## 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 fieldstudy at a helicoptertransmissionmanufacturing plant in Texas on February 9-10, 2004. Atthis facility, n-propyl bromide (uPB) was used as a vapordegreasing solventto remove oils and dirt from transmissionparts priorto the plating operationnecessary 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 withnew methods for measuring exhaledbreath 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 ProtectionAgency (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 thatwere 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 ofcase studies. (Referto the attachment for more detailed informationregarding the toxicity ofnPB and iPB.) Based on the uncertainty regarding the toxicity ofnPB, 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 ofa multi-industry corporationwhich manufactures helicopters, light and mid-size businessjets, fastening systems, tools, pumps, transmissions, fuel tanks, as well as light weight industrial vehicles. Transmissions were manufactured at this plant for a variety ofcommercial 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 heattreatment. 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 

### 1throughoutthe processes. The casings are painted with a chromatedprimer andthe transmissions are assembled and tested, and shipped to helicopter assemblyplants. n-Propyl bromide (Nu Tri Clean, Selig Industries) is used as a vapor degreasing solvent inthe Plating departmentto remove oil and dirt from transmissionparts priorto and between surface treatments. Surface treatments are applied by immersing parts into chemical solutions which include copper, nickel, cadmium, cadmium-chromate andblack 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 inthis department. A series of open-toppedtanks are arranged in series to cleanthe parts and apply a particular surface coating. A number ofacid, alkaline,and chemical solutions are used as well as waterrinses, some ofwhich are heatedto 200-260°F. These include hydrofluoric acid, hydrochloric acid, sulfuric acid, chromic .acid, phosphoric acid, sodium and potassium hydroxide, permanganate, and cyanide solutions. Formany ofthe chemical tanks, local exhaustventilation was installed with back and side slot plenums, but not for the nPB and perchloroethylene degreasers or watertanks. Vapor degreasers utilize a refrigerated cooling coil around the top ofthe interior ofthe vapor chamber, which condenses nPB (orperchloroethylene) vapor into liquid droplets on the surface ofparts to remove oils and dirt. Excess solvent drips back into the solvent sump and is recycled as the parts slowly ascend from the vaporto condensing zones. A secondary function ofthe cooling coil is to control solventvapor 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 coverthat was closed when the degreaser was notinuse, and a mechanical hoistthatremoved the parts rack at a programmed speed to minimize excessive vaporfrom being carried out ofthe unit. During the first shift, the chemical process department was operated by five hourly employees, all ofwhom participated in the monitoring survey; a department supervisor did notparticipate 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 reliefbreaks. Overall, the nPB degreaser was reportedto be used for approximately one and a halfto two hours pershift; it was used slightly less than that on both monitoring days. Personal protective equipmentused by employees included nitrile or latex gloves, safety glasses, and safety shoes. Hearing protection, organic vapor or acidmisthalf-face piece respirators, PVC aprons, and face shields were also available, ifneeded. 

### Evaluation Criteria Atpresent, occupational exposure limits (OELs) for nPB are not available from either OSHA (2006) orMOSH (1992), and suggestedmanufacturers' guidelines are equivocal, ranging from 10 to 100 parts permillion (ppm) (GreatLakes Chemicals, 2005; Enviro-Tech International, 2005). The EPA initially reviewed industry-sponsored animal studies and suggested that 50 to 100ppm shouldprovide adequate protection, but cautionedthatthis was a preliminary decision since it was based on limited datawith considerable uncertainty (EPA, 2000). This proposal was 

### 2largely 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) concludedthat neurotoxicity is the most sensitive endpoint and an OEL for nPB inthe range of60 to 90 ppm should provide an adequate margin ofsafety. On June 03, 2003, the EPA published aproposedrulemaking to accept nPB as a replacement solvent forozone depleting substances for general metals, precision, and electronics cleaning, aerosol products, and adhesives (EPA, 2003). 

### In this proposedrule, the EPA recommends an industrial exposure guideline for nPB of25 ppm over an 8-hrwork shift. The proposed rulemaking is currently being re-assessedby 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-hourtime weighted average (TWA) concentration. In 2005, ACGIH published a newly adopted change to recommend a Threshold LimitValue® (TLV) for nPB as a 10 ppm, 8- hrTWA 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-hourTWA. No other OELs are presently published for iPB. Occupational exposure criteriafor 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 exhaledbreath and urinary metabolites. Employees voluntarily participating in the study were informed ofthe study requirements and providedtheir written consent (in accordance withHuman Subjects Review Boardprotocol.) A total of5 workers were included from this plant, each ofwhom worked inthe chemical plating department (SF). The workers'also wore a light-weight air sampling device on 2 consecutive days, providedpre- and post-shift exhaled breath samples, and all oftheirurine specimens over a 48-hourperiod. The air and breath samples were analyzed for nPB and iPB, .alow level contaminant in nPB solvents. The urine samples were analyzed for bromide ion and another metabolite ofnPB [propyl mercapturic acid (PMA) also calledN-acetyl-S-(n-propyl)-Lcysteine]. Personal breathing zone exposures and exhaled breath samples were collected with Anasorb carbon molecular sieve (CMS) sorbenttubes. The sorbenttubes were desorbed with 1 milliliter (ml) ofcarbon disulfide, and analyzed for nPB by gas chromatography with flame ionization detection (GC-FID) viaNIOSH method 1025 (NIOSH, 2003a). The limit ofdetection (LOD) for this method is Illg which equates to a minimum detectable concentration (MDC) of0.016 ppm ofnPB in airusing the maximum recommended air sampling volume of 12 liters and a MDC of 

### 30.07 ppm ofnPB in an exhaledbreathvolume of3 liters. Qualitative evaluation ofskin contact potential was conducted by visual observation of job 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 excretedby humans, all ofthe workers' urine voids over a 48-hourperiod 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-hourperiod and'started atthe beginning ofthe work week (Monday, pre-shift) following a weekend ofno exposure and endedbefore the work shift on Wednesday. Forcomparison, single "spot" control samples were collected from twenty-one unexposed office workers who were not employedby this company. Urine specimens were collected in nitric acid rinsedNalgene® bottles [high density polyethylene (HDPE)] and immediately chilled in 10 quart coolers with gel ice that were individually supplied to eachparticipant. Upon the end ofthe collectionperiod, 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 collectionperiod 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 priorto analysis. Analytical standards and quality control samples were prepared using Uri-sub, a synthetic urine solution. This was necessary because background concentrations ofbromine may be present inpooled urine from the general population. 

### Propyl mercapturic acid The urine specimens were analyzed forpropyl 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 withthree-ml ofamethanol and acidified watermixture (pH = 3); PMAwas then extractedin four-ml ofacetone, dried under nitrogen and reconstituted 

### in one-ml ofmethanol. Analysis was performed using highperformance liquid chromatography (HPLC) with electrospray ionization-tandem mass spectrometry (ESI-MS/MS) for improved sensitivity and specificity (e.g., confll1llation ofchemical identity).

4Creatinine Creatinine was analyzed using Sigmadiagnostics testkit, procedure #555. Room temperature urine specimens were diluted by a factor of20 (or 40 ifvery concentrated) and mixed with sixml ofalkaline picrate. After 10-15 minutes, color analysis ofthe creatinine-picrate complex was performed with a spectrophotometer (MiltonRoy Spectronic 20 D). A 0.2 ml aliquot ofacid reagentwas then added and the specimen was re-analyzed afterfive minutes; positive results from the second analysis were subtracted from the first measurements as itis due to interfering compounds. Creatinine is a proteinby-productexcreted inurine due to the metabolism ofcreatine from muscle exertion. 

### It is often used to adjusturine data due to different levels ofphysical activity and urine concentrations between differentindividuals. The urine datainthis 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 datawill be adjusted ("normalized") for creatinine (mg Br/gm creatinine or J1g PMAIgm creatinine) for publication in scientificjournals. 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 ofGovernmental Industrial Hygienists (ACGIH)

. Threshold Limit Value® (TLV) of 10 ppm. Much lower concentrations ofiPB were detected with a concentrationranging from 0.017 to 0.097 ppm. The highest iso-propyl bromide (iPB) concentration detected was well belowthe only occupational exposure limit (OEL) available, which is 1 ppm 8-hourtime weighted average, promulgatedby SouthKorea. The platerwho used the vapor degreasermost often had the highestbreathing zone exposures. Table 2 provides a summary ofthe breath concentrations for nPB. The nPB concentrations measured inthe 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 ofurinary Brfor the platers was approximately twice as high as those for the control subjects. The data for anotherurinarymetabolite, propyl mercapturic acid (PMA), are provided inTable 4, which showthe same trends as the average before work week concentrations for platers were nearly twice as high as that ofcontrol subjects. Furthermore, the average 24-hour concentration ofPMA from workers was substantially higher than controls, especially for the mostheavily exposed worker. Twenty-fourhour concentrations 

### 5ofPMA averaged for eachday were over 30 times as high as the average PMA concentration measured from control specimens. Statistical analyses were not conducted for the data collected atthis site since only five workers participatedin the monitoring. Statistical analyses will be performed .after all ofthe data collected at separate sites are pooledinto largerdatabases. 

### Conclusions

• All ofthe workers' full-shift exposures were belowthe industrial guideline of25 ppm proposed by the EPA as well as the ACGIH TLV® of 10 ppm. However, the platerwho used the vapor degreaser mostfrequently was exposed to moderate levels ofnPB that approached the TLV®.
In conjunction with high ceilings and open floor plan, the ventilationprovidedinthe plating department is relatively effective in controlling nPB emissions from the vapor degreasing operation, given the observedproductionrate. Workers' exposures to iPB were not detected except in low concentration well below 1 ppm, the occupational exposure limitpublishedbySouth Korea. The post-shift breath monitoring showed measureable levels ofnPB butnot iPB. Withthe exception ofone sample, breath concentrations ofnPB were not detected in preshift samples. Dermal contactwith 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 Brwere 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 onthe data from the groupedpopulation ofworkers. These data demonstrate that workers inthe plating department are exposed to and are metabolizing nPB. However, thehealth significance ofan 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 criteriaof25 ppm suggested bythe EPA 

### 6and some solventmanufacturers are largely based on limited data observed in animal toxicity studies. As additional scientific informationbecomes available, the OEL currently proposed may, in fact, be lowered. Therefore, NIOSH scientists believe it is prudentto reduce occupational exposure ofnPB to the lowestfeasible levels. To reduce the risk ofhazardous exposures inthe work environment, industrial hygiene principles incorporate the following hierarchy ofexposure control, 

### in decreasing order ofpreference (and effectiveness): i) Eliminate a toxic substance by substituting itwith a less toxic one orby process changes, ii) Install engineering controls to: remove orreduce the airborne contaminants, preferably atthe point ofemissionusing local exhaustventilation; isolate contaminantemissions away from workerpositions; orby process changes, iii) Use ofadministrative controls to reduce individual exposures by altering orrotating job tasks and work schedules, thereby reducing high exposure durations, and iv) Use ofpersonal 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 ofcontrol, itis the least desirable because it is not always effective. NIOSH policyis that PPE should only be used when engineering controls are infeasible; during the interim period when engineering controls are being installed orrepaired; orwhen engineering controls are not effective in reducing exposure below hazardous levels. More specific recommendations to minimize workers' exposures to nPB atthis facility are provided below: 1. Eliminate nPB based solvents iffeasible by using a less toxic substitute. Perchloroethylene is also used in some vapordegreasing tasks atthis facility. However, perchloroethylene should notbe considered as a less toxic alternative since NIOSH considers perchloroethylene as a potential occupational carcinogen. It is advisable to consultwithtechnical 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 exceedrelevant 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 inthe ACGIH Industrial Ventilation Manual, 25th edition (2006). In addition, a routine maintenance schedule mustbeimplementedto ensure effective performance of the equipment. 3. Respiratory protection shouldbe provided for those workers who desire to use it when operating the vapor degreser or ifthe controls are not effective 

### in reducing exposures sufficiently. OnlyNIOSH approved airpurifying respirators with 7organic vapor cartridges orNIOSH approved air supplied respirators should be used. The use ofrespiratory protectionrequires the implementation ofa comprehensive respiratory protectionprogram in accordance with OSHA regulations (29 CFR 1910.134) andNIOSH recommended procedures (NIOSH, 1987). A minimal acceptableprogram includes: written procedures; proper selection; usertraining; routine cleaning and inspection; proper storage; surveillance ofwork conditions and worker exposures; program audits; medical determination ofuser fitness; and use ofapproved respirators. 4. n-Propyl bromide readily penetrates intact skin and common glove materials. When skin contactpotential withnPB orparts recently removed from the degreaser is high, appropriate gloves, arm sleeves, aprons or other PPE should be used. Solventmanufacturers recommend use ofmultiple layerl.aminates for protection against nPB. These include, but are not limited to, Vitonl'M, 4H (pE/EVAL) l'M, and Silver Shieldl'M. Othermore common glovelPPE materials (e.g., latex, nitrile, butyl rubber, PVC, etc.) do not adequately preventnPB from penetrating the PPE material for more than 30 minutes to a few hours. However, these gloves may still'be required inthe plating departmentfor protection against other chemicals used in this area. It is advisable to consult withtechnical experts and safetysupply vendors to select an array ofgloves needed in this department. Periodic training ofemployees is importantto preventthem from using the wrong gloves for different applications. 5. Ifalternative solvents are not feasible, use nPB solvents with the lowestiPB contaminationpossible. The ASTM (2001) standard for iPB contamination in nPB solvents is 0.10%. In the EPAproposedrulemaking (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 managementmust maintain an awareness ofthe latest scientific informationregarding occupational exposure guidelines fornPB as well as relevanthealth, safety, and environmental standards from regulatory agencies. 7. Employees potentially exposedto nPB shouldbe provided withroutine medical examinations. Reports ofhealth effects should be referred to a health care providerwho specializes in occupational orenvironmental medicine.



### 8

### DataTables National Institute for Occupational Safety and Health Centers for Disease Control and Prevention U.S. Public Health Service U.S. Department ofHealth and Human Services

9Table 1. Summary ofworkers' TWAa air sample concentrations ofn-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 shiftto 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 ofbromopropane per 1 million parts of air. d) iPB = isopropyl bromide (also called 2-bromopropane).



### 10Table 2. Summary ofworkers' breath concentrations ofn-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 ofbromopropane in I million parts ofbreath. g) ND = non-detectable. h) Not applicable. Only a "before work" breathsample(e.g. 16-hourpost shift) was collected on day 3. i) nPB was detected in only one breath sample.

11Table 3. Summary ofworkers' bromine concentrations in urine forthe 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 Day2, 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 startofthe work shift, afterthe weekend away from work. k) Units are in milligrams ofbromine per liter ofurine. " I) Control samples were collected from 21office workers unexposed to nPB, not employed by this company. m) 24-Hour concentrations were calculated from 3 combined samples ofall urine specimens collected at work; after work before bedtime; and upon waking.



### 12Table 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 ofpropyl mercapturic acid perliter ofurine. (One microgram is one thousand times less than a milligram.) p) ND = non-detectable.



### 13

### AttachmentI Toxicity ofn-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]. Priorto the last several years, nPB was primarilyusedto manufacture pharmaceuticals, pesticides, and other.chemicals typically in well controlled closed processes. An international agreementbetween 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 .effortto 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 asphaltblending (EPA, 2003; Dead SeaBromine, 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 fornPB, in terms ofquantities 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 occurredin 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 revealedthat 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 hadpancytopenia (e.g., reduced blood cell counts). An exposure-health effect association was obscured inthis study since breathing zone monitoring was notperformed, and the significance ofreported dermal contact andbriefshort-term exposure to very high air concentrations is unclear. Ichihara et al. (1997; 1999) conducted a similar study at a chemical plantmanufacturing iPB in China. Although severe reproductive disorders were not observed, reduced sperm concentrations and motility as well as decreased hemoglobin andhematocrit were suspectedby the authors to be related to iPB exposure. Subsequentto these occupational investigations, a series ofrat studies were conducted in Japan with iPB to evaluate male reproductive andfemale reproductive orhematopoietic toxicity. In a review ofthe literature, Takeuchi et al. (1997) concludedthatiPB impairs: (i) the testes, especially spermatogonia, 

### (ii) ovarian function bydisturbing the estrous cycle, damaging primordial foUi.cles and oocytes, (iii) bone**marrowcaus~~p~cytopenia.** Neurqlogic effects in rats exposedto iPB were also discoveredby Yu et al. (1999; 2001).
14Therehas been incentive to use nPB in lieuofiPB because ofthe perception thatnPB has lower toxicity. There are several reports inthe published literature regarding epidemiological and toxicological studies ofnPB which are contraryto this supposition. 

### In a 2001 report, Yu et aI. (2001) demonstrated peripheral andpossibly central neurotoxicity inrats but did not show reproductive orhematologic effects. Several additional reports have concludedthat nPB produces dose dependant estrous cycle irregularities (Yamadaet aI., 2003; Takeuchi et al., 2001); spermiation destruction (Takeuchi et aI., 2001; !chmaraet aI., 2000a); reproductive and developmental toxicity (NTP, 2002; 2004; Ichihara et aI., 2005); increased liver enzymes (Lee et aI., 2005); and peripheral and centralneurotoxicity (Yu et aI., 2001; Ichihara et aI., 2000b) in rats at similar dose levels thatproduced these effects by iPB. Ichiharaet aI. (2000b) concludedthat nPB appeared to be a more potentneurotoxinthan iPB. This conclusion is supportedby several ratstudies which have shown ataxic gait and hyper-excitability ofthe central nervous system, particularly athigher 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 excretionofnPB following intravenous, inhalation and dermal administration using mice and rats ofboth genders, metabolic inhibitors, and genetically altered animals. The authors concludedthat metabolism and excretion were independent ofroute ofadministration. Elimination ofnPB 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. Minormetabolites were also observed indicating several other pathways for elimination. Two case studies in the US have been published which describe decreasedperipheral 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 oflowerextremities, 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-shiftnPB exposures at these plants identified numerous excursions exceeding 100 ppm, one recommended exposure guideline by some solventdistributers. 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-hourtime-weighted average (TWA). Atthe aircraft seatcushionplant, full-shift nPB exposures ranged from 60 to 381 ppm, and 67 of 69 measurements exceeded 100 ppm (NIOSH, 2002a). Analysis ofcomplete 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 butthe results were also inconclusive.



### 15Toraason et al. (2006) conducted genotoxic studies to assess DNA damage, invitro, and from 64 workers employed attwo ofthe above HHE foam fabricating plants MOSH investigatedusing nPB-based adhesives. The authors concludedthat limited evidence existed atthese facilities to show exposure to nPB was associated with increased DNA damage.



### 16

### References
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