Workers' Exposures to n-Propyl Bromide at a Helicopter

Transmission Factory

Kevin W. Hanley, MSPH, crn, REHS/RS

Kevin Dunn

Industrywide Studies Branch

Division ofSurveillance, Hazard Evaluations and Field Studies

National Institute for Occupational Safety and Health

Centers for Disease Control and Prevention

US Public Health Service

Department ofHealth and Human Services

August 2006
Introduction

The Industrywide Studies Branch ofthe National Institute for Occupational Safety and Health

(NIOSH) conducted a field study at a helicopter transmission manufacturing plant in Texas on

February 9-10, 2004. At this facility, n-propyl bromide (uPB) was used as a vapor degreasing

solvent to remove oils and dirt from transmission parts prior to the plating operation necessary to

affix a protective surface treatment. In this research study, we measured workers' breathing zone

concentrations to n-propyl bromide (uPB) and isopropyl bromide (iPB) with standard air

sampling methods in conjunction with new methods for measuring exhaled breath and urinary

metabolites.

Background

The toxicity ofuPB, also named I-bromopropane, is poorly understood as there is limited

information in the published literature. The Environmental Protection Agency (EPA, 1999;

2003) is evaluating oPB as an alternative to ozone-depleting solvents for vapor-degreasing and

liquid cleaning ofmetal, precision, and electronic components as well as for use as a solvent in

aerosol products and adhesives. n-Propyl bromide has been marketed to replace 1,1,1-

trichloroethane, freons®, and suspect carcinogens trichloroethylene and methylene chloride,

chemicals that were commonly used in industry. Unfortunately, very little data are currently

available to evaluate human exposure to nPB. There is concern, however, that nPB may be a

hematological (blood), reproductive, or neurological toxin, based on analogy to other

brominated-propanes, animal toxicity studies, and a limited number of case studies. (Refer to the

attachment for more detailed information regarding the toxicity of nPB and iPB.)

Based on the uncertainty regarding the toxicity of nPB, the Occupational Safety and Health

Administration (OSHA) and NIOSH requested the National Toxicology Program (NTP) to

evaluate the toxicity ofthis chemical (OSHA, 1999; NTP, 2004). The absence ofnPB exposure

assessment information has prompted this occupational exposure study to evaluate industrial

exposures to nPB by measuring workers' personal breathing zone, exhaled breath, and urinary

metabolite concentrations.

Process Description

This company is a subsidiary of a multi-industry corporation which manufactures helicopters,

light and mid-size business jets, fastening systems, tools, pumps, transmissions, fuel tanks, as

well as light weight industrial vehicles. Transmissions were manufactured at this plant for a

variety of commercial helicopters including those designed for emergency medical transport,

homeland security, law enforcement, corporate and utility markets.

The facility is a large industrial machine shop with affiliated manufacturing processes. Raw

stock ofsteel and magnesium alloys are lathed, milled, machined, ground, and formed into

casings, gears, rods, bushings, etc. and hardened with an emulsion oil heat treatment. Some parts

may require additional processing such as abrasive blasting, precision grinding, finishing, and/or

surface treatments (e.g., plating, anodizing). Quality control inspections and testing occurs

1
throughout the processes. The casings are painted with a chromated primer and the transmissions

are assembled and tested, and shipped to helicopter assembly plants.

n-Propyl bromide (Nu Tri Clean, Selig Industries) is used as a vapor degreasing solvent in the

Plating department to remove oil and dirt from transmission parts prior to and between surface

treatments. Surface treatments are applied by immersing parts into chemical solutions which

include copper, nickel, cadmium, cadmium-chromate and black oxide plating; chemical film; and

aluminum and titanium anodizing. Cadmium and black oxide plating require the most nPB

degreasing. Perchloroethyleneand Stoddard solvent are also used as degreasing solvents in this

department. A series ofopen-topped tanks are arranged in series to clean the parts and apply a

particular surface coating. A number of acid, alkaline,and chemical solutions are used as well as

water rinses, some ofwhich are heated to 200-260°F. These include hydrofluoric acid,

hydrochloric acid, sulfuric acid, chromic .acid, phosphoric acid, sodium and potassium

hydroxide, permanganate, and cyanide solutions.

For many ofthe chemical tanks, local exhaust ventilation was installed with back and side slot

plenums, but not for the nPB and perchloroethylene degreasers or water tanks. Vapor degreasers

utilize a refrigerated cooling coil around the top ofthe interior ofthe vapor chamber, which

condenses nPB (or perchloroethylene) vapor into liquid droplets on the surface of parts to

remove oils and dirt. Excess solvent drips back into the solvent sump and is recycled as the parts

slowly ascend from the vapor to condensing zones. A secondary function ofthe cooling coil is

to control solvent vapor emissions by "capping" the heated vapor zone with a refrigerated air

space, typically six to eight inches in depth. The nPB degreaser also had a roll-top cover that

was closed when the degreaser was not in use, and a mechanical hoist that removed the parts

rack at a programmed speed to minimize excessive vapor from being carried out ofthe unit.

During the first shift, the chemical process department was operated by five hourly employees,

all of whom participated in the monitoring survey; a department supervisor did not participate in

the study. A lead operator oversaw the work flow, monitored the processes, and provided onthe-job training for new employees. Although employees had specific assignments and process

lines, they may be required to service other lines as needed, or for lunch and relief breaks.

Overall, the nPB degreaser was reported to be used for approximately one and a halfto two

hours pershift; it was used slightly less than that on both monitoring days. Personal protective

equipment used by employees included nitrile or latex gloves, safety glasses, and safety shoes.

Hearing protection, organic vapor or acidmist half-face piece respirators, PVC aprons, and face

shields were also available, if needed.

Evaluation Criteria

At present, occupational exposure limits (OELs) for nPB are not available from either OSHA

(2006) or MOSH (1992), and suggested manufacturers' guidelines are equivocal, ranging from

10 to 100 parts per million (ppm) (Great Lakes Chemicals, 2005; Enviro-Tech International,

2005). The EPA initially reviewed industry-sponsored animal studies and suggested that 50 to

100 ppm should provide adequate protection, but cautioned that this was a preliminary decision

since it was based on limited data with considerable uncertainty (EPA, 2000). This proposal was

2
largely based on hepatic toxicity observed in rats, not on reproductive, hematopoietic, or

neurologic effects. After reviewing industry studies (Clintrials Biorecherchesl997a, 1997b; WIL

Research Laboratories, 2000) and published literature, Rozman and Doull (2002) concluded that

neurotoxicity is the most sensitive end point and an OEL for nPB in the range of60 to 90 ppm

should provide an adequate margin ofsafety.

On June 03, 2003, the EPA published a proposed rulemaking to accept nPB as a replacement

solvent for ozone depleting substances for general metals, precision, and electronics cleaning,

aerosol products, and adhesives (EPA, 2003). In this proposed rule, the EPA recommends an

industrial exposure guideline for nPB of 25 ppm over an 8-hr work shift. The proposed

rulemaking is currently being re-assessed by the EPA. Albemarle Co. (2003), one ofthe

domestic suppliers ofnPB solvents, also recommends an exposure guideline for nPB equal to 25

ppm as an 8-hour time weighted average (TWA) concentration. In 2005, ACGIH published a

newly adopted change to recommend a Threshold Limit Value® (TLV) for nPB as a 10 ppm, 8-

hr TWA based on suspected neurological toxicity (ACGIH, 2006). As one can see from these

exposure guidelines, the OELs for nPB recommended by different organizations vary by an order

ofmagnitude.

Following a case study ofreproductive and hematological health effects in workers exposed to

iPB in an electronics plant (Kim et aI., 1996; Park et aI., 1997), the Republic ofSouth Korea

promulgated an OEL for iPB of 1 ppm, measured as an 8-hour TWA. No other OELs are

presently published for iPB. Occupational exposure criteria for two ofthe urinary metabolites of

nPB which were analyzed at these facilities (e.g., bromide and propyl mercapturic acid) are

currently unavailable.

Methods

In this research study, we measured nPB inhalation exposures with standard air sampling

methods in conjunction with new methods for measuring exhaled breath and urinary metabolites.

Employees voluntarily participating in the study were informed ofthe study requirements and

provided their written consent (in accordance with Human Subjects Review Board protocol.) A

total of 5 workers were included from this plant, each of whom worked in the chemical plating

department (SF). The workers' also wore a light-weight air sampling device on 2 consecutive

days, provided pre- and post-shift exhaled breath samples, and all oftheir urine specimens over a

48-hour period. The air and breath samples were analyzed for nPB and iPB, .a low level

contaminant in nPB solvents. The urine samples were analyzed for bromide ion and another

metabolite ofnPB [propyl mercapturic acid (PMA) also called N-acetyl-S-(n-propyl)-Lcysteine].

Personal breathing zone exposures and exhaled breath samples were collected with Anasorb

carbon molecular sieve (CMS) sorbent tubes. The sorbent tubes were desorbed with 1 milliliter

(ml) of carbon disulfide, and analyzed for nPB by gas chromatography with flame ionization

detection (GC-FID) via NIOSH method 1025 (NIOSH, 2003a). The limit ofdetection (LOD) for

this method is Illg which equates to a minimum detectable concentration (MDC) of 0.016 ppm

ofnPB in air using the maximum recommended air sampling volume of 12 liters and a MDC of

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0.07 ppm of nPB in an exhaled breath volume of 3 liters. Qualitative evaluation ofskin contact

potential was conducted by visual observation ofjob tasks since effective quantitative skin

exposure measurement methods do not exist for compounds, such as nPB, that are volatile and

readily penetrate the skin.

To obtain data on nPB metabolites excreted by humans, all ofthe workers' urine voids over a

48-hour period were collected, including the amount excreted while away from work. The

specimens were collected as composite samples over sequential time intervals: 1) at work,

2) after work but before bedtime, and 3) upon wake-up. Each sampling survey occurred over a

48-hour period and'started at the beginning ofthe work week (Monday, pre-shift) following a

weekend of no exposure and ended before the work shift on Wednesday. For comparison, single

"spot" control samples were collected from twenty-one unexposed office workers who were not

employed by this company.

Urine specimens were collected in nitric acid rinsed Nalgene® bottles [high density polyethylene

(HDPE)] and immediately chilled in 10 quart coolers with gel ice that were individually supplied

to each participant. Upon the end ofthe collection period, a 25 ml sample aliquot was dispensed

into nitric acid rinsed HDPE bottles and immediately frozen on carbonic acid (dry-ice). The total

urine volume for this collection period was also measured with a graduated cyclinder. The

specimens were analyzed for bromine, propyl mercapturic acid, and creatinine.

Bromine

Bromine (Br) was measured using inductively coupled plasma/mass spectrometry (ICP/MS;

Varion Ultra-mass 700) using yttrium as an internal standard (Allainet aI., 1990; Ichihara et aI.,

2004; Kawai et aI., 2001). The LOD for bromine was 90 micrograms per liter (J.1g/I). One-ml of

each sample was diluted to 10 ml with I% nitric acid prior to analysis. Analytical standards and

quality control samples were prepared using Uri-sub, a synthetic urine solution. This was

necessary because background concentrations of bromine may be present in pooled urine from

the general population.

Propyl mercapturic acid

The urine specimens were analyzed for propyl mercapturic acid (PMA), the major mercapturic

acid metabolite ofnPB, also calledN-acetyl-S-(n-propyl)-L-cysteine (Grenby and Young, 1960;

Jones and Walsh, 1979). A four-ml aliquot ofthe urine specimens were loaded onto a solid

phase extraction cartridge, rinsed with three-ml ofa methanol and acidified water mixture

(pH = 3); PMA was then extracted in four-ml of acetone, dried under nitrogen and reconstituted

in one-ml ofmethanol. Analysis was performed using high performance liquid chromatography

(HPLC) with electrospray ionization-tandem mass spectrometry (ESI-MS/MS) for improved

sensitivity and specificity (e.g., confll1llation ofchemical identity).

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Creatinine

Creatinine was analyzed using Sigma diagnostics test kit, procedure #555. Room temperature

urine specimens were diluted by a factor of20 (or 40 ifvery concentrated) and mixed with six ml

of alkaline picrate. After 10-15 minutes, color analysis ofthe creatinine-picrate complex was

performed with a spectrophotometer (Milton Roy Spectronic 20 D). A 0.2 ml aliquot of acid

reagent was then added and the specimen was re-analyzed after five minutes; positive results

from the second analysis were subtracted from the first measurements as it is due to interfering

compounds.

Creatinine is a protein by-product excreted in urine due to the metabolism of creatine from

muscle exertion. It is often used to adjust urine data due to different levels ofphysical activity

and urine concentrations between different individuals. The urine data in this report, however,

are only presented as unadjusted concentrations, either mg/l or J1g/1 for Br and PMA,

respectively. Once the data are compiled from multiple sites in this study, the urine data will be

adjusted ("normalized") for creatinine (mg Br/gm creatinine or J1g PMAIgm creatinine) for

publication in scientific journals.

Results

Table 1 presents the air sampling results collected in workers' breathing zones over 2 full work

shifts. The TWA concentrations for the platers ranged from 0.077 to 7.49 ppm with daily

averages of 1.55 and 2.20 ppm. All ofthe platers' TWA exposures were less than 25 ppm, the

industrial exposure guideline proposed by the EPA and Albemarle Corp., a manufacturer ofnPB

solvents as well as the American Conference of Governmental Industrial Hygienists (ACGIH) .

Threshold Limit Value® (TLV) of 10 ppm. Much lower concentrations ofiPB were detected

with a concentration ranging from 0.017 to 0.097 ppm. The highest iso-propyl bromide (iPB)

concentration detected was well below the only occupational exposure limit (OEL) available,

which is 1 ppm 8-hour time weighted average, promulgated by South Korea. The plater who

used the vapor degreaser most often had the highest breathing zone exposures.

Table 2 provides a summary ofthe breath concentrations for nPB. The nPB concentrations

measured in the post-shift samples ranged from 0.12 to 0.28 ppm. Only one sample had

detectable levels ofnPB in the pre-shift samples. Iso-propyl bromide was not detected in any of

the breath samples.

In Table 3, the average Br concentration from urine samples collected before the work-week

began was 10.6 milligrams per liter (mg/l). For comparison, the average Br concentration was

4.0 mg/l in spot samples from control subjects who were not employed by this company.

Moreover, the 24-hour average concentrations of urinary Br for the platers was approximately

twice as high as those for the control subjects. The data for another urinary metabolite, propyl

mercapturic acid (PMA), are provided in Table 4, which show the same trends as the average

before work week concentrations for platers were nearly twice as high as that of control subjects.

Furthermore, the average 24-hour concentration ofPMA from workers was substantially higher

than controls, especially for the most heavily exposed worker. Twenty-four hour concentrations

5
ofPMA averaged for each day were over 30 times as high as the average PMA concentration

measured from control specimens.

Statistical analyses were not conducted for the data collected at this site since only five workers

participated in the monitoring. Statistical analyses will be performed .after all ofthe data

collected at separate sites are pooled into larger data bases.

Conclusions

• All ofthe workers' full-shift exposures were below the industrial guideline of 25 ppm

proposed by the EPA as well as the ACGIH TLV® of 10 ppm. However, the plater who

used the vapor degreaser most frequently was exposed to moderate levels ofnPB that

approached the TLV®.

In conjunction with high ceilings and open floor plan, the ventilation provided in the

plating department is relatively effective in controlling nPB emissions from the vapor

degreasing operation, given the observed production rate.

Workers' exposures to iPB were not detected except in low concentration well below 1

ppm, the occupational exposure limit published by South Korea.

The post-shift breath monitoring showed measureable levels ofnPB but not iPB.

With the exception ofone sample, breath concentrations of nPB were not detected in preshift samples.

Dermal contact with recently degreased parts may contribute to the workers' exposures.

nPB is appreciably absorbed through workers' intact skin, which contributes to their

overall absorbed dose.

Average 24-hour concentrations ofthe urinary Br were approximately twice as high for

platers than for control subjects.

• Average 24-hour, concentrations ofthe urinary PMA measured in worker specimens were

at least 30 times as high as PMA concentrations measured in control specimens.

The conclusions drawn are based on the data from the grouped population ofworkers.

These data demonstrate that workers in the plating department are exposed to and are

metabolizing nPB. However, the health significance of an individual's urine metabolite

level is uncertain.

Recommendations

Human health effects from exposure to nPB are poorly understood as there are only a few reports

in the published literature. The occupational.exposure criteria of25 ppm suggested by the EPA

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and some solvent manufacturers are largely based on limited data observed in animal toxicity

studies. As additional scientific information becomes available, the OEL currently proposed

may, in fact, be lowered. Therefore, NIOSH scientists believe it is prudent to reduce

occupational exposure of nPB to the lowest feasible levels.

To reduce the risk ofhazardous exposures in the work environment, industrial hygiene principles

incorporate the following hierarchy of exposure control, in decreasing order ofpreference (and

effectiveness):

i) Eliminate a toxic substance by substituting it with a less toxic one or by process

changes,

ii) Install engineering controls to: remove or reduce the airborne contaminants,

preferably at the point of emission using local exhaust ventilation; isolate

contaminant emissions away from worker positions; or by process changes,

iii) Use ofadministrative controls to reduce individual exposures by altering or rotating

job tasks and work schedules, thereby reducing high exposure durations, and

iv) Use of personal protective equipment (PPE), such as respiratory protection, gloves,

aprons, etc., to reduce the absorbed dose from potential exposure. Although PPE is

frequently used because it'is a cheaper and easier method of control, it is the least

desirable because it is not always effective. NIOSH policy is that PPE should only be

used when engineering controls are infeasible; during the interim period when

engineering controls are being installed or repaired; or when engineering controls are

not effective in reducing exposure below hazardous levels.

More specific recommendations to minimize workers' exposures to nPB at this facility are

provided below:

1. Eliminate nPB based solvents iffeasible by using a less toxic substitute.

Perchloroethylene is also used in some vapor degreasing tasks at this facility.

However, perchloroethylene should not be considered as a less toxic alternative

since NIOSH considers perchloroethylene as a potential occupational carcinogen.

It is advisable to consult with technical experts and solvent distributors to evaluate

ifthere are any suitable alternative solvents that are less toxic which perform in

accordance with engineering specifications.

2. Employee exposures to nPB should be·periodically re-evaluated. Ifmonitoring

results exceed relevant criteria, install engineering controls consisting oflocal

exhaust for the degreaser and provide make-up air ventilations systems to reduce

airborne nPB concentrations. Design specifications are also available in the

ACGIH Industrial Ventilation Manual, 25th edition (2006). In addition, a routine

maintenance schedule must be implemented to ensure effective performance of

the equipment.

3. Respiratory protection should be provided for those workers who desire to use it

when operating the vapor degreser or ifthe controls are not effective in reducing

exposures sufficiently. Only NIOSH approved air purifying respirators with

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organic vapor cartridges or NIOSH approved air supplied respirators should be

used. The use ofrespiratory protection requires the implementation of a

comprehensive respiratory protection program in accordance with OSHA

regulations (29 CFR 1910.134) and NIOSH recommended procedures (NIOSH,

1987). A minimal acceptable program includes: written procedures; proper

selection; user training; routine cleaning and inspection; proper storage;

surveillance ofwork conditions and worker exposures; program audits; medical

determination of user fitness; and use ofapproved respirators.

4. n-Propyl bromide readily penetrates intact skin and common glove materials.

When skin contact potential with nPB or parts recently removed from the

degreaser is high, appropriate gloves, arm sleeves, aprons or other PPE should be

used. Solvent manufacturers recommend use ofmultiple layer l.aminates for

protection against nPB. These include, but are not limited to, Vitonl'M, 4H

(pE/EVAL) l'M, and Silver Shieldl'M. Other more common glovelPPE materials

(e.g., latex, nitrile, butyl rubber, PVC, etc.) do not adequately prevent nPB from

penetrating the PPE material for more than 30 minutes to a few hours. However,

these gloves may still 'be required in the plating department for protection against

other chemicals used in this area. It is advisable to consult with technical experts

and safety supply vendors to select an array of gloves needed in this department.

Periodic training of employees is important to prevent them from using the wrong

gloves for different applications.

5. If alternative solvents are not feasible, use nPB solvents with the lowest iPB

contamination possible. The ASTM (2001) standard for iPB contamination in

nPB solvents is 0.10%. In the EPA proposed rulemaking (2003) to accept nPB

solvents, a use restriction includes using nPB solvents with an iPB contamination

not exceeding 0.05%, before blending into products.

6. Company management must maintain an awareness ofthe latest scientific

information regarding occupational exposure guidelines fornPB as well as

relevant health, safety, and environmental standards from regulatory agencies.

7. Employees potentially exposed to nPB should be provided with routine medical

examinations. Reports of health effects should be referred to a health care

provider who specializes in occupational or environmental medicine.

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Data Tables

National Institute for Occupational Safety and Health

Centers for Disease Control and Prevention

U.S. Public Health Service

U.S. Department of Health and Human Services

9
Table 1.

Summary ofworkers' TWAa air sample concentrations of n-propyl bromide

and isopropyl bromide for the plating department.

TWA

Chemical Measure (n=5)

Day 1 Day 2

Average 1.55 2.20

nPBb

(ppmt Range 0.077 -3.23 0.084-7.49

Average 0.073 0.022

iPBd

(ppm) Range 0.042 - 0.097 0.017 -0.031

Footnotes:

a) TWA = time weighted average. It is used when multiple samples are collected over the work shift to

calculate the average exposure concentration "pro-rated" for time.

Example:

TWA = [(time 1 x cone. 1) + (time 2 x cone. 2)... + (timei x cone.i)] + total time for both sample I and 2

plus all additional samples (i)

b) nPB = n-propyl bromide (also called l-bromopropane).

c) Units are in parts per million by volume; the amount of bromopropane per 1 million parts ofair.

d) iPB = isopropyl bromide (also called 2-bromopropane).

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Table 2.

Summary ofworkers' breath concentrations of n-propyl bromidee for the plating department.

Date Measure TWA

(ppm)' (n=5)

Pre-shift Post-Shift

Day 1 Average - 0.17

Range NDg 0.12-0.22

Day 2 Average - 0.18

Range ND 0.13 -0.28

Day 3 Average - n.a.b

Range 0.0621 n.a.

Footnotes:

e) iPB was not detected in any ofthe breath samples.

f) Units are in parts per million by volume; the amount of bromopropane in I million parts of breath.

g) ND = non-detectable.

h) Not applicable. Only a "before work" breath sample (e.g. 16-hour post shift) was collected on day 3.

i) nPB was detected in only one breath sample.

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Table 3.

Summary ofworkers' bromine concentrations in urine for the plating department.

Chemical Job Day 1, Before Work'

Ranee Avera2e

Platers 6.0 19.0 10.6

Bromine (n= 5)

(mglliter)k

Controlsl 0.98 - 16.0 4.0

Chemical Job Day 1, 24-Hr. Concentrationm Day 2, 24-Hr. Concentration

Ranee Averaee Ran2e Avera2e

Bromine Platers 4.7 -12.5 8.5 2.9-13.0 7.9

(mglliter) (n = 5)

Footnotes:

j) Sample was collected before or near the start ofthe work shift, after the weekend away from work.

k) Units are in milligrams of bromine per liter of urine. "

I) Control samples were collected from 21 office workers unexposed to nPB, not employed by this company.

m) 24-Hour concentrations were calculated from 3 combined samples of all urine specimens collected at work;

after work before bedtime; and upon waking.

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Table 4.

Summary ofworkers' propyl mercapturic acid concentrations in urine for the plating department.

Chemical Job Day 1, Before Work

Ran2e Avera2e

Platers 29 - 178 104

PMAn (n= 5)

(Jlgllitert

Controls NDP-207.5 59.7

Chemical Job Day 1, 24-Hr. Concentration Day 2, 24-Hr. Concentration

Ran2e Avera2e Ran2e Avera2e

PMA Platers 28 -7551 2134 143 - 9878 2819

(Jlglliter) (n= 5)

Footnotes:

n) PMA = propyl mercapturic acid.

0) Units are in micrograms of propyl mercapturic acid per liter of urine. (One microgram is one thousand

times less than a milligram.)

p) ND = non-detectable.

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Attachment I

Toxicity of n-propyl bromide and isopropyl bromide

The molecular structure ofbromopropanes is a simple three carbon alkane chain containing a

single bromine substitution. There are two bromopropane isomers: n-propyl bromide [(nPB)

also called I-bromopropane; CAS No. 106-94-5] and isopropyl bromide [(iPB) also called 2-

bromopropane; CAS No.75-26-3]. Prior to the last several years, nPB was primarily used to

manufacture pharmaceuticals, pesticides, and other.chemicals typically in well controlled closed

processes. An international agreement between a number ofindustrlal nations restricts the

manufacture and use ofozone depleting substances including some compounds which were

widely used throughout general industry: 1,1,I-trichloroethane and chlorofluorocarbons

(freons®). In an .effort to develop alternatives to replace these ozone depleting solvents, nPB

products have been marketed, or are being considered, for metal.cleaning/degreasing, automotive

degreasing, electronics cleaning, precision cleaning (e.g., plastics, optics, and medical

equipment), aerosol products, adhesive solvents, paint and coating solvents, textile dry cleaning,

printing inks, and asphalt blending (EPA, 2003; Dead Sea Bromine, 1999; Petroferm, 2000).

Products containing potential carcino'gens trichloroethylene and methylene chloride are also

candidates for alternative solvents, especially since the OSHA methylene chloride standard

imposes more stringent occupational exposure and medical surveillance criteria with increased

compliance costs. Currently, the principal application for nPB, in terms of quantities used, is for

a vapor degreasing and liquid cleaning agent as well as spray adhesive solvent (EPA, 2003).

However, the need to find suitable alternative solvents could expand nPB market applications,

substantially increasing the quantities manufactured.

The first reports ofhealth effects for bromopropanes occurred in 1996 in a Korean electronics

plant where iPB was used as a cleaning solvent for electronic switches (Kim et aI., 1996; Park et

aI., 1997). An epidemiology case study of33 workers revealed that approximately two-thirds

were experiencing reproductive disorders affecting both genders (e.g., low sperm concentrations,

low motility or deformed sperm in men; and amenorrhea and elevated follicle stimulating

hormone in women) (Kim et aI., 1996). Further, seven workers had pancytopenia (e.g., reduced

blood cell counts). An exposure-health effect association was obscured in this study since

breathing zone monitoring was not performed, and the significance ofreported dermal contact

and briefshort-term exposure to very high air concentrations is unclear. Ichihara et al. (1997;

1999) conducted a similar study at a chemical plant manufacturing iPB in China. Although

severe reproductive disorders were not observed, reduced sperm concentrations and motility as

well as decreased hemoglobin and hematocrit were suspected by the authors to be related to iPB

exposure.

Subsequent to these occupational investigations, a series ofrat studies were conducted in Japan

with iPB to evaluate male reproductive and female reproductive or hematopoietic toxicity. In a

review ofthe literature, Takeuchi et al. (1997) concluded thatiPB impairs: (i) the testes,

especially spermatogonia, (ii) ovarian function by disturbing the estrous cycle, damaging

primordial foUi.cles and oocytes, (iii) bone marrowcaus~~p~cytopenia. Neurqlogic effects in

rats exposed to iPB were also discovered by Yu et al. (1999; 2001).

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There has been incentive to use nPB in lieu ofiPB because ofthe perception thatnPB has lower

toxicity. There are several reports in the published literature regarding epidemiological and

toxicological studies ofnPB which are contrary to this supposition. In a 2001 report, Yu et aI.

(2001) demonstrated peripheral andpossibly central neurotoxicity in rats but did not show

reproductive or hematologic effects. Several additional reports have concluded that nPB

produces dose dependant estrous cycle irregularities (Yamada et aI., 2003; Takeuchi et al.,

2001); spermiation destruction (Takeuchi et aI., 2001; !chmara et aI., 2000a); reproductive and

developmental toxicity (NTP, 2002; 2004; Ichihara et aI., 2005); increased liver enzymes (Lee et

aI., 2005); and peripheral and central neurotoxicity (Yu et aI., 2001; Ichihara et aI., 2000b) in rats

at similar dose levels that produced these effects by iPB. Ichihara et aI. (2000b) concluded that

nPB appeared to be a more potent neurotoxin than iPB. This conclusion is supported by several

ratstudies which have shown ataxic gait and hyper-excitability ofthe central nervous system,

particularly at higher doses (Fueta et aI., 2000, 2002a, 2002b, 2004; Houma et aI., 2003; Wang et

aI.,2003).

Garner et aI. (2006) published a metabolism study which investigated the disposition and

excretion of nPB following intravenous, inhalation and dermal administration using mice and

rats of both genders, metabolic inhibitors, and genetically altered animals. The authors

concluded that metabolism and excretion were independent ofroute of administration.

Elimination of nPB was very rapid with a halflife under one hour, mostly via exhalation.

Urinary excretion occurred by two principal mechanisms: dehalogenation by cytochrome P-450

and conjugation with glutathione. Minor metabolites were also observed indicating several other

pathways for elimination.

Two case studies in the US have been published which describe decreased peripheral nerve

functioning for three foam cushion workers using spray adhesives containing over 50% nPB

(Ichihara;et al. 2002) and a worker who performed metal stripping using a degreasing solvent

with approximately 95% nPB (Sclar, 1999). Presenting symptoms included numbness, weakness

oflower extremities, staggering, and parasthesia or dysesthesia. The authors concluded that nPB

likely caused the peripheral and central nervous system defects in these workers.

NIOSH has conducted Health Hazard Evaluations (HHEs) at two foam cushion fabricators and

an aircraft seat cushion manufacturer where nPB was used as a spray adhesive solvent (NIOSH,

2003b; 2002a; 2002b); Full-shift nPB exposures at these plants identified numerous excursions

exceeding 100 ppm, one recommended exposure guideline by some solvent distributers. For

comparison, the 2003 proposed EPA industrial exposure guideline is 25 ppm, and the ACGIH

TLV® published in 2005 is 10 ppm, measured as an eight-hour time-weighted average (TWA).

At the aircraft seat cushion plant, full-shift nPB exposures ranged from 60 to 381 ppm, and 67 of

69 measurements exceeded 100 ppm (NIOSH, 2002a). Analysis of complete blood counts

obtained from 43 (61%) ofthe aircraft cushion workers did not establish nor exonerate

abnormalities associated with nPB exposure. A reproductive health questionnaire was also

administered but the results were also inconclusive.

15
Toraason et al. (2006) conducted genotoxic studies to assess DNA damage, in vitro, and from 64

workers employed at two ofthe above HHE foam fabricating plants MOSH investigated using

nPB-based adhesives. The authors concluded that limited evidence existed at these facilities to

show exposure to nPB was associated with increased DNA damage.

16
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