# 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 

## This document is in the public domain and may be freely copied or reprinted.



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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 Con

trol 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 • PeopleTMSkin 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 spec

trum 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). Under

standing 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 con

tact with chemicals. The key step within assignment of the hazard-specific SK is the determina

tion 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 ana

lytical or numerical methods. This Skin Notation Profile provides the SK assignments and supportive data for phenylhydra

zine. 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-manage

ment 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 PreventionSkin 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

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

# Abbreviations
ACGIH American Conference of Governmental Industrial Hygienists ADL approximate dermal lethal CIB Current Intelligence Bulletin

cm 2 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 G lobally 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 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 dose resulting in 50% mortality in the exposed population LD Lo dermal lethal dose 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/kg milligram(s) per kilogram body weight mg/m 3 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 doseSkin Notation Profiles | Phenylhydrazine vii SK skin notation S W solubility SYS skin notation indicating the potential for systemic toxicity following exposure of the skin USEPA United States Environmental Protection Agencyviii 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 expo

sure 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 acknowl

edgment 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 acknowl

edgment 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 inde

pendent, 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, OHSkin Notation Profiles | Phenylhydrazine 1 

# 1 Introduction

1.1 General Substance Information:

Chemical: Phenylhydrazine CAS No: 100-63-0 Molecular weight ( MW ): 108.1 Molecular formula: C 6 H 5 NHNH 2 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 addi

tion 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 phen

ylhydrazine and (2) the rationale behind the hazard-specific skin notation (SK) assign

ment for phenylhydrazine. The SK assign

ment is based on the scientific rationale and logic outlined in the Current Intelligence Bul

letin (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 con

ducted through April 2014 to identify infor

mation 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 rel

evant to assessing the effects of dermal expo

sure to phenylhydrazine.


## 1.3 Overview of SK Assignment Phenylhydrazine is potentially capable of causing numerous adverse health effects fol

lowing skin contact. A critical review of avail

able data has resulted in the following SK as

signment 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 allergy2 Skin Notation Profiles | Phenylhydrazine 

# 2 Systemic Toxicity from Skin Exposure (SK: SYS) No quantitative estimates of the dermal ab

sorption of phenylhydrazine have been iden

tified. The potential of phenylhydrazine to pose a skin absorption hazard was also evalu

ated, 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 refer

ence occupational exposure limit. On the ba

sis 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 sig

nificantly contribute to the overall body bur

den 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 includ

ed in the appendix. No estimated dermal lethal dose (LD Lo ) was identified for humans. No dermal LD 50 val

ues (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) phenyl

hydrazine 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. Du

Pont Company [1963] reported an approxi

mate 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, hematu

ria, and weight loss following a single lethal dose. Although no animal LD 50 values were identified, concentrations significantly below 2000 mg/kg body weight are lethal in rab

bits, with mortality incidence reaching 30% at a dose of 374 mg/kg [Derlanko et al. 1987]. This result would be consistent with an LD 50 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 der

mal and inhalation routes, although no quan

titative measures of exposure were provided. Rukl [1953] reported three cases of hemolytic anemia following dermal exposures to small repeated (unspecified) doses to phenylhydra

zine 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 phenylhydra

zine (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 appli

cations of the material, and another exposed to 100 mg/kg died after receiving two appli

cations in three days [Dow Chemical Com

pany 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 dermalSkin Notation Profiles | Phenylhydrazine 3 

### 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 Occu

pational 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 poten

tial 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 devel

opmental effects and immunotoxicity) fol

lowing dermal exposures were identified for phenylhydrazine. No epidemiology studies or standard rodent cancer bioassays were iden

tified that evaluated the potential of phenyl

hydrazine to cause cancer following dermal exposure. Table 2 summarizes carcinogenic designations of multiple governmental and nongovernmental organizations for phenyl

hydrazine. Toxicokinetic studies that estimated der

mal absorption of phenylhydrazine were not identified. Although no acute dermal toxicity studies that estimated the dermal LD 50 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 phenyl

hydrazine 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 Chemi

cal 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 cor

rosivity 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 num

ber 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 chemi

cal was irritating to the skin of these animals. Dow Chemical Company [1940] reported that both phenylhydrazine and its hydrochlo

ride salt caused moderate skin irritation when applied topically to rabbit skin. Derelanko et4 Skin Notation Profiles | Phenylhydrazine al. [1987] reported that a single dermal ap

plication of phenylhydrazine hydrochloride, under occlusive or semi-occlusive conditions, to the skin of rabbits and rats as a solid moist

ened with distilled water for 24 hours caused skin irritation and some necrosis at the ex

posure sites. The investigators noted that the necrosis was severe when the chemical was applied under occlusive and under semi-oc

clusive conditions [Derlanko et al. 1987]. Ina 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 phenylhy

drazine to be negative for skin irritation. Overall, animal data provide sufficient evi

dence of dermal exposures to phenylhydrazine causing localized effects at the site of contact. Although Derlanko et al. [1987] noted necro

sis under occlusive and semi-occlusive con

ditions, no other data pertaining to the cor

rosivity 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 con

clude that phenylhydrazine is a moderate skin irritant, however, there is insufficient data are available to classify the substance as a corro

sive agent. Therefore, on the basis of the data for this assessment, phenylhydrazine is as

signed the SK: DIR (IRR) notation. 

# 4 Immune-mediated Responses (SK: SEN) The allergenic potential of phenylhydrazine has been demonstrated in humans and ani

mals. 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 fol

lowing occupational exposures to phenylhy

drazine, 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 phenylhy

drazine hydrochloride, but not pure phenyl

hydrazine. Frost and Hjorth [1959] reported cross-reactivity between phenylhydrazine and hydrazine salts when a patient was patch-test

ed 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 in

formation 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 Com

pany 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 as

signed the SK: SEN notation. 

# 5 Summary Although no toxicokinetic studies that esti

mated dermal absorption of phenylhydrazine were identified, predictions of a mathemati

cal 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 LD 50 in animals were identified, but approxi

mate dermal lethal doses of 90 mg/kg and greater were reported [DuPont Company 1963; Derelanko et al. 1987] . Phenylhydra

zine has the potential to cause hemolytic ef

fects in both animals [Derelanko et al. 1987] and humans [Rukl 1953] following acute or repeated dermal exposure. Other potentialSkin Notation Profiles | Phenylhydrazine 5 

### 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 phenylhy

drazine is a skin irritant. There is limited in

formation 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 designa

tions for phenylhydrazine previously issued by NIOSH and other organizations. The equiva

lent dermal designations for phenylhydrazine, according to the Global Harmonization Sys

tem (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) [ Europe

an Parliament 2008]. In addition, phenylhy

drazine has been classified as a Mutagenicity Category 2 (Hazard Statement: Suspected of causing genetic defects) [ European Parlia

ment 2008]. 

# References ACGIH (American Conference of Governmen

tal Industrial Hygienists) [2001]. Phenylhy

drazine. 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, Rine

hart W [1987]. Toxicity of hydroxylamine sul

fate following dermal exposure: variability with exposure method and species. Fund Appl Toxi

col 8 :583–594. Dow Chemical Company [1940]. Toxicity of phenylhydrazine and phenylhydrazine hydro

chloride: 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 Phenyl

hydrazine Compounds—Report of a Case. N Engl J Med 216 :240–241. DuPont Company [1963]. Acute skin absorp

tion toxicity. Newark, DE: DuPont Company, Haskell Laboratory for Toxicology and In

dustrial 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 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]. Phenylhy

drazine. 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, label

ing and packaging of substances and mixtures, amending and repealing Directives 67/548/ EEC and 1999/45/EC, and amending Regu

lation (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 (Haz

ardous 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 Wochen

schrift 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 Pre

vention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publica

tion 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 In

stitute 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 Hu

man 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 Chemi

cals. 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 chemi

cal 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 

# 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 support

ive 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 Bul

letin (CIB) 61: A Strategy for Assigning New NIOSH Skin Notations [NIOSH 2009].


## Overview The SI ratio is a predictive algorithm for esti

mating and evaluating the health hazards of skin exposure to substances. The algorithm is designed to evaluate the potential for a sub

stance to penetrate the skin and induce sys

temic toxicity [NIOSH 2009]. The goals for incorporating this algorithm into the pro

posed strategy for assigning SYS notation are as follows:
1. Provide an alternative method to evalu

ate substances for which no clinical re

ports 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 la

beled with the SYS notation. The algorithm evaluation includes three steps:
1. determining a skin permeation coeffi

cient ( 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 require

ment 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 deter

mine 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 capil

laries of the dermis, is estimated from the compound’s molecular weight ( MW ) and base-10 logarithm of its octanol–water par

tition 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 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 

### )

aq pol psc p 

## k k k k 1 1 1

+ + =

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 biolog

ic mass uptake of the substance from skin8 Skin Notation Profiles | Phenylhydrazine absorption (skin dose) and inhalation (inhala

tion dose) during the same period of exposure. The skin dose is calculated as a mathematical product of the k p , the water solubility ( S W ) of the substance, the exposed skin surface area, and the duration of exposure. Its units are mil

ligrams (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 [cm 2 ]).


### Equation 2: Determination of Skin Dose

= k p × S
w × Exposed skin surface area × Exposure time

= k p (cm/hour) × S
w (mg/cm 3 ) × 360 cm 2 × 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 de

veloped 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 inhala

tion volume of 10 cubic meters (m 3 ) inhaled air in 8 hours, and a factor of 75% for reten

tion 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 indi

cates (1) the significance of dermal absorp

tion 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 calcu

lated SI ratio was 304.6. On the basis of these results, phenylhydrazine is predicted to repre

sent 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 Oc

cupational 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 no

tations. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Dis

ease 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 

### 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 ps c ) cm/hr 3.792 × 10 -3 Permeation coefficient of the protein fraction of the stratum

corneum ( k pol

) cm/hr 1.1461 × 10 -5 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.2404 Molecular weight ( MW ) * amu 108.14 Base-10 logarithm of its octanol–water partition coefficient

(Log K
ow ) * None 1.25 Calculated skin permeation coefficient (k p ) cm/hr 3.7472 × 10 -3 Skin dose

Water solubility ( S w ) * mg/cm 3 127 Calculated skin permeation coefficient ( k p ) cm/hr 3.7472 × 10 -3 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8 Calculated skin dose mg 1370.57 Inhalation dose

Occupational exposure limit (OEL) † mg/m 3 0.6 Inhalation volume m 3 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].