TOXICOLOGICAL PROFILE FOR 

2,3-BENZOFURAN 

Agency for Toxic Substances and Disease Registry

U.S. Public Health Service 

September 1992 
ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and

does not imply endorsement by the Agency for Toxic Substances and Disease

Registry. 










 

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1. PUBLIC HEALTH STATEMENT
 

This Statement was prepared to give you information about 2,3-benzofuran

and to emphasize the human health effects that may result from exposure to it.

The Environmental Protection Agency (EPA) has identified 1,177 sites on its

National Priorities List (NPL). 2,3-Benzofuran has been found in at least 5

of these sites. However, we do not know how many of the 1,177 NPL sites have

been evaluated for 2,3-benzofuran. As EPA evaluates more sites, the number of 

sites at which 2,3-benzofuran is found may change. This information is

important for you to know because 2,3-benzofuran may cause harmful health

effects and because these sites are potential or actual sources of human

exposure to 2,3-benzofuran. 

When a chemical is released from a large area, such as an industrial

plant, or from a container, such as a drum or bottle, it enters the

environment as a chemical emission. This emission, which is also called a 

release, does not always lead to exposure. You can be exposed to a chemical

only when you come into contact with the chemical. You may be exposed to it

in the environment by breathing, eating, or drinking substances containing the

chemical or from skin contact with it. 

If you are exposed to a hazardous chemical such as 2,3-benzofuran,

several factors will determine whether harmful health effects will occur and 

what the type and severity of those health effects will be. These factors

include the dose (how much), the duration (how long), the route or pathway by

which you are exposed (breathing, eating, drinking, or skin contact), the

other chemicals to which you are exposed, and your individual characteristics

such as age, sex, nutritional status, family traits, life style, and state of

health. 

1.1 WHAT IS 2,3-BENZOFURAN? 

2,3-Benzofuran is a colorless, sweet-smelling, oily liquid which does

not mix with water. 2,3-Benzofuran is made by processing coal into coal oil.

2,3-Benzofuran may also be formed during other uses of coal or oil. The part

of the coal oil that contains 2,3-benzofuran is made into a plastic called

coumarone-indene resin. Coumarone-indene resin can then be used to make 

paint, varnish, glue, and floor tiles, and it is allowed on food products and

packages. We know very little about how 2,3-benzofuran might get into the

environment or what happens to it after it gets there. 

More information on the properties and uses of 2,3-benzofuran and how it

behaves in the environment may be found in Chapters 3, 4, and 5. 

1.2 HOW MIGHT I BE EXPOSED TO 2,3-Benzofuran? 

2,3-Benzofuran has been found in a few places in the air and water. In

most instances, when it was found; the amount that was there was not measured. 

We do not know what the levels of 2,3-benzofuran are in soil, air, water, or 

food. The reason that 2,3-benzofuran has not often been found could be that 

2,3-benzofuran usually attaches to particles, and is not free in the air or

water. We do not know where 2,3-benzofuran comes from, except when it is 
 

 

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1. PUBLIC HEALTH STATEMENT
 

found near fuel-processing factories. Workers who make coal oil or coumaroneindene resin might be exposed to 2,3-benzofuran. Cigarette smoke has some

2,3-benzofuran in it. Coumarone-indene resin is allowed in food packages and

as a coating on oranges and grapefruit. .We do not know how often the resin is

used or whether any 2,3-benzofuran in it gets into the food. 

More information on how you might be exposed to 2,3-benzofuran is given

in Chapter 5. 

1.3 HOW CAN 2,3-BENZOFURAN ENTER AND LEAVE MY BODY? 

We know very little about how 2,3-benzofuran can enter or leave your

body. Some 2,3-benzofuran can enter your body from the environment if it is

in the water that you drink, the food that you eat, or the air that you

breathe. We do not know how much you would take in or when and how it would

leave your body. 

More information on how 2,3-benzofuran enters and leaves the body is

given in Chapter 2. 

1.4 HOW CAN 2,3-BENZOFURAN AFFECT MY HEALTH? 

The effect of 2,3-benzofuran on your health depends on how much you take

into your body. In general, the more you take in, the greater the chances

that an effect will occur. No studies have been done to test the effects of 

2,3-benzofuran on the health of humans. Studies in animals show that 

2,3-benzofuran can damage the liver and kidneys if large amounts are given

within a short time, and that very large amounts can kill. We do not know

whether exposure to 2,3-benzofuran can affect your ability to have children or

can harm an unborn baby. 

Studies in animals show that exposure to 2,3-benzofuran at moderate

levels over a long time can damage the liver, kidneys, lungs, and stomach.

The brain, muscles, and heart do not seem to be seriously damaged by long-term

exposure. Some rats and mice that received 2,3-benzofuran for their whole

lives developed cancer of the kidney, lung, liver, or stomach. However, no

cases of cancer in humans have been linked to exposure to 2,3-benzofuran.

More information on the health effects of 2,3-benzofuran in humans and 

animals can be found in Chapter 2. 

1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 2,3-

BENZOFURAN? 

2,3-Benzofuran can be measured in your blood or in your milk if you are

a nursing mother. The test is specific for 2,3-benzofuran but it requires

special equipment and is not easily available. The test may only be able to

detect 2,3-benzofuran for a certain period of time because it is not known how

long 2,3-benzofuran remains in the body after you have been exposed to it. 
 

3
 

1. PUBLIC HEALTH STATEMENT
 

Also, the test only shows that you have been exposed; it cannot predict which

health effects, if any, you will develop. 

More information on how 2,3-benzofuran can be measured in exposed humans is

given in Chapters 2 and 6. 

1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN 

HEALTH? 

No standards have been set for exposure to 2,3-benzofuran. The Food and

Drug Administration specifies the quantity of coumarone-indene resin that may

be used on food and in food packages. 

More information on government regulations for 2,3-benzofuran can be

found in Chapter 7. 

1.7 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns not covered here, 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 

This agency can also provide you with information on the location of the

nearest occupational and environmental health clinic. Such clinics specialize

in recognizing, evaluating, and treating illnesses that result from exposure

to hazardous substances. 

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2. HEALTH EFFECTS
 

2.1 INTRODUCTION
 

The primary purpose of this chapter is to provide public health

officials, physicians, toxicologists, and other interested individuals and

groups with an overall perspective of the toxicology of 2,3-benzofuran and a

depiction of significant exposure levels associated with various adverse

health effects. It contains descriptions and evaluations of studies and

presents levels of significant exposure for 2,3-benzofuran based on

toxicological studies and epidemiological investigations. 

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 information in this section is

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 (less than 15 days), intermediate

(15-364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration 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. They should also help to determine whether or not the effects vary

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 in the tables and figures

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

concerned with the interpretation of clinical findings in exposed persons may

be interested in levels of exposure associated with "serious" effects. Public 

health officials and project managers concerned with appropriate actions to

take at hazardous waste 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) may be of

interest to health professionals and citizens alike. 

Levels of exposure associated with the carcinogenic effects of

2,3-benzofuran are indicated in Figure 2-l. Cancer effects could occur at

lower exposure levels, but excess risks have not been estimated. 

Estimates of exposure levels posing minimal risk to humans (MRLs) have

been made, where data were believed reliable, for the most sensitive noncancer 

effect for each exposure duration. MRLs include adjustments to reflect human

variability from laboratory animal data to humans. 
6 

2. HEALTH EFFECTS 

Although methods have been established to derive these levels (Barnes

et al. 1988; EPA 1989), uncertainties are associated with these techniques.

Furthermore, ATSDR acknowledges additional uncertainties inherent in the

application of the procedures to derive less than lifetime MRLs. As an

example, acute inhalation MRLs may not be protective for health effects that

are delayed in development or are acquired following repeated acute insults,

such as hypersensitivity reactions, asthma, or chronic bronchitis. As these

kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

2.2.1 Inhalation Exposure 

No studies were located regarding the following health effects in humans

or animals after inhalation exposure to 2,3-benzofuran: 

2.2.1.1 Death 

2.2.1.2 Systemic Effects

2.2.1.3 Immunological Effects

2.2.1.4 Neurological Effects

2.2.1.5 Developmental Effects

2.2.1.6 Reproductive Effects

2.2.1.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or animals

after inhalation exposure to 2,3-benzofuran. Other genotoxicity studies are

discussed in Section 2.4. 

2.2.1.8 Cancer 

No studies were located regarding carcinogenic effects in humans or

animals after inhalation exposure to 2,3-benzofuran. 

2.2.2 Oral Exposure 

No studies were located regarding health effects in humans after oral

exposure to 2,3-benzofuran. 

Most information about the health effects of 2,3-benzofuran comes from 

studies of animals (rats and mice) exposed by gavage, particularly a study by

the National Toxicology Program (NTP 1989). Table 2-l and Figure 2-1 present

a summary of studies that provide reliable quantitative data on the toxicity

of 2,3-benzofuran following oral exposure. The main conclusions from these

studies are discussed below. 







14
 

2. HEALTH EFFECTS
 

2.2.2.1 Death 

No studies were located regarding death in humans after oral exposure to

2,3-benzofuran. Oral exposure to 2,3-benzofuran can be lethal to animals.

One female rat given a dose of 500 mg/kg/day died after 4 days, although 4

other female rats and all 5 male rats given this dose survived for 14 days

(NTP 1989). All 10 rats given an oral dose of 1,000 mg/kg/day died within

3 days (NTP 1989). The cause of death was not determined for the rats that

died following acute exposure to 2,3-benzofuran (NTP 1989). Some deaths were

observed among male and female mice in groups orally exposed for 14 days to

doses of 2,3-benzofuran ranging from 31.25 to 250 mg/kg/day (NTP 1989).

However, all mice dying early showed evidence of gavage error (oily fluid in

the pleural cavity), and the pattern of deaths showed no dose-response

relationship (NTP 1989), so that no deaths among mice were attributable to

chemical exposure. 

Some mortality was seen among animals orally exposed to 2,3-benzofuran

for 13 weeks, although the pattern of mortality was somewhat inconsistent.

Among rats, l female out of 10 given 250 mg/kg/day died in week 1, 1 female

out of 10 given 500 mg/kg/day died in week 5, and no male rats died (NTP

1989). The cause of death was not determined for the rats that died following

intermediate-duration exposure to 2,3-benzofuran (NTP 1989). A NOAEL of

125 mg/kg/day and a LOAEL of 250 mg/kg/day is identified for death in rats by

this study. Among mice exposed for 13 weeks, discounting deaths attributable

to gavage error, 1 out of 10 males given 62.5 mg/kg/day died in week 13, no

animals given 125 mg/kg/day died, 1 out of 10 males given 250 mg/kg/day died

in week 12, and 4/7 males and 2/9 females given 500 mg/kg/day died in weeks 1

and 3 (NTP 1989). The cause of death was not determined for the mice that

died following intermediate-duration exposure to 2,3-benzofuran (NTP 1989).

The dose response relationship in this study was inconsistent, but the weight

of evidence is compatible with a NOAEL of 125 mg/kg/day and a LOAEL of

250 mg/kg/day for death in mice. 

Chronic exposure of male rats to 2,3-benzofuran caused a statisticallysignificant decrease in survival at doses of 30 and 60 mg/kg/day, attributed

to increased severity of kidney damage (NTP 1989). The survival of female

rats exposed to 60 and 120 mg/kg/day for 103 weeks was not significantly

different from controls (NTP 1989). Female mice exposed to 120 and

240 mg/kg/day had a statistically-significant reduction in survival after

96 weeks, while the survival of male mice exposed to 60 and 120 mg/kg/day for

103 weeks was not different from controls (NTP 1989). When the dose of

2,3-benzofuran was inadvertently increased from 60 to 240 mg/kg/day for male

mice in weeks 20-21, 10 out of 50 animals died (NTP 1989). No cause of death

was reported for those male mice nor was a cause of decreased survival

reported for female mice (NTP 1989). No NOAEL for mortality following

chronic-duration exposure to 2,3-benzofuran is identified by this study. 

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. 
15
 

2. HEALTH EFFECTS 

2.2.2.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular,

gastrointestinal, hematological, musculoskeletal, hepatic, renal, or

dermal/ocular effects in humans after oral exposure to 2,3-benzofuran. 

The systemic effects observed in animals after oral exposure to

2,3-benzofuran are discussed below. 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 2-1. 

Respiratory Effects. Rats exposed to oral doses of 500 and

1,000 mg/kg/day of 2,3-benzofuran for up to 14 days exhibited a red nasal

discharge, which was not further characterized (NTP 1989). Histological

examinations were performed only on animals in the 250 mg/kg/day dose groups

(NTP 1989). Histological examination of nasal, larynx, trachea, lung, and

bronchial tissues of rats and mice exposed to 2,3-benzofuran by gavage for up

to 2 years showed compound-related hyperplasia in the lungs and nasal mucosa

in chronically-exposed mice (NTP 1989). The lung hyperplasia was seen in all

groups of mice exposed for 103 weeks, in males at doses of 60 and

120 mg/kg/day and in females at doses of 120 and 240 mg/kg/day (NTP 1989).

The hyperplasia occurred in bronchiolar epithelial cells, often extending into

the alveolar ducts (NTP 1989). 

Nasal hyperplasia was observed in both control and chemically-treated

mice in a 103-week study (NTP 1989). The hyperplasia was associated with

inflammation from foreign material (corn oil, hair, and particles of feed and

bedding) lodged in the nasal cavity, and the effect of oral 2,3-benzofuran

exposure was to increase the inflammatory response to such particles,

particularly at the highest dose tested in females, 240 mg/kg/day (NTP 1989). 

Cardiovascular Effects. Histological examination of the heart and

circulatory system of rats and mice exposed to 2,3-benzofuran by gavage for up

to 2 years showed a compound-related increase in mineralization of the

pulmonary artery in chronically-exposed rats (NTP 1989). The NOAEL values for

cardiovascular effects are identified as the highest doses for which

histological examinations were performed (250 mg/kg/day for acute-duration

exposure and 500 mg/kg/day for intermediate-duration exposure).

artery mineralization, Pulmonary nephropathy, which was considered secondary to

increased severity of was seen only in the low-dose groups of rats exposed for

103 weeks (30 mg/kg/day in male rats and 60 mg/kg/day in female rats) (NTP

1989). The lack of effect at the higher doses was attributed to reduced

survival (NTP 1989). 

Gastrointestinal Effects. Histological examination of stomach and

intestines of rats and mice with acute- or intermediate-duration exposure to

2,3-benzofuran by gavage showed no compound-related lesions, but chronic

exposure caused forestomach hyperplasia in rats and mice (NTP 1989). Male

rats exposed for 103 weeks had a significant increase in chronic inflammation

of the forestomach at a dose of 30 mg/kg/day, and significant increases in 
16
 

2. HEALTH EFFECTS
 

epithelial hyperplasia and ulcers at a dose of 60 mg/kg/day (NTP 1989). In

mice exposed for 103 weeks, forestomach hyperplasia was increased in males at

the higher dose (120 mg/kg/day) but not at the lower dose (60 mg/kg/day), and

was increased in females in both dose groups (120 and 240 mg/kg/day) (NTP

1989). Only the increase at 120 mg/kg/day in female mice was statistically

significant (NTP 1989). 

Hematological Effects. Histological examination of tissues from the

hematopoietic system of rats and mice exposed to 2,3-benzofuran by gavage for

up to 2 years showed no compound-related lesions at the highest doses examined

(250 mg/kg/day for acute-duration exposure, 500 mg/kg/day for intermediateduration 

exposure, and 120 mg/kg/day in rats and 240 mg/kg/day in mice for

chronic-duration exposure) (NTP 1989). Effects of oral exposure to

2,3-benzofuran on hemoglobin, hematocrit, red blood cells, white blood cells,

or other hematological parameters have not been examined in any reported

study. The NOAEL values for hematological effects for each species and

duration category are presented in Table 2-l and Figure 2-l. 

Musculoskeletal Effects. Histological examination of tissues from the

musculoskeletal system of rats and mice exposed to 2,3-benzofuran by gavage

for up to 2 years showed a compound-related increase in bone degeneration

(fibrous osteodystrophy) in chronically-exposed male rats (NTP 1989). The

observed increase in bone degeneration, which was not statistically

significant at doses of either 30 or 60 mg/kg/day, was not considered a direct

effect of 2,3-benzofuran exposure, but as secondary to calcium and phosphate

imbalance due to increased severity of nephropathy in male rats caused by

2,3-benzofuran exposure (NTP 1989). 

Hepatic Effects. The liver is a common target organ for substituted

furan compounds (Boyd 1981). Ten days of oral exposure of female mice to a

dose of 591 mg/kg/day of 2,3-benzofuran altered the activity of several

hepatic enzymes, decreasing the rate of reactions which activate electrophiles

and increasing the rate of reactions which deactivate electrophiles (Cha

et al. 1985; Heine et al. 1986). No toxicity was reported in this study (Cha

et al. 1985; Heine et al. 1986). Liver damage was seen in rats exposed to

2,3-benzofuran by gavage for 13 weeks and in mice exposed for 103 weeks (NTP

1989). Necrosis of individual hepatocytes was observed after 13 weeks of

exposure to 2,3-benzofuran in male rats at doses of 125, 250, and

500 mg/kg/day and in female rats at doses of 250 and 500 mg/kg/day (NTP 1989).

No histology was performed on rats exposed at lower doses so confidence in

125 mg/kg/day as a LOAEL for liver damage is low and no NOAEL can be

established. Cells resembling normal hepatocytes were found adjacent to and

within the pancreatic islets of female rats exposed to 120 mg/kg/day of

2,3-benzofuran for 103 weeks, but these cells were considered to have arisen 

by transdifferentiation of pancreatic cells (NTP 1989). This metaplasia of

the pancreatic islets was not accompanied by any other adverse histologic

changes (NTP 1989). The incidence of multinuclear hepatocytes was increased

in the livers of male mice exposed to 2,3-benzofuran for 103 weeks at doses of

60 and 120 mg/kg/day (NTP 1989); since this effect was seen at the lowest dose

tested, no threshold can be determined. 
17
 

2. HEALTH EFFECTS
 

Renal Effects. The kidney appears to be the organ most consistently

affected by 2,3-benzofuran. Male Fisher F344/N rats have a high incidence of

spontaneous nephropathy, characterized by degeneration, necrosis, and

mineralization of tubular cells, and this nephropathy was made more severe by

intermediate- and chronic-duration exposure to 2,3-benzofuran (NTP 1989). The

increased severity of nephropathy was accompanied by additional effects in

chemically-treated rats, including cortical cysts, bone degeneration,

hyperplasia of the parathyroid glands and pelvic epithelium, and

mineralization of the pulmonary artery (NTP 1989). Among male rats exposed

for 13 weeks, increased severity of nephropathy was seen at a dose of

250 mg/kg/day but not at lower doses. Among male rats exposed for 103 weeks,

increased severity of nephropathy contributing to reduced survival was seen at

both doses tested, 30 and 60 mg/kg/day. 

Female rats had a statistically-significant increase in nephropathy

following 13 weeks of exposure to 2,3-benzofuran at doses of 250 and

500 mg/kg/day, but not at 125 mg/kg/day, and exhibited increased severity of

nephropathy following 103 weeks of exposure at both doses tested, 60 and

120 mg/kg/day (NTP 1989). Female rats developed renal tubular cell atypical

hyperplasia following 103 weeks of exposure to a dose of 120 mg/kg/day (NTP

1989). Male mice exhibited kidney lesions (tubular cell necrosis,

inflammation, and focal mineralization) after 13 weeks of 2,3-benzofuran

exposure at a dose of 250 mg/kg/day, but not at lower doses for 13 weeks or at

doses of 60 or 120 mg/kg/day for 2 years (NTP 1989). No kidney damage was

found in female mice at any duration or dose of 2,3-benzofuran, up to

250 mg/kg/day for 14 days, up to 500 mg/kg/day for 13 weeks, or up to

240 mg/kg/day for 2 years (NTP 1989). The highest NOAEL values and all

reliable LOAEL values for renal effects for each species and duration category

are presented in Table 2-l and Figure 2-l. 

Dermal/Ocular Effects. Histological examination of the skin and eyes of

rats and mice exposed to 2,3-benzofuran by gavage for up to 2 years showed no

compound-related lesions at the highest doses examined (250 mg/kg/day for

acute-duration exposure, 500 mg/kg/day for intermediate-duration exposure, and

120 mg/kg/day in rats and 240 mg/kg/day in mice for chronic-duration exposure)

(NTP 1989). Rats exposed to oral doses of 500 and 1,000 mg/kg/day of

2,3-benzofuran for 3-14 days exhibited a red ocular discharge, but this

discharge was not characterized and no histological examinations were

performed on animals in these dose groups (NTP 1989). 

Other Systemic Effects. Oral 2,3-benzofuran exposure resulted in

decreased body weights in some cases (NTP 1989). In rats, reduced body weight

was observed after 14 days of exposure of males at doses of 250 and

500 mg/kg/day and of females at a dose of 500 mg/kg/day, after 13 weeks of

exposure of males at doses of 125, 250, and 500 mg/kg/day and of females at a

dose of 500 mg/kg/day, and after 103 weeks of exposure of males at doses of 30

and 60 mg/kg/day and of females at a dose of 120 mg/kg/day (NTP 1989). In

mice, reduced body weight was observed after 13 weeks of exposure of males at

a dose of 500 mg/kg/day, and after 103 weeks of exposure of males at a dose of

60 mg/kg/day but not 120 mg/kg/day and of females at doses of 120 and 
18
 

2. HEALTH EFFECTS
 

240 mg/kg/day (NTP 1989). No explanation was provided for the reduction in

body weight in male mice in the low dose group but not the high dose group

during chronic exposure (NTP 1989). Body weight reduction does not provide

specific information concerning toxicity, and often occurs only at doses above

those causing other systemic effects. The relative sensitivity to body-weight

reduction does appear to parallel the sensitivity to kidney and liver damage:

male rats are most sensitive, followed by female rats, male mice, and female

mice (NTP 1989). 

Rats exposed to 2,3-benzofuran for 13 weeks had an increased incidence

of cytoplasmic vacuolization of the adrenal glands, which was observed in 1

out of 10 control males, 2 out of 10 males at a dose of 250 mg/kg/day, and in

all 20 males and females at a dose of 500 mg/kg/day (NTP 1989). No adrenal

lesions were seen in rats at shorter or longer exposures, and no tests were

made to determine the effect on adrenal functioning. 

In rats exposed to 2,3-benzofuran for 103 weeks, the occurrence of

cystic follicles in the thyroid glands was increased in males at doses of

30 and 60 mg/kg/day but decreased in females at doses of 60 and 120 mg/kg/day

(NTP 1989). Parathyroid hyperplasia was increased in male rats exposed for

103 weeks to a dose of 30 mg/kg/day, secondary to increased severity of

nephropathy (NTP 1989). 

2.2.2.3 Immunological Effects 

No studies were located regarding immunological effects in humans after

oral exposure to 2,3-benzofuran. No abnormalities in lymphatic tissues were

detected by histological examination of rats and mice exposed to

2,3-benzofuran by gavage for up to 2 years (NTP 1989). However, no

examination of lymphocytes or tests of immune system functioning were made, so

these studies do not identify a reliable NOAEL for immunological effects. 

2.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans after

oral exposure to 2,3-benzofuran. No abnormalities in the nervous systems were

detected by histopathologic examination of rats and mice exposed to

2,3-benzofuran for up to 2 years (NTP 1989). However, no neurochemical or

neurophysiological parameters were monitored, so these studies do not identify

a reliable NOAEL for neurological effects. 

2.2.2.5 Developmental Effects 

No studies were located regarding developmental effects in humans or

animals after oral exposure to 2,3-benzofuran. 
19
 

2. HEALTH EFFECTS
 

2.2.2.6 Reproductive Effects 

No studies were located regarding reproductive effects in humans after

oral exposure to 2,3-benzofuran. No damage to male or female reproductive

organs was detected by histological examination of rats and mice exposed to

2,3-benzofuran by gavage for up to 2 years (NTP 1989). However, no functional

tests of reproductive success have been made, so these studies do not identify

a reliable NOAEL for reproductive effects. 

2.2.2.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or animals

after oral exposure to 2,3-benzofuran. Genotoxicity studies are discussed in

Section 2.4. 

2.2.2.8 Cancer 

No studies were located regarding carcinogenic effects in humans after

oral exposure to 2,3-benzofuran. Chronic gavage exposure to 2,3-benzofuran

increases the frequency of tumors in several organs in rats and mice

(NTP 1989). In rats, a statistically-significant increase in kidney

adenocarcinomas was found in females at a dose of 120 mg/kg/day, but no

carcinogenic effects were seen in males, perhaps because of reduced survival

(NTP 1989). In mice, increased frequencies of tumors were found in lungs,

livers, and forestomachs of both males and females (NTP 1989). Most of these

effects showed a dose-response trend and were statistically significant at

both doses tested, 60 and 120 mg/kg/day in males and 120 and 240 mg/kg/day in

females (NTP 1989). The NTP concluded that the data provided no evidence of

carcinogenicity of 2,3-benzofuran to male rats, some evidence of

carcinogenicity to female rats, and clear evidence of carcinogenicity to male

and female mice (NTP 1989). 

Levels of exposure associated with the observed carcinogenic effects of

2,3-benzofuran are indicated in Figure 2-l. Cancer effects could occur at

lower exposure levels, but no estimate of the individual human lifetime cancer

risks from exposure to 2,3-benzofuran has been made at this time by the EPA. 

2.2.3 Dermal Exposure 

2.2.3.1 Death 

No studies were located regarding death in humans or animals after

dermal exposure to 2,3-benzofuran. 

2.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular,

gastrointestinal, hematological, musculoskeletal, hepatic, or renal effects in

humans or animals after dermal exposure to 2,3-benzofuran. 
20
 

2. HEALTH EFFECTS
 

Dermal/Ocular Effects. No skin lesions or dermatitis were reported in

an early review of the dermatological problems associated with the manufacture

of coumarone-indene resin (a polymer made from 2,3-benzofuran and indene);

however, the manufacturing process essentially prevented contact with monomers

(Schwartz 1936), so the significance of these negative findings is

questionable. Workers continuously exposed to wood varnished with coumaroneindene 

resin developed dermatitis, but the sensitivity was attributed to the

sulfuric acids in the varnish (Schwartz 1936). 

No studies were located regarding the following health effects in humans

or animals after dermal exposure to 2,3-benzofuran: 

2.2.3.3 Immunological Effects

2.2.3.4 Neurological Effects

2.2.3.5 Developmental Effects

2.2.3.6 Reproductive Effects

2.2.3.7 Genotoxic Effects 

No studies were located regarding genotoxic effects in humans or animals

after dermal exposure to 2,3-benzofuran. Genotoxicity studies are discussed

in Section 2.4. 

2.2.3.8 Cancer 

No studies were located regarding carcinogenic effects in humans or

animals after dermal exposure to 2,3-benzofuran. 

2.3 TOXICOKINETICS 

2.3.1 Absorption 

2.3.1.1 Inhalation Exposure . 

No studies were located regarding absorption in humans or animals after

inhalation exposure to 2,3-benzofuran. The partitioning of 2,3-benzofuran

between particulate matter and synthetic alveolar surfactant in vitro was

reported to depend upon the chemical nature of the particles (Sehnert and

Risby 1988). Synthetic lung surfactant was able to dissolve 2,3-benzofuran

adsorbed to particles with few active sites, but not 2,3-benzofuran adsorbed

to particles with many active sites (Sehnert and Risby 1988). These data

indicate that inhalation of particles containing 2,3-benzofuran would result

in some absorption, depending on the nature of the particles. 

2.3.1.2 Oral Exposure 

No studies were located regarding absorption in humans or animals after

oral exposure to 2,3-benzofuran. 
21
 

2. HEALTH EFFECTS
 

2.3.1.3 Dermal Exposure 

No studies were located regarding absorption in humans or animals after

dermal exposure to 2,3-benzofuran. 

2.3.2 Distribution 

No studies were located regarding distribution in humans or animals

after exposure to 2,3-benzofuran by the following routes: 

2.3.2.1 Inhalation Exposure

2.3.2.2 Oral Exposure

2.3.2.3 Dermal Exposure 

2.3.3 Metabolism 

No studies were located regarding metabolism of 2,3-benzofuran in humans

or animals. However, the metabolism of several other substituted furans has 

been shown to involve oxidation by P-450, with the unsubstituted double bond

of the furan ring converted either to an epoxide (Boyd 1981) or to a

dialdehyde (Ravindranath et al. 1984). Pretreatment with inducers and

inhibitors of P-450 modified the toxicity of a single intraperitoneal

injection of 2,3-benzofuran to male mice (McMurtry and Mitchell 1977). Oral

exposure to 2,3-benzofuran altered the activity of P-450 and other enzymes in

the livers of female mice (Heine et al. 1986). These experiments indicate

that cytochrome P-450 may be involved in the toxicity of 2,3-benzofuran, but

do not provide a clear picture of 2,3-benzofuran metabolism. 

2.3.4 Excretion 

No studies were located regarding excretion in humans or animals after

exposure to 2,3-benzofuran by the following routes: 

2.3.4.1 Inhalation Exposure

2.3.4.2 Oral Exposure

2.3.4.3 Dermal Exposure 

2.4 RELEVANCE TO PUBLIC HEALTH 

As discussed in Section 2.2, estimates of levels of exposure to

2,3-benzofuran posing minimal risk to humans (MRLs) were to have been made,

where data were believed reliable, for the most sensitive noncancer effect for 

each route and exposure duration. However, no MRLs could be derived for

2,3-benzofuran. No data were located on effects of acute-duration, 

intermediate-duration, or chronic-duration inhalation exposure to

2,3-benzofuran in humans or animals. Therefore, no inhalation MRLs were 

derived. Available information on acute-duration oral exposure in animals

does not identify the most sensitive effect or any dose-response relationships

(NTP 1989). Available information on intermediate-duration and chronic duration

oral exposure to 2,3-benzofuran in animals suggests that the most 
22
 

2. HEALTH EFFECTS
 

sensitive effect may be liver toxicity following intermediate-duration

exposure and kidney toxicity following chronic-duration exposure (NTP 1989),

but the data do not reliably identify the threshold for liver or kidney

damage. Therefore, no oral MRLs were derived. Acute-duration, intermediate

duration, and chronic-duration dermal MRLs were not derived for 2,3-benzofuran 

due to the lack of an appropriate methodology for the development of dermal

MRLs. 

Essentially nothing is known about the effects of 2,3-benzofuran

exposure on humans. The principal adverse health effects noted in animals

associated with oral exposure to 2,3-benzofuran are kidney and liver damage

(NTP 1989). Intraperitoneal injection of 2,3-benzofuran also causes kidney

and liver damage (McMurtry and Mitchell 1977). Inhalation and dermal

exposures might also produce adverse effects, although this has not been

studied. Because of the limited production and use of 2,3-benzofuran (see

Chapter 4), the average person is unlikely to encounter doses high enough to

cause kidney or liver damage. However, studies in animals indicate that

2,3-benzofuran exposure may increase the risk of cancer (NTP 1989), and so

even low exposure levels may be of concern. Kidney and liver damage, cancer,

and other less common effects are discussed in greater detail below. 

Death. Large oral doses of 2,3-benzofuran can cause death in rats or

mice following acute or intermediate exposure duration, and somewhat lower

chronic doses can reduce survival (NTP 1989). No consistent difference in

sensitivity between male and females has been observed (NTP 1989). The

lethality of 2,3-benzofuran exposure by intraperitoneal injection appears to

be greater than that following gavage exposure, as a single intraperitoneal

injection of 100 mg/kg caused deaths in some male mice (McMurtry and Mitchell

1977), but 14-day gavage exposure caused no deaths in rats or mice at doses up

to 250 mg/kg/day (NTP 1989). The cause of death from 2,3-benzofuran exposure

was not reported in these studies except that reduced survival in male rats

chronically exposed to 2,3-benzofuran was attributed to increased severity of

kidney damage (NTP 1989). An acute dose of 240 mg/kg/day caused death in male

mice in a group which had been exposed to 60 mg/kg/day for 20 weeks, but an

acute dose of 250 mg/kg/day for 14 days caused no deaths in mice which had not

previously been exposed to 2,3-benzofuran (NTP 1989). Although no data were

provided concerning the cause of increased lethality of 2,3-benzofuran

following prior exposure, cumulative organ damage or altered metabolism are

possible explanations. It is unlikely that humans would be exposed to a dose

of 2,3-benzofuran sufficient to cause death. 

Systemic Effects. 

Respiratory Effects. Chronic-duration oral exposure to 2,3-benzofuran

causes hyperplasia of nasal mucosa and lung tissue in mice (NTP 1989).

In vitro exposure of chicken trachea cells to 2,3-benzofuran results in

substantial inhibition of ciliary activity (Pettersson et al. 1982), which may

indicate that ciliotoxicity is involved in the respiratory effects seen in

mice. Certain other furan derivatives exhibit pulmonary toxicity due to

metabolic activation by lung P-450 oxygenases (Boyd 1981), but 2,3-benzofuran 
23
 

2. HEALTH EFFECTS
 

has not been studied specifically. No respiratory effects were seen following

acute-, intermediate-, or chronic-duration oral exposure in rats or following

acute- or intermediate-duration oral exposure in mice. Thus, respiratory

effects are seen fairly infrequently, and only at high doses which also cause

liver damage. 

Cardiovascular Effects. Chronic-duration oral exposure to

2,3-benzofuran causes mineralization of the pulmonary artery in rats, but this

effect was due to mineral imbalances and vascular constriction associated with 

kidney damage (NTP 1989). No cardiovascular effects were seen following

acute-, intermediate-, or chronic-duration oral exposure in mice or following

acute- or intermediate-duration oral exposure in rats. 

Gastrointestinal Effects. Chronic-duration oral exposure to

2,3-benzofuran causes chronic inflammation of the forestomach in rats and mice 

(NTP 1989). No gastrointestinal effects were seen following acute- or

intermediate-duration oral exposure in rats or mice. The gastrointestinal

effects were seen at doses causing severe kidney damage or above doses causing

liver damage. 

Musculoskeletal Effects. Chronic-duration oral exposure to

2,3-benzofuran causes bone degeneration in rats, but this effect is due to

mineral imbalances associated with kidney damage (NTP 1989). No

musculoskeletal effects were seen following acute-, intermediate-, or chronic

duration oral exposure in mice or following acute- or intermediate-duration

oral exposure in rats. 

Hepatic Effects. Liver damage is a consistent systemic effect of oral

exposure to 2,3-benzofuran (NTP 1989). Intermediate-duration oral exposure

causes liver damage in male and female rats and chronic-duration oral exposure

causes liver damage in male mice (NTP 1989). Liver damage is also seen

following a single intraperitoneal injection of 2,3-benzofuran (McMurtry and

Mitchell 1977). The observed liver damage is usually characterized by focal

necrosis of hepatocytes after both oral (NTP 1989) and intraperitoneal

(McMurtry and Mitchell 1977) exposure. Liver damage was the systemic effect

seen at the lowest dose in male rats exposed to 2,3-benzofuran for 13 weeks

(NTP 1989). 

The toxicity of 2,3-benzofuran to the liver may be associated with

activation by P-450 oxygenases. Pretreatment of mice with an inhibitor of

P-450 oxygenases, cobaltous chloride, prevents liver damage from

intraperitoneal injection of 2,3-benzofuran (McMurtry and Mitchell 1977).

Acute-duration oral exposure to 2,3-benzofuran alters the activity of hepatic

enzymes in mice, decreasing the cytochrome P-450 content and increasing the

activity of several enzymes involved in the deactivation of electrophiles (Cha

et al. 1985; Heine et al. 1986). This overall shift in metabolism away from

activation of potential carcinogens was taken to suggest that 2,3-benzofuran

might have anticarcinogenic activity (Cha et al. 1985; Heine et al. 1986). 
24
 

2. HEALTH EFFECTS
 

However, because chronic-duration exposure to 2,3-benzofuran increases the

incidence of cancer in rodents, including liver cancer in mice (NTP 1989), any

possible anticarcinogenic action of 2,3-benzofuran is less relevant. 

Renal Effects. Intermediate- and chronic-duration oral exposure to

2,3-benzofuran causes kidney damage in male and female rats and intermediateduration oral exposure causes kidney damage in male mice (NTP 1989).

Intraperitoneal injection also causes kidney damage in male mice (McMurtry and

Mitchell 1977). Kidney damage involves injury to the tubular cells, with

degeneration, necrosis, and mineralization. In male rats (a group predisposed

to kidney damage), chronic 2,3-benzofuran exposure increases the severity of

the nephropathy to an extent which affects survival at a lifetime dose of

30 mg/kg/day (NTP 1989). Kidney damage seen in rats following chronic-duration

oral exposure to 2,3-benzofuran also involved cortical cysts, bone

degeneration, hyperplasia of the parathyroid glands and pelvic epithelium, and

mineralization of the pulmonary artery (NTP 1989). 

Other Systemic Effects. Oral exposure to 2,3-benzofuran causes

decreased body weight in rats and mice, and damage to adrenal and thyroid

glands in rats (NTP 1989). Reduced body weight is a rather unspecific

indicator of toxicity, and was generally not seen except at doses also causing

liver or kidney damage. Adrenal and thyroid lesions were seen infrequently,

and there was no indication of an effect on organ function (NTP 1989). 

The systemic effects caused by 2,3-benzofuran exposure which are most

relevant to public health are liver and kidney damage. Other systemic

effects, including damage to the adrenal and thyroid glands, lungs, and

pancreas, and reduced body weight, are generally seen only at doses above

those causing kidney or liver damage. High-level exposure to 2,3-benzofuran

would be expected to damage the liver or kidney, and possibly other organs in

some individuals. 

Immunological Effects. Oral lifetime exposure to 2,3-benzofuran caused

no histopathological lesions in lymphatic tissues of rats or mice (NTP 1989).

This provides limited evidence that the immunological system may not be a

major target for 2,3-benzofuran toxicity, but more definitive conclusions are

not possible without further studies. 

Neurological Effects. Oral lifetime exposure to 2,3-benzofuran caused

no histopathological lesions in tissues of the nervous systems of rats or mice

(NTP 1989). However, no tests of neurological function were performed, and so

the significance of these negative findings with regard to public health

cannot be evaluated. 

Developmental Effects. No information is available concerning any

effects on development from 2,3-benzofuran exposure. 
25
 

2. HEALTH EFFECTS
 

Reproductive Effects. Oral lifetime exposure to 2,3-benzofuran caused

no histopathological lesions in male or female reproductive organs of rats or

mice (NTP 1989). However, no studies of organ function or reproductive

success have been made, and so the potential effects of 2,3-benzofuran

exposure on human reproduction cannot be evaluated. 

Genotoxic Effects. No in vivo studies of 2,3-benzofuran genotoxicity

were located. The genotoxicity of 2,3-benzofuran has been studied in a number

of in vitro systems (Table 2-2). 2,3-Benzofuran was found not to be mutagenic

to Salmonella tvphimurium, both with and without exogenous activation (Florin

et al. 1980; Haworth et al. 1983; Weill-Thevenet et al. 1981). However

2,3-benzofuran does give positive responses in genotoxicity assays for

mutagenicity to mouse lymphoma L5178Y cells (McGregor et al. 1988) and for

sister chromatid exchanges in Chinese hamster ovary cells (NTP 1989). Limited

evidence suggests that 2,3-benzofuran could be metabolized to an electrophilic

epoxide or dialdehyde (see Section 2.3.3), and such an intermediate would be

an alkylating agent capable of reacting with DNA. Thus, one possible

explanation for the mixed genotoxicity results is differences among the

metabolic conditions used in the various tests. 

Cancer. 2,3-Benzofuran is carcinogenic to rats and mice (NTP 1989).

Chronic oral exposure increased the incidence of kidney tumors in female rats,

and increased the incidence of lung, forestomach, and liver tumors in male and

female mice (NTP 1989). These findings indicate that chronic exposure to

2,3-benzofuran could be a cause of concern even at low levels; however, 

without more extensive exposure data, it is not possible to characterize the

magnitude of human cancer risk from 2,3-benzofuran exposure. 

No information is available concerning the mechanism of carcinogenicity

of 2,3-benzofuran. All of the tissues showing a carcinogenic response also

exhibited hyperplasia, but there was no evidence that neoplasia was a

progression from hyperplasia (NTP 1989). Substituted furans can be activated

by cytochrome P-450 to electrophilic intermediates (epoxides or dialdehydes)

(Boyd 1981; Ravindranath et al. 1984), and furan and furfural can activate

oncogenes in mouse liver (NTP 1989; Reynolds et al. 1987); however, the

metabolism of 2,3-benzofuran has not been specifically studied. A possible

mechanism for the carcinogenicity of 2,3-benzofuran is electrophilic attack on

DNA. The evidence that 2,3-benzofuran has only limited genotoxicity in vitro

(see Table 2-2) could be the result of inadequate metabolic activation. 

2.5 BIOMARRERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in

biologic systems or samples. They have been classified as markers of

exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). 

A biomarker of exposure is a xenobiotic substance or its metabolite(s)

or the product of an interaction between a xenobiotic agent and some target

molecule(s) or cell(s) that is measured within a compartment of an organism

(NAS/NRC 1989). The preferred biomarkers of exposure are generally the 

27
 

2. HEALTH EFFECTS
 

substance itself or substance-specific metabolites in readily obtainable body

fluid(s) or excreta. However, several factors can confound the use and

interpretation of biomarkers of exposure. The body burden of a substance may

be the result of exposures from more than one source. The substance being

measured may be a metabolite of another xenobiotic substance (e.g., high

urinary levels of phenol can result from exposure to several different

aromatic compounds). Depending on the properties of the substance (e.g.,

biologic half-life) and environmental conditions (e.g., duration and route of

exposure), the substance and all of its metabolites may have left the body by

the time biologic samples can be taken. It may be difficult to identify

individuals exposed to hazardous substances that are commonly found in body

tissues and fluids (e.g., essential mineral nutrients such as copper, zinc,

and selenium). Biomarkers of exposure to 2,3-benzofuran are discussed in

Section 2.5.1. 

Biomarkers of effect are defined as any measurable biochemical,

physiologic, or other alteration within an organism that, depending on

magnitude, can be recognized as an established or potential health impairment

or disease (NAS/NRC 1989). This definition encompasses biochemical or

cellular signals of tissue dysfunction (e.g., increased liver enzyme activity

or pathologic changes in female genital epithelial cells), as well physiologic

signs of dysfunction such as increased blood pressure or decreased lung

capacity. Note that these markers are often not substance specific. They

also may not be directly adverse, but can indicate potential health impairment

(e.g., DNA adducts). Biomarkers of effects caused by 2,3-benzofuran are

discussed in Section 2.5.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired

limitation of an organism's ability to respond to the challenge of exposure to

a specific xenobiotic substance. It can be an intrinsic genetic or other

characteristic or a preexisting disease that results in an increase in

absorbed dose, biologically effective dose, or target tissue response. If

biomarkers of susceptibility exist, they are discussed in Section 2.7,

"POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE." 

2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to 2,3-Benzofuran 

2,3-Benzofuran has been detected in samples of breast milk (Pellizzari

et al. 1982) and in blood from victims who died in fires (Anderson and Harland

1980), but no information was provided by either study on previous exposure to

2,3-benzofuran. No information was located concerning metabolites of

2,3-benzofuran in animals or humans. No information was located concerning

the fate of 2,3-benzofuran in animals or humans, so it is not possible to

predict how long 2,3-benzofuran remains in the body, or how body levels might

correlate with exposure or effects. 
28
 

2. HEALTH EFFECTS
 

2.5.2 Biomarkers Used to Characterize Effects Caused by 2,3-Benzofuran 

No information is available concerning the effects of 2,3-benzofuran in

humans. Acute oral exposure to 2,3-benzofuran has been shown to alter levels

of enzyme activity in the livers of female mice (Heine et al. 1986), but much

more work would need to be done to determine whether there is a pattern of

enzyme alteration specific to 2,3-benzofuran exposure. Other effects found in

animals following oral exposure to 2,3-benzofuran are kidney and liver damage

and kidney, lung, liver, and stomach cancer (see Section 2.2.2). Such

generalized responses do not suggest the basis for any specific biomarker of

clinical or preclinical effects caused by 2,3-benzofuran. 

2.6 INTERACTIONS WITH OTHER CHEMICALS 

Pretreatment of male mice with compounds that affect cytochrome P-450

oxygenases altered the toxicity of a single intraperitoneal injection of

2,3-benzofuran (McMurtry and Mitchell 1977). However, kidney necrosis was

decreased both by phenobarbital, which induces P-450, and by cobaltous

chloride and piperonyl butoxide, which inhibit P-450. Also, one of the P-450

inhibitors, cobaltous chloride, decreased lethality while the other, piperonyl

butoxide, increased lethality. Differential effects on liver and kidney P-450

systems could explain some of these observations. Compounds which affect

P-450 metabolism are likely to alter 2,3-benzofuran toxicity, but the effects

on P-450 are not predictive of the specific effects on 2,3-benzofuran

toxicity. 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

Studies of 2,3-benzofuran toxicity in animals reveal differences in

susceptibility between sexes and between species, with male rats being the

most sensitive (see Section 2.2). Male rats have a high rate of spontaneous

kidney disease, and their greater sensitivity to 2,3-benzofuran toxicity may

be because the target organ is already damaged. Although no studies provide

data concerning human susceptibility, it is reasonable to assume that persons

with kidney or liver disease would be more susceptible to the toxic effects of

2,3-benzofuran. In addition, people who have altered P-450 metabolism, due to

disease, alcoholism, age, or exposure to drugs or chemicals, would be expected

to have altered 2,3-benzofuran toxicity (see Section 2.3.3), but the extent or

the direction of the effect (protective or harmful) cannot be predicted. 

2.8 MITIGATION OF EFFECTS 

This section will describe clinical practice and research concerning methods

for reducing toxic effects of exposure to 2,3-benzofuran. However, because

some of the treatment discussed may be experimental and unproven, this section

should not be used as a guide for treatment of exposures to 2,3-benzofuran.

When specific exposures have occurred, poison control centers and medical

toxicologists should be consulted for medical advice. 
29
 

2. HEALTH EFFECTS
 

Human exposure to 2,3-benzofuran can occur by inhalation, ingestion, or by

dermal contact. Also, 2,3-benzofuran has been detected in human milk and can 

thus be transferred to a nursing infant (Pellizzari et al. 1982). Essentially

nothing is known about the effects of 2,3-benzofuran exposure on humans. No

information was located on treatment for 2,3-benzofuran specifically, but the

sources listed below provided information for the general class of "phenols“

and indicated that this information applied to 2,3-benzofuran exposure;

however, it is not known if all of this information applies to 2,3-benzofuran

exposure. General recommendations for reducing adsorption following acute

exposure have included removal of the chemical with undiluted polyethylene

glycol prior to washing with large quantities of water (HSDB 1992). If the

eyes have been exposed, irrigation with copious amounts of tepid water has

been suggested (HSDB 1992). If ingestion has occurred, gastric lavage may be

indicated if performed soon after ingestion, or in patients who are comatose

or at risk of convulsing (HSDB 1992). Administration of activated charcoal

slurry, aqueous or mixed with saline cathartic or sorbitol has also been

suggested (HSDB 1992). Diazepam may be helpful in controlling seizures (HSDB

1992). 

Very little data is available on the retention of 2,3-benzofuran. Synthetic

lung surfactant was able to dissolve 2,3-benzofuran adsorbed to some particles

(Sehnert and Risby 1988), suggesting that it may be absorbed through the

lungs. Some substituted furans have been shown to be metabolized by the P-450

enzyme system (Boyd 1981; Ravindranath et al. 1984), suggesting that this is a

likely metabolic route for 2,3-benzofuran as well. Certain drugs, such as

cobaltous chloride and piperonyl butoxide, inhibit this enzyme system, and

were shown to alter the liver and kidney toxicity of 2,3-benzofuran (McMurtry

and Mitchell 1977). However, not all treatments with inhibitors and inducers

of the P-450 system gave the expected results in this study. One possible

explanation for these discrepancies could be the differential effects on the

different P-450 systems. It is possible that one or more drugs with this

activity could be developed and used to inhibit metabolism of 2,3-benzofuran

to more toxic metabolites. 

Little is known about the effects of 2,3-benzofuran exposure on humans. The

principal adverse health effects noted in animals associated with oral

exposure to 2,3-benzofuran are kidney and liver damage (NTP 1989). In the

kidney, 2,3-benzofuran causes injury to the tubular cells, with degeneration,

necrosis, and mineralization. In the liver, damage due to 2,3-benzofuran is

usually characterized by focal necrosis of hepatocytes. However, the

mechanism(s) associated with this damage are unknown. A better understanding

of the mechanism of action of 2,3-benzofuran may make it possible to develop

effective methods to reduce toxic effects caused by exposure. 

2.9 ADEQUACY OF THE DATABASE 

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

ATSDR (in consulXation with the Administrator of EPA and agencies and programs

of the Public Health Service) to assess whether adequate information on the

health effects of 2,3-benzofuran is available. Where adequate information is 
30 

2. HEALTH EFFECTS 

not available, ATSDR, in conjunction with the National Toxicology Program

(NTP), is required to assure the initiation of a program of research designed

to determine the health effects (and techniques for developing methods to

determine such health effects) of 2,3-benzofuran. 

The following categories of possible data needs have been identified by

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as

substance-specific informational needs that, if met, would reduce or eliminate

the uncertainties of human health assessment. In the future, the identified 

data needs will be evaluated and prioritized, and a substance-specific

research agenda will be proposed. 

2.9.1 Existing Information on Health Effects of 2,3-Benzofuran 

The existing data on health effects of inhalation, oral, and dermal

exposure of humans and animals to 2,3-benzofuran are summarized in Figure 2-2.

The purpose of this figure is to illustrate the existing information

concerning the health effects of 2,3-benzofuran. Each dot in the figure

indicates that one or more studies provide information associated with that

particular effect. The dot does not imply anything about the quality of the

study or studies. Gaps in this figure should not be interpreted as "data

needs" information (i.e., data gaps that must necessarily be filled). 

No data exist on the health effects of 2,3-benzofuran in humans. No 

data exist on the health effects of 2,3-benzofuran in animals following

inhalation or dermal exposure. Information on the health effects in rats and

mice following oral exposure to 2,3-benzofuran comes primarily from a wellconducted gavage study by NTP of acute-, intermediate-, and chronic-duration

(NTP 1989). However, this NTP study was limited to examining

histopathological endpoints, so information on immunologic, neurologic and

reproductive effects does not include evidence concerning organ or system

function. In addition, developmental and in vivo genotoxic effects of

2,3-benzofuran exposure have not been studied. 

2.9.2 Data Needs 

Acute-Duration Exposure. No data are available on the effects of acuteduration exposure to 2,3-benzofuran in humans. No data are available on the

effects of 2,3-benzofuran in animals following inhalation and dermal exposure.

Lethality in rats was reported in the NTP gavage study but the cause of death

was not known. The only systemic effects observed were red ocular and nasal

discharges and decreased body weights (NTP 1989). Lethality as well as kidney

and liver damage were seen in mice following a single intraperitoneal

injection of 2,3-benzofuran (McMurtry and Mitchell 1977). Currently, little

or no information is available concerning the target organ or the doseresponse of toxicity following inhalation, oral, or dermal exposure, and no

oral or inhalation MRLs could be derived. Toxicokinetic data for acuteduration exposure are insufficient to identify targets or to allow conclusions

to be made across routes of exposure. Such data are unlikely to become

available from human studies, but establishing the end points and levels 

32
 

2. HEALTH EFFECTS
 

causing toxicity from acute exposure of animals to 2,3-benzofuran by all three

routes would be useful to evaluate risk to populations surrounding hazardous

waste sites who might be exposed to 2,3-benzofuran for brief periods. 

Intermediate-Duration Exposure. No data are available on the effects of 

intermediate-duration exposure to 2,3-benzofuran in humans. No information is

available on the effects of 2,3-benzofuran in animals following inhalation or

dermal exposure of intermediate duration, and no inhalation MRL could be

derived. Histological evidence of liver damage in male rats exposed to

2,3-benzofuran by gavage for 13 weeks was reported in the lowest dose group

examined (125 mg/kg/day) (NTP 1989). Thus, no threshold for liver damage was

established by these studies and no oral MRL could be calculated. No renal

effects were observed in rats or mice at the dose causing necrosis of liver

cells in male rats, but kidney damage was observed at the next higher dose

tested, 250 mg/kg/day, in rats and mice (NTP 1989). Studies to establish an

oral MRL would be helpful in evaluating risk to populations near hazardous

waste sites who might be exposed to 2,3-benzofuran for intermediate durations.

Such studies would be valuable if they included examination of liver and

kidney function in addition to histopathology. Toxicokinetic data for

intermediate-duration exposure are insufficient to identify targets or to

allow conclusions to be made across routes of exposure. As for acute-duration

exposure, human data are unlikely to become available, but go-day animal

studies using several doses and investigating a number of end points would be

helpful for assessing the levels which may cause health effects in humans

following inhalation or dermal exposure to 2,3-benzofuran. 

Chronic-Duration Exposure and Cancer. No data are available on the 

effects of chronic-duration exposure to 2,3-benzofuran in humans. The NTP

study of oral exposure established the kidney as the most sensitive target

organ in rats (NTP 1989), but no oral MRL could be derived because the kidney

damage in male rats at the lowest dose used, 30 mg/kg/day, was too severe to

establish a threshold. Studies using lower doses would establish a LOAEL for

less serious effects and a NOAEL, which could also be better defined by tests

of kidney function as well as histopathology. Currently, no information is

available concerning the target organ or the dose-response of toxicity

following inhalation or dermal exposure, and no inhalation MRL could be

derived. Toxicokinetic data are insufficient to identify targets or to allow

conclusions to be made across routes of exposure. Such information would be

useful to evaluate risks to population near hazardous waste sites who might be

exposed to 2,3-benzofuran for long periods of time. As for acute- and

intermediate-duration exposure, human data are unlikely to become available,

but animal studies would help define levels expected to cause adverse health

effects in humans chronically exposed to 2,3-benzofuran by oral, inhalation,

and dermal routes. 

No epidemiologic studies were located concerning the potential human

carcinogenicity of 2,3-benzofuran. Lifetime oral exposure increases cancer

incidence in female rats and in male and female mice (NTP 1989). The

carcinogenicity in both sexes and both species, as well as in multiple organs,

strengthens the likelihood of a carcinogenic potential in humans. Studies of 
33
 

2. HEALTH EFFECTS
 

the carcinogenicity of 2,3-benzofuran by inhalation or dermal exposure would

be useful if toxicokinetic studies were to show substantial route-specific

differences in absorption, distribution, metabolism, or excretion. 

Genotoxicity. No data are available on the genotoxicity of

2,3-benzofuran in humans or animals. Genotoxicity results in vitro are mixed,

with negative results in the most widely used genotoxicity test,

S. tvphimurium mutagenicity (Florin et al. 1980; Haworth et al. 1983; McGregor

et al. 1988; NTP 1989; Weill-Thevenet et al. 1981). Other substituted furans

appear to be activated by P-450 oxygenases to epoxide (Boyd 1981) or

dialdehyde (Ravindranath et al. 1984) intermediates, which are electrophilic

and hence likely to react with DNA; however, the metabolism of 2,3-benzofuran

has not been studied. The mixed genotoxicity in vitro could reflect

inadequate activation, and so additional studies of in vivo metabolism and

genotoxicity in animals (e.g., 32P post-labeling to detect DNA adducts

following exposure to 2,3-benzofuran) would be useful to confirm or refute the

genotoxic potential of 2,3-benzofuran. 

Reproductive Toxicity. No data are available on the reproductive

toxicity of 2,3-benzofuran in humans. No histopathologic lesions were

reported in male or female reproductive organs in rats or mice following

acute-, intermediate-, or chronic-duration oral exposure to 2,3-benzofuran

(NTP 1989). However, no tests of organ function or reproductive success were

done. Thus, limited data indicate that the reproductive system may not be a

major target for 2,3-benzofuran toxicity, but further studies in animals by

all three routes of exposure examining reproductive organ pathology and organ

functions would be useful for assessing the possible effects of 2,3-benzofuran

exposure on human reproduction. 

Developmental Toxicity. No data are available on the developmental

toxicity of 2,3-benzofuran in humans or animals. Thus, a complete

investigation of the effects of 2,3-benzofuran on development, studying one

rodent and one nonrodent species exposed by all three routes, would be useful

to evaluate potential developmental toxicity in humans. 

Immunotoxicity. No data are available on the immunotoxicity of

2,3-benzofuran in humans. No histopathologic abnormalities in lymphatic

tissues of rats or mice were found following acute-, intermediate-, or

chronic-duration oral exposure to 2,3-benzofuran (NTP 1989), indicating that

the immune system may not be a target for 2,3-benzofuran toxicity. However, a

battery of immune function tests has not been performed. A more thorough

investigation could begin by examining peripheral lymphocytes in exposed

animals, followed by more detailed studies if effects were found. 

Neurotoxicity. No data are available on the neurotoxicity of

2,3-benzofuran in humans. No histopathologic lesions were noted in the

nervous systems of rats or mice following acute-, intermediate-, or chronicduration oral exposure to 2,3-benzofuran (NTP 1989), but no neurochemical or

neurophysiological parameters were monitored. It would be helpful to conduct 
34
 

2. HEALTH EFFECTS
 

neurological tests on animals exposed to 2,3-benzofuran by all three routes to

establish if the nervous system may be a target for 2,3-benzofuran toxicity. 

Epidemiological and Human Dosimetry Studies. No epidemiological or

human dosimetry studies on the effects of 2,3-benzofuran were located.

Production of coumarone-indene resin involves potential exposure to

2,3-benzofuran (Powers 1980), and so an occupationally exposed subpopulation

could be identified. Animal studies suggest that kidney and liver damage and

increased risk of cancer would be end points of concern (NTP 1989). Potential

difficulties with epidemiological investigations include a small cohort of

exposed workers, the difficulty of defining exposure levels, and the

possibility that exposure to other chemicals could confound the results.

Information from epidemiological and human dosimetry studies would be useful

in establishing cause/effect relationships and in planning future monitoring

of individuals living near hazardous waste sites. 

Biomarkers of Exposure and Effect. The presence of 2,3-benzofuran has

been detected in breast milk (Pellizzari et al. 1982) and in blood from

victims who died in fires (Anderson and Harland 1980), indicating that the

concentration of 2,3-benzofuran in biological samples could serve as a

biomarker of exposure. However, more studies on absorption, distribution,

metabolism, and excretion would be useful to determine the lifetime of 

2,3-benzofuran in the body and to correlate levels with duration and degree of

exposure. Indirect evidence suggests that 2,3-benzofuran may be activated by

P-450 oxygenases to an epoxide or dialdehyde intermediate which could react

with cellular components (Heine et al. 1986; McMurtry and Mitchell 1977).

Thus, an assay for adducts of 2,3-benzofuran in proteins or DNA could possibly

be developed as a useful marker of exposure to 2,3-benzofuran. 

The effects of 2,3-benzofuran exposure in humans are not known.

Activities of enzymes in the liver are altered by acute exposure to

2,3-benzofuran in female mice (Heine et al. 1986), which suggests the

possibility that there may be a specific response of serum enzyme levels to

2,3-benzofuran exposure that could be developed as a biomarker of effect.

Other effects in animals include kidney and liver damage and an increased rate

of kidney, lung, liver, and forestomach cancer (NTP 1989). Such effects are

too general and severe to serve as biomarkers of 2,3-benzofuran effects. 

Absorption, Distribution, Metabolism, and Excretion. No data are 

available on the absorption, distribution, metabolism, or excretion of

2,3-benzofuran in humans. Limited data suggest the involvement of P-450

oxygenases in the metabolism of 2,3-benzofuran in animals (Heine et al. 1986;

McMurtry and Mitchell 1977), and further investigations would be valuable to

define the role of organ-specific oxygenases in the toxicity and potential

genotoxicity of 2,3-benzofuran. Absorption, distribution, and excretion in

animals have not been studied at all via inhalation, oral, or dermal routes. 

Such information would be valuable because the relative rates and extent of 

absorption, distribution, metabolism, and excretion following exposure by

different routes may account for differences in the toxicity of a chemical

administered by different routes. These investigations could start with 
35
 

2. HEALTH EFFECTS
 

monitoring levels as a function of exposure, by the inhalation, oral, and

dermal routes, and at acute, intermediate, and chronic durations. It is 

likely that 2,3-benzofuran exists in the environment primarily adsorbed to

particles (see Chapter 5), and the extent of desorption of 2,3-benzofuran by

artificial lung surfactant in vitro depends on the nature of the particles

(Sehnert and Risby 1988). Thus, studies of absorption would be most useful if

they included exposure to 2,3-benzofuran on particles representative of those

found in the environment. 

Comparative Toxicokinetics. No data are available on toxicokinetics in 

animals or humans. There is some commonality of target organs (the kidney and

liver) between rats and mice (NTP 1989), making it reasonable to assume that

both species, and perhaps humans, would handle 2,3-benzofuran similarly.

Establishing which animal species serves as the best model for extrapolating

results to humans would be a useful first step in investigating comparative

toxicokinetics. 

Mitigation of Effects. No information was located concerning mitigation

of effects of exposure to 2,3-benzofuran. Information on techniques to

mitigate low-level, long-term effects would be useful in determining the

safety and effectiveness of possible methods for treating 2,3-benzofuran exposed

populations in the vicinity of hazardous waste sites. 

2.9.3 On-going Studies 

No information concerning research projects in progress to investigate

2,3-benzofuran was located. 

37 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY 

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

identification information for 2,3-benzofuran. 

3.2 PHYSICAL AND CHEMICAL PROPERTIES

 Table 3-2 lists important physical and chemical properties of

2,3-benzofuran. 



41
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.1 PRODUCTION 

2,3-Benzofuran is produced as a component of the crude heavy solvent

fraction of the coal-tar light oil formed by the coking of bituminous coal

(HSDB 1989; Windholz et al. 1983). 2,3-Benzofuran is not isolated for

commercial purposes (HSDB 1989). The fraction of this coal-tar oil distilling

at 167-184°C contains small quantities (probably less than 10%) (Powers 1980)

of 2,3-benzofuran (also known as coumarone) and also indene (approximately

30%) (NTP 1989), indan, substituted benzenes, and related compounds (CFR

1989a). This fraction of coal oil is used to produce a polymer called

coumarone-indene resin (Powers 1980). The polymerization is accomplished by

addition of an acid catalyst such as boron trifluoride (NTP 1989) or sulfuric

acid (HSDB 1989). Coumarone-indene resin hardens when heated and is used to

make floor tiles and other products (HSDB 1989; Morris 1953; NTP 1989).

Coumarone-indene resin is produced by the Neville Chemical Company of Neville

Island, Pennsylvania (SRI 1989). 

No quantitative data were located regarding the production of

2,3-benzofuran or coumarone-indene resin, although it is reported that

virtually all of the resin-forming fraction produced by destructive

distillation of coal is polymerized (Powers 1980). No information was located

concerning the stability or decomposition products of coumarone-indene resin. 

4.2 IMPORT/EXPORT 

Imports of 2,3-benzofuran in 1977 and 1979 have been reported to be

1,840 metric tons and 0.0009 metric tons, respectively (HSDB 1989). Current

information regarding 2,3-benzofuran import was not located. 

No data were located regarding the export of 2,3-benzofuran. 

4.3 USE 

2,3-Benzofuran is not isolated for commercial purposes, and no

information was located regarding uses of isolated 2,3-benzofuran. However,

the coumarone-indene resin may be used as a coating on grapefruit, lemons,

limes, oranges, tangelos, and tangerines (CFR 1989a). Coumarone-indene resin

is also used in the production of paints and varnishes for corrosion-resistant

coatings (Morris 1953; NTP 1989) and water-resistant coatings on paper

products and fabrics (NTP 1989) and as adhesives in food containers (CFR

1989d). Coumarone-indene resin has been used in asphalt floor tiles (Morris

1953; Wilson and McCormick 1960). 

No data were located which would indicate the extent to which 

2,3-benzofuran or coumarone-indene resin is currently used in these products. 
42 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.4 DISPOSAL 

2,3-Benzofuran is not listed as a hazardous waste by the EPA. No data

were located regarding rules or regulations which control the disposal of

2,3-benzofuran. 

No data were located regarding disposal methods or disposed quantities

of waste 2,3-benzofuran. 
43
 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW 

2,3-Benzofuran is a colorless organic liquid with an aromatic odor. It

is produced by the destructive distillation of coal, and may also be formed

during processing of fossil fuels, such as coke production and coal

gasification. Limited data indicate that 2,3-benzofuran may partition to

soils and sediments from water, but the information available is insufficient 

to predict the environmental fate of this compound. Substantial

bioconcentration in aquatic organisms is not expected based on the

physical/chemical properties of 2,3-benzofuran. 

Monitoring data on 2,3-benzofuran in environmental media are scarce.

Potential human exposure to 2,3-benzofuran may occur by ingestion of foods

treated with coumarone-indene resin; however, migration of 2,3-benzofuran from

this resin has not been confirmed. Occupational exposure to 2,3-benzofuran

may occur in several energy-related industries, and individuals living in the

vicinity of hazardous waste sites at which this compound has been detected may

also be exposed. The EPA has identified 1,177 NPL sites. 2,3-Benzofuran has

been found at 5 of the sites evaluated for the presence of this chemical (View

1989). However, it is not known how many of the 1,177 NPL sites have been

evaluated for 2,3-benzofuran. As more sites are evaluated by the EPA, the

number may change. The frequency of the sites in the United States at which

2,3-benzofuran was found can be seen in Figure 5-l. 

5.2 RELEASES TO THE ENVIRONMENT 

2,3-Benzofuran may be released to the environment from production and

use of 2,3-benzofuran-containing products, and from coke production, coal

gasification, and oil-shale facilities. 2,3-Benzofuran is not listed on the

SARA Section 313 Toxics Release Inventory (TRI). 

5.2.1 Air 

Data on 2,3-benzofuran air emissions are sparse. No information was

located regarding 2,3-benzofuran releases from production facilities.

However, 2,3-benzofuran was detected in emissions from a Swedish floor finish 

used on domestic flooring (van Netten et al. 1988), and in emissions from the

pyrolysis of silk (Junk and Ford 1980), and in combustor flue gas emissions

from fluidized-bed coal combustion at a concentration of 900 ng/g (Hunt et al.

1982). Exhaust produced by an automobile burning simple hydrocarbon fuels

contained 2,3-benzofuran at concentrations ranging from less than 0.1 to

2.8 ppm (Seizinger and Dimitriades 1972), but an analysis of air in a highway

tunnel in use by both diesel- and gasoline-powered vehicles indicated no

2,3-benzofuran (Hampton et al. 1982). 

5.2.2 Water 

2,3-Benzofuran may be released to water from coal gasification

facilities. 2,3-Benzofuran was detected in coal gasification facility

effluents at concentrations ranging from 6 to 267 ppb, but was not detected 

45
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

(detection limit 0.1 ppb) in effluents from oil shale processing facilities

(Pellizzari et al. 1979). 2,3-Benzofuran was also detected in 1 of 18 waste

water concentrates (Lucas 1984). Data from the Contract Laboratory Program

(CLP) Statistical Database indicate that 2,3-benzofuran was found at a

concentration of 770 ppb in a groundwater sample, but was not found in any

surface water samples, taken at one hazardous waste site (CLPSD 1990). It is

not known how many hazardous waste sites have been evaluated for

2,3-benzofuran. Note that these data from the CLP Statistical Database 

represent frequency of occurrence and concentration information for NPL sites

only. 

5.2.3 Soil 

2,3-Benzofuran was found at a concentration of 60 ppb in one

soil/sediment sample taken at one hazardous waste site (CLPSD 1990). It is

not known how many hazardous waste sites have been evaluated for

2,3-benzofuran. Note that these data from the CLP Statistical Database 

represent frequency of occurrence and concentration information for NPL sites

only. 

5.3 ENVIRONMENTAL FATE 

5.3.1 Transport and Partitioning 

No information was located on the transport and partitioning of

2,3-benzofuran in the atmosphere. Based on the high boiling point of

2,3-benzofuran, volatilization would be expected to be slow, but because the

vapor pressure of the chemical is unknown, it is not possible to predict how

2,3-benzofuran will partition in the atmosphere. 

2,3-Benzofuran is reported not to be soluble in water (Windholz et al.

1983). However, based on its octanol/water partition coefficient (Table 3-2),

the solubility of 2,3-benzofuran may be on the order of 200 mg/L, using the

empirical regressions of Hassett et al. (1983) for hydrophobic organic

chemicals. 

2,3-Benzofuran may partition from water to soils and sediments. The

extent of adsorption of neutral organic compounds by soils is often correlated

with the organic-carbon content of the soil (Hassett et al. 1983). When

adsorption is expressed as a function of organic-carbon content, an organic

carbon/water partition coefficient (Koc) is generated, and may be used to

classify the relative mobility of the chemical in soil. Based on its

octanol/water partition coefficient, an estimated Koc for 2,3-benzofuran is 

about 330, using the empirical regression of Hassett et al. (1983). This Koc 

implies that 2,3-benzofuran has a medium mobility in soil, using the mobility

classifications of Roy and Griffin (1985), and would be most mobile in soils

and groundwater where the organic-carbon content is low. No soil adsorption

studies on 2,3-benzofuran were located. A coal-tar/water partition

coefficient of 912 for 2,3-benzofuran was derived that was similar in 

magnitude to the octanol/water partition coefficient (Rostad et al. 1985). 
46
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Lignite coal is able to adsorb 2,3-benzofuran from aqueous solution (Humenick

et al. 1982), which indirectly confirms the expectation that the mobility of

the chemical will be influenced by the distribution of organic carbon. 

The potential for 2,3-benzofuran to be bioconcentrated by aquatic

organisms is likely to be moderate. A bioconcentration factor (BCF) is the

ratio of the concentration of a chemical in the tissues of aquatic animals to

the concentration of the chemical in the water in which they live. No

experimentally measured value for the BCF of 2,3-benzofuran was located, but

the octanol-water partition coefficient (KOW) of 2,3-benzofuran has been

measured as 468 (Leo et al. 1971). The empirical regressions of Neeley et al.

(1974) relate the values of KOW, and BCF for other compounds, and can be used

to estimate that the BCF of 2,3-benzofuran is approximately 40. If this

estimate is correct, substantial bioconcentration of 2,3-benzofuran by aquatic

organisms would not be expected. 

5.3.2 Transformation and Degradation 

5.3.2.1 Air 

No information was located on the transformation or degradation of

2,3-benzofuran in the atmosphere. 

5.3.2.2 Water 

No information was located on the transformation or degradation of

2,3-benzofuran in water. 

5.3.2.3 Soil 

No information was located on the transformation or degradation of

2,3-benzofuran in soils, sediments, or waste water treatment processes. 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

5.4.1 Air 

2,3-Benzofuran was detected, but not quantitated, in 1 of 10 samples of

ambient air taken in an industrial area in the Kanawha Valley, West Virginia

(Erickson and Pellizzari 1978). No other monitoring data for 2,3-benzofuran

in the United States were located. However, one study identified

2,3-benzofuran among pollutants in the air of the Southern Black Forest in

Germany (Juttner 1986). 

5.4.2 Water 

No information was located regarding 2,3-benzofuran in surface water in

the United States. 2,3-Benzofuran was detected in contaminated groundwater at

a coal-tar distillation and wood-preserving facility in Minnesota (Rostad

et al. 1985). 
47
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.4.3 Soil 

No studies were located regarding occurrence of 2,3-benzofuran in soils.

2,3-Benzofuran was among those chemicals selected as representative compounds

of waste chemicals from energy production for, subsurface transport research

(Zachara et al. 1984). 

5.4.4 Other Environmental Media 

2,3-Benzofuran has not generally been reported in foods. However,

2,3-benzofuran was detected among the volatile constituents of freeze-dried

whey powder subjected to accelerated browning (Ferretti and Flanagan 1971).

It was also detected in three samples of human milk (Pellizzari et al. 1982)

and is reportedly a constituent of cigarette smoke (Curvall et al. 1984;

Florin et al. 1980; Schlotzhauer and Chortyk 1987). 

Although 2,3-benzofuran is a component of coumarone-indene resin and

this resin has been approved by the FDA for use as a coating on citrus fruits,

as a component of food-preparation utensils, and as an adhesive in food

packages (see Table 7-l), no information was located confirming that

coumarone-indene resin is currently used on food in the United States.

Furthermore, no data were located to indicate that 2,3-benzofuran migrates

from the resin into foodstuffs. 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Humans may be exposed to 2,3-benzofuran by inhalation, ingestion, or

dermal absorption. Based on the limited data available, exposure of the

general population to 2,3-benzofuran does not appear to be substantial.

However, since this compound has been detected at hazardous waste sites, is

reported to be a component of cigarette smoke, and is one monomer in a resin

which may be used as a coating on citrus fruits and in packaging materials for

foods, human exposure may be possible from these sources. People in Britain

who had died in fires had 2,3-benzofuran in some blood samples, but no source

of exposure was identified (Anderson and Harland 1980). 2,3-Benzofuran was

detected in human milk (Pellizzari et al. 1982); this indicates possible

exposure of the mother and is an exposure source for the infant. 

Occupational exposure to 2,3-benzofuran may occur in several energyrelated industries. 2,3-Benzofuran is part of the naphtha fraction of coal

distillates and exposure is possible in coke production and coal gasification

facilities (see Chapter 4). Exposure may also occur during the polymerization

process used to produce coumarone-indene resin. 2,3-Benzofuran was not

included in the NIOSH National Occupational Hazard Survey or the National

Occupational Exposure Survey. However, the naphtha fraction of coal tar is

considered in the NIOSH (1978) evaluation of occupational hazards associated

with coal gasification. 
48
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Individuals occupationally exposed to coal tars or the naphtha fraction

of coal-tar distillate have potentially high exposure to 2,3-benzofuran.

Persons living near industrial sources or hazardous waste sites contaminated

with 2,3-benzofuran may be exposed to 2,3-benzofuran. There are insufficient

data to identify any other populations with potentially high exposure to this

compound. 

5.7 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, 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 2,3-benzofuran is available. Where adequate information is

not available, ATSDR, in conjunction with the NTP, is required to assure the

initiation of a program of research designed to determine the health effects

(and techniques for developing methods to determine such health effects) of

2,3-benzofuran. 

The following categories of possible data needs have been identified by

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as

substance-specific informational needs that, if met, would reduce or eliminate

the uncertainties of human health assessment. In the future, the identified 

data needs will be evaluated and prioritized, and a substance-specific

research agenda will be proposed. 

5.7.1 Data Needs 

Physical and Chemical Properties. Measured values of the physical and

chemical properties of 2,3-benzofuran necessary to predict the environmental

fate and transport of this chemical are not available. Reliable measurements

of the vapor pressure, solubility in water, Henry's law constant, and Koc 

would be useful for more accurate prediction of the behavior of 2,3-benzofuran

in environmental media. 

Production, Import/Export, Use, and Disposal. No recent quantitative

data were located on the production, import/export, use, or disposal of

2,3-benzofuran. Virtually all of the 2,3-benzofuran produced by the

destructive distillation of coal is reportedly used in the production of

coumarone-indene resin (Powers 1980), but no information was located detailing

the current uses of this resin, the composition of this resin, the amount of

2,3-benzofuran emitted from the resin, or the current production volume of the

resin. 2,3-Benzofuran is not listed as a hazardous waste by the EPA;

therefore, no regulations restricting land disposal apply to this chemical.

Data required to assess potential human exposure to this chemical include the

amount of production and import/export of 2,3-benzofuran and coumarone-indene

resin, and emission rates of 2,3-benzofuran from the resin. If the data 

indicate that 2,3-benzofuran is emitted from the resin, then current 

information on the nature and extent of use of the resin will also be 
49
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

necessary. Data on environmental releases of 2,3-benzofuran from production

facilities and disposal methods employed for wastes containing this chemical

would also be helpful to assess potential human exposure. 

Environmental Fate. The available data on partitioning, transport, and

transformation are insufficient to predict the environmental fate of

2,3-benzofuran. Measurements of the rate of photodegradation of

2,3-benzofuran in the atmosphere and determination of the composition and fate

of the decay products would be useful to predict the atmospheric fate of this

compound. Information regarding the potential for 2,3-benzofuran to

photodegrade or oxidize in water or to biodegrade in water or soil, and the

rates at which these reactions occur, would be useful in predicting the fate

of the compound in these media. Physical/chemical properties suggest that

2,3-benzofuran can partition to soils (Hassett et al. 1983; Roy and Griffin

1985). Verification of this prediction by measurements of the adsorption and

desorption of 2,3-benzofuran by soils and sediments, and measurement of the

rate of volatilization of the compound from water, would be useful in

predicting the transport and partitioning of 2,3-benzofuran among

environmental media. 

Bioavailability from Environmental Media. The available data are 

insufficient to assess the bioavailability of 2,3-benzofuran from

environmental media. In vitro evidence suggests that 2,3-benzofuran would be

less available from organic-rich particles than from organic-poor particles

(Sehnert and Risby 1988), but confirmation of this prediction with in vivo

studies would be useful. Animal studies have used gavage in oil for exposure

to 2,3-benzofuran (NTP 1989) but no quantitative information concerning

absorption is available. Additional information on the bioavailability of

2,3-benzofuran would be useful to assess the extent of absorption of

2,3-benzofuran from environmental media. 

Food Chain Bioaccumulation. No data were located regarding the

bioconcentration of 2,3-benzofuran in plants, aquatic organisms, or animals.

Based on physical/chemical properties, substantial bioconcentration of

2,3-benzofuran is not expected (Leo et al. 1971; Neeley et al. 1974). No data

on biomagnification in terrestrial or aquatic food chains are available. Data

on bioconcentration of this compound in aquatic species would be useful in

confirming the predicted low bioconcentration potential of this compound. 

Exposure Levels in Environmental Media. Monitoring data for

2,3-benzofuran are sparse and are insufficient to assess the potential for

human exposure to this compound, so no estimates of human intake of this

substance are available. Since 2,3-benzofuran is a coal-tar product (Powers

1980), monitoring data for this compound in all environmental media in the

vicinity of fossil fuel facilities would help to determine the potential for

both general population and occupational exposure. In addition, monitoring

foods which come in contact with coumarone-indene resin for 2,3-benzofuran 

would be useful to assess the potential for human exposure from food. 
50
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Remedial investigations and feasibility studies at hazardous waste sites are

potential sources of information on possible exposures of populations

surrounding hazardous waste sites. 

Exposure Levels in Humans. 2,3-Benzofuran has been detected in several 

samples of breast milk (Pellizzari et al. 1982). It is unknown whether the

presence of this compound in milk is a result of exposure to 2,3-benzofuran

itself, or whether it is a metabolite of other compounds. Biological

monitoring of workers in coal gasification or related facilities and of

c populations surrounding hazardous waste sites would be useful to evaluate

human exposure to this compound. 

Exposure Registries. No exposure registries for 2,3-benzofuran were

located. This compound is not currently one of the compounds for which a

subregistry has been established in the National Exposure Registry. The

compound will be considered in the future when chemical selection is made for

subregistries to be established. The information that is amassed in the

National Exposure Registry facilitates the epidemiological research needed to

assess adverse health outcomes that may be related to the exposure to this

compound. 

5.7.2 On-going Studies 

No information was located on any on-going studies on the fate,

transport, or potential for human exposure to 2,3-benzofuran. Remedial

investigations and feasibility studies at hazardous waste sites may provide

information on environmental levels, transport, and transformation of

2,3-benzofuran. 
51
 

6. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods that

are available for detecting and/or measuring and monitoring 2,3-benzofuran in

environmental media and in biological samples. The intent is not to provide

an exhaustive list of analytical methods that could be used to detect and

quantify 2,3-benzofuran. Rather, the intention is to identify well-established

methods that are used as the standard methods of analysis. No

methods approved by federal agencies or other groups specifically for

detection of 2,3-benzofuran were located. 

Environmental media or biological samples which contain 2,3-benzofuran

are also likely to contain numerous other organic compounds with similar

chemical and physical properties. Analysis of such samples generally proceeds

by first extracting or concentrating some subset of the organic compounds and

then separating and identifying them. Techniques for extraction of organic

compounds from environmental media or biological samples include absorption

onto a polymer and extraction with an organic solvent. Recovery is generally

not complete, and so accurate quantification requires using matrix spikes (EPA

1986c). This has not been done in any studies for 2,3-benzofuran. Sensitive

and selective techniques for identification of organic compounds in extracts

are well established, using high-resolution gas chromatography (HRGC) to

separate the compounds and mass spectrometry (MS) to identify them. HRGC

achieves higher resolution than standard gas chromatography (GC) by using

wall-coated capillary columns rather than packed columns for separation of

compounds. Flame ionization detection is not specific enough for the analysis

of 2,3-benzofuran in samples containing numerous other compounds, although it

has been used to monitor the stability of 2,3-benzofuran in oil for animal

feeding studies (NTP 1989). Accurate quantification of the concentration of

chemicals in extracts can be achieved with GC/MS by daily calibration using

actual and surrogate standards (EPA 1986c), although this has not been done

specifically for 2,3-benzofuran. 

6.1 BIOLOGICAL MATERIALS 

2,3-Benzofuran has been detected, but not quantified, in samples of

blood (Anderson and Harland 1980) and breast milk (Pellizzari et al. 1982).

In both cases, volatile and semi-volatile organic compounds were purged from

the biological fluids by bubbling with an inert gas at an elevated

temperature. The compounds were trapped by adsorption onto a Tenax®

cartridge. The percent recovery of 2,3-benzofuran by this purge-and-trap

collection method was not examined. The Tenax® cartridge was heated to desorb

the organic compounds directly into the inlet of the HRGC equipment. Mass

spectrometry was used to identify the compounds, including 2,3-benzofuran, by

mass fragmentation patterns. The percent recovery or concentration was not

quantified in either study (Anderson and Harland 1980; Pellizzari et al.

1982). 

Methods for detection of 2,3-benzofuran in biological.materials are

summarized in Table 6-1. 

53
 

6. ANALYTICAL METHODS
 

6.2 ENVIRONMENTAL SAMPLES 

2,3-Benzofuran can be trapped and concentrated from air samples by

passing a large volume of air through a Tenax® (Erikson and Pellizzari 1978;

Juttner 1986; van Netten et al. 1988) or Chromosorb (Seizinger and Dimitriades

1972) cartridge. The cartridge is then thermally desorbed into an HRGC/MS

detection system similar to that used for biological samples. 2,3-Benzofuran

can be concentrated from water samples using the purge-and-trap method

(Pellizzari et al. 1979), or extraction with dichloromethane (Rostad et al.

1985), and analyzed by HRGC/MS. 2,3-Benzofuran can be extracted from

particulate samples with dichloromethane and analyzed by HRGC/MS (Ferretti and

Flanagan 1971; Hunt et al. 1982). The percent recovery of 2,3-benzofuran by

these extraction methods has not been analyzed. The amount of 2,3-benzofuran

in some environmental samples has been quantified (Pellizzari et al. 1979;

Seizinger and Dimitriades 1972), but the precision of the quantification was

not examined. 

Methods for the determination of 2,3-benzofuran in environmental samples

are summarized in Table 6-2. 

6.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, 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 2,3-benzofuran is available. Where adequate information is

not available, ATSDR, in conjunction with the NTP, is required to assure the

initiation of a program of research designed to determine the health effects

(and techniques for developing methods to determine such health effects) of

2,3-benzofuran. 

The following categories of possible data needs have been identified by

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as

substance-specific informational needs that, if met, would reduce or eliminate

the uncertainties of human health assessment. In the future, the identified 

data needs will be evaluated and prioritized, and a substance-specific

research agenda will be proposed. 

6.3.1 Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. The only

known biomarker of exposure to 2,3-benzofuran is its presence in blood

(Anderson and Harland 1980) or breast milk (Pellizzari et al. 1982).

2,3-Benzofuran was not found in all samples of blood or. breast milk tested,

but since existing methods for detection of 2,3-benzofuran in biological

samples are not quantitative, it is not possible to assess whether those

samples contained no 2,3-benzofuran or whether the method used was not

sufficiently sensitive to measure background levels in the population. The

levels at which human health effects occur are not known. Only the

administered doses, not the target organ concentrations, are known for 

55
 

6. ANALYTICAL METHODS
 

biological effects occurring in animals (NTP 1989), but these doses are

relatively high (30 mg/kg/day or greater, see Chapter 2). Based on the

general sensitivity of HRGC/MS methods, it is likely that levels of

2,3-benzofuran at which biological effects occur should be achievable with

routine quantification procedures. The overall techniques of extraction

followed by HRGC/MS analysis can be made precise, accurate, reliable, and

specific, so that the opportunity exists to develop methods for sensitive

quantitation of 2,3-benzofuran in biological samples. Refinement of existing

purge-and-trap extraction techniques and investigation of alternative

concentration techniques such as cryotrapping (Pankow and Rosen 1988) and

supercritical fluid extraction (King 1989) would be useful. High-performance

liquid chromatography as an alternative to HRGC and Fourier transform infrared

spectroscopy and photodiode array detectors as alternatives to MS detection

might offer advantages. Investigation of possible metabolites of

2,3-benzofuran as biomarkers of exposure would be most useful if accompanied

by development of methods for their detection, such as immunoassay techniques

and 32P post-labelling for identifying macromolecular adducts. 

No known biomarkers of effect were located in the literature. 

Investigation of biomarkers of effect of 2,3-benzofuran would be most useful

if it were also to focus on developing precise, accurate, reliable, and

specific methods for measuring background levels of the biomarker of effect in

the population and also levels at which adverse effects occur. 

Methods for Determining Parent Compounds and Degradation Products in

Environmental Media. The purpose of the analytical methods for 2,3-benzofuran

is to identify contaminated areas and to determine if contaminant levels

constitute a concern for human health. The media of most concern for human 

exposure to 2,3-benzofuran are drinking water, soil, and air. It is likely

that 2,3-benzofuran exists in these media primarily adsorbed to organic-rich

particulates (Hassett et al. 1983). 2,3-Benzofuran has been found relatively

infrequently in environmental media, but most samples have excluded

particulates. Insufficient work has been done on quantification of

2,3-benzofuran, particularly percent recovery, to determine whether the

methods are sensitive enough to measure background levels in the environment

(Erikson and Pellizzari 1978; Hunt et al. 1982; Juttner 1986; Pellizzari

et al. 1979; Rostad et al. 1985; Seizinger and Dimitriades 1972). The levels

of 2,3-benzofuran at which health effects occur in animals are equivalent to

400 ppm in the diet or more (NTP 1989). Existing methods have nominal

detection limits of 0.1 ppb (Pellizzari et al. 1979; Seizinger and Dimitriades

1972), indicating that existing methods are probably sensitive enough to

detect levels at which health effects occur. The basic techniques of HRGC/MS

have the potential for excellent precision, accuracy, reliability, and

specificity, with sufficient research and development. One novel technique

which may be suitable for in situ monitoring of 2,3-benzofuran in water is

surface-enhanced Raman spectroscopy using silver electrodes (Carrabba et al.

1987). No information is available concerning degradation products of

2,3-benzofuran; investigation of 2,3-benzofuran degradation would be most

useful if it included development of reliable analytical methods. 
56 

6. ANALYTICAL METHODS 

6.3.2 On-going Studies 

No information was located concerning studies directed towards improving

methods for detection of 2,3-benzofuran specifically. 
57 

7. REGULATIONS AND ADVISORIES 

No regulations or advisories that apply specifically to 2,3-benzofuran

were located. 2,3-Benzofuran is one component of coumarone-indene resin and a

number of regulations and guidelines have been established for coumaron-eindene

resin by various national agencies. These values are summarized in

Table 7-l. 

________ 

59
 

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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 period. 

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

of studies, that produces significant increases in the incidence of cancer (or

tumors) between the exposed population and its appropriate control. 

Carcinogen -- A chemical capable of inducing cancer. 

Ceiling Value -- 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. 

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. 
70
 

9. GLOSSARY
 

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. 

Lethal Time(50) (LT50) -- 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. 

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

a study or group of studies, that produces statistically or biologically

significant increases in frequency or severity of adverse effects between the

exposed population and its appropriate control. 

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 chemical. 
71
 

9. GLOSSARY
 

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

there were 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-hour shift. 

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

curve as determined by the multistage procedure. The ql* 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-hour 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. 
72
 

9. GLOSSARY 

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-hour workday or 40-hour workweek. 

Toxic Dose (TD50) -- 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. 

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 human, (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. 
A-l 

APPENDIX A 

USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in nontechnical

language. Its intended audience is the general public especially people living

in the vicinity of a hazardous waste site or substance release. If the Public

Health Statement were removed from the rest of the document, it would still 

communicate to the lay public essential information about the substance. 

The major headings in the Public Health Statement are useful to find specific

topics of concern. The topics are written in a question and answer format. The

answer to each question includes a sentence that will direct the reader to

chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables (2-1, 2-2, and 2-3) and figures (2-l and 2-2) are used to summarize health

effects by duration of exposure and endpoint and to illustrate graphically levels

of exposure associated with those effects. All entries in these tables and

figures represent studies that provide reliable, quantitative estimates of

No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed- Adverse-Effect

Levels (LOAELs) for Less Serious and Serious health effects, or Cancer Effect

Levels (CELs). In addition, these tables and figures illustrate differences in

response by species, Minimal Risk Levels (MRLs) to humans for noncancer end

points, and EPA's estimated range associated with an upper-bound individual

lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and 

figures can be used for a quick review of the health effects and to locate data

for a specific exposure scenario. The LSE tables and figures should always be

used in conjunction with the text. 

The legends presented below demonstrate the application of these tables and

figures. A representative example of LSE Table 2-l and Figure 2-l are shown.

The numbers in the left column of the legends correspond to the numbers in the

example table and figure. 

LEGEND 

See LSE Table 2-l 

(1). Route of Exposure One of the first considerations when reviewing the

toxicity of a substance using these tables and figures should be the

relevant and appropriate route of exposure. When sufficient data exist, 
A-2
 

APPENDIX A
 

three LSE tables and two LSE figures are presented in the document. The

three LSE tables present data on the three principal routes of exposure,

i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3,

respectively). LSE figures are limited to the inhalation (LSE Figure 2-l)

and oral (LSE Figure 2-2) routes. 

(2). Exposure Duration Three exposure periods: acute (14 days or less);

intermediate (15 to 364 days); and chronic (365 days or more) are

presented within each route of exposure. In this example, an inhalation

study of intermediate duration exposure is reported. 

(3).	 Health Effect The major categories of health effects included in

LSE tables and figures are death, systemic, immunological,

neurological, developmental, reproductive, and cancer. NOAELs and

LOAELs can be reported in the tables and figures for all effects but

cancer. Systemic effects are further defined in the "System" column

of the LSE table. 

(4). Key to Figure Each key number in the LSE table links study information

to one or more data points using the same key number in the corresponding

LSE figure. In this example, the study represented by key number 18 has

been used to define a NOAEL and a Less Serious LOAEL (also see the two

"18r" data points in Figure 2-l). 

(5). Species The test species, whether animal or human, are identified in this

column. 

(6). Exposure Frequency/Duration The duration of the study and the weekly and

daily exposure regimen are provided in this column. This permits

comparison of NOAELs and LOAELs from different studies. In this case (key

number 18), rats were exposed to [substance x] via inhalation for 13

weeks, 5 days per week, for 6 hours per day. 

(7). System This column further defines the systemic effects. These systems

include: respiratory, cardiovascular, gastrointestinal, hematological,

musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any

systemic effect (e.g., a decrease in body weight) not covered in these

systems. In the example of key number 18, one systemic effect

(respiratory) was investigated in this study. 

(8).	 NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure

level at which no harmful effects were seen in the organ system studied.

Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was

used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see

footnote "c"). 

(9). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest

exposure level used in the study that caused a harmful health effect.

LOAELs have been classified into "Less Serious" and "Serious" effects. 

These distinctions help readers identify the levels of exposure at which

adverse health effects first appear and the gradation of effects with 
A-3
 

APPENDIX A
 

increasing dose. A brief description of the specific end point used to

quantify the adverse effect accompanies the LOAEL. The "Less Serious"

respiratory effect reported in key number 18 (hyperplasia) occurred at a

LOAEL of 10 ppm. 

(10). Reference The complete reference citation is given in Chapter 8 of the

profile. 

(11). CEL A Cancer Effect Level (CEL) is the lowest exposure level associated

with the onset of carcinogenesis in experimental or epidemiological

studies. CELs are always considered serious effects. The LSE tables and

figures do not contain NOAELs-for cancer, but the text may report doses

which did not cause a measurable increase in cancer. 

(12). Footnotes Explanations of abbreviations or reference notes for data in

the LSE tables are found in the footnotes. Footnote "c" indicates the 

NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. 

LEGEND 

See LSE Figure 2-l 

LSE figures graphically illustrate the data presented in the corresponding LSE

tables. Figures help the reader quickly compare health effects according to

exposure levels for particular exposure duration. 

(13). Exposure Duration The same exposure periods appear as in the LSE table.

In this example, health effects observed within the intermediate and

chronic exposure periods are illustrated. 

(14). Health Effect These are the categories of health effects for which

reliable quantitative data exist. The same health effects appear in the

LSE table. 

(15). Levels of Exposure Exposure levels for each health effect in the LSE

tables are graphically displayed in the LSE figures. Exposure levels are

reported on the log scale "y" axis. Inhalation exposure is reported in

mg/m3

 or ppm and oral exposure is reported in mg/kg/day. 

(16). NOAEL In this example, 18r NOAEL is the critical end point for which an

intermediate inhalation exposure MRL is based. As you can see from the

LSE figure key, the open-circle symbol indicates a NOAEL for the test

species (rat). The key number 18 corresponds to the entry in the LSE

table. The dashed descending arrow indicates the extrapolation from the

exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005

ppm (see footnote "b" in the LSE table). 

(17). CEL Key number 38r is one of three studies for which Cancer Effect Levels

(CELs) were derived. The diamond symbol refers to a CEL for the test

species (rat). The number 38 corresponds to the entry in the LSE table. 
A-4 

APPENDIX A 

(18). Estimated Upper-Bound Human Cancer Risk Levels This is the range

associated with the upper-bound for lifetime cancer risk of 1 in 10,000

to 1 in 10,000,000. These risk levels are derived from EPA's Human Health 

Assessment Group's upper-bound estimates of the slope of the cancer dose

response curve at low dose levels (q1*). 

(19). Key to LSE Figure The Key explains the abbreviations and symbols used in

the figure. 


A-7
 

APPENDIX A 

Chapter 2 (Section 2.4) 

Relevance to Public Health 

The Relevance to Public Health section provides a health effects summary based

on evaluations of existing toxicological, epidemiological, and toxicokinetic

information. This summary is designed to present interpretive,

weight-of-evidence discussions for human health end points by addressing the

following questions. 

1.	 What effects are known to occur in humans? 

2.	 What effects observed in animals are likely to be of concern to

humans? 

3.	 What exposure conditions are likely to be of concern to humans,

especially around hazardous waste sites? 

The section discusses health effects by end point. Human data are presented

first, then animal data. Both are organized by route of exposure (inhalation,

oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro

data and data from parenteral routes (intramuscular, intravenous, subcutaneous,

etc.) are also considered in this section. If data are located in the

scientific literature, a table of genotoxicity information is included. 

The carcinogenic potential of the profiled substance is qualitatively evaluated,

when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data.

ATSDR does not currently assess cancer potency or perform cancer risk

assessments. MRLs for noncancer end points if derived, and the end points from

which they were derived are indicated and discussed in the appropriate

section(s). 

Limitations to existing scientific literature that prevent a satisfactory

evaluation of the relevance to public health are identified in the Identification

of Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information was available, MRLs were derived. MRLs

are specific for route (inhalation or oral) and duration (acute, intermediate,

or chronic) of exposure. Ideally, MRLs can be derived from all six exposure

scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, ­

intermediate, - chronic). These MRLs are not meant to support regulatory action,

but to aquaint health professionals with exposure levels at which adverse health

effects are not expected to occur in humans. They should help physicians and

public health officials determine the safety of a community living near a

substance emission, given the concentration of a contaminant in air or the

estimated daily dose received via food or water. MRLs are based largely on

toxicological studies in animals and on reports of human occupational exposure. 
A-8
 

APPENDIX A
 

MRL users should be familiar with the toxicological information on which the

number is based. Section 2.4, "Relevance to Public Health," contains basic 

information known about the substance. Other sections such as 2.6, "Interactions 

with Other Chemicals" and 2.7, "Populations that are Unusually Susceptible"

provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are

derived using a modified version of the risk assessment methodology used by the

Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA 1989a) to

derive reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the end point which, in its best

judgement, represents the most sensitive human health effect for a given exposure

route and duration. ATSDR cannot make this judgement or derive an MRL unless

information (quantitative or qualitative) is available for all potential effects

(e.g., systemic, neurological, and developmental). In order to compare NOAELs

and LOAELs for specific end points, all inhalation exposure levels are adjusted

for 24hr exposures and all intermittent exposures for inhalation and oral routes

of intermediate and chronic duration are adjusted for continuous exposure (i.e.,

7 days/week). If the information and reliable quantitative data on the chosen

end point are available, ATSDR derives an MRL using the most sensitive species

(when information from multiple species is available) with the highest NOAEL that

does not exceed any adverse effect levels. The NOAEL is the most suitable end

point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL

can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed.

MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10

each are used for human variability to protect sensitive subpopulations (people

who are most susceptible to the health effects caused by the substance) and for

interspecies variability (extrapolation from animals to humans), In deriving an

MRL, these individual uncertainty factors are multiplied together. The product

is then divided into the adjusted inhalation concentration or oral dosage

selected from the study. Uncertainty factors used in developing a

substance-specific MRL are provided in the footnotes of the LSE Tables.