i



# Skin Notation (SK) Profile

1

- Bromopropane

[CAS No. 106

- 94

- 5]

Department of Health and Human Services Centers for Disease Control and Prevention National Institute for Occupational Safety and Healthii

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. 

## Disclaimer

Mention of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health (NIOSH). In addition, citations to Web sites external to NIOSH do not constitute NIOSH endorsement of the sponsoring organization s or their programs or products. Furthermore, NIOSH is not responsible for the content of these Web sites.


## Ordering Information

To receive this document or information about other occupational safety and health topics, contact NIOSH:

Telephone: 1

- 800

- CDC

- INFO (1

- 800

- 232

- 4636) TTY: 1

- 888

- 232

- 6348 E

- mail: cdcinfo@cdc.gov Or visit the NIOSH Web site: www.cdc.gov/niosh

For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting www.cdc.gov/niosh/eNews. 

## Suggested Citation

NIOSH [20XX ]. NIOSH skin notation profile: 1

- Bromopropane. 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) Publicati on 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 He alth (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 potent ial 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 1

- bromopropane (1

- BP)

. In particular, this document evaluates and summarizes the literature describing the hazard potential of the substance and its assessment according to the scientific rationale and framework outlined in CIB 61. In meeting this objective, this Skin Notation Profile intends to inform the audience

— mostly occupational health practitioners, researchers, policy

- and decision

makers, employers, and workers in potentially hazardous workplaces

— so that improved risk

management practices may be developed to better protect workers from the risks of skin contact with the chemicals of interest.

John Howard, M.D. Director National Institute for Occupational Safety and Health Centers for Disease Control and Preventioniv

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. 

### Contents

FOREWORD

................................ ................................ ................................ ................................ ............................ III

ABBREVIATIONS

................................ ................................ ................................ ................................ ..................... V

GLOSSARY

................................ ................................ ................................ ................................ ............................. VII

ACKNOWLEDGMENTS

................................ ................................ ................................ ................................ ..... VIII

1.0 INTRODUCTION

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

1.1 G ENERAL S UBSTANCE I NFORMATION

................................ ................................ ................................ .................. 1 1.2 P URPOSE

................................ ................................ ................................ ................................ .............................. 1 1.3 O VERVIEW OF SK A SSIGNMENT FOR 1

- B ROMOPROPANE

................................ ................................ ..................... 2

2.0 SYSTEMIC TOXICIT Y FROM SKIN EXPOSURE (SK: SYS)

................................ ................................ ...... 2

3.0 DIRECT EFFECTS O N SKIN (SK: DIR)

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

4.0 IMMUNE

- MEDIATED RESPONSES ( SK: SEN)

................................ ................................ ............................. 6

5.0 SUMMARY

................................ ................................ ................................ ................................ ............................ 6

REFERENCES

................................ ................................ ................................ ................................ ............................ 8v

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. 

## 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

contact 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 co efficient 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 weig ht 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 nmol/cm 2 /hr nanomoles per square centimeter per hourvi

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. NOAEL no

- observed

- adverse

- effect level 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 of 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

th e skin USEPA United States Environmental Protection Agency
μg microgram(s) μg/cm 2 microgram(s) per square centimeter μg/cm 2 /hr microgram(s) per square centimeter per hour μL microliter(s) μmol micromole(s)vii

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. 

## 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.

Ca ncer

— 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 a t 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, upo n 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 ch emicals after exposure of the skin.viii

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. 

## 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, Stacey Anderson, and Clayton B’Hymer, 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 John Snawder, Ph.D.

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

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

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

Health Effects Laboratory Division Stacey Anderson, Ph.D. H. Fredrick Frasch, Ph.D. Anna Shvedova, Ph.D. Paul Siegel, Ph.D. Berran Yucesoy, 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, JD, M.Sc. Gregory Day, Ph.D. Angie Shepherd

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, MD, Ph.D., Division of Dermatology, Vanderbilt School of Medicine, Nashville, TN

 Jennifer Sahmel, MSc, CIH, ChemRisk, Boulder, CO

 James Taylor, MD, Industrial Dermatology, The Cleveland Clinic , Cleveland, OH1

SK Profile for Group C Draft: Sept 2013 

## 1.0 Introduction

1.1 General Substance Information

Chemical: 1

- Bromopropane (1

- BP) CAS No: 106

- 94

- 5 Molecular weight (

MW ): 123.00

Molecular formula: CH 3 CH 2 CH 2 Br

Structural formula:

Synonyms: 1

- BP; N

- Propyl bromide; nPB; Propyl bromide; n

- Propyl bromide; Propane, 1

- bromo

Uses: 1

- Bromopropane (1

- BP) is used primarily as a solvent in vapor degreasing and cold cleaning operations, as well as adhesive and coating spray applications [USEPA 2003]. An estimated 8.2 million pounds (3.8 million kilograms) of 1

- BP was used in the US in 2 002 [NTP 2004].


### 1.2 Purpose

This skin notation profile presents ( 1 ) a brief summary of epidemiological and toxicological data associated with skin contact with 1

- BP and ( 2 ) the rationale behind the hazard

- specific skin notation (SK) assignment for 1

- BP

. 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 1

- BP and the potential for direct skin injuries from 1

- BP . A literature search was conducted through January 2013 to identify 1

- BP toxicokinetics, acute toxicity, repeated

- dose systemic to xicity, 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 s ystems that are relevant to assessing the effects of dermal exposure to 1

- BP

. Br

CH 32

This information is distributed solely for the purpose of pre

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

### 1.3 Overview of SK Assignment for 1

- Bromopropane

1

- Bromopropane 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 1

- BP : SK: SYS

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

- BP.

Table 1. Summary of the SK Assignment for 1

- BP

Skin Notation Critical Effect Available Data SK: SYS Neurotoxicity; reproductive

and developmental toxicity Human data and animal toxicity data from studies of alternative exposure routes (inhalation, oral, and subcutaneous injection)

SK: DIR(IRR) Skin irritation Limited animal data



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

There were no toxicokinetic studies involving humans identified; however an in vitro dermal penetration study was identified. Frasch et al. [2011] used heat

- separated epidermal membranes from Caucasian female breasts or abdominal skin samples with 3 different dosing regimens. The skin samples were dosed with 10 microlit ers per square centimeter (μL/cm 2 ), equivalent to 13.5 milligrams per square centimeter (mg/cm 2 ), in an non occluded environment to simulate splash exposures; had a transient exposure where 1

- BP was applied to donor compartments in an occluded environment, and then removed after 10 minutes of exposure with the skin surfaces wiped to remove excess 1

- BP; or were exposed to an infinite dose of 1

- BP in an occluded environment for 3 hours [Frasch et al. 2011]. The authors noted that the total amount of 1

- BP abso rbed from the 13.5 mg/cm 2 dose was 22 μg/cm 2 , corresponding to an average penetration of 0.16% of the applied dose [Frasch et al. 2011]. The total amount of 1

- BP absorbed from transient and infinite exposures was 179 μg/cm 2 , and 1,322 μg/cm 2

, respectively [Frasch et al. 2011]. These data indicate that 1

- BP has the potential for substantial dermal penetration dependent of type and duration of exposure. The potential of 1

- BP to pose a skin absorption hazard has also been evaluated with use of a predictive alg orithm for estimating and evaluating the health hazards of dermal exposure to chemical substances [NIOSH 2009]. The evaluation method compares the chemical dose accumulated in the body from skin absorption and the dose from respiratory absorption during th e same period. The ratio of the skin dose to the inhalation dose (SI ratio) calculated for 1

- BP by this alternative method was 17.02. An SI ratio of ≥0.1 indicates that skin absorption may significantly contribute to the overall body burden of a substance3

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. [NIOSH 2009]; therefore, 1

- BP is considered to be absorbed through the skin following dermal exposure. Additional information on the SI ratio can be found in the appendix.

N o dermal lethal doses (LD Lo ) of 1

- BP for humans have been identified. Only one acute dermal toxicity study was identified, in which 1

- BP (2,000 milligrams per kilogram body weight [mg/kg]; 99.3% purity) was applied to the shaved dorsal skin of rats under semi

- occlusive wrap for 24 hours [Elf Atochem 1995a] . In this study, no clinical signs of toxicity were observed, and the authors concluded that the dermal LD 50 ( the dose resulting in 50% mortality in the exposed population) was higher than 2,000 mg/kg, indicating that 1

- BP is not acutely toxic upon dermal expsoure. However, 1

- BP is h ighly volatile, and the use of semi

- occlusive instead of occlusive wrap is likely to have resulted in evaporation of the chemical, leading to a less

- than

- optimal exposure period.

Because of a paucity of toxicokinetic and toxicity data concerning skin expo sures to 1

- BP, a review of data associated with alternative exposure pathways (e.g., inhalation, oral, and subcutaneous injections) was conducted. Numerous studies of rats revealed systemic effects, including neurotoxicity, hepatotoxicity, hematotoxicity, reproductive toxicity, and developmental toxicity, attributed to the inhalation of airborne 1

- BP below 1,000 parts per million (ppm) [ClinTrials Bioresearch 1997; Ichihara et al. 2000a, b; WIL Research Laboratories 2001; Wang et al. 2002, 2003; Yamada et a l. 2003; NTP 2004; Banu et al. 2007; Fueta et al. 2007]. Anderson et al. [2010] reported significant decreases in the spleen IgM responses to sheep red blood cells in mice (125

- 500 ppm) and rats (1000 ppm) after whole body inhalation exposure to 1

- BP for 1 0 weeks . Lee et al. [2005, 2007] treated mice with a single dose of 1

- BP at levels of 200, 500, and 1,000 mg/kg via the oral route. At 500

- and 1000

- mg/kg treatment levels, the authors reported a significant increase in relative liver weight and changes in liver enzyme levels [Lee et al. 2005, 2007]. In another investigation, Zhao et al. [1999] treated rats with daily injections of 1

- BP at treatment levels of 3.7 millimoles (mmol)/kg (corresponding to 455 mg/kg) and 11.0 mmol/kg (corresponding to 1,353 mg/k g) for 20 days. At both treatment levels, neurotoxic effects were reported.

There were no human epidemiological studies or repeated

- dose (subchronic or chronic) studies in animals that evaluated the potential of 1

- BP to cause systemic toxicity following dermal exposure identified. However, occupational (presumably a combination of dermal and respiratory) exposure to 1

- BP resulted in neuropathy in a male worker after he was exposed for 2 months to a degreasing solvent (containing 95.5% 1

- BP , less than 0.5% butylene oxide, less than 2.5% 1,3

- dioxolane, and less than 0.25% nitromethane) [Sclar 1999]. In addition, central nervous system effects were noted in a cohort of workers who had sprayed an adhesive (containing 70% 1

- BP, 0.3% 1,2

- epoxybutane, 10% styrene

- butadiene rubber, and 20% rosin ester) without proper personal protective equipment in a poorly ventilated area for 30 to 40 hours a week for 3 months [Beck and Caravati 2003]. Other case reports also detailed nervous system effects [Ichihara et al. 2002, 2004a, 2004b; Majersik et al. 2007; Raymond and Ford 2007]. Hanley et al. [2006] assessed occupational exposures to 1

- BP through air sampling and urinary testing for bromide (Br - ) concentrations (a known biomarker of 1

- BP exposure) in workers employed as either adhesive sprayers or nonsprayers at foam

- fabricating plants that used a spray adhesive4

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. containing within 1

- BP during the manufacture of polyurethane seat cushions. One of t he reported findings included a lower than expected correlation between urinary Br concentration and time

- weighted average (TWA) for sprayers. The authors stated that this disparity may be due to the absorption of 1

- BP by the skin when the sprayers handle d the wet adhesive with bare hands. The results of Hanley et al. [2006] indicate that 1

- BP may be absorbed via the skin, thus contributing to the systemic dose.

No standard toxicity or specialty studies evaluating biological system/function

– specific effe cts (including reproductive and developmental effects and immunotoxicity) following dermal exposure to 1

- BP were identified. Table 2 summarizes the carcinogenic designations for 1

- BP from NIOSH and other governmental and nongovernmental organizations.

Table 2. Summary of the carcinogenic designations for 1

- BP by numerous governmental and nongovernmental organizations

Organization Carcinogenic Designation NIOSH No designation NTP [2014] Reasonably anticipated to be a human carcinogen European Parliament [2008] No GHS designation USEPA [2015] No designation IARC [2012] No designation ACGIH [2014] A3, Confirmed animal carcinogen with unknown relevance to humans

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

Although the mathematical model predicted that 1

- BP was not readily absorbed by the skin, there was an in vitro dermal penetration study identified th at indicates that 1

- BP has the potential for substantial dermal penetration dependent on type and duration of exposure [Frasch et al. 2011]. Studies of workers exposed to 1

- BP indicate that the solvent may be absorbed by the skin and contribute to systemic toxicity, but the results of these investigations are confounded by the inhalation of 1

- BP vapors [Sclar 1999; Ichihara et al. 2002, 2004a, 2004b; Beck and Caravati 2003; NTP 2004; Hanley et al. 2006; Majersik et al. 2007; Raymond and Ford 2007]. A review of animal toxicity data from several non

- dermal exposure routes indicated that 1

- BP is capable of inducing a range of systemic effects, including neurotoxicity, hepatotoxicity, hematotoxicity, reproductive toxicity, and developmental toxicity in a dose

- re sponse manner [ ClinTrials Bioresearch 1997; Zhao et al. 1999; Ichihara et al. 2000a, 2000b; WIL Research Laboratory 2001; Wang et al. 2002, 2003; Lee et al. 2005, 2007; Banu et al. 2007; Fueta et al. 2007 ]. Therefore, on the basis of these data, 1

- BP is assigned the SK: SYS notation.5

This information is distributed solely for the purpose of pre

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

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

No evidence of skin corrosivity of 1

- BP, no in vitro tests for corrosivity in human or animal skin models, and no in vitro tests of skin integrity using cadaver skin were identified . Frasch et al. [2011] evaluated the corrosivity of 1

- BP using the EpiDerm human reconstructed epidermis model. Using this model, a chemical is classified as corrosive to skin if the cell viability after a 3 minute exposure is less than 50% and less than 1 5% after a one hour exposure [Frasch et al. 2011]. Frasch et al. [2011] found that after the 3 minute exposure, the viability for cells exposed to 1

- BP was 101% compared to the water

- exposed control and a one hour exposure of 1

- BP had a cell viability of 2 2%, indicating that 1

- BP is not considered corrosive to the skin. No studies on the skin

- irritating potential of 1

- BP in humans were identified, but there is limited evidence that the substance is a skin irritant in animals. Using a Draize scale, Jacobs et al. [1987] reported 1

- BP was a skin irritant, and observed a limit concentration (defined as the highest tested concentration at which the mean erythema score remains below 2) for skin irritation of 50% for 1

- BP solution in sweet almond oil in rabbits. In another test, performed according to the chemical testing guidelines of the Organization for Economic Co

- operation and Development (OECD), topical application of 1

- BP to rabbit skin produced erythema and edema and complete regeneration of the skin occurre d within 8 days [ Pálovics 2004]

. Pálovics [2004] also tested the irritation potential of 1

- BP on the chorioallantoic membrane of hen’s egg according to the ECVAM/INVITTIX Protocol. In this test, local application of 1

- BP caused copious hemorrhage and moder ate lysis of blood vessels in the chorioallantoic membrane, indicating severe irritation after exposure to 1

- BP; however, this procedure is typically used to evaluate ocular irritancy. Although rats administered 2,000 mg/kg 1

- BP covered by a semi

- occlusive dressing for 24 hours exhibited no cutaneous reaction [Elf Atochem 1995a], use of the semi

- occlusive rather than occlusive wrap in this study was likely to result in less

- than

- optimal exposure. This may explain the lack of irritation observed by those inv estigators. The structure

– activity relationship model (Deductive Estimation of Risk from Existing Knowledge, or DEREK, for Windows) predicted 1

- BP to be negative for skin irritation.

A study using the EpiDerm human reconstructed epidermis model [Frasch et al. 2011] indicated that 1

- BP is not corrosive to the skin following exposure to 1

- BP. Two in vivo tests conducted with standard methods [Jacobs et al. 1987 1 ; Pálovics 2004] , provide limited evidence that 1

- BP is irritating to the skin of rabbits. Therefore, on the basis of the findings for this assessment, 1

- BP is assigned a skin notation of SK: DIR (IRR).

1 References in bold text indicate studies that served as the basis of the SK assignment.6

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. 

## 4.0 Immune

- mediated Responses (SK: SEN)

No diagnostic human patch tests tha t evaluated the potential of 1

- BP to cause skin sensitization were identified. However, one study evaluated the skin sensitization potential of 1

- BP with use of the guinea pig maximization test. In this study, Elf Atochem [1995b] intradermally injected 0.1 ml of 1

- BP solution at a concentration of 25% on day 1, and applied 0.5ml of 1

- BP in occlusive conditions to the skin of guinea pigs for 48 hours on day 8. A challenge dose of 0.5 ml 1

- BP was given on day 12 on the left flank in occlusive conditions for 2 4 hours [Elf Atochem 1995b]. The investigators did not observe any cutaneous reactions that can be attributed to the sensitization potential of 1

- BP [Elf Atochem 1995b]. DEREK predicted 1

- BP to have skin sensitization potential. However, because of the absence of human data and insufficient animal data, a skin notation of SK: SEN is not assigned to 1

- BP. 

## 5.0 Summary

Although the mathematical model predicted that 1

- BP was not readily absorbed by the skin, there was an in vitro dermal penetration study identified that indicates that 1

- BP has the potential for substantial dermal penetration dependent of type and duration of exposure [Frasch et al. 2011]. A review of the available literature indicates that 1

- BP is capable of inducing a wide array of adverse systemic health effects, including neurotoxicity, hepatotoxicity, hematotoxicity, reproductive toxicity, and developmental toxicity, regardless of exposure route [ClinTrials Bio research 1997; Zhao et al. 1999; Ichihara et al. 2000a, 2000b; WIL Research Laboratory 2001; Wang et al. 2002, 2003; Lee et al. 2005, 2007; Banu et al. 2007; Fueta et al. 2007] . Although the exact systemic hazards associated with skin contact and absorptio n of 1

- BP are unknown, 1

- BP is assigned the SK: SYS notation; this notation is based on the recognition of adverse health effects in test animals exposed via the inhalation, oral, and subcutaneous injection routes. Although a study using the EpiDerm human reconstructed epidermis model [Frasch et al. 2011] indicated that 1

- BP is not corrosive to the skin following exposure to 1

- BP, two in vivo tests, conducted with standard methods [Jacobs et al. 1987 2 ; Pálovics 2004] , provide limited evidence that 1

- BP is i rritating to the skin of rabbits. Although no human patch tests that evaluated the sensitization potential of 1

- BP were identified, one guinea pig maximization test [Elf Atochem 1995b] showed that the substance is not a skin sensitizer. Therefore, on the b asis of this assessment, 1

- BP is assigned the composite skin notation SK: SYS

- DIR (IRR).

Table 3 summarizes the skin designations for 1

- BP from NIOSH and other organizations. The equivalent skin designation for 1

- BP from the Globally Harmonized System (G HS) of Classification and Labelling is Reproductive Category 1B (Presumed human reproductive toxicant) and Skin Irritation Category 2 (Causes skin irritation) [European Parliament 2008].

2 References in bold text indica te studies that served as the basis of the SK assignment.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. Table 3. Summary of previous skin hazard designations for 1

- BP

Organization Dermal Classification NIOSH [2005] No designation OSHA [2015] * No designation ACGIH [2014] No designation EC [2013] * R38: Irritating to skin

ACGIH = American Conference of Governmental Industrial Hygienists; EC = European Commission, Joint Research, Institute for Health and Consumer Protection; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration. *Date accessed.8

This information is distributed solely for the purpose of pre

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

## References

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

*ACGIH (American Conference of Governmental Industrial Hygienists) [2014]. 1

- Bromopropane. In: 2014 TLVs and BEIs: Based on the documentation of the threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*Anderson SE, Munson, AE, Butterworth LF, Germolec D, Morgan DL, Roycroft JA, Dill J, Meade BJ [2010]. Whole

- body inhalation exposure to 1

- b romopropane suppresses the IgM response to sheep red blood cells in female B6C3F1 mice and Fisher 344/N rats. Inhal Toxicol 22 (1): 125

- 132.

*Banu S, Ichihara S, Huang F, Ito H, Inaguma Y, Furuhashi K, Fukunaga Y, Wang O, Kitoh J, Ando H, Kikkawa F, Ichihara G [2007]. Reversibility of the adverse effects of 1

- bromopropane exposure in rats. Toxicol Sci 100 (2):504

– 512.

* Beck BR, Caravati EM [200 3]. Neurotoxicity associated with 1

- bromopropane exposure: Utah Poison Control Center, University of Utah, Salt Lake City, UT. J Toxicol Clin Toxicol 41 (5):729.

*ClinTrials BioResearch [1997]. A 28

- day inhalation study of a vapor formulation of ALBTA1 in the albino rat. Bio

- Research Project No. 91189 (sponsored by Albermarle Corporation). Senneville, Quebec, Canada: ClinTrials BioResearch, H9X 3R3, EPA Docket A

- 91

- 42, Document X

- A

- 4.

*EC (European Commission) [ND]. 1

- Bromopropane. In: EINECS (European IN ventory of Existing Commercial Chemical Substances), http://esis.jrc.ec.europa.eu/. Accessed: 02

- 28

- 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, 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://eur

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

- 29

- 15

.

*Elf Atochem [1995a]. Acute dermal toxicity in rats: n

- propyl bromide. Study No. 13113 TAR. Document OAR

- 2002

- 0064, available from U.S. Environmental Protection Agency, Washington, DC.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. *El f Atochem [1995b]. Skin sensitization test in guinea

- pigs: n

- propyl bromide. Study No. 12094 TSG. Document OAR

- 2002

- 0064, available from U.S. Environmental Protection Agency, Washington, DC.

*Frasch, HF, Dotson GS, Barbero AM [2011]. In vitro human epide rmal penetration of 1

- bromopropane. J Toxicol Environ Health Part A 74 (19):1249

- 1260.

* Fueta Y, Ishidao T, Ueno S, Yoshida Y, Kunugita N, Hori H [2007]. New approach to risk assessment of central neurotoxicity induced by 1

- bromopropane using animal model s. Neurotoxicology 28 (2):270

– 273.

*Hanley KW, Petersen BD, Curwin BD, Sanderson ET [2006]. Urinary bromide and breathing zone concentrations of 1

- Bromopropane from workers exposed to flexible foam spray adhesives. Ann Occup Hyg 50 (6):599

– 607.

*IARC (International Agency for Research on Cancer) [2009]. Agents reviewed by the IARC monographs. In: IARC monographs on the evaluation of carcinogenic risks to humans, http://monographs.iarc.fr/ENG/Classification/ClassificationsAlphaOrder.pdf. Accessed: 01

- 29

- 15.

*Ichihara G, Yu X, Kitoh J, Asaeda N, Kumazawa T, Iwai H, Shibata E, Yamada T, Wang H, Xie Z, Maeda K, Tsukamura H, Takeuchi Y [2000a]. Reproductive toxicity of 1

- bromopropane, a newly introduced alternative to ozone layer depleting solvents, in male rats. Toxicol Sci 54 :416

– 423.

*Ichihara G, Kitoh J, Yu X, Asaeda N, Iwai H, Kumazawa T, Kumazawa T, Shibata E, Yamada T, Wang H, Xie Z, Takeuchi Y [2000b]. 1

- Bromopropane, an alternative to ozone depleting solvents, is dose dependently neurotoxic to rats in l ong

- term inhalation exposure. Tox Sci 55 :116

– 123.

*Ichihara G, Miller JK, Ziolkowska A, Itohara S, Takeuchi Y [2002]. Neurological disorders in three workers exposed to 1

- bromopropane. J Occup Health 44 :1

– 7.

*Ichihara G, Li W, Ding X, Peng S, Yu X, Shi bata E, Yamada T, Wang H, Itohara S, Kanno S, Sakai K, Ito H, Kanefusa K, Takeuchi Y [2004a]. A survey on exposure level, health status, and biomarkers in workers exposed to 1

- bromopropane. Am J Ind Med 45 :63

– 75.

*Ichihara G, Li W, Shibata E, Ding X, Wan g H, Liang Y, Peng S, Itohara S, Kamijima M, Fan O, Zhang Y, Zhong E, Wu X, Valentine WM, Takeuchi Y [2004b]. Neurological abnormalities in workers of 1

- bromopropane factory. Environ Health Perspect 112 (13):1319

– 1325.10

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. *Jacobs G, Martens M, Mosselmans G [1 987]. Proposal of limit concentrations for skin irritation within the context of a new EEC directive on the classification and labeling of preparations. Regul Toxicol Pharmacol 7 (4):370

– 378.

*Lee SK, Jo SW, Jeon TW, et al. [2005]. Hepatotoxic effect of 1

- bromopropane and its conjugation with glutathione in male ICR mice. Arch Pharm Res 28 (10):1177

– 1182.

* Lee SK, Jo SW, Kim YB, et al. [2007]. Role of glutathione conjugation in the hepatotoxicity and immunotoxicity induced by 1

- bromopropane in female BALB /c mice. J Appl Toxicol 27 (4):358

– 367.

*Majersik JJ, Caravati EM, Steffens JD [2007]. Severe neurotoxicity associated with exposure to the solvent 1

- bromopropane (n

- propyl bromide). Clin Toxicol 45 :270

– 276.

*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/. Accessed: 01

- 29

- 15.

*NIOSH [2009]. Current intelligence bulletin 61: a strategy for assigning new NIOSH skin notations. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention , National 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

- 29

- 15.

*NTP (National Toxicology Program) [2004]. NTP

- CERHR Expert Panel report on the

r eproductive and development toxicity of 1

- bromopropane. Reproductive Toxicol 18 :157

– 188.

*NTP [2014]. Report on Carcinogens. Thirteenth Edition; U.S. Department of Health and Human Services, Public Health Service. National Toxicology Program, http://ntp. niehs.nih.gov/pubhealth/roc/roc13/index.html. Accessed: 01

- 29

- 15.

*Occupational Safety and Health Administration (OSHA) [ND]. OSHA Occupational chemical database, https://www.osha.gov/chemicaldata/ . Acces sed: 01

- 29

- 15.
*Pálovics Á [ 2004] . Epithelial irritation effect of 1

- bromopropane, an alternative solvent to chlorofluorocarbons. CEJOEM 10 (4): 333

– 337.

*Raymond LW, Ford MD [2007]. Severe illness in furniture makers using a new glue: 1

- bromopropane toxicity confounded by arsenic. J Occup Environ Med 49 (9): 1009

– 1019.

†RTI (Research Triangle Institute) [2005]. Report on uptake and metabolism of 1

- bromopro pane in rats and mice. Research Triangle Institute report for the National Toxicology Program, Documents EPA

- HQOAR

- 2002

- 0064

- 0077,

- 0080,

- 0081,

- 0082,

- 0101,

- 0104,

- 0137,

- 0137.1.11

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. *Sclar G [1999]. Encephalomyeloradiculoneuropathy following exposure to a n industrial solvent. Clin Neurol Neurosurg 101 :199

– 202.

† UNECE (United Nations Economic Commission for Europe) [2005]. Globally harmonized system of classification and labeling of chemicals (GHS). ST/SG/AC.10/30. New York and Geneva: United Nations Econo mic Commission for Europe.

*USEPA (United States Environmental Protection Agency) [2003]. Protection of stratospheric ozone: listing of substitutes for ozone

- depleting substances

- n

- propyl bromide: proposed rule. Federal Register, Part III, 40 CFR Part 82, Vol. 68, No. 106, June 3, 2003, pp. 33284

– 33316.

*USEPA (United States Environmental Protection Agency) [2015]. Integrated Risk Information System (IRIS), http://w ww.epa.gov/iris/ . Accessed: 01

- 29

- 15.

*Wang H, Ichihara G, Ito H, et al. [2002]. Biochemical changes in the central nervous system of rats exposed to 1

- bromopropane for seven days. Toxicol Sci 67 :114

– 120.

*Wang H, Ichihara G, Ito H, et al. [2003]. Dose

- dependent biochemical changes in rat central nervous system after 12

- week exposure to 1

- BP. Neurotoxicology 24 :199

– 206.

*WIL Research Laboratories [2001]. An inhalation two

- generation reproductive toxicity s tudy of 1

- bromopropane in rats. Study No. WIL

- 380001. Ashland, OH: Brominated Solvents Committee (sponsor).

*Yamada T, Ichihara G, Wang H, et al. [2003]. Exposure to 1

- bromopropane causes ovarian dysfunction in rats. Toxicol Sci 71 :96

– 103.

*Zhao K, Xie AT, Misumi J [1999]. Electrophysiological changes induced by different doses of 1

- bromopropane and 2

- bromopropane. J Occup Health 41 : 1

– 7.12

This information is distributed solely for the purpose of pre

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

## Appendix: Calculation of the SI Ratio for 1

- Bromopropane

This appendix presents an overview of the SI ratio and a s ummary of the calculation of the SI ratio for 1

- BP. 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 experimentall y 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 r epresents 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].13

This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the National Institute for Occupational Safety and Health. It does not represent and should not be construed to represent any agency determination or policy. 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 meters (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 derm al 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.14

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 1

- BP. The calculated SI ratio was 8.43. On the basis of these results, 1

- BP is predicted to represent a skin absorption hazard.

Table A1. Summary of Data used to Calculate the SI Ratio for 1

- BP

Variables Used in Calculation Units Value Skin permeation coefficient Permeation coefficient of stratum corneum lipid path( k psc ) cm/hr 0.00941 Permeation coefficient of the protein fraction of the stratum corneum ( k

pol ) cm/hr 1.3696 × 10 - 6 Permeation coefficient of the watery epidermal layer ( k aq ) cm/hr 0.22542 Molecular weight ( MW

) * amu 123 Base

- 10 logarithm of its octanol

– water partition coefficient (Log K

ow ) * None 2.1 Calculated skin permeation coefficient ( k p ) cm/hr 0.00904575 Skin dose Water solubility ( S w ) * mg/cm 3 2.45 Calculated skin permeation coefficient ( k p ) cm/hr 0.00904575 Estimated skin surface area (palms of hand) cm 2 360 Exposure time hr 8 Calculated skin dose mg 63.8268 Inhalation Dose Occupational exposure limit (OEL) † mg/m 3 1.01 Inhalation volume m 3 10 Retention factor (RF) None 0.75 Inhalation dose mg 7.575 Skin dose

– to

– inhalation dose (SI) ratio None 8.42598

* Variables identified from SRC [ND]. † The OEL used in calculation of the SI ratio for 1

- BP was the ACGIH threshold limit value (TLV) [ACGIH 2014].15

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

ACGIH (American Conference of Governmental Industrial Hygienists) [2014]. 1

- Bromopropane. In: 2014 TLVs and BEIs, Based on the docum entation of the threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

NIOSH [2009]. Current intelligence bulletin 61: a strategy for a ssigning 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/ni osh/docs/2009

- 147/pdfs/2009

- 147.pdf. Accessed: 01

- 29

- 15.

SRC [2009]. Interactive PhysProp database demo, http://esc.syrres.com/fatepointer/webprop.asp?CAS=106945 . Accessed 01

- 29

- 15.