ified Buehler test [Wang and Suskind 1988], 10 guinea pigs were administered 0.1 g morpholine in 5% petrolatum under occlusion on clipped napes for 1 hour for 3 days/week for 2 weeks. Two weeks after the final dose, the guinea pigs were challenged with 0.1 , 0.5, and 2 % morpholine concentrations, and no sensitization was observed; however, Wang and Suskind [1988] reported cross

- sensitization reactions when animals were initially sensitized with 4,4

- dithiodimorpholine (DTDM) or morpholinyl

- mercaptobenzothiaz ole (MMBT) and then challenged with morpholine. The structure activity relationship model, DEREK for Windows, predicted morpholine to be negative for skin sensitization.

The modified Buehler test identified suggests that morpholine is not a skin sensitize r, but can cross

- react with structurally similar chemicals. However, this information is considered insufficient as the basis for assigning a SK

- SYS notation for morpholine. Therefore, on the basis of the data for this assessment, morpholine is not assigne d the SK: SEN notation.



## 5.0 Summary

No toxicokinetic data were identified to evaluate the potential of morpholine to be absorbed through the skin. However, data from acute dermal toxicity study in rabbits [ Smyth et al. 1954] and a short

- term dermal toxicity study in guinea pigs and rabbits [ Shea 1939] are sufficient to indicate that morpholine has the potential to be absorbed through the skin, be systemically available and toxic, with the potential to cause liver, kidney and spleen effects following repeated exposure. Available studies in animals5

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. indicate that undiluted morpholine is corrosive to the skin [Shea 1939; Smyth 1954] . Results from a modified Buehler test suggest that morpholine is not likely to cause skin sensitiza tion, but can cross

react with structurally similar chemicals. Therefore, on the basis of these assessments, morpholine is assigned a composite skin notation of SK: SYS

- DIR (COR)

.

Table 3 summarizes the skin hazard designations for morpholine previously issued by NIOSH and other organizations. The equivalent dermal designation for morpholine, according to the Global Harmonization System (GHS) of Classification and Labelling of Chemicals, is Acute Toxicity Category 4 (Harmful in contact with the skin) and Skin Corrosion Category 1B (Causes severe skin burns and eye damage) [European Parliament 2008].

Table 3. Summary of previous skin hazard designations for morpholine

Organization Skin hazard designation
NIOSH [2005] [skin]: Potential for dermal absorption OSHA [2015] * [skin]: Potential for dermal absorption ACGIH [2001] [skin]: Based on report of human dermal penetration and a dermal

LD 50 for 24

- hour skin contact of 0.5 mL/kg in rats EC [2013] * R21: Harmful if in contact with skin

R34: Causes burns

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration.

*Date accessed.6

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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. 

## References

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

*ACGIH [2001]. Morpholine. In: Documentation of threshold limit values and biological exposure indices 7th ed., Vol. 2. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*EC (European Commission) [ND]. Morpholine. In: EINICS (European Inventory of Existing Commercial Chemical Substances), htt p://esis.jrc.ec.europa.eu/. Accessed: 05

- 14

- 13.

*European Parliament, Council of the European Union [2008]. Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, 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

– 1355, http://eur

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

- 28

- 15

.

† Fisher AA. [1978]. Reports from the Second International Contact Dermatitis Symposium. Part III [proceedings]. Cutis 22 : 272

- 289.

*Gay R, Swiderek M, Nelson D, Ernesti A. [1992]. The living skin equivalent as a model in vitro for ranking the toxic potential of dermal irritants. Toxic in Vitro 6 (4): 303

- 315.

† Harbison RD, Marino DJ, Conaway CC, Rubin LF, Gandy J. [1989]. Chronic morpholine exposure of rats. Fund. Appl. Toxicol. 12 :491

– 507.

*HS DB (Hazardous Substances Data Bank) [2014]. Morpholine. In: HSDB (Hazardous Substances Data Bank), http://toxnet.nlm.nih.gov/cgi

- bin/sis/search2/f?./temp/~iHMM77:1. Accessed: 01

- 28

- 15.

*IARC (International Agency for Research on Cancer) [2012]. Agents rev iewed by the IARC monographs. In: IARC monographs on the evaluation of carcinogenic risks to humans, http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed: 01

- 28

- 15.

*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,

h ttp://www.cdc.gov/niosh/npg/npgd0211.html. Accessed: 01

- 28

- 15.

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

2009

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

- 147/pdfs/2009

- 147.pdf]. Accessed 01

- 28

- 15.7

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or
policy. *NTP [2014]. Report on Carcinogens. Thirteenth Edition; U.S. Depart ment of Health and Human Services, Public Health Service. National Toxicology Program, http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01

- 28

- 15.

*OSHA [ND]. Morpholine. In: OSHA occupational chemical database, http://www.osha.gov/chemi caldata/chemResult.html?recNo=120. Accessed: 01

- 28

- 15.

*Shea TE [1939]. The acute and sub

- acute toxicity of morpholine. J. Ind. Hyg. Toxicol., 21 (7): 236

- 245.

*Smyth Jr. HF, Carpenter CP, Weil CS, Pozzani UC [1954]. Range

- Finding Toxicity Data. List V. A rch. Ind. Hyg. Occup. Med. 10 :61

– 68.

†UNECE (United Nations Economic Comission for Europe) [2007]. Part 3: health hazards. In: Globally harmonized system of classification and labeling of chemical (GHS): third revised edition, http://www.unece.org/trans/ danger/publi/ghs/ghs_rev02/English/03e_part3.pdf. Accessed: 01

- 28

- 15.

*USEPA [2015]. Morpholine. In: Integrated Risk Information System, http://www.epa.gov/iris/.

Accessed: 01

- 28

- 15.

*Van De Sandt JJM, Rutten AAJJL [1995]. Differential effects of chemica l irritants in rabbit and human skin organ cultures. Toxic in Vitro 9 (2): 157

- 168.

*Wang X, Suskind RR. [1988]. Comparative Studies of the Sensitization Potential of Morpholine, 2

- Mercaptobenzothiazole and 2 of Their Derivatives in Guinea Pigs. Contact Dermatitis 19 (1): 11

- 5.8

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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. 

## Appendix: Calculation of the SI Ratio for Morpholine

This appendix presents an overview of the SI ratio and a summary of the calculation of the SI ratio for morpholine. Although the SI ratio is considered in the determi nation 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 th e 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 met hod 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 absorpt ion

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

- 10 logarithm of its octanol

– water partition coefficient ( log K

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

- consistent set

of units must be used, such as centimeters per hour (cm/hr), outlined in Table A1. Other model

- based

estimates of k

p may also be used [NIOSH 2009].9

This information is distributed solely for the purpose of pre

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

substance

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

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation volume × RF

= OEL (mg/m 3 ) × 10 m 3 × 0.75

The final step is to compare the calculated skin and inhalation doses and to present the result as a ratio of skin dose to inhalation dose (the SI ratio). This ratio quantitatively indicates ( 1 ) the significance of dermal absorption as a route of occupational exposure to the substance and ( 2 ) the contribution 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.10

This information is distributed solely for the purpose of pre

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

### Calculation

Table A1 summarizes the data applied in the previously described equations to determine the SI ratio for morpholine. The calculated SI ratio was 1.76. On the basis of these results, morpholine is predicted to represent a skin absorption hazard.

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

Variables Used in Calculation Units Value Skin permeation coefficient Permeation coefficient of stratum corneum lipid path( k psc ) cm/hr 0.0003 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hr 1.628 × 10 - 5

Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.2679 Molecular weight ( MW

) * amu 87.1
Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None

- 0.86 Calculated skin permeation coefficient ( k p ) cm/hr 0.0003

Skin dose

Water solubility ( S w ) * mg/cm 3 1000 Calculated skin permeation coefficient ( k p ) cm/hr 0.0003
Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8

Calculated skin dose mg 921.2

Inhalation Dose
Occupational exposure limit (OEL) † mg/m 3 70

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

Inhalation dose mg 525

Skin dose

– to

– inhalation dose (SI) ratio None 1.755

* Variables identified from SRC [ND].

† The OEL used in calculation of the SI ratio for morpholine was the NIOSH recommended exposure limit (REL) [NIOSH 2005].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. 

### 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

- 28

- 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

- 28

- 15.

SRC [2009]. Interactive PhysProp database demo, http://esc.syrres.com/fatepointer/webprop.asp?CA S=110918 . Accessed: 01

- 28

- 15.