TOXICOLOGICAL PROFILE FOR
 

BIS(CHLOROMETHYL)ETHER
 

Agency for Toxic Substances and Disease Registry
 

U.S. Public Health Service
 

In collaboration with:
 

U.S. Environmental Protection Agency
 

December 1989
 
ii
 

DISCLAIMER
 

Mention of company name or product does not constitute endorsement
 

by the Agency for Toxic Substances and Disease Registry.
 










1.1 

1
 

1. PUBLIC HEALTH STATEMENT
 

WHAT IS BIS(CHLOROMETHYL) ETHER?
 

Bis(chloromethy1) ether (BCME) is a man-made chemical with a
 

strong, unpleasant odor. It is a clear liquid at room temperature, but
 

it readily evaporates into air. BCME undergoes chemical reactions
 

easily, so it is broken down very rapidly when it comes into contact
 

with water. Consequently, any BCME that might escape from a chemical
 

plant or a chemical waste site into water or moist soil would be
 

destroyed within a few minutes. BCME that escapes into air is also
 

broken down by reacting with water and other chemicals, but this takes
 

a few hours.
 

BCME was used in the past to make several types of polymers,
 

resins and textiles. However, because BCME is believed to cause cancer
 

in humans, these uses have been stopped. BCME is now used only in small
 

amounts inside fully enclosed systems in chemical plants. More
 

information on the properties and uses of BCME is presented in Chapters
 

3 and 4.
 

1.2 HOW MIGHT I BE EXPOSED TO BIS(CHLOROMETHYL)ETHER?
 

Since BCME has such limited use in the United States, chances for
 

exposure to BCME are low. Some BCME can form as an impurity during the
 

production of other chemicals, so exposure might occur in chemical
 

plants that make or use these chemicals. Also, some BCME may exist in
 

chemical waste sites, although this is not certain. Because BCME
 

evaporates easily, the most likely way to be exposed to BCME in the
 

workplace or around a waste site is by breathing air containing BCME
 

vapors. However, information on levels of BCME which exist in air is
 

not available.
 

More information on possible ways that people can be exposed to
 

BCME is presented in Chapter 5.
 

1.3 HOW CAN BIS(CHLOROMETHYL) ETHER ENTER AND LEAVE MY BODY?
 

Because BCME is so quickly broken down by water, most BCME that
 

contacts the body is quickly changed into other chemicals (formaldehyde
 

and hydrochloric acid) before it passes through the outermost layer of
 

cells contacted (e.g., the cells that line the nose, windpipe and
 

lungs). Some BCME may enter into the blood or internal tissues, but
 

this has not been studied and the amount may be too small to measure.
 
2
 

1. PUBLIC HEALTH STATEMENT
 

More information on how BCME enters the body is presented in Chapter 2.
 

1.4 	HOW CAN BIS(CHLOROMETHYL) ETHER AFFECT MY HEALTH?
 

Studies of people exposed to BCME in the workplace show that
 

breathing of BCME vapors causes irritation to the nose, throat, and
 

lungs. Contact with the liquid is also highly irritating to skin. In
 

animals, breathing in high levels of BCME causes swelling and bleeding
 

in the lung and can cause death. Workers exposed to BCME have been
 

shown to have a higher-than-expected incidence of lung cancer. This
 

observation is supported by studies in animals which also show that
 

BCME can cause cancer. More information on the harmful effects of BCME
 

is presented in Chapter 2.
 

1.5	 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO
 

BIS(CHLOROMETHYL) ETHER?
 

Because BCME is broken down so rapidly in the body, there are no
 

specific tests to determine if a human has been exposed to this
 

compound. The only available medical tests are physical examination of
 

the nose and throat, chest X-ray, and examination of the sputum for
 

abnormal cell types. Unfortunately, these tests are not specific for
 

this compound, and would reveal effects of the compound only after
 

damage to the tissues had already occurred. More information on ways to
 

measure BCME is provided in Chapter 6.
 

1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
 

Tables l-1 through 1-4 show the relationship between exposure to
 

BCME and known health effects besides cancer. Chapter 2 provides
 

information on levels that have been shown to cause cancer in animals.
 

Although no direct information is available from studies in
 

humans, a Minimal Risk Level (MRL) is included in Table l-l., This MRL
 

was derived from animal data for long-term exposure, as described in
 

Chapter 2 and in Table 2-1. The MRL provides a basis for comparison
 

with levels that people might encounter in the air or in food or
 

drinking water. If a person is exposed to BCME at an amount below the
 

MRL, it is not expected that harmful noncancer health effects will
 

occur. Because this level is based only on information currently
 




7
 

1. PUBLIC HEALTH STATEMENT
 

available, some uncertainty is always associated with it. Also, because
 

the method for deriving MRLs does not use any information about cancer,
 

a MRL does not imply anything about the presence, absence or level of
 

risk of cancer.
 

No information exists for either animals or humans on toxic
 

effects following oral exposure (Tables l-3 and l-4), but oral exposure
 

is of little concern since BCME breaks down in water or moist foods and
 

exposure is not likely by this route. Direct skin contact with even
 

small amounts (less than a drop) of the liquid form of BCME causes
 

severe skin irritation at the site of contact. Further information on
 

the exposure levels that have been found to cause harmful health
 

effects in humans and animals is presented in
 

Chapter 2.
 

1.7	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
 

HUMAN HEALTH?
 

The government has taken a series of steps to reduce the risk of
 

human exposure to BCME. The Occupational Safety and Health
 

Administration (OSHA) regulates BCME as a potential human carcinogen.
 

An average concentration of 1 part per billion (ppb) is considered to
 

be the highest acceptable level in the workplace, and strict controls
 

have been established to minimize exposure to this compound. The U.S.
 

Environmental Protection Agency (EPA) has developed standards which
 

limit the amount of this compound that can be discharged into water or
 

air or disposed of at waste sites, Further information on regulations
 

concerning BCME is provided in Chapter 7.
 

1.8 WHERE CAN I GET MORE INFORMATION?
 

If you have further questions or concerns, please contact your
 

State Health or Environmental Department or:
 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology
 

1600 Clifton Road, E-29
 

Atlanta, Georgia 30333
 

9
 

2. HEALTH EFFECTS
 

2.1 INTRODUCTION
 

This chapter contains descriptions and evaluations of studies and
 

interpretation of data on the health effects associated with exposure
 

to BCME. Its purpose is to present levels of significant exposure for
 

BCME based on toxicological studies, epidemiological investigations,
 

and environmental exposure data. This information is presented to
 

provide public health officials, physicians, toxicologists, and other
 

interested individuals and groups with (1) an overall perspective of
 

the toxicology of BCME and (2) a depiction of significant exposure
 

levels associated with various adverse health effects.
 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
 

To help public health professionals address the needs of persons
 

living or working near hazardous waste sites, the data in this section
 

are organized first by route of exposure--inhalation, oral, and dermal­

- and then by health effect--death, systemic, immunological,
 

neurological, developmental, reproductive, genotoxic, and carcinogenic
 

effects. These data are discussed in terms of three exposure periods-­

acute, intermediate, and chronic.
 

Levels of significant exposure for each exposure route and
 

duration (for which data exist) are presented in tables and illustrated
 

in figures. The points in the figures showing no-observed-adverseeffect levels (NOAELS) or lowest-observed-adverse-effect levels
 

(LOAELs) reflect the actual doses (levels of exposure) used in the
 

studies. LOAELs have been classified into "less serious" or "serious"
 

effects. These distinctions are intended to help the users of the
 

document identify the levels of exposure at which adverse health
 

effects start to appear, determine whether or not the intensity of the
 

effects varies with dose and/or duration, and place into perspective
 

the possible significance of these effects to human health.
 

The significance of the exposure levels shown on the tables and
 

graphs may differ depending on the user's perspective. For example,
 

physicians concerned with the interpretation of clinical findings in
 

exposed persons or with the identification of persons with the
 

potential to develop such disease may be interested in levels of
 

exposure associated with "serious" effects. Public health officials and
 

project managers concerned with response actions at Superfund sites may
 

want information on levels of exposure associated with more subtle
 

effects in
 
 

10
 

2. HEALTH EFFECTS
 

humans or animals (LOAEL) or exposure levels below which no adverse
 

effects (NOAEL) have been observed. Estimates of levels posing minimal
 

risk to humans (minimal risk levels, MRLs) are of interest to health
 

professionals and citizens alike.
 

For certain chemicals, levels of exposure associated with
 

carcinogenic effects may be indicated in the figures. These levels
 

reflect the actual doses associated with the tumor incidences reported
 

in the studies cited. Because cancer effects could occur at lower
 

exposure levels, the figures also show estimated excess risks, ranging
 

from a risk of one in 10,000 to one in 10,000,000 (10-4 to 10-7), as
 

developed by EPA.
 

Estimates of exposure levels posing minimal risk to humans (MELs)
 

have been made, where data were believed reliable, for the most
 

sensitive noncancer end point for each exposure duration. MRLs include
 

adjustments to reflect human variability and, where appropriate, the
 

uncertainty of extrapolating from laboratory animal data to humans.
 

Although methods have been established to derive these levels (Barnes
 

et al. 1987; EPA 1980c), uncertainties are associated with the
 

techniques.
 

2.2.1 Inhalation Exposure
 

A number of cases of inhalation exposure of humans to BCME have
 

occurred in the workplace. However, data on BCME concentrations in
 

workplace air are rarely available, and exposure to BCME often occurs
 

in conjunction with exposure to other chemicals, particularly
 

chloromethyl methyl ether (CME). Consequently, there are no reliable
 

dose-response data in humans. The effects of inhalation of BCME have
 

been investigated in animals, with principal emphasis on carcinogenic
 

effects. Available data on the health effects of inhalation of BCME are
 

summarized in Table 2-l and Figure 2-l and are discussed below.
 

2.2.1.1 Death
 

No reports of acute human lethality due to inhalation of BCME were
 

located. Increased mortality from cancer has been observed in humans
 

exposed to BCME in the workplace, as discussed in detail in Section
 

2.2.1.7.
 



14
 

2. HEALTH EFFECTS
 

In rats, the acute inhalation LC50 for a 7-hour exposure has been
 

estimated to be 7 ppm (Drew et al. 1975). The cause of death was acute
 

lung irritation that resulted in congestion, edema and hemorrhage. A
 

similar LC50 of 5.3 ppm for a 6-hour exposure was estimated in mice
 

(Leong et al. 1971). A single 7-hr exposure to 0.7 ppm did not cause
 

acute or delayed mortality in rats or hamsters, but a single exposure
 

to 2.1 ppm lead to marked reduction in life span in both species (Drew
 

et al. 1975). Repeated exposures (6 hr/d) to 1 ppm lead to a duration
 

dependent increase in mortality. In rats, 3 exposures to 1 ppm lead to
 

50% mortality after about 20 weeks, and 10 exposures lead to 100%
 

mortality within 10 weeks. In hamsters, 3 exposures caused 50%
 

mortality after about one year, and 30 exposures caused 100% mortality
 

within about 10 weeks (Drew et al. 1975). The data on lethality
 

following three exposures to 1 ppm have been presented in Table 1-2.
 

Exposure to as little as 0.1 ppm caused increased mortality in rats
 

when exposure was extended to six months (Leong et al. 1981), primarily
 

because of the occurrence of nasal tumors (see Section 2.2.1.7, below).
 

The highest NOAEL values and all reliable LOAEL values for death
 

in each species and duration category are recorded in Table 2-1 and
 

plotted in Figure 2-1.
 

2.2.1.2 Systemic Effects
 

Respiratory Effects. As noted above, BCME is acutely irritating to
 

the lungs, causing congestion, edema and hemorrhage in rats and
 

hamsters at exposure levels of 0.7 ppm and higher (Drew et al. 1975).
 

This value has been presented in Table 1-2.
 

Exposure of mice to BCME at 1.0 ppm (6 hr/d, 5 d/wk) for 82 days
 

caused marked respiratory distress (Leong et al. 1971), while exposure
 

of rats to 0.1 ppm (6 hr/d, 5 d/wk) for six months did not result in
 

edema, hemorrhage or any effects on the histological appearance of the
 

lung (Leong et al. 1981). The value of 0.1 ppm has been used to
 

calculate the intermediate inhalation MRL value of 0.0003 ppm, as shown
 

in Figure 2-1 and described in the footnote in Table 2-1. This value
 

has also been presented in Table 1-1.
 

In humans, exposure to vapors of chloromethyl methyl ether (CME)
 

containing BCME as a contaminant lead to increased incidence of chronic
 

bronchitis, manifest as chronic cough and impaired respiratory function
 
15
 

2. HEALTH EFFECTS
 

(Weiss and Boucot 1975; Weiss 1976). Since CME is itself a lung
 

irritant, it is not possible to determine the degree to which BCME may
 

have contributed to the observed respiratory effects.
 

The highest NOAEL values and all reliable LOAEL values for
 

respiratory effects in each species and duration category are recorded
 

in Table 2-1 and plotted in Figure 2-l.
 

Other Systemic Effects. Systemic effects other than on the lungs
 

have not been observed following inhalation exposure to BCME. Leong et
 

al. (1981) observed no effects on cardiovascular, hematological,
 

gastrointestinal, musculoskeletal, endocrine and subcutaneous tissues
 

in rats exposed to 0.1 ppm for six months (6 hr/day, 5 days/week). This
 

is consistent with the hypothesis that rapid hydrolysis of BCME
 

precludes direct action at tissues beyond the respiratory epithelium.
 

The resulting hydrolysis product (formaldehyde and HCl) are presumably
 

absorbed and distributed throughout the body, but at levels
 

sufficiently low that no effect from these degradation products are
 

expected.
 

2.2.1.3 Neurological Effects
 

Leong et al. (1981) reported that exposure of male rats to 0.1 ppm
 

for six months did not result in observable histopathology in the
 

nervous system, but no tests of nervous system function were performed.
 

Drew et al. (1975) noted extreme irritability in rats and hamsters
 

exposed 10 to 30 times to 1 ppm of BCME, and concluded that this was
 

evidence of central nervous system effects. However, these symptoms were
 

probably due to treatment-related stress associated with the dis-comfort
 

of BCME exposure. An apparent dose-dependent increase in the frequency
 

of subarachnoid hemorrhage was noted, but the cause of these lesions and
 

the significance were not discussed. As detailed in Section 2.2.1.7
 

(below), nasal tumors of neural cells esthesioneuroepitheliomas) have
 

been noted in rats exposed to 0.1 ppm for 5-6 months (Kuschner et al.
 

1975: Leong et al. 1981).
 

2.2.1.4 Immunological Effects
 

No studies were located regarding immunological effects in humans
 

or animals following inhalation exposure to BCME.
 
16
 

2. HEALTH EFFECTS
 

2.2.1.5 Developmental Effects
 

No studies were located regarding developmental effects in humans
 

or animals following inhalation exposure to BCME.
 

2.2.1.6 Reproductive Effects
 

No studies were located regarding effects on reproductive capacity
 

in humans following inhalation exposure to BCME.
 

Leong et al. (1981) found no histological evidence of injuries to
 

the testes of rats exposed to 0.1 ppm of BCME in air for six months.
 

However, no tests of reproductive function were performed, and rio
 

tests were performed on females.
 

2.2.1.7 Genotoxic Effects
 

No studies were located regarding genotoxic effects in humans
 

following inhalation exposure to BCME. Leong et al. (1981) did not
 

observe any effects on bone marrow chromosomes in rats exposed to 0.1
 

ppm for six months (6 hr/day, 5 days/week). However, the data as
 

reported are not sufficient to conclude definitely that BCME is
 

inactive
 

in this system.
 

2.2.1.8 Cancer
 

A number of case studies and epidemiological studies of
 

occupationally-exposed workers indicate that inhalation of BCME or CME
 

containing BCME is associated with increased risk of lung cancer
 

(Figueroa et al. 1973; Thiess et al. 1973; Sakabe 1973; Albert et al.
 

1975; Weiss and Boucot 1975; DeFonso and Kelton 1976; Lemen et al.
 

1976; Weiss 1976; Pasternack et al. 1977; Reznik et al. 1977; Weiss
 

1982; Roe 1985; Maher and DeFonso 1987; Collingwood et al. 1987). Table
 

2-2 summarizes the data from some of these studies. Although the study
 

populations in these reports were often exposed not only to BCME but to
 

CME and other chemicals as well, the consistent findings strongly
 

support the conclusion that BCME is a lung carcinogen in humans.
 

Although quantitative data on exposure levels were not available,
 

increased risk as a function of exposure duration and/or qualitative
 

estimates of exposure intensity was noted in some cases (DeFonso and
 

Kelton 1976). A high proportion of the respiratory tumors were oat cell
 

18
 

2. HEALTH EFFECTS
 

carcinomas (Lemen et al. 1976; Figueroa et al. 1973; Weiss et al.
 

1979). Some tumors appeared after only 5 to 10 years of exposure (Weiss
 

and Boucot 1975; Weiss 1976) in young workers (Figueroa et al. 1973;
 

Reznick et al. 1977).
 

A number of studies in animals confirm that BCME is a potent
 

carcinogen with a short latency period. Some of the key data from these
 

studies are summarized in Table 2-3. As shown in the table, levels as
 

low as 0.1 ppm of BCME produce a high incidence (60% to 86%) of
 

respiratory tract tumors in exposed rats, and some tumors developed in
 

animals that had been exposed for periods as short as two weeks
 

(Kuschner et al. 1975; Laskin et al. 1971; Leong et al. 1981). Most of
 

the tumors were nasal tumors, although some lung tumors also developed.
 

Under similar conditions, mice exposed to 0.1 to 1.0 ppm did not
 

develop nasal tumors, but they did have a slight increase in the
 

incidence of mice with pulmonary adenomas (Leong et al. 1981) and in
 

the number of tumors per tumor-bearing mouse (Leong et al. 1971). No
 

increased incidence of nasal tumors or lung adenomas was noted in rats
 

or mice exposed to 0.01 or 0.001 ppm (Leong et al. 1981). Hamsters
 

appear to be more resistant to the carcinogenic effects of BCME than
 

are mice or rats. However, Drew et al. (1975) observed nasal tumors
 

after two years in two hamsters that had been exposed only one to three
 

times to 1.0 ppm BCME. Hamsters exposed for 10 times or more to 1.0 ppm
 

had shortened lifespans, so tumors may not have had time to develop.
 

Based on the evidence reviewed above, EPA has concluded that BCME
 

is a known human carcinogen (EPA Group A). Employing the data of
 

Kuschner et al. (1975), EPA (1988) has calculated an upper bound cancer
 

potency factor (q1*) of 220 (mg/kg/day)-1. Assuming that a 70-kg adult
 

inhales 20 m3

/day, the concentrations of BCME associated with upper
 

bound human risk levels of 10-4, 10-5, 10-6 and l0-7 are 3.4 x l0-7, 3.4 x
 

10-8
, 3.4 x l0-9 and 3.4 x 10-l0 ppm, respectively. These values, and
 

doses which have been observed to cause cancer, are plotted in Figure
 

2-l.
 

2.2.2 Oral Exposure
 

2.2.2.1 Death
 

No studies were located regarding acute lethality in humans
 

following oral exposure to BCME. The acute oral LD50 in rats for
 

undiluted BCME is estimated to be 280 mg/kg (Union Carbide 1968).
 

20
 

2. HEALTH EFFECTS
 

No studies were located regarding the following effects in humans
 

or animals following oral exposure to BCME:
 

2.2.2.2 Systemic Effects
 

2.2.2.3 Neurological Effects
 

2.2.2.4 Immunological Effects
 

2.2.2.5 Developmental Effects
 

2.2.2.6 Reproductive Effects
 

2.2.2.7 Genotoxic Effects
 

2.2.2.8 Cancer
 

2.2.3 Dermal Exposure
 

2.2.3.1 Death
 

The estimated LD50 for a single dermal application of undiluted
 

BCME to rabbit skin is 370 mg/kg (Union Carbide 1968). No other
 

estimates of lethal dermal doses were located.
 

2.2.3.2 Systemic Effects
 

Dermal/Ocular Effects. Because BCME is highly reactive, it is 

directly irritating to skin and other epithelial tissues. Chronic 

(lifetime) application of BCME (1 mg/dose) to the skin of mice produced 

a strong corrosive response, including hair loss, hemorrhagic rash and 

edema of subcutaneous tissue (Van Duuren et al. 1968). In rabbits, a 

single application of undiluted BCME lead to moderate erythema and 

marked necrosis, and a primary dermal irritation score of 6 was 

assigned (Union Carbide 1968). A dose of 5 /μL (7 mg) applied to the 

eye of rabbits produced severe cornea1 necrosis (Union Carbide 1968). 

Other Systemic Effects. No studies were located regarding
 

respiratory, cardiovascular, gastrointestinal, hematological,
 

musculoskeletal, hepatic or renal effects in humans or animals
 

following dermal exposure to BCME.
 
21
 

2. HEALTH EFFECTS
 

No studies were located regarding the following effects in humans
 

or animals following dermal exposure to BCME:
 

2.2.3.3 Neurological Effects 

2.2.3.4 Immunological Effects 

2.2.3.5 Developmental Effects 

2.2.3.6 Reproductive Effects 

2.2.3.7 Genotoxic Effects 

2.2.3.8 Cancer 

The first report of the carcinogenicity of BCME was that of Van
 

Duuren et al. (1968). Following dermal exposure (skin painting), BCME
 

was found to produce skin papillomas and carcinomas in over 50% of mice
 

tested after 325 days of treatment. The carcinomas appeared early, with
 

the first appearing after only 196 days of skin application. Subsequent
 

reports confirmed these findings (Van Duuren et al. 1969, 1972; Zajdela
 

et al. 1980). BCME has also been shown to be a skin tumor-initiator.
 

Thus a single skin application of 1 mg of BCME followed by treatment
 

with a known tumor-promoter (phorbol myristate acetate) produced
 

papillomas in a high percentage of treated mice (Van Duuren et al.
 

1968, 1969; Zajdela et al. 1980).
 

2.3 RELEVANCE TO PUBLIC HEALTH
 

Available data indicate that the toxic effects of BCME are
 

restricted to the epithelial tissue where exposure occurs, and this is
 

consistent with the short half-life of BCME in aqueous media. Since
 

exposure is most likely to occur by inhalation, the tissues at greatest
 

risk of injury are those of the respiratory tract. In particular,
 

inhalation of BCME leads to acute irritation, hemorrhage and edema of
 

the lung, and resulting respiratory distress can lead to acute or
 

delayed mortality.
 

At present, opportunities for exposure to levels of BCME causing
 

acute lung injury are considered to be remote. However, low levels of
 

exposure may still occur, and these are of concern because of the high
 

carcinogenic potency of BCME. Nasal and lung tumors have been observed
 
22
 

2. HEALTH EFFECTS
 

in animals following both intermediate and chronic exposure to BCME
 

vapor, and epidemiological studies in exposed workers strongly suggest
 

that BCME causes lung tumors in humans as well. This is supported by
 

the carcinogenic activity of BCME following dermal and parenteral
 

exposure in animals (Gargus et al. 1969; Van Duuren et al. 1968, 1969,
 

1972; Zajdela et al. 1980).
 

An important aspect of the carcinogenicity of BCME is that chronic
 

exposure is not required for tumorigenesis. Respiratory tumors have
 

been noted in rats after as few as 20 exposures, and, although the
 

results are not statistically significant, nasal tumors occurred in a
 

few animals after only one to three exposures. Although no cases of
 

human cancer have been noted after acute exposures, the latency in
 

exposed workers is shorter for BCME than for most other carcinogens,
 

and lung cancer can develop at an early age relative to lung cancer in
 

United States cigarette smokers. In addition, the respiratory tumors
 

produced in humans are predominantly oat-cell carcinomas, a
 

particularly rapid-growing and highly lethal tumor. These observations
 

emphasize the marked carcinogenic hazard of BCME.
 

BCME is a powerful alkylating agent (Van Duuren et al. 1968), and
 

as such would be expected to react readily with DNA and be a powerful
 

genotoxin. However, in vitro tests of mutagenicity have yielded mixed
 

results (Table 2-4), and no effect on bone marrow chromosomes were
 

observed in rats exposed to BCME vapors for six months (Leong et al.
 

1981). Reaction of BCME with DNA in vitro did not affect the melting
 

temperature or the buoyant density of the DNA, nor did it yield
 

isolatable products on reaction with purines or DNA as did other
 

alkylating agents (Van Duuren et al. 1972). These observations suggest
 

that BCME may be hydrolyzed so quickly in an aqueous environment (such
 

as a cell) that interaction with nucleic acids is very limited.
 

However, the data do not establish that low levels of binding do not
 

occur.
 

The hydrolysis products of BCME are formaldehyde and HCl. Since
 

formaldehyde has been shown to produce nasal tumors in rats (Albert et
 

al. 1982; Sellakumar et al. 1985), it is possible that at least some of
 

the carcinogenic potential of BCME may be due to this degradation
 

product. However, it is apparent from the difference in potency (BCME
 

is much more potent than formaldehyde) that this cannot be the sole
 

mechanism of carcinogenicity. It is also possible that BCME,
 

24
 

2. HEALTH EFFECTS
 

formaldehyde and HCl interact synergistically within the cell, but
 

there are no data to clearly support this possibility. Rather, studies
 

by Albert et al. (1982) and Sellakumar et al. (1985) indicate that
 

inhalation exposure of rats to mixtures of formaldehyde and HCl results
 

in little change in the frequency of nasal tumors compared with
 

exposure to formaldehyde alone. However, one animal in this study
 

developed an esthesioneuroepithelioma, a rare kind of tumor which is
 

characteristic of BCME exposure.
 

2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS
 

No studies were located regarding the presence of BCME in human
 

tissues and fluids. It is expected that BCME does not endure in tissues
 

due to its rapid hydrolysis. Measurement of the hydrolysis products
 

(formaldehyde and HCl) is unlikely to be a useful index of exposure,
 

since levels of these products are highly variable due to formation
 

from other sources, and the contribution from BCME would be extremely
 

small and almost certainly would not be detectable against
 

background.levels.
 

2.5	 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES
 

AND/OR HEALTH EFFECTS
 

As previously noted, there are no data available on the levels of
 

BCME or its metabolites in tissues of humans or animals. Although there
 

are a number of epidemiological studies involving occupational exposure
 

to BCME, there are no data on the concentrations of BCME to which
 

workers were exposed. Consequently, there is no information on the
 

relationship between environmental levels of BCME and any health effect
 

or tissue level in exposed humans.
 

2.6 TOXICOKINETICS
 

No information was located on the toxicokinetics of BCME in
 

animals or humans. It is expected that BCME is rapidly degraded in the
 

aqueous environment of tissues, forming formaldehyde and HCl.
 
25
 

2. HEALTH EFFECTS
 

2.7 INTERACTIONS WITH OTHER CHEMICALS
 

No information was located regarding interactive effects of BCME
 

with other chemicals that would be relevant to its toxicity. Chemicals
 

of special interest include chloromethyl methyl ether, formaldehyde and
 

HCl, since exposure to BCME frequently occurs along with exposure to
 

CME, and formaldehyde and HCl are formed as BCME decomposes.
 

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
 

No evidence was located to suggest that any one group of humans
 

are more susceptible to BCME than another. Since no data are available
 

on pharmacokinetics or mechanisms of action, it is not possible to
 

predict populations that might be unusually susceptible to BCME on the
 

basis of genetic traits or health status.
 

2.9 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR
 

(in consultation with the Administrator of EPA and agencies and
 

programs of the Public Health Service) to assess whether adequate
 

information on the health effects of BCME is available. Where adequate
 

information is not available, ATSDR, in cooperation with the National
 

Toxicology Program (NTP), is required to assure the initiation of a
 

program of research designed to determine these health effects (and
 

techniques for developing methods to determine such health effects).
 

The following discussion highlights the availability, or absence, of
 

exposure and toxicity information applicable to human health
 

assessment. A statement of the relevance of identified data needs is
 

also included. In a separate effort, ATSDR, in collaboration with NTP
 

and EPA, will prioritize data needs across chemicals that have been
 

profiled.
 

2.9.1 Existing Information on Health Effects of BCME
 

As shown in Figure 2-2, no data exist on the effects of BCME in
 

humans, except for data on lung cancer risk following inhalation
 

exposure. In animals, there are limited data on the effects of
 

inhalation exposure, but only one observation is available for oral
 

exposure (an estimate of the oral LD50). This is probably not a major
 

limitation, since BCME is not stable in water or moist foods. There are
 

27
 

2. HEALTH EFFECTS
 

limited data on dermal lethality and direct dermal and ocular
 

irritation, but none on any systemic effects following dermal exposure.
 

Most research has focused on the carcinogenic effects of inhaled BCME,
 

since this is the most common route of human exposure.
 

2.9.2 Data Needs
 

Single Dose Exposure. Several studies have been performed in
 

animals on the effects of single inhalation exposures to BCME, and
 

exposure conditions leading to acute lethality are reasonably well
 

defined. However, the acute does-response curve for sub- lethal effects
 

on the lung has not been determined, and further studies to identify
 

the acute NOAEL would be valuable. Due to the rapid hydrolysis of BCME,
 

effects are not likely to occur in nonepithelial tissues, but careful
 

studies to investigate this would still be appropriate.
 

Repeated Dose Exposure. Available studies on the effects of
 

repeated inhalation exposure of animals to BCME (Leong et al. 1971,
 

1981) indicate that an exposure level of 0.1 ppm is a NOAEL for most
 

systemic effects in rats, while 1.0 ppm leads to significant injury to
 

lung in mice. Further studies to confirm these estimates and to
 

determine both NOAEL and LOAEL values in each species would be useful
 

in the protection of occupationally exposed workers.
 

Chronic Exposure and Carcinogenicity. A number of studies in
 

animals indicate that inhalation of BCME is associated with risk of
 

nasal or lung tumors. In order to assess the potential risks in the
 

workplace, further studies in animals might be helpful in improving
 

information on the dose and time-dependency of BCME-induced
 

tumorigenesis. In particular, studies would be valuable to investigate
 

why BCME induces tumors with such a short latency, and why it results
 

in nasal tumors in some species and lung tumors in others. Studies on
 

the interaction of BCME with other chemicals such as CME (with which it
 

is often associated in the workplace) would also be valuable.
 

Genotoxicity. The genotoxicity of BCME has been investigated in
 

several strains of bacteria but such systems may not be optimal for
 

investigating the effects of such a rapidly hydrolyzed material.
 

Specifically, if BCME acts as an alkylating agent to damage DNA, then
 

tests which favor hydrolysis before entry into the cell can occur may
 
28
 

2. HEALTH EFFECTS
 

yield misleading results. Tests in prokaryotic and eukaryotic systems
 

designed to minimize the degree of hydrolysis in the medium prior to
 

cell penetration would be valuable in estimating the potential
 

genotoxic effect of BCME on the respiratory epithelium.
 

Reproductive Toxicity. Only one study, Leong et al. (1981), was
 

located which addressed the toxic effects of BCME on reproductive
 

organs. This study examined the histological appearance of reproductive
 

tissues in male rats only, and no test of reproductive function was
 

performed. No studies were located on reproductive effects in females.
 

On this basis, more extensive tests of BCME exposure on reproductive
 

function in both male and female animals would be valuable in
 

predicting the possible risk of reproductive effects in workers exposed
 

to BCME.
 

Developmental Toxicity. No studies were located on the
 

developmental toxicity of BCME. Although the rapid hydrolysis of BCME
 

makes it unlikely that BCME could act on the fetus directly, effects
 

might still occur as a consequence of maternal toxicity.
 

Immunotoxicity. No studies were located on the effects of BCME
 

exposure on the immune system. Because the immune system is often
 

observed to be especially sensitive to chemical toxicants,
 

investigations in animals on the effects of BCME on the immune system
 

would be valuable.
 

Neurotoxicity. Drew et al. (1975) reported that inhalation
 

exposure of rats and hamsters lead to subarachnoid hemorrhage, but the
 

severity or significance of this finding was not discussed. These
 

limited data suggest that a more thorough study of the affects of BCME
 

on the nervous system would be useful, including tests both of
 

functions (behavior, electrophysiological tests, etc.) and of structure
 

(histopathology).
 

Epidemiological and Human Dosimetry Studies. A number of
 

epidemiological studies have been performed on workers exposed to BCME
 

in the past. While these studies are limited by the absence of reliable
 

dosimetry data and the presence of other risk factors (smoking, other
 

chemicals), the data nevertheless constitute strong evidence that BCME
 

increases risk of lung cancer in humans. Although prospective
 
29
 

2. HEALTH EFFECTS
 

epidemiological studies may not be feasible since exposure to BCME in
 

the workplace is now so limited, continued follow-up of populations
 

exposed in the past will be helpful in refining estimates of the
 

latency and the incidence of cancer in these cohorts.
 

Biomarkers of Disease. No biomarkers are known that are
 

specific for BCME-induced lung injury. Standard chemical examination of
 

nose and throat can provide an index of local irritation, and
 

examination of sputum for abnormal cell types can provide information
 

on the state of the respiratory epithelium. However, these tests cannot
 

distinguish BCME-induced effects from effects caused by smoking or
 

exposure to other chemicals, and can only discover changes after damage
 

to the tissue has already occurred. Continued efforts to devise more
 

sensitive and more specific early biomarkers of disease (especially
 

lung cancer) would be valuable.
 

Disease Registries. There is no registry of humans with
 

BCMEinduced disease. The identities of individuals who have died from
 

lung cancer (particularly oat cell carcinoma) can be found by searching
 

death certificates, but it is expected that only a small fraction of
 

all such cases would be related to BCME exposure. Creation of a disease
 

registry for BCME would be valuable in helping to establish a clearer
 

understanding of the association between BCME exposure and lung cancer.
 

Bioavailability from Environmental Media. No studies were
 

located on bioavailability of BCME in environmental media. However,
 

this is not a significant limitation, since BCME is not expected to
 

occur in significant quantities in any medium except air.
 

Food Chain Bioaccumulations. No studies were located on food
 

chain bioaccumulation of BCME. This is not a significant limitation,
 

however, since it is expected that BCME is rapidly hydrolyzed in living
 

organisms and will not bioaccumulate.
 

Absorption, Distribution, Metabolism, and Excretion. No studies were
 

located on the toxicokinetics of BCME in animals or humans. Although
 

acquisition of such data is made difficult by the rapid hydrolysis of
 

BCME, studies focusing on the rate of entry of BCME into epithelial
 

cells, the half-time for hydrolysis in the tissue environment, the fate
 

of the degradation products, and interaction with DNA, if any, would be
 

valuable in understanding the toxicity of this compound.
 
30
 

2. HEALTH EFFECTS
 

Comparative Toxicokinetics. No studies were located on the
 

toxicokinetics of BCME in different species. Such studies might be
 

helpful in understanding the differences that have been observed
 

between species with respect to carcinogenic potency and tissue
 

specificity (see Table 2-3).
 

2.9.3 Ongoing Studies
 

No information was located regarding ongoing research on the
 

health effects of BCME.
 
31
 

3. CHEMICAL AND PHYSICAL INFORMATION
 

3.1 CHEMICAL IDENTITY
 

Table 3-1 lists common synonyms, trade names and other pertinent
 

identification information for BCME.
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

Table 3-2 lists important physical and chemical properties of
 

BCME.
 



35
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

4.1 PRODUCTION
 

Production of BCME in this country was curtailed in 1974 following
 

stringent regulation by the Occupational Safety and Health
 

Administration (EPA 1979; OSHA 1974). Available information indicates
 

that BCME is no longer produced for sale in the United States (EPA
 

1980a; USITC 1987; HSDB 1988), although at least one facility
 

manufactures BCME as a non-isolated, site-limited intermediate used in
 

the production of other chemicals (Brothers 1989; Ress 1977). BCME is
 

produced as a contaminant during the manufacture of chloromethyl methyl
 

ether, usually at estimated levels of approximately 0.5 to 5% (DeFonso
 

and Kelton 1976).
 

4.2 IMPORT
 

No data were located on imports of BCME.
 

4.3 USE
 

In the past, BCME was used for crosslinking of cellulose,
 

preparation of styrene and other polymers, surface treatment of
 

vulcanized rubber to increase adhesion, and in the manufacture of
 

flameretardant fabrics (EPA 1980a). These applications have been
 

discontinued, and no uses of BCME other than as a nonisolated
 

intermediate were identified.
 

4.4 DISPOSAL
 

Any products, residues or container liners contaminated with BCME
 

are considered acute hazardous waste under the Resource Conservation
 

and Recovery Act (RCRA) (40 CFR 261.33 (c)), and must be disposed of by
 

transport to a RCRA waste storage and disposal facility. The preferred
 

method of disposal is incineration (OSHA 1974; Sittig 1985).
 

4.5 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR
 

(in consultation with the Administrator of EPA and agencies and
 

programs of the Public Health Service) to assess whether adequate
 

information on the health effects of BCME is available. Where adequate
 

information is not available, ATSDR, in cooperation with the National
 

Toxicology Program (NTP), is required to assure the initiation of a
 

program of research
 
36
 

4. PRODUCTION, IMPORT, USE AND DISPOSAL
 

designed to determine these health effects (and techniques for
 

developing methods to determine such health effects). The following
 

discussion highlights the availability, or absence, of exposure and
 

toxicity information applicable to human health assessment. A statement
 

of the relevance of identified data needs is also included. In a
 

separate effort,ATSDR, in collaboration with NTP and EPA, will
 

prioritize data needs across chemicals that have been profiled.
 

4.5.1 Data Needs
 

Production, Import, Use and Disposal. Although BCME is not
 

produced as a commercial product in the United States, available
 

information indicates that small quantities are produced and used in
 

captive processes within at least one chemical factory. Determination
 

of the amounts involved and whether BCME is used at other locations
 

would be useful in evaluating whether risk of BCME exposure from
 

current industrial practices remains of concern. In addition,
 

compilation of data on typical contaminant levels of BCME currently
 

found in other products such as CME would be helpful in determining
 

whether or not this is a source of concern.
 

According to the Emergency Planning and Community Right to Know
 

Act
 

of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313),
 

industries are required to submit release information to the EPA. The
 

Toxic Release Inventory (TRI), which contains release information for
 

1987, became available in May of 1989. This database will be updated
 

yearly and should provide a more reliable estimate of industrial
 

production and
 

emission.
 
37
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.1 OVERVIEW
 

Because BCME is not currently used as an isolated material in this
 

country, and because it is rapidly degraded in the environment, the
 

probability of human exposure to BCME is low. The most likely means of
 

exposure is inhalation of BCME vapors in the workplace during the
 

production and use of chemicals such as CME, in which BCME may occur as
 

a contaminant or be formed inadvertently. Inhalation of BCME in ambient
 

air might also occur near such a facility, but there is no evidence
 

that this occurs. Exposure through other media (water, food, soil) is
 

unlikely to be significant.
 

5.2 RELEASES TO THE ENVIRONMENT
 

No information was located on the amount of BCME released to air,
 

water or soil. Because BCME is readily volatile at room temperature,
 

emissions into the atmosphere could occur, but OSHA regulations require
 

that processes involving BCME be contained (OSHA 1974). Releases into
 

water could occur but would be of little significance, due to the rapid
 

hydrolysis of BCME in water.
 

5.3 ENVIRONMENTAL FATE
 

5.3.1 Transport and Partitioning
 

No information was located on the transport and partitioning of
 

BCME in the environment. Due to the relatively short half-life in both
 

air and water, it is unlikely that significant transport or
 

partitioning between media occurs.
 

5.3.2 Transformation and Degradation
 

5.3.2.1 Air
 

The primary process for BCME degradation in air is believed to be
 

reaction with photochemically-generated hydroxyl radicals,. Reaction
 

products are believed to include chloromethyl formate, ClHCO,
 

formaldehyde and HCl (Cupitt 1980; EPA 1987a). The atmospheric halflife
 

due to reaction with hydroxyl radicals is estimated to be
 
38
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

1.36 hours. Hydrolysis in the vapor phase is slower, with an estimated
 

half-life of 25 hours in moist air (80% relative humidity at 25°C) (Tou
 

and Kallos 1974). Reaction of BCME with molecular oxygen may also
 

occur, but the rate of this reaction is not known. Other calculations
 

suggest an atmospheric residence time of 0.2 to 2.9 days (Cupitt 1980).
 

Although hydrolysis of BCME to formaldehyde and HCl is highly
 

favored thermodynamically, low levels of BCME may form by the reverse
 

reaction when high concentrations of formaldehyde and HCl are mixed.
 

Frankel et al. (1974) studied this reaction, and found that although
 

BCME levels increased exponentially in proportion to reactant
 

concentrations, yields were only 0.002 to 0.01 mol% at reactant
 

concentrations ranging from 20 to 1,000 ppm. For example, the BCME
 

concentration was 3 ppb in a mixture of 100 ppm formaldehyde and 100
 

ppm HCl. Based on the data of Frankel et al. (1974), Travenius (1982)
 

proposed the empirical equation:
 

log(BCME) -2.25 + 0.67 ppb = • log(HCHO) + 0.77 ppm • log(HCl)ppm
 

Employing this equation, the concentration of BCME likely to form from
 

any mixture of formaldehyde and HCl may be calculated. In the
 

workplace, assuming that exposure occurred at the Threshold Limit
 

Values for each (1 ppm for formaldehyde and 5 ppm for HCl), the
 

resulting BCME concentration would be 0.02 ppb. Concentrations in the
 

home and the ambient environment are likely to be significantly lower
 

for one or both reactants, and concentrations of BCME would be expected
 

to be essentially negligible.
 

5.3.2.2 Water
 

BCME is rapidly hydrolyzed in water to yield formaldehyde and HCl,
 

with a hydrolysis rate constant of 0.018 sec-1 at 20°C (Tou et al.
 

1974). This corresponds to a half-life of approximately 38 seconds.
 

Under laboratory conditions (a sealed vessel from which formaldehyde
 

and HCl cannot escape), an equilibrium is established in which about
 

80% of the BCME is rapidly hydrolyzed, with about 20% of the BCME
 

remaining (Van Duuren et al. 1972). In the environment, formaldehyde
 

and HCl formed by hydrolysis of BCME would be expected to dissipate by
 

diffusion or volatilization, and BCME hydrolysis would rapidly proceed
 

to completion.
 
39
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.3.2.3 Soil
 

No information was located on the fate of BCME in soil. However,
 

it is probable that BCME would rapidly hydrolyze upon contact with
 

moisture in soil or would react with soil constituents. Consequently,
 

it is not expected that BCME would persist for significant periods in
 

soil.
 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
 

5.4.1 Air
 

BCME has not been detected in ambient air. Some early reported
 

industrial air concentrations ranged from 0.7 to 5.2 ppm, but increased
 

care in the handling of this compound has reduced workplace levels to
 

the sub-ppb range (NIOSH 1972a). No other quantitative data on BCME
 

levels in air were located.
 

5.4.2 Water
 

BCME has not been detected in ambient waters, but has been
 

reported to be present in groundwater at one chemical waste site being
 

investigated under Superfund (CLPSD 1988). Because BCME hydrolyzes so
 

quickly in water, this observation must be considered with skepticism.
 

5.4.3 Soil
 

BCME was reported to be present at 0.5% of the waste sites being
 

investigated under Superfund (CLPSD 1988), but quantitative data were
 

not available. As with the data regarding occurrence in water, these
 

data must be considered with caution, since BCME is unlikely to endure
 

at measurable levels in soil.
 

5.4.4 Other Media
 

No studies were located regarding the occurrence of BCME in other
 

media.
 
40
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
 

The most likely route of human exposure to BCME is by inhalation,
 

but available data are not adequate to estimate typical dose levels.
 

Doses are'likely to be close to zero for the general population, but
 

could be of concern inside or close by industrial sites where
 

chloromethylation processes occur (Roe 1985).
 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
 

As discussed above, the individuals most likely to have potential
 

exposure to BCME are industrial workers who manufacture or use
 

chemicals such as CME that might contain BCME as a contaminant. The
 

possibility exists that residents near a facility or a waste site that
 

permits escape of BCME could also be exposed, but there are no data to
 

establish whether or not this occurs or is of concern.
 

5.7 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR
 

(in consultation with the Administrator of EPA and agencies and
 

programs of the Public Health Service) to assess whether adequate
 

information on the health effects of BCME is available. Where adequate
 

information is not available, ATSDR, in cooperation with the National
 

Toxicology Program (NTP), is required to assure the initiation of a
 

program of research designed to determine these health effects (and
 

techniques for developing methods to determine such health effects).
 

The following discussion highlights the availability, or absence, of
 

exposure and toxicity information applicable to human health
 

assessment. A statement of the relevance of identified data needs is
 

also included. In a separate effort, ATSDR, in collaboration with NTP
 

and EPA, will prioritize data needs across chemicals that have been
 

profiled.
 

5.7.1 Data Needs
 

Physical and Chemical Properties. The physical and chemical
 

properties most important in evaluating the environmental fate of BCME
 

have been determined (see Table 3-2). Although some of these values
 

(eg, solubility in water) are calculated, this is not a significant
 

limitation, and additional studies on the physical or chemical
 

properties of BCME do not appear essential.
 
41
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Environmental Fate. Available data make it clear that BCME is not
 

likely to endure in the environment. No further studies appear to be
 

required on fate in water or other moist media (food, soil), since the
 

principal fate is rapid hydrolysis. Additional studies on the kinetics
 

of BCME destruction in air by oxidation and hydrolysis would be
 

valuable in refining mathematical models used to calculate levels of
 

BCME in air around a point source.
 

Exposure Levels in Environmental Media. Information on the
 

occurrence of BCME in environmental media is very limited. No
 

information was located on levels in ambient air, water or soil. BCME
 

has been reported to occur in water or soil near a few waste sites, but
 

these findings may not be reliable. Because of the instability of BCME
 

in water and soil, further efforts to measure BCME in these media are
 

unlikely to produce useful information. However, the volatility and
 

atmospheric lifetime of BCME are such that monitoring air for BCME in
 

the vicinity of waste sites, industrial facilities or other possible
 

sources could provide valuable information on the occurrence of this
 

chemical in the environment.
 

Exposure Levels in Humans. No data exists on present-day exposure
 

levels of humans to BCME. Exposure is likely to be close to zero for
 

the general public. However, because BCME is such at potent carcinogen,
 

even low levels of exposure are of potential concern, and additional
 

data on exposure levels in the workplace and in the environment near
 

waste sites would be valuable.
 

Exposure Registries. No exposure registries exist for humans
 

exposed to BCME. Although the exposed population is likely to be quite
 

small, creation of such a registry would provide the opportunity to
 

obtain valuable additional data on the health effects of BCME.
 

5.7.2 Ongoing Studies
 

No information was located regarding any ongoing studies on the
 

occurrence of BCME in the environment or the potential for human
 

exposure to BCME.
 

43
 

6. ANALYTICAL METHODS
 

6.1 BIOLOGICAL MATERIALS
 

There is little need or opportunity to measure BCME in biological
 

samples because of its rapid hydrolysis in water to yield formaldehyde
 

and chloride. The abundance of chloride and, to a lesser extent, of
 

formaldehyde, in biological materials precludes use of these hydrolysis
 

products as an index of exposure to BCME. Therefore, the analysis of
 

BCME in biological samples from exposed humans is virtually impossible.
 

6.2 ENVIRONMENTAL SAMPLES
 

Methods for the determination of BCME in environmental samples are
 

currently confined to monitoring of air. It is possible, to monitor
 

BCME in air at extremely low levels, and several analytical methods
 

have detection limits of a few tenths of a ppb. Most methods for the
 

analysis of BCME in air call for collecting samples on a solid
 

adsorbent, followed by thermal desorption and gas chromatographic
 

analysis. A typical procedure (ASTM 1987) uses a sampling tube packed
 

with Chromosorb 101 adsorbent through which up to 25 L of air can be
 

drawn for a period as long as 24 hours. For analyte determination, the
 

sampling tube is attached to a gas chromatograph so that carrier gas
 

can be passed through it and through the analytical column. With the
 

carrier gas flowing, the collection column is heated to 150°C for four
 

minutes and the analyte flows onto the analytical column, which is
 

maintained at room temperature. Following desorption of the BCME, the
 

analytical column is heated to 130°C with a programmed temperature
 

increase and the eluted BCME is detected and measured quantitatively by
 

mass spectrometry.
 

It has been noted (Travenius 1982) that common adsorption methods
 

of sampling BCME from air are prone to giving inaccurate results
 

because of hydrolysis of the analyte by coadsorbed water. For this
 

reason, most procedures for methods involving collection of BCME on
 

solid adsorbents require that samples in collection tubes be processed
 

within a few days and protected from humidity.
 

Methods for determination of BCME in air are given in Table 6-l.
 

45
 

6. ANALYTICAL METHODS
 

6.3 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR
 

(in consultation with the Administrator of EPA and agencies and
 

programs of the Public Health Service) to assess whether adequate
 

information on the health effects of BCME is available. Where adequate
 

information is not available, ATSDR, in cooperation with the National
 

Toxicology Program (NTP), is required to assure the initiation of a
 

program of research designed to determine these health effects (and
 

techniques for developing methods to determine such health effects).
 

The following discussion highlights the availability, or absence, of
 

exposure and toxicity information applicable to human health
 

assessment. A statement of the relevance of identified data needs is
 

also included. In a separate effort, ATSDR, in collaboration with NTP
 

and EPA, will prioritize data needs across chemicals that have been
 

profiled.
 

6.3.1 Data Needs
 

Methods for Determining Parent Compound and Metabolites in
 

Biological Materials. No methods were located for determining BCME
 

in biological samples. It does not appear that this is a significant
 

limitation, however, since BCME is not expected to endure in tissues or
 

fluids. Although there are adequate methods for the detection of
 

formaldehyde and chloride, these are not likely to be useful for
 

assessing exposure to BCME, since any change in the levels of these
 

compounds would be well within normal biological variability.
 

Methods for Biomarkers of Exposure. No methods were located for
 

measuring any biomarkers of exposure to BCME. Although covalent adducts
 

of BCME with cellular proteins or DNA have not yet been reported,
 

development of sensitive and specific immunological assays for such
 

adducts would provide a valuable means of detecting and perhaps
 

quantifying human exposure levels.
 

Methods for Determining Parent Compound and Degradation Products
 

in Environmental Media. Air is the only environmental medium
 

susceptibleto significant contamination by BCME and methods for the
 

determination of this compound in air are straightforward. The greatest
 

need for improvement in the analysis of BCME is the development of
 

methodologies
 
46
 

6. ANALYTICAL METHODS
 

that enable its efficient collection from large volumes of air without
 

hydrolysis during collection or storage. Since health concern might
 

extend to concentrations well below 1 ppb, improvement in sensitivity
 

would also be valuable.
 

6.3.2 Ongoing Studies
 

Because of evidence that BCME is carcinogenic even at very low
 

levels in the atmosphere, current studies of its analysis are
 

concentrating on extending the detection limit to even lower levels.
 

Because of its chlorine content, BCME can be measured with extreme
 

sensitivity by electron capture detection after gas chromatographic
 

separation of this analyte. Efforts are underway by Dr. Robert Sievers
 

(University of Colorado, Boulder) to improve collection methods that
 

meet the criteria of (1) highly efficient collection of BCME at sub-ppb
 

levels in air, (2) no loss of analyte from hydrolysis resulting from
 

atmospheric humidity, and (3) rapid, efficient, nondestructive
 

desorption of analyte from the collection medium.
 
47
 

7. REGULATIONS AND ADVISORY STANDARDS
 

Because of its potential to cause adverse health effects in
 

exposed people, a number of regulations and advisory values have been
 

established for BCME by various international, national and state
 

agencies. These values are summarized in Table 7-l.
 

___________________________ 

49
 

8. REFERENCES
 

* ACGIH. 1986. Documentation of the threshold limit values and
 

biological exposure indices. 5th ed. American Conference of
 

Governmental Industrial Hygienists, Inc., Cincinnati, OH.
 

* Albert RE, Sellakumar AR, Laskin S, et al. 1982. Gaseous formaldehyde
 

and hydrogen chloride induction of nasal cancer in the rat. J Nat
 

Cancer Inst 68:597-603.
 

* Albert RE, Pasternack BS, Shore RE, et al. 1975. Mortality patterns
 

among workers exposed to chloromethyl ethers- a preliminary report.
 

Environ Health Perspect 2:109-214.
 

* Anderson D, Styles JA. 1978. The bacterial mutation test. Br J Cancer
 

37:924-930.
 

* ASTM. 1987. Bis(chloromethy1) ether (bis CME) in workplace
 

atmospheres (gas chromatography - mass spectrometry - Method D 3476­

79). 1987 Annual book of ASTM standards, Vol. 11.03, Atmospheric
 

analysis; occupational health and safety. American Society for Testing
 

and Materials, Philadelphia, PA: 259-264.
 

* Barnes D, Bellin J, DeRosa C, et al. 1987. Reference dose (RfD):
 

description and use in health risk assessments. Volume I, Appendix A:
 

Integrated risk information system supportive documentation.
 

Washington, DC: US Environmental Protection Agency, Office of Health
 

and Environmental Assessment. EPA/600/8-86/032a.
 

* Brothers RF. 1989. Written communication (May 5) to Director, Office
 

of External Affairs, Agency for Toxic Substances and Disease Registry,
 

regarding manufacture of BCME. Director, Issues Development, Eastman
 

Kodak Company.
 

Bruner F, Bertonic G, Severni C. 1978. Gas chromatographic
 

determination of bis(chloromethy1) ether emissions in the atmosphere of
 

industrial plants. Anal Chem 50:53.
 

*Cited in the text
 
50
 

8. REFERENCES
 

*Callahan MA, Slimak MW, Gabel NW, et al. 1979. Water-related
 

environmental fate of 129 priority pollutants. Vol. II. Halogenated
 

aliphatic hydrocarbons, halogenated ethers, monocyclic aromatics,
 

phthalate esters, polycyclic aromatic hydrocarbons, nitrosamines, and
 

miscellaneous compounds. Washington, DC: U.S. Environmental Protection
 

Agency, EPA 440/4/79/029b. PB80-2043816.
 

Chovil AC. 1979. Occupational lung cancer and smoking: a review in the
 

light of current theories of carcinogenesis. Chem Manuf Assoc J
 

121:548-555.
 

*CLPSD. 1988. Contract laboratory program statistical database. Viar
 

and Company, Alexandria VA: September 6, 1988.
 

*Cole P, Merletti F. 1980. Chemical agents and occupational cancer.
 

J Environ Pathol 3:399-417.
 

*Collier L. 1972. Determination of bis-chloromethyl ether at the ppb
 

level in air samples by high-resolution mass spectropy. Environ Sci
 

Technol 6:930-932.
 

*Collingwood KW, Pasternack BS, Shore RE. 1987. Industry-wide study of
 

respiratory cancer in chemical workers exposed to chloromethyl ether. J
 

Nat Cancer Inst 78:1127-1135.
 

*Cupitt LT. 1980. Fate of toxic and hazardous materials in the air
 

environment. Research Triangle Park, NC: U.S. Environmental Sciences
 

Research Laboratory PB80-22194b.
 

*DeFonso LR, Kelton SC. 1976. Lung cancer following exposure to
 

chloromethyl methyl ether. Arch Environ Health 31:125-130.
 

*Drew R, Laskin S, Kuschner M, et al. 1975. Inhalation carcinogenicity
 

of alpha halo ethers. Arch Environ Health 30:61-69.
 

EPA. 1975. Investigation of selected potential environmental
 

contaminants, haloethers. Washington, DC: U.S. Environmental Protection
 

Agency. NTIS PB-246-356
 

*EPA. 1979. Toxic Substances Control Act. Chemical substances
 

inventory. Washington, DC: U.S. Environmental Protection Agency, Office
 

of Toxic Substances.
 
51
 

8. REFERENCES
 

* EPA. 1980a. An exposure and risk assessment for bis(chloromethy1)
 

ether. Washington, DC: U.S. Environmental Protection Agency, Office of
 

Water Regulations and Standards (Interim Draft).
 

* EPA. 1980b. U.S. Environmental Protection Agency. Hazardous waste;
 

identification and listing; final and interim rules. Federal Register.
 

45:3384-33133.
 

EPA. 1980c. Guidelines and methodology used in the preparation of
 

health effect assessment chapters of the consent decree water criteria
 

documents. U.S. Environmental Protection Agency. Federal Register
 

45:79347-79357.
 

EPA. 1980d. Ambient water quality criteria document for haloethers.
 

Washington, DC: U.S. Environmental Protection Agency, Office of Water
 

Regulations and Standards. EPA 440/5-80-050. NTIS PB81-117616.
 

* EPA. 1985. U.S Environmental Protection Agency. Part II. Notification
 

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rule. Federal Register. 50:13456-13522.
 

* EPA. 1987a. Health and environmental effects document for haloethers.
 

Cincinnati, OH: U.S. Environmental Protection Agency, Office of Health
 

and Environmental Assessment. ECAO-CIN-G014.
 

* EPA 1987b. U.S. Environmental Protection Agency. Part II. Hazardous
 

substances, reportable quantity adjustments; proposed rules. Federal
 

Register. 52:8140-8171.
 

* EPA. 1987c. U.S. Environmental Protection Agency. Part II. Extremely
 

hazardous substances list and threshold planning quantities; emergency
 

planning and release notification requirements; final rule. Federal
 

Register. 52:13378-13410.
 

* EPA. 1988. Integrated risk information system (IRIS). Printout for
 

bis(chloromethy1) ether. Washington, DC: U.S. Environmental Protection
 

Agency. November.
 

Evans HJ. 1982. Cytogenetic studies on industrial populations exposed
 

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* Fishbein L. 1979. Potential halogenated industrial carcinogenic and
 

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Science Total Environ 11:223-257.
 

* Frankel LS, McCallum KS, Collier L. 1974. Formation of
 

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Frost JK, Gupta PK, Erozan YS, et al. 1973. Pulmonary cytologic
 

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* FSTRAC. 1988. Summary of state and federal drinking water standards
 

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Gilbert D, Eschenroeder A, Goyer M, et al. 1979. An exposure and risk
 

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Gosselin RE. 1984. Clinical toxicology of commercial products. 5th
 

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* HSDB. 1988. Hazardous Substances Data Base - computer printout for
 

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* IARC. 1982. IARC Monographs on the evaluation of the carcinogenic
 

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Cancer.
 

* Kallos GJ. 1981. Oxygen-induced response enhancement in determination
 

of bis(chloromethy1) ether by gas chromatography with 63Ni electron
 

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* Krost KJ, Pellizzari ED, Walburn SG, et al. 1982. Collection and
 

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* Kuschner M, Laskin S, Drew RT, et al. 1975. Inhalation
 

carcinogenicity of alpha halo ethers. Arch Environ Health 30:73-77.
 

* Laskin S, Kuschner M, Drew RT, et al. 1971. Tumors of the respiratory
 

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Lemen RA. 1986. Occupationally induced lung cancer epidemiology. In:
 

Merchant JA, ed. Occupational respiratory diseases. U.S. Department of
 

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* Lemen RA, Johnson WM, Wagoner JK, et al. 1976 a Cytologic
 

observations and cancer incidence following exposure to BCME. Ann NY
 

Acad Sci 271:71-80.
 

* Leong BK, MacFarland HN, Reese WH. 1971. Induction of long adenomas
 

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22:663-666.
 

* Leong BKJ, Kociba RI, Jersey GC. 1981. A lifetime study of rats and
 

mice exposed to vapors of bis(chloromethy1) ether. Toxicol Appl
 

Pharmacol 58:269-281
 

* Mabey WR, Smith JH, Pod011 RT, et al. 1982. Aquatic fate process data
 

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* Maher KV, DeFonso IX. 1987. Respiratory cancer among chloromethyl
 
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Worcester, England: British Crop Protection Council, 177.
 

McCallum RI, Woolley V, Petrie A. 1983. Lung cancer associated with
 

chloromethyl methyl ether manufacture: an investigation at two
 

factories in the United Kingdom. Brit J Ind Med 40:384-389.
 

* Mueller G, Norpoth K, Travenius SZM. 1981. Quantitative determination
 

of bis(chloromethy1) ether (BCME) in the ppb range using portable air
 

sample collectors. Int Arch Occup Environ Health 48:325-329.
 

* NIOSH. 1972a. Field survey of Dow Chemical Company chloromethyl ether
 

facilities, Midland, MI. Cincinnati, OH: National Institute for
 

Occupational Safety and Health. PB82-151598.
 

* NIOSH. 1972b. Field survey of Rohm and Haas Company Bridesburg
 

Facilities Philadelphia, PA. Cincinnati, OH: National Institute for
 

Occupational Safety and Health. PB82-162561.
 

NIOSH. 1973. Hazard review of bis(chloromethy1) ether. Cincinnati, OH:
 

National Institute for Occupational Safety an Health. PB87-210779.
 

NIOSH. 1974. Survey of Burlington Industries, Inc. Burlington House
 

Finishing Plant, Form Fabrics Plant, Durham Domestics Plant, Brookneal
 

Finishing Plant. PB82-151077.
 

* NIOSH. 1977. Manual of Analytical Methods. Vol. 1. Method 213.
 

Cincinnati, OH: National Institute for Occupational Safety and Health.
 

* NIOSH. 1986. NIOSH recommendations for occupational safety and health
 

standards. Atlanta, GA: U.S. Department of Health and Human Services,
 

National Institute for Occupation Safety and Health. September, 1986.
 

* NLM. 1988. National Library of Medicine - chemline database printout
 

for bis(chloromethy1) ether. August, 1988.
 

* Norpoth K, Mueller G, Zilius Z, et al. 1981. Sensitive
 

spectrophotometric determination of carcinogenic alpha chloro ethers.
 

Int Arch Occup Environ Health 49: 151-155.
 
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*Pasternack BBS, Shore R, Albert RE. 1977. Occupational exposure to
 

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Pepelko WE. 1984. Experimental respiratory carcinogenesis in small
 

laboratory animals. Environ Research 33:144-188.
 

*Ress JF. 1977. Tight control prevents exposure to bis(chloromethy1)
 

ether. Occupational Health and Safety. May/June 1977:40-43.
 

*Reznik G, Wagner HH, Atay Z. 1977. Lung cancer following exposure to
 

bis(chloromethy1) ether: a case report. J Environ Pathol Toxicol 1:105­

111.
 

Roe FJC. 1985 Chloromethylation: three lung cancer deaths in young men.
 

The Lancet 2:268.
 

*Sakabe H. 1973. Lung cancer due to exposure to bis(chloromethy1)
 

ether. Ind Health 11:145-148.
 

Sax NI, Lewis RJ, eds. 1987. Hawley's condensed chemical dictionary.
 

11th edition. New York, NY: Van Nostrand Reinhold Co. 149.
 

*Sellakumar AR, Snyder CA, Solomon JJ, et al. 1985. Carcinogenicity of
 

formaldehyde and hydrogen chloride in rats. Toxicol Appl Pharmacol
 

81:401-406.
 

*Sittig M. 1985. Handbook of toxic and hazardous chemicals and
 

carcinogens. Park Ridge, NJ: Noyes Publications. 133-135.
 

Sram RJ, Samkova I, Hola N. 1983. High-dose ascorbic prophylaxis
 

inworkers occupationally exposed to halogenated ethers. J Hyg Epidemiol
 

Microbial Immunol 27:305-318.
 
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* Thiess AM, Hey W, Zeller H. 1973. Zur Toxikologie von
 

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applications to occupational exposures, smoking, and lung cancer. Am J
 

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* Tou JC, Kallos GJ. 1974. Kinetic study of the stabilities of
 

chloromethyl methyl ether and bis(chloromethy1) ether in humid air.
 

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* Tou JC, Westover LB, Sonnabend LF. 1974. Kinetic studies of
 

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78:1096-1098.
 

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ether and its prevention in the chemical industry. Stand J Work Environ
 

Health 8 (Suppl. 3): l-86.
 

* Union Carbide. 1968. Summary of acute toxicity and irritancy studies
 

of bis(chloromethyl)ether. Union Carbide Corporation, Danbury, CT. Rpt
 

31-85; 1968.
 

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*Weiss W, Moser RL, Auerbach 0. 1979. Lung cancer in chloromethyl ether
 

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* Zajdela F, Croisy A, Barbin A, et al. 1980. Carcinogenicity of
 

chloroethylene oxide, an ultimate reactive metabolite of vinyl
 

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59
 

9. GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or
 

less, as specified in the Toxicological Profiles.
 

Adsorption Coefficient (KOC) -- The ratio of the amount of a chemical
 

adsorbed per unit weight of organic carbon in the soil or sediment to
 

the concentration of the chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a
 

sediment or soil (i.e., the solid phase) divided by the amount of
 

chemical in the solution phase, which is in equilibrium with the solid
 

phase, at a fixed solid/solution ratio. It is generally expressed in
 

micrograms of chemical sorbed per gram of soil or sediment.
 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a
 

chemical in aquatic organisms at a specific time or during a discrete
 

time period of exposure divided by the concentration in the surrounding
 

water at the same time or during the same time period.
 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
 

group of studies which produces significant increases in incidence of
 

cancer (or tumors) between the exposed population and its appropriate
 

control.
 

Carcinogen -- A chemical capable of inducing cancer.
 

Ceiling value (CL) -- A concentration of a substance that should not be
 

exceeded, even instantaneously.
 

Chronic Exposure -- Exposure to a chemical for 365 days or more, as
 

specified in the Toxicological Profiles.
 

Developmental Toxicity -- The occurrence of adverse effects on the
 

developing organism that may result from exposure to a chemical prior
 

to conception (either parent), during prenatal development, or
 

postnatally to the time of sexual maturation. Adverse developmental
 

effects may be detected at any point in the life span of the organism.
 
60
 

9. GLOSSARY
 

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as
 

a result of prenatal exposure to a chemical; the distinguishing feature
 

between the two terms is the stage of development during which the
 

insult occurred. The terms, as used here, include malformations and
 

variations, altered growth, and in utero death.
 

EPA Health Advisory -- An estimate of acceptable drinking water levels
 

for a chemical substance based on health effects information. A health
 

advisory is not a legally enforceable federal standard, but serves as
 

technical guidance to assist federal, state, and local officials.
 

Immediately Dangerous to Life or Health (IDLH) -- The maximum
 

environmental concentration of a contaminant from which one could
 

escape within 30 min without any escape-impairing symptoms or
 

irreversible health effects.
 

Intermediate Exposure -- Exposure to a chemical for a duration of 15­

364 days, as specified in the Toxicological Profiles.
 

Immunologic Toxicity -- The occurrence of adverse effects on the immune
 

system that may result from exposure to environmental agents such as
 

chemicals.
 

In vitro -- Isolated from the living organism and artificially
 

maintained, as in a test tube.
 

In vivo -- Occurring within the living organism.
 

Lethal Concentration (LC ) (L0) LO
 -- The lowest concentration of a


chemical in air which has been reported to have caused death in humans
 

or animals.
 

Lethal Concentration (LC ) (50) 50
 -- A calculated concentration of a


chemical in air to which exposure for a specific length of time is
 

expected to cause death in 50% of a defined experimental animal
 

population.
 

Lethal Dose(L0) (LD LO) -- The lowest dose of a chemical introduced by a
 

route other than inhalation that is expected to have caused death in
 

humans or animals.
 
61
 

9.GLOSSARY
 

Lethal Dose (LD ) (50) 50
 -- The dose of a chemical which has been


calculated to cause death in 50% of a defined experimental animal
 

population.
 

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of
 

chemical in a study or group of studies which produces statistically or
 

biologically significant increases in frequency or severity of adverse
 

effects between the exposed population and its appropriate control.
 

LT50 (lethal time) -- A calculated period of time within which a
 

specific concentration of a chemical is expected to cause death in 50%
 

of a defined experimental animal population.
 

Malformations -- Permanent structural changes that may adversely affect
 

survival, development, or function.
 

Minimal Risk Level -- An estimate of daily human exposure to a chemical
 

that is likely to be without an appreciable risk of deleterious effects
 

(noncancerous) over a specified duration of exposure.
 

Mutagen -- A substance that causes mutations. A mutation is a change in
 

the genetic material in a body cell. Mutations can lead to birth
 

defects, miscarriages, or cancer.
 

Neurotoxicity -- The occurrence of adverse effects on the nervous
 

system following exposure to a chemical.
 

No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
 

which there are no statistically or biologically significant increases
 

in frequency or severity of adverse effects seen between the exposed
 

population and its appropriate control. Effects may be produced at this
 

dose, but they are not considered to be adverse.
 

Octanol-Water Partition Coefficient (KOW) -- The equilibrium ratio of
 

the concentrations of a chemical in n-octanol and water, in dilute
 

solution.
 

Permissible Exposure Limit (PEL) -- An allowable exposure level in
 

workplace air averaged over an 8-h shift.
 
62
 

9.GLOSSARY
 

q1* -- The upper-bound estimate of the low-dose slope of the 

doseresponse 

curve as determined by the multistage procedure. The q1* can be used to 

calculate an estimate of carcinogenic potency, the incremental excess 

cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for 

food, and μg/m3 for air). 

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps
 

an order of magnitude) of the daily exposure of the human population to
 

a potential hazard that is likely to be without risk of deleterious
 

effects during a lifetime. The RfD is operationally derived from the
 

NOAEL (from animal and human studies) by a consistent application of
 

uncertainty factors that reflect various types of data used to estimate
 

RfDs and an additional modifying factor, which is based on a
 

professional judgment of the entire database on the chemical. The RfDs
 

are not applicable to nonthreshold effects such as cancer.
 

Reportable Quantity (RQ) -- The quantity of a hazardous substance that
 

is considered reportable under CERCLA. Reportable quantities are: (1) 1
 

lb or greater or (2) for selected substances, an amount established by
 

regulation either under CERCLA or under Sect. 311 of the Clean Water
 

Act. Quantities are measured over a 24-h period.
 

Reproductive Toxicity -- The occurrence of adverse effects on the
 

reproductive system that may result from exposure to a chemical. The
 

toxicity may be directed to the reproductive organs and/or the related
 

endocrine system. The manifestation of such toxicity may be noted as
 

alterations in sexual behavior, fertility, pregnancy outcomes, or
 

modifications in other functions that are dependent on the integrity of
 

this system.
 

Short-Term Exposure Limit (STEL) -- The maximum concentration to which
 

workers can be exposed for up to 15 min continually. No more than four
 

excursions are allowed per day, and there must be at least 60 min
 

between exposure periods. The daily TLV-TWA may not be exceeded.
 

Target Organ Toxicity -- This term covers a broad range of adverse
 

effects on target organs or physiological systems (e.g., renal,
 

cardiovascular) extending from those arising through a single limited
 

exposure to those assumed over a lifetime of exposure to a chemical.
 
63
 

9.GLOSSARY
 

TD50 (toxic dose) -- A calculated dose of a chemical, introduced by a
 

route other than inhalation, which is expected to cause a specific
 

toxic effect in 50% of a defined experimental animal population.
 

Teratogen -- A chemical that causes structural defects that affect the
 

development of an organism.
 

Threshold Limit Value (TLV) -- A concentration of a substance to which
 

most workers can be exposed without adverse effect. The TLV may be
 

expressed as a TWA, as a STEL, or as a CL.
 

Time-weighted Average (TWA) -- An allowable exposure concentration
 

averaged over a normal 8-h workday or 40-h workweek.
 

Uncertainty Factor (UF) -- A factor used in operationally deriving the
 

RfD from experimental data. UFs are intended to account for (1) the
 

variation in sensitivity among the members of the human population, (2)
 

the uncertainty in extrapolating animal data to the case of humans, (3)
 

the uncertainty in extrapolating from data obtained in a study that is
 

of less than lifetime exposure, and (4) the uncertainty in using LOAEL
 

data rather than NOAEL data. Usually each of these factors is set equal
 

to 10.
 

65
 

APPENDIX: PEER REVIEW
 

A peer review panel was assembled for BCME. The panel consisted of
 

the following members: Dr. Douglas Arnold, Toxicologist, Banting
 

Research Center, Health and Welfare, Canada; Dr. James Bruckner,
 

Director, Toxicology Programs, Department of Pharmacology and
 

Toxicology, University of Georgia; Dr. Chon Shoaf, Research Associate,
 

Duke University Medical Center; Dr. Dietrich Hoffman, Associate
 

Director, American Health Foundation, Valhalla, NY; and Dr. Benjamin
 

Van Duuren, Professor of Environmental Medicine, New York University
 

Medical Center. These experts collectively have knowledge of BCME's
 

physical and chemical properties, toxicokinetics, key health end
 

points, mechanisms of action, human and animal exposure, and
 

quantification of risk to humans. All reviewers were selected in
 

conformity with the conditions for peer review specified in the
 

Superfund Amendments and Reauthorization Act of 1986, Section 110.
 

A joint panel of scientists from ATSDR and EPA has reviewed the
 

peer reviewers' comments and determined which comments will be included
 

in the profile. A listing of the peer reviewers' comments not
 

incorporated in the profile, with a brief explanation of the rationale
 

for their exclusion, exists as part of the administrative record for
 

this compound. A list of databases reviewed and a list of unpublished
 

documents cited are also included in the administrative record.
 

The citation of the peer review panel should not be understood to
 

imply their approval of the profile's final content. The responsibility
 

for the content of this profile lies with the Agency for Toxic
 

Substances and Disease Registry.
 

* U.S GOVERNMENT PRINTING OFFICE 99l 535.152/