TOXICOLOGICAL PROFILE FOR 

BIS(2-CHLOROETHYL)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. PUBLIC HEALTH STATEMENT 

1.1 WHAT IS BIS(2-CHLOROETHYL) ETHER? 

Bis(2-chloroethyl) ether (BCEE) is a colorless non-flammable liquid 

with a strong, unpleasant odor. It does not occur naturally, but is 

manufactured by humans for use in the production of pesticides and other 

chemicals. Limited amounts of BCEE will dissolve in water, and it also 

will slowly evaporate into air. In the environment, BCEE is broken down 

by bacteria in soil and water and by chemical reactions in the air, so 

it does not tend to persist for long periods. Further information on 

the properties and uses of BCEE, and how it behaves in the environment, 

is presented in Chapters 3, 4 and 5. 

1.2 HOW MIGHT I BE EXPOSED TO BCEE? 

Exposure to BCEE is most likely to occur in or near chemical plants 

where it is made or used, or near waste sites where it has been 

improperly disposed of. One way exposure might occur is through 

consumption of drinking water that contains BCEE. Low levels (0.01 to 

0.5 parts per billion (ppb)) of BCEE have been detected in the drinking 

water supplies of several cities, and higher levels (840 ppb) have been 

detected in underground water near some chemical waste sites. Although 

BCEE evaporates relatively slowly, exposure might also occur through 

breathing BCEE vapors near areas where it is used or stored. However, 

no information exists on the levels of BCEE in outdoor air. Further 

discussion of how people may be exposed to BCEE is presented in 

Chapter 5. 

1.3 HOW CAN BCEE ENTER AND LEAVE MY BODY? 

BCEE enters the body easily after being swallowed in food or water, 

or after being inhaled in air. It may also enter by crossing the skin 

when dermal contact occurs. Once inside the body, BCEE is broken down 

to a number of different chemicals, and these are eliminated in the 

urine or the breath. Most BCEE which enters the body is removed in this 

way within two to three days, so BCEE does not tend to accumulate in the 

body. Further information on how BCEE enters and leaves the body is 

presented in Chapter 2. 

1.4 HOW CAN BCEE AFFECT MY HEALTH? 

People exposed to BCEE vapors report that it is highly irritating 

to the eyes and the nose. Animal studies show that BCEE vapors can 

cause severe injury to the lungs, and may lead to death. Mice given 

repeated doses of BCEE through the mouth developed liver tumors. This 
2 

1. PUBLIC HEALTH STATEMENT

suggests that BCEE might cause cancer in humans, although no cases of 

cancer due to BCEE have been reported in people and BCEE was also not 

found to induce excess cancer after feeding to rats. Effects of BCEE on 

other organs and body functions have not been well studied, and it is 

not known if BCEE impairs reproduction or the development of fetuses. 

Further information on the possible health effects of BCEE is presented 

in Chapter 2. 

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

BCEE? 

Although there are chemical tests that can identify and measure 

BCEE, these have not been developed for measuring BCEE in humans. 

Further information on the methods used to measure BCEE is presented in 

Chapter 6. 

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

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

BCEE and known health effects. A Minimal Risk Level (MRL) is also 

included in Table l-l. This MRL was derived from animal data for longterm 

exposure, as described in Chapter 2 and in Table 2-1. This MRL 

provides a basis for comparison with levels that people might encounter 

in air. If a person is exposed to BCEE at an amount below the long-term 

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

occur. Because this level is based only on information currently 

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. 

Based on studies in animals, if an amount of BCEE equal to 1 to 

2 fluid ounces entered the body across the skin, death could result. 

Skin contact with even small amounts (less than a drop) of liquid BCEE 

will cause irritation to the skin. 

Further information on the amounts of BCEE that cause health 

effects in humans and animals is presented in Chapter 2. 




7 

1. PUBLIC HEALTH STATEMENT 

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN 

HEALTH ? 

The Federal government has taken a number of steps to reduce the 

possibility of human exposure to BCEE. The U.S. Environmental 

Protection Agency (EPA) has developed rules and regulations that limit 

the amount of BCEE that can be discharged into water or air from

industrial sources as well as how it is to be disposed of at waste 

sites. Levels of BCEE exposure in the workplace are strictly regulated 

by the Occupational Safety and Health Administration (OSHA), since BCEE 

is considered a probable human carcinogen. Further information on 

regulations which apply to BCEE is presented 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 

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

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 .(l) an overall perspective of the toxicology 

of BCEE and (2) a depiction of significant exposure levels associated 

with various adverse health effects. 

Bis(chloroethy1) ether (BCEE) occurs in two isomeric forms: 

bis(l-chloroethyl) ether, or alpha BCEE, and bis(2-chloroethyl) ether, 

or beta BCEE. The alpha isomer is chemically more reactive than the 

beta isomer, but it has had little industrial use and there are very few 

data on the toxicological effects of this isomer. The beta form is more 

stable and has been widely produced and used by industry. It is the 

beta isomer (bis(2-chloroethyl) ether) that is referred to as BCEE in 

the remainder of this document. 

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-adverse-effect 

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. 
10 

2. HEALTH EFFECTS 

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 

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 (MRLs) 

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 

Table 2-l and Figure 2-1 summarize the available toxicity data for 

inhalation exposure to BCEE, and these data are discussed below. 

2.2.1.1 Death 

One case of a human fatality attributed to inhalation of BCEE 

vapors in a fulling mill was reported by Elkins (1959), but no details 

were provided. In animals, acute inhalation lethality depends on the 

level and duration of exposure to BCEE. Exposure of animals (rats, mice 

guinea pigs, rabbits) to concentrations of 500-1,000 ppm caused death 

within 1 to 2 hours (Schrenk et al. 1933; Smyth and Carpenter 1948; 



14 

2. HEALTH EFFECTS 

 

Union Carbide 1948). Exposure of rats to 250 ppm for 4 hours caused 

death in about half the animals (Carpenter et al. 1949), while exposure 

of mice, rats, and rabbits to 200 ppm for 1 hour did not cause any 

deaths (Union Carbide 1948). Four of six guinea pigs exposed to 105 ppm 

for 13 hours died within four hours after the exposure, while no deaths 

occurred in animals exposed to 35 ppm for 13.5 hours (Schrenk et al. 

1933). Animals exposed to BCEE vapors display marked signs of 

respiratory distress, and acute lung injury appears to be the principal 

cause of death (Carpenter et al. 1949). The highest NOAEL values and 

all reliable LOAEL values for death in each species and duration 

category are recorded in Table 2-l and plotted in Figure 2-l. The 

values of 105 ppm (Schrenk et al. 1933) and 250 ppm (Carpenter et al. 

1949) are presented in Table l-2. 

2.2.1.2 Systemic Effects 

Respiratory Effects. The principal acute effect of inhalation 

exposure to BCEE vapor is irritation and injury to the cells of the 

respiratory epithelium. In humans, exposure to concentrations of 

550 ppm or higher produces extreme irritation and cannot be tolerated 

for more than a few moments (Schrenk et al. 1933). Exposure to 260 ppm 

is highly irritating, but is tolerable for brief periods. Irritation is 

mild at 100 ppm, and minimal at 35 ppm (Schrenk et al. 1933). These 

values have been presented in Table l-l. 

Studies in guinea pigs provide similar findings, with 35 ppm 

producing mild nasal irritation within minutes, and higher 

concentrations producing proportionately greater and more rapid signs of 

irritation to nose and eyes (Schrenk et al. 1933). Histological 

examination of animals exposed to concentrations of 100 ppm or higher 

revealed marked congestion, edema and hemorrhage of the lung. Moderate 

congestion of brain, liver and kidneys was also noted in some animals, 

but this was judged to be secondary to the marked lung injury (Schrenk 

et al. 1933). Animals that survived the exposures recovered fully 

within 4 to 8 days, and had no histological signs of residual injury. 

Exposure of rats or guinea pigs to 69 ppm BCEE for 130 days did not 

result in significant changes in lung/body weight ratios, and did not 

lead to histological changes in lung (Dow Chemical 1958). 

Other Systemic Effects. As noted above, short-term exposure of 

guinea pigs to 100 ppm resulted in moderate congestion of brain, liver, 

and kidneys, but this was judged to be secondary to lung injury (Schrenk 

et al. 1933). Longer-term exposure (130 days) of rats and guinea pigs 

to 69 ppm of BCEE did not result in hematological effects or gross or 
15 

2. HEALTH EFFECTS 

histological signs of injury to liver, kidney, heart, spleen, adrenal or 

pancreas, but did result in a significant decrease in body weight gain 

in both rats and guinea pigs (Dow Chemical 1958). Based on this, an 

intermediate inhalation MRL of 0.02 ppm has been calculated, as 

described in the footnote on Table 2-l. This value is also presented in 

Table l-l. 

The highest NOAEL values and all reliable LOAEL values for systemic 

effects in each species and duration category are recorded in Table 2-l 

and plotted in Figure 2-l. 

2.2.1.3 Immunological Effects 

No studies were located regarding immunological effects in humans 

or animals following inhalation exposure to BCEE. 

2.2.1.4 Neurological Effects 

No studies were located regarding neurological effects of BCEE 

inhalation in humans. However, data from animal studies indicate that 

BCEE is a central nervous system depressant, Schrenk et al. (1933) 

observed that guinea pigs exposed to concentrations of 100 ppm or higher 

began to become lethargic and uncoordinated within several hours, and 

that unconsciousness and death could follow. No effects on behavior 

were noted in guinea pigs or rats exposed to 69 ppm for 130 days (Dow 

Chemical 1958), but no details were provided on how behavior was 

evaluated. 

The highest NOAEL values and all reliable LOAEL values for 

neurological effects in each species and duration category are recorded 

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

2.2.1.5 Developmental Effects 

No studies were located regarding the developmental effects in 

humans or animals following inhalation exposure to BCEE. 

2.2.1.6 Reproductive Effects 

No studies were located regarding reproductive effects in humans 

following inhalation exposure to BCEE. In animals, no gross or 

histological effects were observed in reproductive tissues of rats and 

guinea pigs exposed to 69 ppm of BCEE for 18 weeks (Dow Chemical 1958), 

but no tests of reproductive function or success were performed. 
16 

2. HEALTH EFFECTS 

2.2.1.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or 

animals following inhalation exposure to BCEE. 

2.2.1.8 Cancer 

Although no studies have been performed on the carcinogenic 

potential of BCEE following inhalation exposure, studies by the oral 

route (see Section 2.2.2.8, below) indicate that BCEE is carcinogenic in 

animals. Based on the oral data, EPA has calculated an inhalation unit 

risk of 3.3 x 10-4,( μg/m 3 )-1 (EPA 1988). Based on this, the 

concentrations of BCEE in air corresponding to estimated upper-bound 

excess lifetime cancer risk levels of 10-4, 10-5 and 10-6 are 0.05, 0.005 

and 0.0005 ppb, respectively. These values are shown in Figure 2-l. 

2.2.2 Oral Exposure 

No studies were located regarding health effects in humans 

following oral exposure to BCEE. Table 2-2 and Figure 2-2 summarize 

available toxicity data for oral exposure of animals to BCEE, and these 

data are discussed below. 

2.2.2.1 Death 

The acute oral LD50 for BCEE in rats is 75 mg/kg (Smyth and 

Carpenter 1948). This value has been converted to a corresponding 

concentration of 530 ppm in water for presentation in Table l-4. 

Similar acute oral LD50 values (105 to 136 mg/kg) were reported for 

mice, rabbits, and rats by Union Carbide (1948). Little information 

exists regarding lethality following chronic exposure. Decreased 

survival was reported in female rats dosed twice a week with 50 mg/kg 

for 18 months (Weisburger et al. 1981). The cause of the increased 

mortality was not determined. The dose of 50 mg/kg/day has been 

converted to an equivalent concentration of 360 ppm in water for 

presentation in Table l-4. 

The highest NOAEL values and all reliable LOAEL values for death in 

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

in Figure 2-2. 


19 

2. HEALTH EFFECTS 

2.2.2.2 Systemic Effects 

No studies were located regarding systemic effects in humans 

following oral exposure to BCEE. Weisburger et al. (1981) reported that 

oral exposure to doses of 25 or 50 mg/kg (twice a week for 78 weeks) 

resulted in decreased body weights in rats, but the magnitude of this 

effect was not described. The dose of 25 mg/kg/day has been converted 

to an equivalent concentration of 180 ppm in water for presentation in 

Table l-4. 

No studies were located on the following effects in humans or 

animals following oral exposure to BCEE: 

2.2.2.3 Immunological Effects 

2.2.2.4 Neurological Effects 

2.2.2.5 Developmental Effects 

2.2.2.6 Reproductive Effects 

2.2.2.7 Genotoxic Effects 

Jorgenson et al. (1978) dosed male mice for eight weeks with BCEE 

and observed no evidence of heritable reciprocal translocation of 

chromosomes. Since dose levels were not reported, the significance of 

these findings is difficult to judge. 

2.2.2.8 Cancer 

Innes et al. (1969) reported an increased incidence of hepatomas in 

two strains of mice exposed to an average dose of 41 mg/kg/day for 

80 weeks. The effect was most marked in the males, with liver tumors 

occurring in 53% and 88% of the exposed males of the two strains, 

compared with 10% and 6% in unexposed controls, respectively. A smaller 

effect (22% vs. 0%) was observed in females from one strain, but no 

effect was seen in females of the other strain. The authors of the 

study emphasized that although the tumors were described as hepatomas, 

the majority of tumors might have had malignant potential. No increased 

incidence of tumors was observed in male or female rats exposed twice a 

week to doses of 25 or 50 mg/kg (Weisburger et al. 1981). 

Based on the results of the study by Innes et al. (1969), and 

supported by positive mutagenicity studies (see below), EPA (1988) has 
20 

2. HEALTH EFFECTS 

ranked BCEE as a probable human carcinogen (Group B2). This category is 

for chemicals with adequate evidence of carcinogenicity in animals but 

inadequate evidence in humans. The slope of the linear portion of the 

cancer dose-response curve at low doses (the ql*) was calculated to be 

1.1 (mg/kg/day)-1. Based on this, daily intake of 9.1 x 10-7 mg/kg/day 

of BCEE for a lifetime corresponds to an excess cancer risk of no more 

than 1 x 10-6. If exposure occurred by ingestion of water, this would 

correspond to a concentration of 3 x 10-5 mg/L for a 70-kg adult 

consuming 2 L/day. If exposure occurred via food, this would correspond 

to a concentration of 3.2 x 10-5 ppm, assuming consumption of 0.028 kg 

of food per kg of body weight per day. 

2.2.3 Dermal Exposure 

Table 2-3 summarizes available quantitative animal data on the 

toxic effects of BCEE following dermal or ocular exposure. 

2.2.3.1 Death 

BCEE has moderate dermal toxicity, with an estimated LD50 in 

rabbits of 870 mg/kg (Union Carbide 1948). Smyth and Carpenter (1948) 

and Union Carbide (1948) estimated that the amount absorbed through the 

skin of guinea pigs leading to death in 50% of the animals was about 

370-390 mg/kg. 

2.2.3.2 Systemic Effects 

Direct Dermal and Ocular Irritation. Smyth and Carpenter (1948) 

found that 10 mg of BCEE applied to the skin of rabbits caused 

irritation, and Carpenter and Smyth (1946) reported that 25 mg of BCEE 

(0.02 mL of undiluted liquid) instilled in the eye of rabbits caused 

moderate irritation (a grade of 4 out of 10 was assigned). 

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 BCEE. 

No studies were located regarding the following effects in humans 

or animals following dermal exposure to BCEE: 

2.2.3.3 Immunological Effects 

2.2.3.4 Neurological Effects 

22 

2. HEALTH EFFECTS 

2.2.3.5 Developmental Effects 

2.2.3.6 Reproductive Effects 

2.2.3.7 Genotoxic Effects 

2.2.3.8 Cancer 

Van Duuren et al. (1972) performed a two-stage initiation-promotion 

test for tumor production in mouse skin, using a single dose of BCEE (as 

the initiator) followed by repeated doses of phorbol myristate acetate 

(as promotor) for two years. The frequency of skin papillomas in the 

BCEE-treated mice (3/20) was not significantly different from the 

control group (2/20). Tests were not performed to investigate whether 

BCEE had any promotor activity, or if it was carcinogenic if applied 

repeatedly itself. 

2.3 RELEVANCE TO PUBLIC HEALTH 

Death. Death in animals can occur from an exposure to high levels 

of BCEE by either inhalation (Carpenter et al. 1949; Schrenk et al. 

1933), ingestion (Smyth and Carpenter 1948), or dermal contact (Smyth 

and Carpenter 1948; Union Carbide 1948). However, only one instance of 

human death thought to be due to BCEE exposure has been reported (Elkins 

1959). This was in a textile factory where exposure was probably quite 

high. In the environment, exposure to acutely lethal concentrations of 

BCEE is believed to be very unlikely. 

Systemic Effects. The chief systemic health effect following 

inhalation exposure to BCEE is irritation to the respiratory tract 

(Schrenk et al. 1933). Because BCEE is so irritating, inhalation 

exposure conditions that are likely to cause significant injury to lung 

are easily detectable, and most people would presumably avoid such 

exposures. BCEE is similarly irritating to the skin following dermal 

contact (Smyth and Carpenter 1948), but no information was located on 

SystemicToxicity following dermal exposure. Oral exposure has been 

noted to result in decreased weight gain in animals (Weisburger et al. 

1981), but no information exists on toxicity to specific organ systems 

following oral exposure. 

Neurological Effects. Inhalation exposure to BCEE has been 

observed to cause central nervous system depression (lethargy, ataxia, 

sedation) in animals (Schrenk et al. 1933). Presumably this occurs by a 
23 

2. HEALTH EFFECTS 

nonspecific mechanism similar to other volatile halocarbon anesthetics, 

and such effects are likely to be reversible once exposure ceases. 

Other Noncarcinogenic Effects. Studies have not been performed to 

determine whether BCEE exposure leads to immunologic, reproductive, 

developmental, or genotoxic effects in animals or humans. In the 

absence of more information on the toxicity and metabolism of this 

compound, it is difficult to predict whether such effects are likely to 

be of concern in exposed humans or not. 

Cancer. The principal reason for concern with BCEE is its apparent 

carcinogenic potential. The most direct evidence indicating that BCEE 

is carcinogenic is the increased incidence of hepatomas in two strains 

of mice dosed orally for 80 weeks (Innes et al. 1969). This is 

supported by limited data indicating that BCEE is mutagenic in some 

bacterial test systems, although several studies have yielded negative 

results (Table 2-4). On the other hand, increased incidence of mouse 

liver hepatomas has been questioned as a reliable indication of true 

carcinogenic potential (Maronpot et al. 1987), and BCEE was not observed 

to cause a significant increase in tumors in a chronic feeding study in 

rats (Weisburger et al. 1981) or in parenteral exposure studies in mice 

(Theiss et al. 1977; Van Duuren et al. 1972) and rats (Norpoth et al. 

1986). Also, no binding of BCEE to DNA and no foci of ATPase-deficient 

cells (a sign of pre-neoplastic effects) were detected in liver of rats 

exposed to BCEE (Gwinner et al. 1983), and no evidence of heritable 

chromosome damage was detected in a preliminary study in mice (Jorgenson 

et al. 1978). Consequently, while the positive carcinogenicity findings 

in mice are adequate to conclude that BCEE may be a human carcinogen, 

the evidence on this point is limited. 

2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS 

No studies were located regarding levels of BCEE or its metabolites 

in human tissues or fluids. 

2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES 

AND/OR HEALTH EFFECTS 

No studies were located regarding the relationship between exposure 

levels in air, food or water and resulting fluid levels or health 

effects in humans. 

25 

2. HEALTH EFFECTS 

2.6 TOXICOKINETICS 

2.6.1 Absorption 

2.6.1.1 Inhalation Exposure 

Quantitative data on BCEE absorption across the lung are limited. 

Gwinner et al. (1983) reported that rats placed in a chamber containing 

BCEE vapor absorbed over 95% of the compound within 18 hours. This 

indicates that BCEE is well absorbed following inhalation exposure, but 

it is not possible to estimate the inhalation absorption fraction from 

this observation. 

2.6.1.2 Oral Exposure 

Lingg et al. (1982) reported that only 2% of a single oral dose of 

BCEE administered to rats was excreted in the feces, indicating that 

absorption across the gastrointestinal tract was essentially complete. 

2.6.1.3 Dermal Exposure 

No studies were located regarding the rate or the extent of 

absorption by the dermal route. However, acute dermal toxicity studies 

(Smyth and Carpenter 1948) suggest that BCEE is well absorbed across the 

skin. 

2.6.2 Distribution 

2.6.2.1 Inhalation Exposure 

No studies were located regarding the distribution of BCEE in human 

or animal tissues following inhalation exposure. 

2.6.2.2 Oral Exposure 

Lingg et al. (1982) administered a single oral dose of 14C-labelled 

BCEE to rats, and measured the radioactive content of tissues 48 hours 

later. Only a small fraction of the dose (2.3%) was found in organs and 

tissues, with 0.96% in muscle, 0.56% in kidney, 0.49% in blood, 0.19% in 

liver, and 0.1% in other tissues. These findings suggest that BCEE is 

not preferentially accumulated or retained in any one tissue or organ of 

the body. 
26

2. HEALTH EFFECTS

2.6.2.3 Dermal Exposure

No studies were located regarding the distribution of BCEE in human

or animal tissues following dermal exposure.

2.6.3 Metabolism

Studies in animals indicate that BCEE is extensively metabolized,

with thiodiglycolic acid (TDGA) being the principal endproduct (Lingg

et al. 1979; Norpoth et al. 1986). The pathway leading to TDGA

formation is not certain, but probably involves oxidative cleavage of

the ether bond to yield chloroacetaldehyde and 2-chloroethanol, as shown

in Figure 2-3 (Bolt 1984; Gwinner et al. 1983; Norpoth et al. 1986;

Lingg et al. 1979, 1982; Muller and Norpoth 1979). TDGA recovered in

urine usually accounts for 50% to 80% of a dose of BCEE (Lingg et al.

1979, 1982). Smaller amounts of BCEE (3% to 5%) are metabolized by

oxidation or substitution at a chlorine without ether cleavage (see

Figure 2-3), and about 12% is degraded to CO2 (Lingg et al. 1982). Only

about 2% of the dose is excreted via the lungs as unchanged BCEE (Lingg

et al. 1979).

Gwinner et al. (1983) exposed rats to 14C-labelled BCEE vapor, and

measured the amount of radioactivity irreversibly bound to tissue

proteins 24 hours later. Distribution of unbound parent or metabolites

was not measured. Highest levels were found in liver, kidney and small

intestine, with much lower levels in lung, spleen and muscle. The

presence of protein-bound label in these tissues suggested to the

authors that reactive intermediates were formed that led to covalent

adducts, but incorporation of label into protein might also have

occurred through normal synthetic pathways involving non-toxic breakdown

products from BCEE. No label was detectable in liver DNA or RNA.

2.6.4 Excretion

Lingg et al. (1979, 1982) found that approximately 80% of an oral

dose of BCEE administered to rats was excreted within 48 hours. Most of

the dose (65%) was excreted as urinary metabolites (mostly

thiodiglycolic acid), with smaller amounts excreted in feces (3%) or

expired air (11% as CO2 and less than 2% as parent BCEE). Only 2% of

the dose remained in the body. This indicates that BCEE is effectively

excreted, and that it has a low tendency to accumulate in tissues.

28 

2. HEALTH EFFECTS 

2.7 INTERACTIONS WITH OTHER CHEMICALS 

No information was located on the interaction of BCEE with other 

chemicals. 

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

No information was located to indicate that any human population 

might be especially susceptible to the toxic effects of BCEE. Based on 

the observation that BCEE is a powerful irritant of the respiratory 

tract, it may be expected that individuals with lung disease or other 

forms of respiratory distress might be particularly vulnerable to the 

effects of BCEE vapors. 

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 BCEE 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 BCEE 

As shown in Figure 2-4, there is very little information on the 

health effects of BCEE in humans. In animals, limited data exist on 

acute lethality and direct irritant effects, and there is some 

information on systemic effects following inhalation exposure. Several 

studies have investigated carcinogenicity following oral or dermal 

exposure, but carcinogenicity following inhalation exposure has not been 

examined. 

30

2. HEALTH EFFECTS

2.9.2 Data Needs

Single Dose Exposure. The effects of single exposures to BCEE have

not been thoroughly investigated. Estimates of acute inhalation

exposures that cause death in animals are available, but only one study

(Schrenk et al. 1933) provides dose-response data for more sensitive

endpoints of toxicity (lung irritation and edema). Further inhalation

studies using modern analytical and histological techniques would be

valuable in confirming and refining the limited data available on lung

injury, and in determining whether other tissues are injured as well.

Essentially no acute oral toxicity data exist except for one estimate of

the LD50 (Smyth and Carpenter 1948). For this reason, a thorough

investigation of the toxic effects following oral exposure in animals

would be useful.

Repeated Dose Exposure. Only limited data (Dow Chemical 1958) are

available on the effects of repeated inhalation exposure to BCEE. This

study employed only one exposure level (69 ppm), so thresholds were not

established for any adverse effects following repeated exposures. For

this reason, further studies using modern histological and biochemical

tests would be useful in determining the NOAEL and LOAEL values for

injury to lung and other tissues. Although several chronic oral studies

have been performed (Innes et al. 1969, Weisburger et al. 1981), very

little information has been obtained on noncarcinogenic endpoints.

Consequently, studies to determine thresholds for systemic injury

following oral exposure would be valuable. Since residents near

industrial sources or waste sites that discharge BCEE are probably most

likely to be exposed through drinking water, studies using BCEE in water

would be especially helpful.

Chronic Exposure and Carcinogenicity. Oral studies in mice are

adequate to establish that BCEE causes liver tumors in this species, but

there is debate over the relevance of this to other species, including

humans. For this reason further studies on the oral and inhalation

carcinogenicity of BCEE in several different species would be valuable.

Genotoxicity. Several studies have been performed on the

genotoxicity of BCEE, and the results have been mixed (e.g., see

Table 2-4). Further studies to clarify the mutagenic and genotoxic

potential of BCEE would be valuable, especially if information could be

gained on the role of metabolic activation and on the identity of

genotoxic intermediates.
31 

2. HEALTH EFFECTS 

Reproductive Toxicity. No studies were located on reproductive 

effects of BCEE. Single generation tests of reproductive toxicity 

following BCEE exposure (both oral and inhalation) would be valuable in 

determining whether this may be an effect of concern for humans. 

Developmental Toxicity. No studies were located on the 

developmental effects of BCEE. Studies of teratogenic and fetotoxic 

potential would be valuable. 

Immunotoxicity. No studies were located on the immunotoxicity of 

BCEE. Since the immune system is sometimes found to be sensitive to 

chemical agents, studies of the effects of BCEE on this system could be 

helpful. 

Neurotoxicity. Inhalation exposure to high doses of BCEE appears 

to cause CNS depression and sedation (Schrenk et al. 1933), but the 

dose-response curve for this effect is not well defined. Further 

studies to identify the threshold for CNS depression and other effects 

on behavior following both oral and inhalation exposure would be 

helpful. In addition, studies employing modern histological and 

electrophysiological techniques would be valuable in determining if 

cells of the CNS are structurally injured by exposure to BCEE. 

Epidemiological and Human Dosimetry Studies. No epidemiological 

studies were located in humans exposed to BCEE. Performance of such 

studies could be helpful in evaluating the chronic human health risk 

from BCEE exposure, especially cancer. 

Biomarkers of Disease. No biomarkers of BCEE-induced disease in 

humans are known. Since the principal effect associated. with inhalation 

exposure is nonspecific lung irritation, it may be difficult to develop 

preclinical indices of potential lung injury that are specific for BCEE. 

Bioavailability from Environmental Media. No studies were located 

on the relative bioavailability of BCEE in different environmental 

media. Based on the physical properties of BCEE, it would not be 

expected that bioavailability would vary widely between media, but 

studies to investigate this would be helpful in risk assessments 

involving exposure to BCEE in soil or food. 
32 

2. HEALTH EFFECTS 

Food Chain Bioaccumulation. No studies were located on food chain 

bioaccwnulation of BCEE. Based on the observation that BCEE metabolism 

is rapid and essentially complete in rats, accumulation of BCEE in the 

tissues of mammals does not appear likely. Studies on BCEE retention in 

several species besides rat would be helpful to confirm this, however. 

The studies on BCEE accumulation in fish and plants would also be 

valuable. 

Absorption, Distribution, Metabolism, and Excretion. Although 

there are limited toxicokinetic data on BCEE from studies of animals, 

there are several areas where additional information would be valuable. 

Since available information is derived from studies employing single 

exposures, studies of uptake, distribution and excretion patterns 

following repeated exposures would be useful. Quantitative studies of 

absorption rates across the lungs and the skin would be helpful is 

estimating absorbed doses and resultant health effects following 

inhalation and dermal exposure. Additional metabolism studies would be 

valuable in identifying intermediate metabolites which might be involved 

in the genotoxic or carcinogenic effects of BCEE. Finally, further 

studies of the kinetics of BCEE metabolism and clearance would be 

valuable in evaluating the potential for cumulative toxicity. 

Comparative Toxicokinetics. Toxicokinetic studies of BCEE 

metabolism and excretion have been performed in rats (Gwinner et al. 

1983; Lingg et al. 1979; Muller and Norpoth 1979; Norpoth et al. 1986). 

Consequently, studies of metabolism in other species would be valuable, 

especially in mice (since a carcinogenic response has been observed in 

mice but not in rats). In addition, studies of the pattern of BCEE 

degradation products in human urine would be helpful in evaluating 

whether BCEE is metabolized in humans as it is in rats. 

2.9.3 Ongoing Studies 

No information was located on any ongoing studies on the health 

effects or toxicokinetics of BCEE in humans or animals. 
33 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY 

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

identification information for BCEE. 

3.2 PHYSICAL AND CHEMICAL PROPERTIES 

Table 3-2 lists important physical and chemical properties of BCEE. 



37 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.1 PRODUCTION 

All BCEE produced in the United States is made by direct 

chlorination of ethylene glycol (Buckman Laboratories 1988). BCEE can 

also be produced by the treatment of ethylene chlorohydrin or 

2-chloroethanol with sulfuric acid, or by chlorination of ethylene 

chlorohydrin at 80°C. Production of BCEE in the United States in 1986 

was estimated to be 1,200 kkg (Buckman Laboratories 1988). 

4.2 IMPORT 

Imports of BCEE in 1977 were estimated to be about 590 kkg (HSDB 

1988). Imports of BCEE in 1986 were estimated to be about 60 kkg 

(Buckman Laboratories 1988). 

4.3 USE 

In the past, BCEE has been used as a solvent for fats, waxes, 

greases and esters (Schrenk et al. 1933). It has also been used as a 

constituent of paints and varnishes, as a cleaning fluid for textiles, 

in the purification of oils and gasoline, in the manufacture of 

medicines and pharmaceuticals, as an intermediate in the synthesis of 

other chemicals, and as an insecticide and a soil fumigant (Browning 

1965; Hake and Rowe 1963; HSDB 1988; Verschueren 1977; Windholz 1983). 

BCEE is currently used primarily as a chemical intermediate for the 

manufacture of pesticides. The two major pesticide products made from 

BCEE are WSCP, an isoprene polymer used primarily as an algicide, and 

CDQ, a diquaternary ammonium compound used as a microbicide and 

corrosion inhibitor in the petroleum industry. A small amount of BCEE 

(about 1%) is still used as a solvent. 

4.4 DISPOSAL 

No information was located on the amounts of BCEE disposed of to 

the environment or to waste sites. Because BCEE is classified as a 

hazardous waste under the Resource Conservation and Recovery Act (RCRA), 

all BCEE waste must be disposed of in an authorized RCRA facility. 

Permitted disposal methods include incineration and land disposal, 

although EPA is currently considering possible restrictions on land disposal 

methods (40 CFR 268.11). 
38 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

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 BCEE 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. 

4.5.1 Data Needs 

Production, Import, Use, and Disposal. Data are available on the 

production, import and general use patterns, but more complete 

information on present disposal volumes and methods would be valuable in 

estimating the likelihood and possible magnitude of further 

environmental contamination with BCEE. 

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. 
39 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW 

Relatively little information is available on human exposure to 

BCEE. In the workplace, the most likely exposure routes are inhalation 

or dermal contact. For the general public, the most likely route is 

ingestion of BCEE in drinking water. Low levels of BCEE have been 

detected in some drinking water systems, and BCEE has been detected in 

groundwater at about 2% of the waste sites being investigated under 

Superfund. The most likely means of exposure near these sites is 

consumption of contaminated water, but dermal contact and inhalation 

exposure might also occur. 

5.2 RELEASES TO THE ENVIRONMENT 

No studies were located regarding the amount of BCEE being released 

from industrial processes or waste sites into air, water or soil. 

5.3 ENVIRONMENTAL FATE 

5.3.1 Transport and Partitioning 

Little information was located on the transport or partitioning of 

BCEE in the environment. The vapor pressure of BCEE at 20°C is 

0.7 mm Hg (Verschueren 1977), suggesting that volatilization from soil 

or water, while probably very slow, could be significant (Callahan 

et al. 1979). EPA (1987a) calculated a half-time for volatilization of 

BCEE from a river to be 3.4 days. Because BCEE is quite soluble in 

water (10,200 mg/L) (Verschueren 1977), it is expected that BCEE in air 

would tend to be removed by wet deposition, resulting in a cycle between 

water, soil and air (Callahan et al. 1979). The relative distribution 

between these phases, however, is not known. 

Because BCEE has good solubility in water and a relatively low log 

octanol-water partition coefficient (measured to be 1.1 by Veith et al. 

1980), BCEE in aqueous media is not expected to adsorb strongly to 

sediments, nor is it likely to be bioaccumulated by aquatic organisms 

(Callahan et al. 1979). Consistent with this, a bioconcentration factor 

of 11 has been measured in sunfish by Veith et al. (1980). 
40

5. POTENTIAL FOR HUMAN EXPOSURE

For the same reasons, BGEE is not expected to adsorb strongly to

soils, and would be expected to migrate in soil water. Consistent with

this, Wilson et al. (1981) reported a soil retardation factor of <1.5

for sandy soil with low organic content, while other contaminants (e.g.,

di- and trichlorobenzene) had retardation factors of 3.4 to 9.4.

5.3.2 Transformation and Degradation

5.3.2.1 Air

Callahan et al. (1979) reviewed the potential fate of BCEE in the

environment and suggested that BCEE in a smog-like atmosphere would

probably undergo photooxidative destruction with a half-life of

approximately four hours. The rate of atmospheric photooxidation under

other conditions was not estimated. Direct photolysis was judged to be

an unimportant process, since BCEE does not absorb visible or near ultraviolet

light (Callahan et al. 1979).

5.3.2.2 Water

Most ethers are very resistant to hydrolysis, and the rate of

cleavage of the carbon-oxygen bond by abiotic processes is expected to

be insignificant (Callahan et al. 1979). The carbon-chlorine bond is

also quite stable to abiotic cleavage. Based on a measured hydrolysis

rate constant of 1.5x10-5min –1 at l00oC, Mabey et al. (1982) estimated

the half-life of the carbon-chlorine bond to be about 22 years at 20°C.

This rate is somewhat slower than observed for simple alkyl halides

(Callahan et al. 1979; Mabey et al. 1982), an effect which Mabey et al.

(1982) attributed to the effect of the chloro-ethoxy group on the

adjacent carbon.

Biodegradation may be an important fate process for BCEE in water.

In laboratory studies, Tabak et al. (1981) found that in aqueous media

inoculated with sewage, BCEE underwent 100% transformation within seven

days, and there was a rapid adaptation of the degradative

microorganisms. Similar results were reported by Ludzack and Ettinger

(1963), although in this case there was a 25 day lag before adaption

occurred, and 30 more days were required to convert 80% of the BCEE to

CO2. A second dose of BCEE added to the adapted medium was 80% oxidized

in 15 days. Monsen (1986) reported that BCEE also underwent significant

biodegradation (68%) in an anaerobic laboratory test pond designed to

simulate an industrial primary lagoon. Losses via evaporation and

sorption were minimal. In contrast to these findings, Dojlido (1979)

did not observe significant biodegradation of BCEE in several laboratory
41 

5. POTENTIAL FOR HUMAN EXPOSURE 

test systems. The reason for this discrepancy is not certain, but may 

be due to insufficient incubation time (two weeks) for the adaptation to 

occur. Biodegradation in surface waters would likely be slower than 

observed in the laboratory, but could lead to significant destruction of 

BCEE. 

5.3.2.3 Soil 

Wilson et al. (1981) observed no significant transformation of BCEE 

percolated through soil for 45 days, but Kincannon and Lin (1986) found 

that BCEE was significantly degraded in a 97-day laboratory soil column 

study. The initial rate constant for degradation was reported to be 

0.042 day-1 (half-time of 16.7 days). After 48 days, the rate increased 

to 0.086 day-1 (half-time of 8.0 days), suggesting that there was an 

acclimation of soil microbes occurring. 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

5.4.1 Air 

No studies were located with regard to concentrations of BCEE in 

ambient air. Based on the physical-chemical properties of BCEE, some 

release of BCEE into air from contaminated chemical waste sites or 

industrial settings is expected, but no quantitative data were located. 

5.4.2 Water 

In 1977, the EPA carried out an extensive study (the National 

Organics Monitoring Survey) of organic contaminants in finished drinking 

water supplies across the United States. BCEE was not detected in any 

samples in Phase I of the study, but the detection limit was only 

5 μg/L. In phase II, the detection limit was lowered to 0.005 μg/L, and 

BCEE was detected in water from 13 of 113 cities sampled. The values 

ranged from 0.01 to 0.36 μg/L, with a mean concentration (for the 13 

positive samples) of 0.1 μg/L (Dressman et al. 1977). In phase III of 

the Survey, BCEE was detected in drinking water from 8 of 110 cities, 

with a mean concentration of 0.024 μg/L. Trace quantities of BCEE have 

been reported in several rivers, including the Mississippi, the Delaware 

and the Kanawha (Staples et al. 1985; EPA 1987a). BCEE was detected in 

ground water at about 2% of waste disposal sites being investigated 

under Superfund, at a geometric mean concentration of around 840 μg/L 

(CLPSD 1988). 
42 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.4.3 Soil 

BCEE was detected in soil at only 0.4% of waste sites monitored 

under Superfund, at geometric mean concentration of 140 ppb (CLPSD 

1988). 

5.4.4 Other Media 

No studies were located regarding the occurrence of BCEE in food or 

other media. 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The primary known source of exposure for the general population is 

via the water supply. The reports of quantities in several drinking 

water supplies provided a mean value of approximately 0.1 ppb. 

Ingestion of approximately 2 liters of water per day by an adult would 

provide a daily intake of 0.003 μg/kg/day of BCEE. Based on the slope 

factor of 1.1 (mg/kg/day)-1 (see Section 2.2.2.8), this corresponds to 

an upperbound lifetime cancer risk from this source of about 3 x 10-6. 

No studies were located regarding exposure of workers to BCEE. 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Even though there are no exposure data, those at greatest risk of 

exposure to BCEE are probably workers who are exposed to BCEE while on 

the job. Residents who live near waste sites or industrial facilities 

that permit escape of BCEE may also experience higher than average 

exposure to BCEE. Exposure would be most likely by ingestion of 

contaminated water, but inhalation exposure might also occur. The level 

and significance of such exposures can only be evaluated on a site-by site 

basis. 

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 BCEE 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 
43 

5. POTENTIAL FOR HUMAN EXPOSURE 

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 of BCEE have been determined (Table 3-l), and further 

research on these properties does not appear to be essential. 

Environmental Fate. Although there is information which provides a 

general prediction of the likely fate and transport of BCEE in the 

environment, quantitative data are not available for most fate 

processes. Reliable quantitative data on rates of volatilization from 

water and soil, atmospheric oxidation, hydrolysis in water, and 

biodegradation in soil and water would be useful in estimating likely 

concentrations of BCEE in air, soil and water around waste sites and 

other possible sources of BCEE emissions. 

Exposure Levels in Environmental Media. Available data suggest 

that contamination of water may occur around chemical waste sites or 

industrial facilities where BCEE is present. For this reason, 

additional monitoring data on BCEE concentrations in water (both surface 

water and ground water) around such sites would be valuable. Monitoring 

of BCEE levels in air, soil, fish, and possibly other foods would be 

helpful in estimating the significance of exposures through these media. 

Exposure Levels in Humans. Information on exposure of the general 

population to BCEE is limited. The compound has been reported in 

drinking water in some locations, but many water supplies have not been 

tested. It would appear that an increased monitoring of drinking water 

supplies for this compound would be beneficial. Similarly, data on 

typical occupational exposure levels and durations would be valuable in 

estimating doses to workers, and data on exposure levels around chemical 

waste sites would be valuable in determining whether nearby residents 

are likely to be subject to significant health risk. 
44 

5. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Registries. No registry exists for humans known to have 

been exposed to BCEE. Creation of such a registry would be valuable in 

collection of further information on the health effects of BCEE on 

humans, especially chronic effects (such as cancer) that do not become 

manifest at the time of exposure. 

5.7.2 On-going Studies 

No information was located regarding on-going studies on the 

environmental fate of BCEE, or on BCEE levels in the ambient 

environment. Remedial investigations being performed under Superfund at 

chemical waste sites will provide additional data on the occurrence of 

BCEE in water, soil and possibly in air at these locations, and on the 

levels of human exposure that result. 
45 

6. ANALYTICAL METHODS 

6.1 BIOLOGICAL MATERIALS 

No methods were located that are routinely used for the detection 

of BCEE in biological materials. Norpoth et al. (1986) reported a 

method for measuring thiodiglycolic acid (the principal animal 

metabolite of BCEE) in the urine of rats. This method employed an ion 

exchange isolation of TDGA followed by gas chromatographic analysis 

using a flame ionization detector. Sensitivity was not reported, but 

the method was able to detect a two-fold increase in thiodiglycolic acid 

(TDGA) excretion (from 0.37 to 0.72 μmo1/24 hours) resulting from an 8- 

hour exposure to 10 ppm BCEE. 

6.2 ENVIRONMENTAL SAMPLES 

BCEE in environmental samples is most commonly determined by gas 

chromatography with a halogen-specific detector (GC/HSD) (Dressman 

et al. 1977; EPA 1982a), gas chromatography/mass spectrometry (GC/MS) 

(EPA 1986a), or capillary column gas chromatography/Fourier transform 

infrared (GC/FT-IR) spectrometry (EPA 1986c). 

The determination of BCEE in air requires passing the air samples 

through a sorbent, followed by elution of adsorbed BCEE from the sorbent 

and gas chromatographic measurement. Coconut shell charcoal is the 

favored sorbent, carbon disulfide is used for elution, and gas 

chromatography is employed for analysis (NIOSH 1984). 

The EPA has developed a method of analysis specifically for 

haloethers in water (EPA 1982a). These compounds include bis(2- 

chloroethyl), bis(2-chloroisopropyl), 4-chlorophenol phenyl, and 4- 

bromophenol phenyl ethers, and bis(2-chloroethoxy) methane. The 

analysis involves an extraction into dichloromethane solvent, 

concentration by evaporation with exchange to hexane, and Florisil 

cleanup prior to gas chromatographic measurement. Other standard EPA 

methods are adapted to the determination of BCEE in wastes. 

If BCEE is identified in a sample by a GC procedure other than 

GC-MS, it is important to confirm the identification by a second method. 

For example, in a survey of water samples from 113 cities, 44 samples 

were tentatively found to contain BCEE. Reanalysis of these samples 

(either by using a different GC column, or by separating interfering 

components with Florisil prior to GC analysis) indicated that only 13 of 

the 44 tentatively-identified samples actually contained BCEE (Dressman 

et al. 1977). Thus, false positive results are likely if confirmatory 

tests are not performed. 
46 

6. ANALYTICAL METHODS 

Methods for the determination of BCEE in environmental samples are 

summarized in Table 6-l. 

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 BCEE 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. Since there are no standard methods for analysis 

of BCEE in biological materials, development of such methods would be 

useful. The properties of this compound suggest that it should be 

amenable to determination in biological samples. It is a relatively 

high-boiling liquid (178°C) with a low log octanol/water partition 

coefficient, extractable from water into dichloromethane, relatively 

stable to hydrolysis, and easily measured by gas chromatography. The 

high boiling temperature suggests that purge-and-trap and headspace 

techniques may not be readily applicable to the determination of BCEE in 

biological samples, but techniques based upon solvent extraction should 

work well. 

Norpoth et al. (1986) reported a method for measuring TDGA in 

urine. Although this is the principal animal metabolite of BCEE, it 

occurs naturally in the urine of control animals and is also formed by 

metabolism of other chemicals. For these reasons, it would be helpful 

to develop methods for the detection and quantification of urinary 

metabolites that are unique to BCEE, such as N-acetyl-S-[2- 

(chloroethoxy)ethyl] cysteine or 2-chloroethoxyacetic acid. 

48 

6. ANALYTICAL METHODS 

Methods for Biomarkers of Exposure. No routine tests for 

biomarkers of exposure to BCEE were located. Using radioactively labeled 

BCEE, Gwinner et al. (1983) reported incorporation of label into 

cellular proteins of animals exposed to BCEE. Studies to determine if 

this is due to protein adduct formation would be valuable. If so, 

immunological assays might be developed to detect such adducts formed 

from reaction of unlabeled BCEE with proteins such as albumin or 

hemoglobin. Gwinner et al. (1983) did not detect label in DNA or RNA 

from animals exposed to BCEE, suggesting that adduct formation with 

these macromolecules might not be a sensitive biomarker of exposure. 

Methods for Determining Parent Compounds and Degradation Products 

in Environmental Media. Although methods exist for the determination of 

BCEE in environmental samples, detection limits (see Table 6-l) are not 

adequate to measure BCEE in water or air at the concentrations estimated 

to correspond to the l0-6 risk level for cancer (0.03 ppb in water, 

0.003 μg/m3 in air). Consequently, improvements in sensitivity would be 

helpful. The problem of high humidity interfering with the collection 

of BCEE from air (lowered breakthrough volume) should also be addressed. 

6.3.2 Ongoing Studies 

Supercritical fluid extraction/chromatography and immunoassay are 

two areas of intense current activity from which substantial advances in 

the determination of BCEE and metabolites in biological samples can be 

anticipated. The two techniques are complementary in that supercritical 

fluid extraction is especially promising for the removal of analytes 

from sample material (Hawthorne 1988) while immunoassay is very 

selective and sensitive (Vanderlaan et al. 1988). 

An especially promising approach to the determination of BCEE in 

biological samples is supercritical fluid extraction coupled with 

supercritical fluid chromatography. This combination has been described 

for the determination of sulfonylurea herbicides and their metabolites 

in complex matrices, including soil, plant materials, and cell culture 

medium (McNally and Wheeler 1988). The approach described in this work 

should be applicable to BCEE. 
49 

6. ANALYTICAL METHODS 

Thermospray techniques interfaced with mass spectrometry, with or 

without high performance liquid chromatographic separation, are proving 

useful for the determination of thermally labile compounds (as are some 

toxicant metabolites), and should be applicable to the determination of 

BCEE and its metabolites in biological materials (Korfmacher et al. 

1987; Betowski et al. 1987). 

The EPA is funding an ongoing effort to develop a master analytical 

scheme for organic compounds in water (Michael et al. 1988). The 

overall goal is the development of a technology capable of detecting and 

quantifying organic compounds at 0.1 μg/L in drinking water, 1 μg/L in 

surface waters, and 10 μg/L in effluent waters. Analytes are to include 

numerous semivolatile compounds and some compounds that are only semisoluble 

in water, as well as volatile compounds. A comprehensive review 

of the literature leading to these efforts has been published 

(Pellizzari et al. 1985). It may be anticipated that improved methods 

for the determination of BCEE in environmental samples will be developed 

as part of this effort. 

The current high level of activity in supercritical fluid 

extraction of solid and semisolid samples should yield improved 

recoveries and sensitivities for the determination of BCEE in solid 

wastes, and the compound should be amenable to supercritical fluid 

chromatographic analysis. Immunoassay analysis (Vanderlaan et al. 1988) 

is an area of intense current activity from which substantial advances 

in the determination of BCEE in environmental samples can be 

anticipated. 

51 

7. REGULATlONS AND ADVISORIES 

Because of its potential to cause adverse health effects in exposed 

people, a number of regulations and advisory values have been 

established for BCEE by various international, national and state 

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



55 

8. REFERENCES 

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biological exposure indices. 5th ed. Cincinnati, OH: American 

Conference of Governmental Industrial Hygienists, Inc. 

* Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: odor 

thresholds compare with threshold limit values and volatilities for 214 

industrial chemicals in air and water dilution. J Applied Toxicol 

3:272-290. 

AOAC. 1984. Fumigant residues. Volatile fumigants in grain. Gas 

chromatographic method. Section 29.071. Official methods of analysis 

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VA: Association of Official Analytical Chemists Inc. pp. 547-548. 

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

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ntegrated risk information system supportive documentation. 

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

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Bell A, Jones AT. 1958. Fumigation with dichloroethyl ether and 

chlordane: hysterical sequelae. Med J Australia 2:258-263. 

* Berck B. 1965. Determination of fumigant gases by gas chromatography. 

J Agric Food Chem 13:373-377. 

Berg GL, ed. 1981. Farm chemicals handbook. Willoughby, OH: Meister 

Publishing Company. C-109. 

* Betowski LD, Pyle SM, Ballard JM, et al. 1987. Thermospray LC/MS/MS/ 

analysis of wastewater for disperse azo dyes. Biomedical and 

Environmental Mass Spectrometry. 14:343-354. 

* Bolt HM. 1984. Metabolism of genotoxic agents: halogenated compounds. 

In: Monitoring human exposure to carcinogenic and mutagenic agents. 

Proceedings of a Joint Symposium, Espoo, Finland, December 1983. IARC 

Scientific Publication 59. 

* Browning E. 1965. Toxicity and metabolism of industrial solvents. New 

York: Elsevier 513. 

_______________ 

* = Cited in text.
56 

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65 

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. 

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. 
66 

9. GLOSSARY 

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(LO) (LCLO) -- The lowest concentration of a 

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

or animals. 

Lethal Concentration(50) (LC50) -- 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(LO) (LDLO) -- The lowest dose of a chemical introduced by a 

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

humans or animals. 

Lethal Dose(50) (LD50) -- The dose of a chemical which has been 

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

population. 
67

9. GLOSSARY

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.

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).
68 

9. GLOSSARY 

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. 

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. 
69 

9. GLOSSARY 

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 (UP) -- 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. 

71 

APPENDIX: PEER REVIEW 

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

the following members: Dr. Mohammad G. Mustafa, Professor, UCLA School 

of Public Health; Dr. Charles Baxter, Associate Professor of 

Environmental Health, University of Cincinnati Medical Center; 

Dr. Martin Alexander, Professor, Department of Agronomy, Cornell 

University. Unpublished studies were also peer reviewed by Dr. Nancy 

Tooney, Associate Professor of Biochemistry, Polytechnic University, 

Brooklyn, NY. These experts collectively have knowledge of BCEE'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: 1991-535-152