NIOSH Skin Notation (SK) Profiles

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health

Phenylhydrazine

[CAS No. 100-63-0]
ii Skin Notation Profiles | Phenylhydrazine

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Suggested Citation

NIOSH [2014]. NIOSH skin notation profiles: phenylhydrazine. 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. 2014-147.

DHHS (NIOSH) Publication No. 2014-147

August 2014

Safer • Healthier • PeopleTM
Skin Notation Profiles | Phenylhydrazine 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 (e.g., irritant contact dermatitis 

and corrosion) to induction of immune-mediated responses (e.g., allergic contact dermatitis 

and pulmonary responses), or systemic toxicity (e.g., neurotoxicity and hepatoxicity). Understanding the hazards related to skin contact with chemicals is a critical component of modern 

occupational safety and health programs. 

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

Current Intelligence Bulletin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations 

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

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

systemic effects, direct (localized) effects, and immune-mediated 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 (e.g., skin permeation) by means of analytical or numerical methods. 

This Skin Notation Profile provides the SK assignments and supportive data for phenylhydrazine. 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 nterest.

John Howard, M.D.

Director, National Institute for 

 Occupational Safety and Health

Centers for Disease Control and Prevention
This page intentionally left blank.
Skin Notation Profiles | Phenylhydrazine 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) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

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

5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

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

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

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

Appendix References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
vi Skin Notation Profiles | Dichloropropene

Abbreviations

ACGIH American Conference of Governmental Industrial Hygienists 

ADL approximate dermal lethal

CIB Current Intelligence Bulletin

cm2 square centimeter(s)

cm/hour centimeter(s) per hour

DEREK Deductive Estimation of Risk from Existing Knowledge

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

contact with a chemical

EC European Commission 

GHS Globally Harmonized System for Classification and Labelling of Chemicals

GPMT guinea pig maximization test

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 

kpol coefficient in the protein fraction of the stratum corneum

k

psc permeation coefficient in the lipid fraction of the stratum corneum 

LD50 dose resulting in 50% mortality in the exposed population

LDLo dermal lethal dose

LOAEL lowest-observed-adverse-effect level 

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

M molarity

m3 cubic meter(s)

mg milligram(s)

mg/kg milligram(s) per kilogram body weight

mg/m3 milligram(s) per cubic meter

mL milliliter(s)

MW molecular weight

NIOSH National Institute for Occupational Safety and Health

NOAEL no-observed-adverse-effect level

NTP National Toxicology Program

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration

REL recommended exposure limit

RF retention factor 

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

exposure of the skin

SI ratio ratio of skin dose to inhalation dose
Skin Notation Profiles | Phenylhydrazine vii

SK skin notation

SW solubility 

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

the skin

USEPA United States Environmental Protection Agency 
viii Skin Notation Profiles | Phenylhydrazine

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 Profiles | Phenylhydrazine ix

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, H. Fredrick Frasch, Ph.D., 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 Information Division

Devin Baker, M.Ed. 

Charles L. Geraci, Ph.D. 

Thomas J. Lentz, Ph.D. 

Richard Niemeier, Ph.D.

Sudha Pandalai. M.D., Ph.D. 

Health Effects Laboratory Division

Stacey Anderson, Ph.D. 

Vic Johnson, Ph.D.

Michael Luster, Ph.D. 

Anna Shvedova, Ph.D.

Paul Siegel, Ph.D.

National Personal Protection Technology Laboratory

Heinz Ahlers, 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.
x Skin Notation Profiles | Phenylhydrazine

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:

Frank A Barile, Ph.D., St. John’s University, College of Pharmacy, Queens, NY

Glenn Sipes, Ph.D., University of Arizona, College of Medicine, Tucson, AZ

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
Skin Notation Profiles | Phenylhydrazine 1

Phenylhydrazine

1 Introduction 

1.1 General Substance Information: 

Chemical: Phenylhydrazine

CAS No: 100-63-0

Molecular weight (MW): 108.1

Molecular formula: C6H5NHNH2

Structural formula:

Synonyms: 

Hydrazinobenzene; monophenylhydrazine; 

hydrazinobenzen

Uses:

Phenylhydrazine is used as an intermediate, 

reducing agent, and reagent in the production 

of dyes, sugars, organic compounds, in addition to pharmaceuticals [HSDB 2011]. 

1.2 Purpose 

This skin notation profile presents (1) a brief 

summary of epidemiological and toxicological 

data associated with skin contact with phenylhydrazine and (2) the rationale behind the 

hazard-specific skin notation (SK) assignment for phenylhydrazine. 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 

phenylhydrazine. A literature search was conducted through April 2014 to identify information on phenylhydrazine, including but not 

limited to data relating to its toxicokinetics, 

acute toxicity, repeated-dose systemic toxicity, 

carcinogenicity, biological system/function–

specific effects (including reproductive and 

developmental effects and immunotoxicity), 

irritation, and sensitization. Information was 

considered from studies of humans, animals, 

or appropriate modeling systems that are relevant to assessing the effects of dermal exposure to phenylhydrazine. 

1.3 Overview of SK Assignment

Phenylhydrazine 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 phenylhydrazine: SK: SYS-DIR 

(IRR)-SEN. Table 1 provides an overview of 

the critical effects and data used to develop 

the SK assignment for phenylhydrazine. 

Table 1. Summary of the SK assignment for phenylhydrazine

Skin notation Critical effect Data available

SK: SYS Hemolytic effects; Nephrotoxicity; 

Hepatotoxicity

Limited human and animal data

SK: DIR (IRR) Skin irritant Sufficient human data

SK: SEN Skin allergy
2 Skin Notation Profiles | Phenylhydrazine

Phenylhydrazine

2 Systemic Toxicity from Skin 

Exposure (SK: SYS)

No quantitative estimates of the dermal absorption of phenylhydrazine have been identified. The potential of phenylhydrazine 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 body 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 304.6 was 

calculated for phenylhydrazine. An SI ratio of 

≥0.1 indicates that skin absorption may significantly contribute to the overall body burden of a substance [NIOSH 2009]; therefore, 

phenylhydrazine is 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 estimated dermal lethal dose (LDLo) was 

identified for humans. No dermal LD50 values (the dose resulting in 50% mortality in 

the exposed animals) have been identified. 

In a study by Derelanko et al. [1987], rabbits 

topically exposed to a dose of 500 milligrams 

per kilogram body weight (mg/kg) phenylhydrazine hydrochloride [corresponding to 

374 mg/kg phenylhydrazine] under a plastic 

cover or gauze for 24 hours experienced 20 to 

30% mortality, respectively, but no mortality 

at 10 mg/kg. No fatalities were observed in 

rats administered the same dose. Derelanko 

et al. [1987] reported hematological effects 

(destruction of red blood cells, reduction 

in erythrocyte count, increased reticulocyte 

count, methemoglobin formation (rats only), 

and enlargement of the spleen as systemic 

effects following acute dermal exposure. DuPont Company [1963] reported an approximate dermal lethal (ALD) dose of 90 mg/kg 

for the chemical following single dermal dose 

study in rabbits, with the animals exhibiting 

initial weight loss, hematuria and pallor for 

2 days when administered a single nonlethal 

dose, and cyanosis, rapid respiration, hematuria, and weight loss following a single lethal 

dose. Although no animal LD50 values were 

identified, concentrations significantly below 

2000 mg/kg body weight are lethal in rabbits, with mortality incidence reaching 30% at 

a dose of 374 mg/kg [Derlanko et al. 1987]. 

This result would be consistent with an LD50

value below 2000 mg/kg and is sufficient to 

conclude that phenylhydrazine is acutely toxic 

following dermal exposure [NIOSH 2009]. 

Hemolytic anemia was observed in several 

cases of occupational exposure by both dermal and inhalation routes, although no quantitative measures of exposure were provided. 

Rukl [1953] reported three cases of hemolytic 

anemia following dermal exposures to small 

repeated (unspecified) doses to phenylhydrazine over a period ranging from 2 weeks to 

9 months. No subchronic (21-day or 28-day) 

or chronic (at least 12 months) studies were 

identified in animals. However, a repeat-dose 

study was identified in which Dow Chemical 

Company [1940], administered phenylhydrazine (as the hydrochloride) to the skin of an 

unspecified number of rabbit at doses of 1, 10, 

or 100 mg/kg for a total of 20 times over a 29-

day period. No deaths were observed in the 1 

mg/kg dose group, while an animal exposed 

to 10 mg/kg died after receiving four applications of the material, and another exposed 

to 100 mg/kg died after receiving two applications in three days [Dow Chemical Company 1940]. Histological examination showed 

slight damage to the liver of the rabbit dosed 

at 1 mg/kg per day and marked damage to the 

spleen and liver and a less marked damage in 

the lung and kidney of the animal exposed to 

10 mg/kg [Dow Chemical Company 1940]. 

No histological examination was performed 

in the animal dosed daily at 100 mg/kg, but 

blood examination revealed marked anemia 

and leukocytosis. Although the quality of 

this study is limited, the results suggest that 

the liver, kidney and the spleen are potential 

targets for phenylhydrazine following dermal 
Skin Notation Profiles | Phenylhydrazine 3

Phenylhydrazine

Table 2. Summary of the carcinogenic designations* for phenylhydrazine 

by numerous governmental and nongovernmental organizations

Organization Carcinogenic designation

NIOSH [2005] Potential occupational carcinogen

NTP [2011] No designation

US EPA [2014] No designation

European Parliament [2008] Carcinogenicity Category 1B: May cause cancer

IARC [2012] No designation

EC [2014]† R45: May cause cancer

ACGIH [2001] Group 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; 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 rather than dermal exposure.

†

Date accessed.

exposure and that the chemical has the potential to elicit systemic effects at doses as low as 

1 mg/kg per day. 

No standard toxicity or specialty studies 

evaluating biological system/function specific 

effects (including reproductive and developmental effects and immunotoxicity) following dermal exposures were identified for 

phenylhydrazine. No epidemiology studies or 

standard rodent cancer bioassays were identified that evaluated the potential of phenylhydrazine to cause cancer following dermal 

exposure. Table 2 summarizes carcinogenic 

designations of multiple governmental and 

nongovernmental organizations for phenylhydrazine. 

Toxicokinetic studies that estimated dermal absorption of phenylhydrazine were not 

identified. Although no acute dermal toxicity 

studies that estimated the dermal LD50 values 

in animals were identified, ADL doses of 90 

mg/kg and greater were reported [DuPont 

Company 1963; Derelanko et al. 1987]*

. The 

limited data identified indicate that phenylhydrazine can cause hemolytic effects in both 

*References in bold text indicate studies that serve 

as the basis of the SK assignments.

animals [Derelanko et al. 1987] and humans 

[Rukl 1953] following dermal exposure. A 

repeat-dose dermal toxicity study suggests 

that phenylhydrazine may cause systemic 

toxicity, including effects on liver, kidney and 

spleen, following skin contact [Dow Chemical Company 1940]. Therefore, on the basis of 

the data for this assessment, phenylhydrazine 

is assigned the SK: SYS notation. 

3 Direct Effects on Skin

(SK: DIR)

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

for corrosivity using human or animal skin 

models or in vitro tests of skin integrity using 

cadaver skin were identified. However, a number of skin irritation tests were identified in 

animals. For example, Roudabush et al. [1965] 

conducted primary irritation tests in which 50 

mg of undiluted phenylhydrazine was applied 

to the abraded or intact skin of rabbits and 

guinea pigs. Results indicated that the chemical was irritating to the skin of these animals. 

Dow Chemical Company [1940] reported 

that both phenylhydrazine and its hydrochloride salt caused moderate skin irritation when 

applied topically to rabbit skin. Derelanko et 
4 Skin Notation Profiles | Phenylhydrazine

Phenylhydrazine

al. [1987] reported that a single dermal application of phenylhydrazine hydrochloride, 

under occlusive or semi-occlusive conditions, 

to the skin of rabbits and rats as a solid moistened with distilled water for 24 hours caused 

skin irritation and some necrosis at the exposure sites. The investigators noted that the 

necrosis was severe when the chemical was 

applied under occlusive and under semi-occlusive conditions [Derlanko et al. 1987]. In 

a study by von Oettingen and DeichmannGruebler [1936], skin irritation was reported 

in rats following repeated topical application 

of 1% phenylhydrazine ointment in Vaseline. 

The structure activity relationship model, 

Deductive Estimation of Risk from Existing 

Knowledge (DEREK), predicted phenylhydrazine to be negative for skin irritation. 

Overall, animal data provide sufficient evidence of dermal exposures to phenylhydrazine 

causing localized effects at the site of contact. 

Although Derlanko et al. [1987] noted necrosis under occlusive and semi-occlusive conditions, no other data pertaining to the corrosivity of phenylhydrazine were identified. 

A weight of evidence analysis indicates that 

sufficient data exist from animal studies [von 

Oettingen and Deichmann-Gruebler 1936; 

Dow Chemical Company 1940; Roudabush 

et al. 1965; Derelanko et al. 1987] to conclude that phenylhydrazine is a moderate skin 

irritant, however, there is insufficient data are 

available to classify the substance as a corrosive agent. Therefore, on the basis of the data 

for this assessment, phenylhydrazine is assigned the SK: DIR (IRR) notation. 

4 Immune-mediated 

Responses (SK: SEN)

The allergenic potential of phenylhydrazine 

has been demonstrated in humans and animals. Downing [1937] reported dermatitis in 

a case report resulting from dermal exposure 

to phenylhydrazine compounds. Patch-testing 

with the dry powder moistened with water 

produced positive skin reactions in the patient, 

indicating skin sensitivity to phenylhydrazine 

[Downing 1937]. Wright and Joyner [1930] 

reported a case of skin hypersensitivity following occupational exposures to phenylhydrazine, phenylhydrazine salts, or a mixture of 

phenylhydrazine hydrochloride and sodium 

acetate; however following a series of patch 

tests with potential compounds, this patient 

was found to be hypersensitive to phenylhydrazine hydrochloride, but not pure phenylhydrazine. Frost and Hjorth [1959] reported 

cross-reactivity between phenylhydrazine and 

hydrazine salts when a patient was patch-tested with aqueous solutions of phenylhydrazine 

(0.2%). The chemical is also a skin sensitizer 

in animals. Solutions of phenylhydrazine as 

low as 1% were found to be sensitizing to 

guinea pigs [Eastman Kodak Company 1957; 

Stevens 1967]. Predictions using structure 

activity relationship models provide some information regarding this endpoint. DEREK

predicted phenylhydrazine to be a plausible 

skin sensitizer.

Limited number of case reports [Downing 

1937; Frost and Hjorth 1959] and predictive 

tests in guinea pigs [Eastman Kodak Company 1957; Stevens 1967] demonstrate that 

phenylhydrazine has the potential to be a skin 

sensitizer. Therefore, on the basis of the data 

for this assessment, phenylhydrazine is assigned the SK: SEN notation. 

5 Summary

Although no toxicokinetic studies that estimated dermal absorption of phenylhydrazine 

were identified, predictions of a mathematical algorithm suggest that the chemical has 

the potential to be absorbed through the skin 

following dermal exposure. No acute dermal 

toxicity studies that estimated the dermal 

LD50 in animals were identified, but approximate dermal lethal doses of 90 mg/kg and 

greater were reported [DuPont Company 

1963; Derelanko et al. 1987]. Phenylhydrazine has the potential to cause hemolytic effects in both animals [Derelanko et al. 1987]

and humans [Rukl 1953] following acute or 

repeated dermal exposure. Other potential 
Skin Notation Profiles | Phenylhydrazine 5

Phenylhydrazine

Table 3. Summary of previous skin hazard designations for phenylhydrazine

Organization Skin hazard designation

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

OSHA [2014]* [skin]: Based on the potential contribution to overall exposure by 

the cutaneous route

ACGIH [2001] [skin]: Based on observed significant reduction in body weight of 

rodents following topical application of phenylhydrazine

EC [2014]* R24 - Toxic in contact with skin 

R38 - Irritating to skin 

R43 -May cause sensitization by skin contact

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.

systemic effects following repeated dermal 

exposure include effects on liver, kidney and 

spleen [Dow Chemical Company 1940]. 

Based on the information identified from skin 

irritation studies conducted in animals [von 

Oettingen and Deichmann-Gruebler 1936; 

Dow Chemical Company 1940; Roudabush 

et al. 1965; Derelanko et al. 1987], there is 

sufficient evidence to conclude that phenylhydrazine is a skin irritant. There is limited information from case reports [Downing 1937; 

Frost and Hjorth 1959] and predictive tests 

in guinea pigs [Eastman Kodak Company 

1957; Stevens 1967] that indicate that the 

chemical is a skin sensitizer. Therefore, on the 

basis of these assessments, phenylhydrazine 

is assigned a composite skin notation of SK: 

SYS-DIR (IRR)-SEN. 

Table 3 summarizes the skin hazard designations for phenylhydrazine previously issued by 

NIOSH and other organizations. The equivalent dermal designations for phenylhydrazine, 

according to the Global Harmonization System (GHS) of Classification and Labeling 

of Chemicals, are Acute Toxicity Category 

3 (Hazard statement: Toxic in contact with 

skin), Skin Irritation Category 2 (Hazard 

statement: Causes skin irritation) and Skin 

Sensitization Category 1 (Hazard statement: 

May cause an allergic skin reaction) [European Parliament 2008]. In addition, phenylhydrazine has been classified as a Mutagenicity 

Category 2 (Hazard Statement: Suspected of 

causing genetic defects) [European Parliament 2008].

References

ACGIH (American Conference of Governmental Industrial Hygienists) [2001]. Phenylhydrazine. In: Documentation of threshold limit 

values and biological exposure indices 7th ed., 

Vol. 3. Cincinnati, OH: American Conference 

of Governmental Industrial Hygienists.

Derelanko M, Gad S, Gavigan F, Babich P, Rinehart W [1987]. Toxicity of hydroxylamine sulfate following dermal exposure: variability with 

exposure method and species. Fund Appl Toxicol 8:583–594.

Dow Chemical Company [1940]. Toxicity of 

phenylhydrazine and phenylhydrazine hydrochloride: a review. Midland, MI: Dow Chemical 

Company. On file with the U.S. Environmental 

Protection Agency under TSCA Section 8D. 

OTS #0557236. Document # 86940000826S.

Downing JG [1937]. Dermatitis from Phenylhydrazine Compounds—Report of a Case. N 

Engl J Med 216:240–241.

DuPont Company [1963]. Acute skin absorption toxicity. Newark, DE: DuPont Company, 

Haskell Laboratory for Toxicology and Industrial Medicine, Medical Research Project 

#MR-531-3, Report #106-63. On file with the 

U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS #0546542. Document 

#88-920010157.
6 Skin Notation Profiles | Phenylhydrazine

Phenylhydrazine

Eastman Kodak Company [1957]. Toxicity report 

on phenylhydrazine EK #329. Rochester, NY: 

Eastman Kodak Company. On file with the 

U.S. Environmental Protection Agency under 

TSCA Section 8D. OTS #0557375. Document 

#86940000965.

EC (European Commission) [ND]. Phenylhydrazine. In: EINICS (European Inventory of 

Existing Commercial Chemical Substances), 

http://esis.jrc.ec.europa.eu/. Accessed: 05-02-14.

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, labeling 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://eurex.europa.eu/

LexUriServ/LexUriServ.do?uri=OJ:L:2008:35

3:0001:1355:EN:PDF. Accessed: 05-02-14.

Frost J, Hjorth N [1959]. Contact dermatitis from 

hydrazine hydrochloride in soldering flux. Cross 

sensitization to Apresoline and isoniazid. Acta 

Dermato-Venereologica 39:82–86. 

HSDB (Hazardous Substances Data Bank) 

[2011]. Phenylhydrazine. In: HSDB (Hazardous Substances Data Bank), http://toxnet.

nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB. 

Accessed: 05-02-14.

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/Monographs/

PDFs/index.php. Accessed: 05-02-14.

Jadassohn W [1930]. Sensitization of guinea-pig 

skin to phenylhydrazine. Klinische Wochenschrift 9:551. 

NIOSH [2005]. Phenylhydrazine. In: 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: 05-02-14.

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: 05-02-14.

NTP [2011]. Report on Carcinogens. Twelfth 

Edition; U.S. Department of Health and Human Services, Public Health Service. National 

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

ntp/roc/twelfth/roc12.pdf. Accessed 05-02-14.

OSHA [ND]. Phenylhydrazine. In: Chemical 

sampling information, http://www.osha.gov/

chemicaldata/chemResult.html?recNo=18.

Accessed: 05-02-14.

Roudabush R, Terhaar C, Fassett D, Dziuba S 

[1965]. Comparative acute effects of some 

chemicals on the skin of rabbits and guinea 

pigs. Toxicol Appl Pharmacol 7:559–565.

Rukl V [1953]. Phenylhydrazine Poisoning. Prac 

Lek 5:272–274. 

Stevens MA [1967]. Use of Albino Guinea-Pig to 

Detect the Skin-Sensitizing Ability of Chemicals. Br J Ind Med 24:189–202

USEPA (United States Environmental Protection 

Agency) [2010]. Integrated Risk Information 

System (IRIS), http://www.epa.gov/ncea/iris/. 

Accessed: 05-02-14.

von Oettingen WF, Deichmann-Gruebler W 

[1936]. On the relation between the chemical constitution and pharmacological action of 

phenylhydrazine derivatives. J Ind Hyg Toxicol. 

18(1):1–16.

Wright I, Joyner E [1930]. Skin hypersensitivity 

to phenylhydrazine hydrochloride. Report of a 

case. Am J Med Sci 179:683–687.
Skin Notation Profiles | Phenylhydrazine 7

Phenylhydrazine

Appendix: Calculation of the SI Ratio for Phenylhydrazine

This appendix presents an overview of the SI 

ratio and a summary of the calculation of the 

SI ratio for phenylhydrazine. 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 (k

p

) for the substance of interest,

2. estimating substance uptake by the skin 

and respiratory absorption routes, and 

3. evaluating whether the substance poses a 

skin exposure hazard.

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

the physicochemical properties of a substance 

and the relevant exposure parameters. Thus, 

the algorithm is independent of the need for 

biologic data. Alternatively, it can function 

with both the physicochemical properties and 

the experimentally determined permeation 

coefficient when such data are available and 

appropriate for use.

The first step in the evaluation is to determine the k

p

 for the substance to describe 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 KOW). In this example, 

k

p

is determined for a substance with use of 

Equation 1. A self-consistent set of units must 

be used, such as outlined in Table A1. Other 

model-based estimates of k

p

 may also be used 

[NIOSH 2009].

Equation 1: Calculation of Skin Permeation 

Coefficient (k

p

)

psc pol aq

p

k k k

k 1 1

1

+

+

=

where k

psc is the permeation coefficient in the 

lipid fraction of the stratum corneum, kpol is 

the coefficient in the protein fraction of the 

stratum corneum, and kaq is the coefficient in 

the watery epidermal layer. These components 

are individually estimated by

log k

psc = −1.326 + 0.6097 × log Kow − 

0.1786 × MW 0.5

kpol = 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 
8 Skin Notation Profiles | Phenylhydrazine

Phenylhydrazine

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 

continues for 8 hours to unprotected skin on 

the palms of both hands (a surface area of 360 

square centimeters [cm2]). 

Equation 2: Determination of Skin Dose 

= k

p

 × Sw × Exposed skin surface area 

 × Exposure time

 = k

p

(cm/hour) × Sw (mg/cm3) × 

 360 cm2 × 8 hours

The inhalation dose (in mg) is derived on 

the basis of the occupational exposure limit 

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

effects rather than sensory/irritant effects or 

direct effects on the respiratory tract. Assume 

a continuous exposure of 8 hours, an inhalation volume of 10 cubic 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).

Equation 3: Determination of Inhalation Dose

Inhalation dose = OEL × Inhalation 

 volume × RF

 = OEL (mg/m3) × 10 m3

 × 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.

Calculation 

Table A1 summarizes the data applied in the 

previously described equations to determine 

the SI ratio for phenylhydrazine. The calculated SI ratio was 304.6. On the basis of these 

results, phenylhydrazine is predicted to represent a skin absorption hazard.

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: 05-02-14.

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: 05-02-14.

SRC [2009]. Interactive PhysProp database demo 

http://www.srcinc.com/what-we-do/database

forms.aspx?id=386. Accessed: 05-02-14.
Skin Notation Profiles | Phenylhydrazine 9

Phenylhydrazine

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

Variables used in calculation Units Value

Skin permeation coefficient

Permeation coefficient of stratum corneum lipid path(k

psc

) cm/hr 3.792 × 10-3

Permeation coefficient of the protein fraction of the stratum 

corneum (kpol)

cm/hr 1.1461 × 10-5

Permeation coefficient of the watery epidermal layer (kaq) cm/hr 0.2404

Molecular weight (MW)

* amu 108.14

Base-10 logarithm of its octanol–water partition coefficient 

(Log Kow)

*

None 1.25

Calculated skin permeation coefficient (kp) cm/hr 3.7472 × 10-3

Skin dose

Water solubility (Sw)

* mg/cm3 127

Calculated skin permeation coefficient (k

p

) cm/hr 3.7472 × 10-3

Estimated skin surface area (palms of hand) cm2 360

Exposure time hr 8

Calculated skin dose mg 1370.57

Inhalation dose

Occupational exposure limit (OEL)† mg/m3 0.6

Inhalation volume m3 10

Retention factor (RF) None 0.75

Inhalation dose mg 4.5

Skin dose–to–inhalation dose (SI) ratio None 304.6

*

Variables identified from SRC [2009].

†

The OEL used in calculation of the SI ratio for phenylhydrazine was the NIOSH recommended exposure limit (REL) 

[NIOSH 2005].
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