TOXICOLOGICAL PROFILE FOR

1,2,3-TRICHLOROPROPANE

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.
iii

FOREWORD

The Superfund Amendments and Reauthorization Act (SARA) of 1986

(Public Law 99-499) extended and amended the Comprehensive Environmental

Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).

This public law directed the Agency for Toxic Substances and Disease

Registry (ATSDR) to prepare toxicological profiles for hazardous

substances which are most commonly found at facilities on the CERCLA

National Priorities List and which pose the most significant potential

threat to human health, as determined by ATSDR and the Environmental

Protection Agency (EPA). The lists of the 250 most significant

hazardous substances were published in the Federal Register on April 17,

1987; on October 20, 1988; on October 26, 1989; and on October 17, 1990.

A revised list of 275 substances was published on October 17, 1991.

Section 104(i)(3) of CERCLA, as amended, directs the Administrator

of ATSDR to prepare a toxicological profile for each substance on the

lists. Each profile must include the following content:

(A) An examination, summary, and interpretation of available

toxicological information and epidemiological evaluations on the

hazardous substance in order to ascertain the levels of significant

human exposure for the substance and the associated acute,

subacute, and chronic health effects.

(B) A determination of whether adequate information on the health

effects of each substance is available or in the process of

development to determine levels of exposure which present a

significant risk to human health of acute, subacute, and chronic

health effects.

(C) Where appropriate, an identification of toxicological testing

needed to identify the types or levels of exposure that may present

significant risk of adverse health effects in humans.

This toxicological profile is prepared in accordance with

guidelines developed by ATSDR and EPA. The original guidelines were

published in the Federal Register on April 17, 1987. Each profile will

be revised and republished as necessary.

The ATSDR toxicological profile is intended to characterize

succinctly the toxicological and adverse health effects information for

the hazardous substance being described. Each profile identifies and

reviews the key literature (that has been peer-reviewed) that describes

a hazardous substance's toxicological properties. Other pertinent

literature is also presented but described in less detail than the key

studies. The profile is not intended to be an exhaustive document;

however, more comprehensive sources of specialty information are

referenced.









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1. PUBLIC HEALTH STATEMENT

This Statement was prepared to give you information about

1,2,3-trichloropropane and to emphasize the human health effects that may

result from exposure to it. The Environmental Protection Agency (EPA) has

identified 1,300 National Priorities List (NPL) sites. 1,2,3-Trichloropropane

has been found at 8 of these sites. However, we do not know how many of the

1,300 NPL sites have been evaluated for 1,2,3-trichloropropane. As EPA

evaluates more sites, the number of sites at which 1,2,3-trichloropropane is

found may change. The information is important for you because

1,2,3-trichloropropane may cause harmful health effects and because these

sites are potential or actual sources of human exposure to

1,2,3-trichloropropane.

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 substance such as 1,2,3-trichloropropane,

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 1,2,3-TRICHLOROPROPANE?

1,2,3-Trichloropropane is a colorless, heavy liquid with a sweet but

strong odor. It evaporates almost as fast as water does at normal

temperatures. Small amounts of 1,2,3-trichloropropane will dissolve in water.

1,2,3-Trichloropropane can dissolve several substances, such as oils and

waxes, the way water dissolves salt. For this reason, it has been and may

continue to be used as an industrial solvent, paint remover, and cleaner. We

do not know exactly how much of it is made or used now, but it may be a large

amount. Most of the 1,2,3-trichloropropane is used to make other substances.

In sunlight, 1,2,3-trichloropropane in the air will break down. Most of

the 1,2,3-trichloropropane that is released to the air will disappear in a

month. In water, half of it will evaporate into the air within hours or

several days. Very little of it will stick to the soil at the bottom of

rivers, lakes, or ponds, and very little of it will be expected to concentrate

in fish or other seafoods. 1,2,3-Trichloropropane will not stick to soil. If

it is spilled onto most soils, some will evaporate and some will travel

through the soil into the groundwater, where it may stay for a long time. It
2

1. PUBLIC HEALTH STATEMENT

may slowly change to a simpler form in water and soil by natural biological

and chemical processes.

You will find more information on the properties of 1,2,3-trichloropropane

in Chapters 3, 4, and 5.

1.2 HOW MIGHT I BE EXPOSED TO 1,2,3-TRICHLOROPROPANE?

If you live near a hazardous waste disposal site in which

1,2,3-trichloropropane is not stored properly, you could be exposed to

1,2,3-trichloropropane from breathing air or drinking water. Because

1,2,3-trichloropropane easily changes into a vapor, you are more likely to be

exposed from breathing air than from drinking water. A child playing in this

waste disposal site could be exposed by drinking liquids containing

1,2,3-trichloropropane, by eating soil coated with 1,2,3-trichloropropane, or

getting this soil or liquid on his or her skin.

You could be exposed to 1,2,3-trichloropropane in other ways that have

nothing to do with hazardous waste sites. For example, you may be exposed to

higher levels of 1,2,3-trichloropropane if you are using paint- and varnishremovers that contain it; however, some of these products may no longer

contain this chemical. If you breathe air near an accidental spill of

1,2,3-trichloropropane, you can be exposed to higher levels of the chemical.

Exposure in the workplace may result from spills or other accidents or from

normal operations in the workplace.

1,2,3-Trichloropropane is not common in the environment (air, water, and

soil), but it has been found in a few rivers, bays, drinking water,

groundwater, and hazardous waste sites at low levels. This is because

1,2,3-trichloropropane can enter the environment while it is being made, where

it is used to make or to dissolve other substances, or where it is released in

the waste that is made during these processes. Although 1,2,3-trichloropropane

is usually not found in the environment, disposal at hazardous waste

sites in the past, or release during spills and accidents have lead to higher

levels in nearby water, soil, and groundwater. Although we do not know

exactly how much 1,2,3-trichloropropane the general public or workers are

exposed to, the information that we have shows that the levels are probably

low and exposure probably does not occur often.

You can find more information in Chapter 5 on how much 1,2,3-

trichloropropane is in the environment and how you can be exposed to it.

1.3 HOW CAN 1,2,3-TRICHLOROPROPANE ENTER AND LEAVE MY BODY?

If you were to drink water containing 1,2,3-trichloropropane, most of

the chemical would pass into your body from your stomach and intestines within

the same day. 1,2,3-trichloropropane would also pass into your body from your

lungs if you were to breathe in air containing it or from your skin if you
3

1. PUBLIC HEALTH STATEMENT

were to touch it. However, we do not know how quickly or completely

1,2,3-trichloropropane passes into your body from your lungs or skin.

1,2,3-Trichloropropane that enters your body leaves your body almost

completely within a few days in your breath, urine, and feces. More

information on how 1,2,3-trichloropropane can enter and leave your body is

presented in Chapter 2.

1.4 HOW CAN 1,2,3-TRICHLOROPROPANE AFFECT MY HEALTH?

Some people who breathed air containing high levels of 1,2,3-

trichloropropane for several minutes had eye and throat irritation. These levels

of 1,2,3-trichloropropane are ikely to be much higher than levels usually found

in outdoor air, including air at hazardous waste sites. We do not know what

effects might occur in people who breath 1,2,3-trichloropropane for days,

weeks, or longer durations. We also do not know the possible effects of

1,2,3-trichloropropane in people who swallow 1,2,3-trichloropropane or get

1,2,3-trichloropropane on their skin.

Animals that breathed air containing 1,2,3-trichloropropane at levels

higher than those usually found in the environment developed other health

effects. Rats and mice died after they breathed air containing high levels of

1,2,3-trichloropropane for several hours, but we do not know the exact cause

of death. These levels of 1,2,3-trichloropropane are several times higher

than those that can cause eye and throat irritation in humans. Rats that

breathed 1,2,3-trichloropropane for a few months at levels lower than those

that affected humans developed eye, nose, and lung irritation and liver and

kidney disease.

Rats and mice usually died from damage to the liver and kidney within a

few days after they swallowed a large amount of 1,2,3-trichloropropane. Most

rats and mice that swallowed small amounts of 1,2,3-trichloropropane every day

for a few months also died from liver and kidney damage. Rats that swallowed

even smaller amounts of 1,2,3-trichloropropane every day for a few months did

not die but developed stomach irritation, blood disorders, and minor liver and

kidney damage.

Rabbits had severe skin irritation and even injury to internal organs,

including the liver, kidneys, and stomach after 1,2,3-trichloropropane was

applied to their skin in large amounts for 1 day. These injuries can result

in death. 1,2,3-Trichloropropane also caused eye irritation in rabbits and

rats when it was applied to the eyes.

We have limited knowledge of the effects in animals exposed to very

small amounts of 1,2,3-trichloropropane by breathing, swallowing, or skin

contact for many months or years leads to serious disease or death. Rats that

breathed low levels of 1,2,3-trichloropropane for several weeks or swallowed

large amounts of 1,2,3-trichloropropane for a few days did not develop

fertility problems, but we do not know whether breathing high levels of
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1. PUBLIC HEALTH STATEMENT

1,2,3-trichloropropane or swallowing 1,2,3-trichloropropane for more than a

few days affects fertility in animals. 1,2,3-Trichloropropane has not been

found to cause birth defects when injected in rats. We do not know whether

1,2,3-trichloropropane causes cancer in humans, but animals that swallowed low

doses of 1,2,3-trichloropropane for most of their lives developed cancer in a

number of organs.

More information on how 1,2,3-trichloropropane can affect health can be

found in Chapter 2.

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

1,2,3-TRICHLOROPROPANE?

Scientists can measure 1,2,3-trichloropropane in blood, urine, and

breath, but there are no readily available tests to determine whether you have

been exposed. We do not think these tests would be adequate to allow doctors

to predict harmful health effects. More information about tests for exposure

and effects can be found in Chapters 2 and 6.

1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH?

The federal government has a rule designed to protect workers who may be

exposed to 1,2,3-trichloropropane. The Occupational Safety and Health

Administration (OSHA) states that workers may not be exposed to average levels

of 1,2,3-trichloropropane greater than 10 ppm in air during an 8-hour workday.

The federal government has no recommendations on environmental exposure to

1,2,3-trichloropropane. More information on regulations and advisories 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 1,2,3-trichloropropane

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 1,2,3-trichloropropane 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 (more than 365 days).

Levels of significant exposure for each route and duration are presented

in Tables 2-1, 2-2 and 2-3 and illustrated in Figures 2-1 and 2-2. The points

in the figures showing no-observed-adverse-effect levels (NOAELS) or lowestobserved-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.

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.
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2. HEALTH EFFECTS

Although methods have been established to derive these levels (Barnes et

al. 1988; EPA 1989a), 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

2.2.1.1 Death

No studies were located regarding death in humans after inhalation

exposure to 1,2,3-trichloropropane.

Exposure to 1,2,3-trichloropropane of unknown purity for 4-6 hours

caused death in mice at concentrations as low as 343 ppm (Gushow and Quast

1984) and rats at concentrations as low as 500 ppm (Union Carbide 1958). An

intermediate-duration study showed that intermittent exposure to 297 ppm and

higher concentrations of 1,2,3-trichloropropane for 4 weeks was lethal in rats

(Johannsen et al. 1988). The available data suggest that 1,2,3-trichloropropane

concentrations producing death in rodents may be similar (i.e.,

approximately 300 ppm) for acute- and intermediate-duration exposures of

several weeks. The cause of death is unclear, but signs suggestive of central

nervous system (CNS) impairment (e.g., incoordination and convulsions) have

been observed prior to death in both species. The highest NOAEL values and

all reliable LOAEL values for death in both species and duration categories

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

2.2.1.2 Systemic Effects ,

Systemic effects of inhaled 1,2,3-trichloropropane are discussed below.

The highest NOAEL values and all reliable LOAEL values for these effects in

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

Figure 2-l.

Respiratory Effects. Limited information indicates that brief exposure

(15 minutes) to 100 ppm 1,2,3-trichloropropane (purity unknown) can cause

throat irritation in humans (Silverman et al. 1946).

Repeated exposure of animals to 1,2,3-trichloropropane concentrations

much lower than 100 ppm causes respiratory system effects that are indicative

of irritant action. Intermittent 4-hour exposures for 11 days produced

alterations in nasal tissues of rats and mice, particularly of the olfactory

epithelium (Miller et al. 1986a, 1986b). These changes included decreased

thickness of the olfactory epithelium in rats at 3 ppm, degeneration of the





12

2. HEALTH EFFECTS

olfactory epithelium in rats at 10 ppm and higher concentrations, and

inflammation and decreased thickness of the olfactory epithelium in mice at

lo-13 ppm with degeneration at higher concentrations. Based on the NOAEL of

1 ppm for these effects in rats, an acute inhalation MEL of 0.0003 ppm was

calculated as described in the footnote in Table 2-l. Intermittent exposure

to slightly higher concentrations of 1,2,3-trichloropropane (4.5 ppm) or more

for 13 weeks caused focal peribronchial hyperplasia in rats (Johannsen et al.

1988). Intermittent exposure to 132 ppm for 11 days caused nasal submucosal

fibrosis in rats (Miller et al. 1986a).

Cardiovascular Effects. No studies were located regarding

cardiovascular effects in humans after inhalation exposure to

1,2,3-trichloropropane.

There were no histopathological changes in the hearts of rats and mice

that were intermittently exposed to concentrations as high as 132 ppm

1,2,3-trichloropropane for 11 days (Miller et al. 1986a) or rats that were

similarly exposed to up to 49 ppm 1,2,3-trichloropropane for 13 weeks

(Johannsen et al. 1988).

Gastrointestinal Effects. No studies were located regarding

gastrointestinal effects in humans after inhalation exposure to

1,2,3-trichloropropane.

There were no histopathological changes in the stomach and intestines of

rats and mice that were intermittently exposed to concentrations as high as

132 ppm 1,2,3-trichloropropane for 11 days (Miller et al. 1986a) or rats that

were similarly exposed to up to 49 ppm 1,2,3-trichloropropane for 13 weeks

(Johannsen et al. 1988).

Hematological Effects. No studies were located regarding hematological

effects in humans after inhalation exposure to 1,2,3-trichloropropane.

Hematological evaluations were normal in rats and mice that were

intermittently exposed to concentrations as high as 132 ppm

1,2,3-trichloropropane for 11 days (Miller et al. 1986a). Hematological

evaluations of rats that were similarly exposed to up to 49 ppm

1,2,3-trichloropropane for 13 weeks also were normal, but splenic

hematopoiesis was increased at 4.5 ppm or more (Johannsen et al. 1988).

Although increased splenic hematopoiesis was observed, other hematology

parameters were unremarkable. Spleen weights were decreased in rats that were

intermittently exposed to 579 ppm 1,2,3-trichloropropane for 4 weeks, but the

hematological significance of this effect cannot be determined because

evaluation of hematology and histology was not performed (Johannsen et al.

1988).
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2. HEALTH EFFECTS

Musculoskeletal Effects. No studies were located regarding

musculoskeletal effects in humans after inhalation exposure to

1,2,3-trichloropropane.

There were no histopathological changes in the skeletal muscle or bone

of rats and mice that were intermittently exposed to concentrations as high as

132 ppm 1,2,3-trichloropropane for 11 days (Miller et al. 1986a) or rats that

were similarly exposed to up to 49 ppm 1,2,3-trichloropropane for 13 weeks

(Johannsen et al. 1988).

Hepatic Effects. No studies were located regarding hepatic effects in

humans after inhalation exposure to 1,2,3-trichloropropane.

Acute and intermediate duration inhalation exposure to

1,2,3-trichloropropane causes increased liver weight in rats and mice.

Increased liver weight was produced by intermittent exposure to 132 ppm for

11 days (Miller et al. 1986a), 95 ppm or more for 4 weeks (Johannsen et al.

1988), and 4.5 ppm or more for 13 weeks (Johannsen et al. 1988). Mild

hepatocellular hypertrophy occurred in most of the rats exposed to 4.5 ppm or

more in the 13-weeks study. Although not accompanied by serious histological

alterations, the increased liver weight may represent an adverse effect

because oral exposure studies (see discussion of Hepatic Effects in

Section 2.2.2.2) indicate that this effect is a manifestation of

1,2,3-trichloropropane-induced hepatotoxicity.

Renal Effects. No studies were located regarding renal effects in

humans after inhalation exposure to 1,2,3-trichloropropane.

Intermittent exposure to 297 ppm or more 1,2,3-trichloropropane for

4 weeks and 49 ppm for 13 weeks caused increased kidney weights without

histopathology in rats (Johannsen et al. 1988). As with liver weight changes,

the increased kidney weight may represent an adverse effect because oral

exposure studies indicate that the increased weight is a manifestation of

1,2,3-trichloropropane-induced nephrotoxicity (see discussion of Renal Effects

in Section 2.2.2.2.).

Dermal/Ocular Effects. Limited information indicates that brief

(15-minute) exposure to 100 ppm 1,2,3-trichloropropane vapor causes eye

irritation in humans (Silverman et al. 1946).

A single 4-hour exposure to vapor concentrations as low as 126 ppm

1,2,3-trichloropropane (Gushow and Quast 1984) caused eye irritation in rats

and mice. Repeated intermittent exposure to vapor concentrations as low as

15 ppm for 13 weeks (Johannsen et al. 1988) caused eye irritation in rats.

Other Systemic Effects. No studies were located regarding other

systemic effects in humans after inhalation exposure to

1,2,3-trichloropropane.
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2. HEALTH EFFECTS

Intermittent exposure to 1,2,3-trichloropropane concentrations as high

as 132 ppm for 11 days did not adversely affect body weight gain in rats or

mice (Miller et al. 1986a). Body weight gain was decreased in rats that were

intermittently exposed to lethal concentrations (297 ppm or more) of

1,2,3-trichloropropane for 4 weeks and concentrations as low as 15 ppm

1,2,3-trichloropropane for 13 weeks (Johannsen et al. 1988). The decreased

weight gain was more severe at higher concentrations and there was initial

weight loss at 600 ppm in the 4-week study.

2.2.1.3 Immunological Effects

No studies were located regarding immunological effects in humans after

inhalation exposure to 1,2,3-trichloropropane.

There were no histopathological alterations in the thymus, spleen,

lymphoid tissue, or bone marrow of rats and mice that were intermittently

exposed to concentrations as high as 132 ppm 1,2,3-trichloropropane for

11 days (Miller et al. 1986a) or rats that were similarly exposed to up to

49 ppm for 13 weeks (Johannsen et al. 1988). Intermittent exposure to a

higher (lethal) concentration (579 ppm) for 4 weeks caused decreased spleen

weight in rats (Johannsen et al. 1988). Due to the lack of histological

examinations and immunoassays, the immunological significance of the decreased

spleen weight cannot be determined.

2.2.1.4 Neurological Effects

No studies were located regarding neurological effects in humans after

inhalation exposure to 1,2,3-trichloropropane.

No histopathological effects were observed in the brain, spinal cord,

and peripheral nerves of rats and mice that were intermittently exposed to

concentrations as high as 132 ppm 1,2,3-trichloropropane for 11 days (Miller

et al. 1986a). No effect was observed on brain and spinal cord histology and

brain weight in rats that were intermittently exposed to up to 49 ppm for

13 weeks (Johannsen et al. 1988). These data do not necessarily mean that

1,2,3-trichloropropane is not neurotoxic, however, due to a lack of

neurological evaluations. Brain weight was increased in rats exposed to 297

or 579 ppm 1,2,3-trichloropropane for 4 weeks (Johannsen et al., 1988), but it

is unclear if absolute or relative brain weight was increased. The rats in

the 4-week study were hypoactive and had labored breathing, but were not

subjected to histological and neurological evaluations. Due to the lack of

histological and neurological evaluations, signs attributable specifically to

CNS impairment, and sufficient information to determine if relative brain

weight was increased (which could reflect decreased body weight), the

neurological significance of the increased brain weight cannot be determined.
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2. HEALTH EFFECTS

2.2.1.5 Developmental Effects

No studies were located regarding developmental effects in humans after

inhalation exposure to 1,2,3-trichloropropane.

Limited information regarding developmental effects of inhaled

1,2,3-trichloropropane in animals is available from a reproduction study in

which male and female rats were intermittently exposed to concentrations as

high as 15 ppm prior to mating, during mating, and during gestation (Johannsen

et al. 1988). There were no effects on gestation length, and pup viability

and weight at birth and during lactation were normal. These data incompletely

characterize developmental toxicity because the fetuses were not examined for

teratogenicity.

2.2.1.6 Reproductive Effects

No studies were located regarding reproductive effects in humans after

inhalation exposure to 1,2,3-trichloropropane.

In the only inhalation reproductive study of 1,2,3-trichloropropane,

male and female rats were intermittently exposed to concentrations of

0.49-15 ppm prior to mating, during mating, and during gestation (Johannsen et

al. 1988). There were no effects on mating performance or fertility in either

sex, but the data for the males at 4.5 ppm and higher concentrations are

inconclusive because the control group for these males had low mating

performance compared to another male control group. The highest NOAEL value

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

Studies with animals exposed to higher concentrations of

1,2,3-trichloropropane have examined effects on reproductive organs.

Intermittent expcsure to less than or equal to 132 ppm for 11 days (Miller et

al. 1986b) and less than or equal to 49 ppm 1,2,3-trichloropropane for

13 weeks (Johannsen et al. 1988) had no effect on the weights or histology of

the reproductive organs of male and female rats. Intermittent exposure to

1,2,3-trichloropropane for 4 weeks at concentrations that caused some deaths

decreased ovary weights (greater than or equal to 297 ppm) and testes weights

(579 ppm) in rats, but these organs were not examined histologically

(Johannsen et al. 1988). Reproductive function was not evaluated in any of

these studies. Because of incomplete information on reproductive organ

histology and lack of information regarding sperm counts and reproductive

function, conclusions regarding the reproductive toxicity of

1,2,3-trichloropropane cannot be drawn from these studies.

2.2.1.7 Genotoxic Effects

No studies were located regarding genotoxicity in humans or animals

after inhalation exposure to 1,2,3-trichloropropane. Other mutagenicity

studies are discussed in Section 2.4.
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2. HEALTH EFFECTS

2.2.1.8 Cancer

No studies were located regarding carcinogenicity in humans or animals

after inhalation exposure to 1,2,3-trichloropropane.

2.2.2 Oral Exposure

2.2.2.1 Death

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

1,2,3-trichloropropane.

Oral LD50 values as low as 150 mg/kg have been determined for rats

(Alpert 1982; Smyth et al. 1962). Variations in LD50 .values are apparent,

which could be due to differences in animal strain, sex, fed/fasted state or

compound purity. The cause of death is unclear, but signs suggestive of CNS

impairment (e.g., piloerection, salivation, ataxia, coma) prior to death and

hemorrhagic damage in visceral tissues (e.g., liver, kidney) were observed.

Daily gavage administration of 1,2,3-trichloropropane caused death due to

liver and kidney toxicity in 15% of female rats by the 13th week at a dose of

125 mg/kg, in 100% of female rats by week 2 at 250 mg/kg, and in 80% of female

mice by week 4 at 250 mg/kg (NTP 1983a, 1983b). Mortality occurred at a lower

rate or occurred later in similarly treated male rats and mice. Lethal gavage

doses of 1,2,3-trichloropropane in rodents, therefore, appear to be similar

for acute exposures and intermediate-duration exposures of several weeks.

Doses as high as 149 mg/kg/day were not lethal in rats, however, when

administered in the drinking water for the 13 weeks (Villeneuve et al. 1985).

Although absorption of 1,2,3-trichloropropane from drinking water could have

been decreased due to use of a solubilizer, this suggests that

1,2,3-trichloropropane may be less toxic when ingested gradually throughout

the day than when administered as a bolus. The highest NOAEL values and all

reliable LOAEL values for death for both species and duration categories are

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

2.2.2.2 Systemic Effects

Systemic effects resulting from oral exposure to 1,2,3-trichloropropane

are discussed below. The highest NOAEL values and all reliable LOAEL values

for these effects in each species and duration category are recorded in

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

Respiratory Effects. No studies were located regarding respiratory

effects in humans after oral exposure to 1,2,3-trichloropropane.

Two animal studies showed that 1,2,3-trichloropropane produced

pathologic changes in the nasal turbinates of rats and mice when administered

by oral intubation (NTP 1983a, 1983b). These changes were produced by daily






23

2. HEALTH EFFECTS

doses of 250 mg/kg (rats and mice) for 2 weeks and 125 mg/kg (rats) or

250 mg/kg (mice) for up to 17 weeks. Effects were similar in both species;

these typically included inflammation, attenuation of the epithelial lining, '

and necrotic alterations, and principally occurred in the dorsal posterior of

the nasal passages. These effects are similar to those caused by inhalation

exposure to 1,2,3-trichloropropane (see discussion of Respiratory Effects in

Section 2.2.1.2.) The oral doses that produced the nasal alterations were in

the near lethal range. Repeated daily exposure of mice to lower doses of

1,2,3-trichloropropane (as low as 63 mg/kg) by oral intubation over a period

of 17 weeks caused regenerative changes (e.g., hyperplasia) in the bronchiolar

epithelium that did not progress or regress with continued exposure. It is

possible that the nasal and pulmonary effects caused by oral treatment were

due to inadvertent local exposure (see discussion of Systemic Effects in

Section 2.4.) or excretion of 1,2,3-trichloropropane or its metabolites in the

breath (see Section 2.3.4).

Cardiovascular Effects. No studies were located regarding

cardiovascular effects in humans after oral exposure to

1,2,3-trichloropropane.

Two animal studies found that daily administration of

1,2,3-trichloropropane by gavage over a period of 17 weeks caused decreased

heart weight without histological alterations in rats and mice at doses up to

125 and 250 mg/kg, respectively (NTP 1983a, 1983b). This effect is not

considered adverse, due to the lack of histopathology. There was no effect on

heart weight or histology in rats that were administered

1,2,3-trichloropropane in the drinking water at doses as high as 149 mg/kg/day

for 13 weeks (Villeneuve et al. 1985).

Gastrointestinal Effects. No studies were located regarding

gastrointestinal effects in humans after oral exposure to

1,2,3-trichloropropane.

Two animal studies found that daily administration of

1,2,3-trichloropropane over a period of 17 weeks caused gastrointestinal

effects indicative of irritant action, particularly increased hyperkeratosis

and/or acanthosis of the esophagus and stomach (NTP 1983a, 1983b). These

effects occurred at doses of 63 mg/kg/day and higher in mice and 125 mg/kg/day

in rats.

Hematological Effects. No studies were located regarding hematological

effects in humans after oral exposure to 1,2,3-trichloropropane.

One study found evidence of anemia, indicated by decreased hematocrit,

hemoglobin, and erythrocyte counts, in rats that were administered

1,2,3-trichloropropane by gavage at doses as low as 16 mg/kg/day over a period

of 17 weeks (NTP 1983a). The anemia was mild at the lower doses and appears

to be nonregenerative and associated with depressed erythropoiesis. Higher
24

2. HEALTH EFFECTS

doses (63 mg/kg/day or more) in this gavage study produced histological

alterations in the spleen (lymphoid depletion) of rats, and mice similarly

treated with 250 mg/kg/day 1,2,3-trichloropropane had splenic lymphoid

depletion with occasional lymphoid necrosis (NTP 1983b). The hematological

significance of these splenic effects is unknown because hematology was normal

except for the anemia in rats. 1,2,3-Trichloropropane did not produce

significant hematological alterations in rats when administered in the

drinking water at doses as high as 149 mg/kg/day for 13 weeks (Villeneuve et

al. 1985).

Musculoskeletal Effects. No studies were located regarding

musculoskeletal effects in humans after oral exposure to

1,2,3-trichloropropane.

There were no pathological effects in bone or skeletal muscle of rats

and mice that were administered 1,2,3-trichloropropane at doses as high as 125

and 250 mg/kg, respectively, over a period of 17 weeks (NTP 1983a, 1983b).

Hepatic Effects. No studies were located regarding hepatic effects in

humans after oral exposure to 1,2,3-trichloropropane.

Liver toxicity is a major systemic effect of orally administered

1,2,3-trichloropropane in animals. Daily gavage doses of 250 mg/kg produced

hepatotoxicity (e.g., necrosis) severe enough to contribute to death in rats

and mice within 2 weeks (NTP 1983a, 1983b). Necrotic changes also occurred in

the livers of rats and mice treated with daily gavage doses as low as

125 mg/kg over a period of 17 weeks (NTP 1983a, 1983b). Similar doses of

1,2,3-trichloropropane (113 or 149 mg/kg) administered in drinking water for

13 weeks produced mild hepatic changes (e.g., occasional fatty vacuolization

and biliary hyperplasia) in rats (Villeneuve et al., 1985), suggesting that

1,2,3-trichloropropane may be less toxic when ingested gradually throughout

the day than when administered as a bolus. One study found hepatic effects in

rats treated by gavage with doses as low as 16 mg/kg/day over a period of

17 weeks (NTP 1983a). These effects included decreased serum

pseudocholinesterase activity and increased liver weight. It is likely that

the decreased serum pseudocholinesterase activity is attributable to depressed

synthesis resulting from hepatocellular damage, but it could indicate that

1,2,3-trichloropropane inhibits pseudocholinesterase. Based on the NOAEL

(8 mg/kg) for these effects, which is the same as the NOAEL for anemia in rats

(see discussion of Hematologic Effects in Section 2.2.2.2), an intermediate

oral MRL of 0.06 mg/kg/day was calculated as described in a footnote to

Table 2-2.

Renal Effects. No studies were located regarding renal effect in humans

after oral exposure to 1,2,3-trichloropropane.

Kidney toxicity is a major systemic effect of orally administered

1,2,3-trichloropropane in animals. Daily gavage doses of 250 mg/kg produced
25

2. HEALTH EFFECTS

serious renal toxicity (e.g., tubular nephropathy, necrosis) in rats and mice

within 2 weeks (NTP 1983a, 1983b). The kidney damage in rats was severe

enough to contribute to death. Necrotic changes occurred in the kidneys of

rats and mice treated with daily gavage doses as low as 125 mg/kg over a

period of 17 weeks (NTP 1983a, 1983b). Similar doses of

1,2,3-trichloropropane (113 or 149 mg/kg) administered in drinking water for

13 weeks produced mild renal changes (e.g., pyknosis, fine glomular adhesions,

and occasional histologic proteinuria) in rats (Villeneuve et al. 1985). The

term "histologic proteinuria" presumably refers to protein in the lumen of

tubules. The mild renal changes suggest that 1,2,3-trichloropropane may be

less toxic when ingested gradually throughout the day than when administered

as a bolus. Daily gavage doses as high as 60 mg/kg for 2 weeks did not

produce renal histological alterations in rats (Dix 1979), but rats treated

with gavage doses as low as 32 mg/kg/day over a period of 17 weeks displayed

less serious renal effects consisting of increased kidney weight and minimal

inflammation (NTP 1983a).

Dermal/Ocular Effects. No studies were located regarding dermal or

ocular effects in humans after oral exposure to 1,2,3-trichloropropane.

Daily gavage administration of 1,2,3-trichloropropane at doses of

63 mg/kg or more for up to 17 weeks caused alopecia but no gross eye

irritation in rats (NTP 1983a). Mice that were similarly treated with up to

250 mg/kg 1,2,3-trichloropropane had no macroscopic skin lesions or gross eye

irritation (NTP 1983b).

Other Systemic Effects. No studies were located regarding other

systemic effects in humans after oral exposure to 1,2,3-trichloropropane.

Reduced body weight gain occurred in rats treated with

1,2,3-trichloropropane by gavage at doses of 60 mg/kg/day for 2 weeks (Dix

1979) or 63 or 125 mg/kg/day for up to 17 weeks (NTP 1983a). Thyroid

histology, evaluated in the rats treated for up to 17 weeks, was normal.

Doses of 113 or 149 mg/kg/day, when administered in the drinking water for

13 weeks, caused reduced body weight gain and thyroid histological alterations

in rats (Villeneuve et al. 1985). Decreased weight gain without abnormal

thyroid histology occurred in mice that were treated with 250 mg/kg/day by

gavage for up to 17 weeks (NTP 1983b).

2.2.2.3 Immunological Effects

No studies were located regarding immunological effects in humans after

oral exposure to 1,2,3-trichloropropane.

Lymphoid depletion was observed in the spleen and thymus of rats that

were administered 1,2,3-trichloropropane at doses greater than or equal to

63 mg/kg/day over 17 weeks (NTP 1983a). Mice that were similarly treated with

lethal doses (250 mg/kg) showed splenic lymphoid depletion with occasional
26

2. HEALTH EFFECTS

lymphoid necrosis and increased thymus weight. The immunological significance

of these effects are not known.

2.2.2.4 Neurological Effects

No studies were located regarding neurological effects in humans after

oral exposure to 1,2,3-trichloropropane.

There were no treatment-related changes in brain weight or brain

histology in rats and mice that were administered 1,2,3-trichloropropane doses

as high as 250 mg/kg/day for periods as long as 17 weeks (NTP 1983a, 1983b).

These data do not necessarily mean that 1,2,3-trichloropropane is not

neurotoxic, however, due to a lack of neurological evaluations.

2.2.2.5 Developmental Effects

No studies were located regarding developmental effects in humans or

animals after oral exposure to 1,2,3-trichloropropane.

2.2.2.6 Reproductive Effects

No studies were located regarding reproductive effects in humans after

oral exposure to 1,2,3-trichloropropane.

No effects on mating, fertility, or histological appearance of the

testes were found in male rats that were treated with 80 mg/kg/day

1,2,3-trichloropropane for 5 days in a dominant lethal mutation study (SaitoSuzuki et al. 1982). Testis and epididymis weights were decreased in rats and

mice that were administered 1,2,3-trichloropropane doses as high as 125 mg/kg

for 60-120 days, but testicular histology, sperm counts, and sperm morphology

were normal or inconclusive (NTP 1983a, 1983b). Although a definite

conclusion regarding the reproductive toxicity of 1,2,3-trichloropropane in

this study is precluded by a lack of information on reproductive function and

the short exposure duration, the doses are considered NOAELs because the lack

of testicular histological lesions and effects on sperm reduces concern that

the decreased testicular and epididymal weights reflect a biologically

significant change. The NOAEL values for reproductive effects in both species

and duration categories are recorded in Table 2-2 and plotted in Figure 2-2.

2.2.2.7 Genotoxic Effects

No studies were located regarding genotoxic effects in humans after oral

exposure to 1,2,3-trichloropropane.

As indicated in Section 2.2.2.6, orally administered

1,2,3-trichloropropane did not produce dominant lethal mutations in male rats

(Saito-Suzuki et al. 1982). Other mutagenicity studies are discussed in

Section 2.4.
27

2. HEALTH EFFECTS

2.2.2.8 Cancer

No studies were located regarding carcinogenicity in humans after oral

exposure to 1,2,3-trichloropropane.

1,2,3-Trichloropropane has been demonstrated to be carcinogenic in a

variety of organs in Fischer-344 rats and B6C3Fl mice when administered by

gavage in corn oil in a 2-year study (NTP 1991). In male rats treated with

23 mg/kg/day, clear evidence of carcinogenicity was found, based on increased

incidences of squamous cell papilloma and carcinoma of the oral mucosa and/or

forestomach, pancreatic acinar adenoma, renal tubule adenoma, and preputial

gland adenoma and carcinoma. In female rats similarly treated, clear evidence

of carcinogenicity was also found, based on increased incidences of squamous

cell papilloma and carcinoma of the oral mucosa and forestomach, clitoral

gland adenoma and carcinoma, and mammary gland adenocarcinoma. High

incidences of Zymbal's gland carcinoma and intestinal adenocarcinoma were also

found in the male and female rats, and may be related to the

1,2,3-trichloropropane exposure.

Clear evidence of carcinogenicity was also found in male and female mice

treated with 6 mg/kg/day or greater (NTP 1991). The evidence consisted of

increased incidences of squamous cell carcinoma of the oral mucosa (females),

squamous cell papilloma and carcinoma of the forestomach (males and females),

hepatocellular adenoma or carcinoma (males and females), Harderian gland

adenoma (male and female), and uterine adenoma, adenocarcinoma, and stromal

polyp (females). High dose male mice (60 mg/kg/day) also had squamous cell

papilloma of the oral mucosa, which occurred in low incidence, but was

probably related to 1,2,3-trichloropropane treatment.

The lowest doses associated with cancer in rats and mice are recorded in

Table 2-2 and plotted in Figure 2-2 as Cancer Effect Levels (CELs).

2.2.3 Dermal Exposure

2.2.3.1 Death

No studies were located regarding death in humans after dermal exposure

to 1,2,3-trichloropropane.

Single dermal doses as low as 250 mg/kg caused death in rabbits (Alpert

1982). A dermal LD50 of 836 mg/kg has been determined for rats using

1,2,3-trichloropropane of relatively low purity (92%) (Clark 1977). The

treated skin of the animals in these studies was covered with an impervious

barrier for 24 hours to prevent evaporation of the volatile compound. The

cause of death is unclear, but symptoms suggestive of CNS impairment (e.g.,

ataxia, tremors, coma) and internal hemorrhage have been observed. Lethal
28

2. HEALTH EFFECTS

dermal doses of 1,2,3-trichloropropane in these species are recorded in

Table 2-3.

2.2.3.2 Systemic Effects

Systemic effects resulting from dermal exposure to 1,2,3-trichloropropane

are discussed below. The highest NOAEL values and all reliable LOAEL

values for these effects in each species and duration category are recorded in

Table 2-3.

No studies were located regarding cardiovascular, hematological, or

musculoskeletal effects in humans or animals after dermal exposure to

1,2,3-trichloropropane.

Respiratory Effects. No studies were located regarding respiratory

effects in humans after dermal exposure to 1,2,3-trichloropropane.

Lung hemorrhage and apparently related effects (e.g., discoloration of

the lungs and liquid in the thoracic cavity) have been observed in rabbits

exposed to lethal dermal doses of 1,2,3-trichloropropane (Alpert 1982; Union

Carbide 1958).

Gastrointestinal Effects. No studies were located regarding

gastrointestinal effects in humans after dermal exposure to

1,2,3-trichloropropane.

Ulceration of the stomach wall was observed in rabbits exposed to lethal

dermal doses of 1,2,3-trichloropropane (Alpert 1982).

Hepatic Effects. No studies were located regarding hepatic effects in

humans after dermal exposure to 1,2,3-trichloropropane.

Turgid and discolored livers were observed in rabbits exposed to lethal

dermal doses of 1,2,3-trichloropropane (Alpert 1982; Union Carbide 1958).

These macroscopic alterations are consistent with oral and inhalation evidence

of hepatotoxicity.

Renal Effects. No studies were located regarding renal effects in

humans after dermal exposure to 1,2,3-trichloropropane.

Discolored kidneys and hematuria were observed in rabbits exposed to

lethal dermal doses of 1,2,3-trichloropropane (Alpert 1982; Union Carbide

1958). These macroscopic alterations are consistent with oral and inhalation

evidence of renal toxicity.

Dermal/Ocular Effects. No studies were located regarding dermal effects

in humans after dermal exposure to 1,2,3-trichloropropane. Limited

information indicates that brief (15-minute) exposure to 100 ppm


31

2. HEALTH EFFECTS

1,2,3-trichloropropane vapor causes eye irritation in humans (Silverman et al.

1946).

1,2,3-Trichloropropane vapor caused eye irritation in rats and mice

exposed for 4 hours to concentrations as low as 126 ppm (Gushow and Quast

1984) and in rats exposed intermittently to concentrations as low as 15 ppm

over a period of 13 weeks (Johannsen et al. 1988). Ocular application of

1,2,3-trichloropropane caused eye irritation in rabbits (Alpert 1982; Clark

1977).

Dermal application of 1,2,3-trichloropropane causes severe skin

irritation in rabbits. Evidence suggests that prolonged exposure (e.g., for

24 hours) or repeated daily application (e.g., for 2 weeks) may be necessary

to cause irritation (Clark 1977; McOmie and Barnes 1949). The results of one

study suggest that 1,2,3-trichloropropane in corn oil vehicle was a very mild

skin sensitizer in guinea pigs (Clark 1977). Another study that used a less

sensitive procedure found no evidence of skin sensitization by undiluted

1,2,3-trichloropropane in guinea pigs (Alpert 1982). This study also found

that corn oil itself was a mild skin sensitizer in guinea pigs, indicating

that there is a possibility that the vehicle may enhance the weak effect

observed by Clark (1977).

2.2.3.3 Immunological Effects

No studies were located regarding immunological effects in humans after

dermal exposure to 1,2,3-trichloropropane.

As indicated in the discussion of Dermal/Ocular Effects in

Section 2.2.3.2, one study provides limited evidence that

1,2,3-trichloropropane may be a very weak dermal sensitizer in animals (Clark

1977).

No studies were located regarding the following effects in humans or

animals after dermal exposure to 1,2,3-trichloropropane:

2.2.3.4 Neurological Effects

2.2.3.5 Developmental Effects

2.2.3.6 Reproductive Effects

2.2.3.7 Genotoxic Effects

Other mutagenicity studies are discussed in Section 2.4.

2.2.3.8 Cancer

No studies were located regarding carcinogenicity in humans or animals

after inhalation exposure to 1,2,3-trichloropropane.
32

2. HEALTH EFFECTS

2.3 TOXICOKINETICS

2.3.1 Absorption

2.3.1.1 Inhalation Exposure

No quantitative information was located regarding absorption of

1,2,3-trichloropropane in humans or animals following inhalation exposure;

however, since liver and kidney toxicity has been reported in animals exposed

by the inhalation route (see discussions of Hepatic Effects and Renal Effects

in Section 2.2.1.2), it can be concluded that absorption occurs to some

extent.

2.3.1.2 Oral Exposure

No quantitative information was located regarding absorption of

1,2,3-trichloropropane in humans following oral exposure.

The results of studies performed in rats indicate that near complete

absorption (greater than 80%) from the gastrointestinal tract occurs within

the first day following oral exposure (Sipes et al. 1982; Volp et al. 1984).

2.3.1.3 Dermal Exposure

No quantitative information was located regarding absorption of

1,2,3-trichloropropane in humans or animals following dermal exposure.

However, internal pathology and death have been reported in animals exposed by

the-dermal route (see Sections 2.2.3.1 and 2.2.3.2). Since vapor exposure was

unlikely due to occlusive covering of the treatment area, it can be concluded

that dermal absorption occurs to some extent.

2.3.2 Distribution

2.3.2.1 Inhalation Exposure

No information was located regarding the distribution of

1,2,3-trichloropropane in humans or animals following inhalation exposure.

2.3.2.2 Oral Exposure

No information was located regarding the distribution of

1,2,3-trichloropropane in humans following oral exposure.

Muscle, blood, liver, skin, and adipose tissue contained the largest

amounts of 1,2,3-trichloropropane following oral exposure in rats (Sipes et

al. 1982). Retention in all tissues was low, however, as elimination of

1,2,3-trichloropropane-derived radioactivity from tissues was nearly complete

(greater than 97%) within 8 days after exposure.
33

2. HEALTH EFFECTS

Elimination of 1,2,3-trichloropropane from tissues is nearly complete

(greater than 97%) within 8 days after oral exposure in rats (Sipes et al.

1982).

2.3.2.3 Dermal Exposure

No information was located regarding the distribution of

1,2,3-trichloropropane in humans or animals following dermal exposure.

2.3.2.4. Other Routes of Exposure

No information was located regarding the distribution of

1,2,3-trichloropropane in humans following exposure by other routes.

Distribution studies of intravenously injected 1,2,3-trichloropropane in

rats have provided a quantitative description of the distribution kinetics

from which predictions can be made regarding other routes of exposure (Sipes

et al. 1982; Volp et al. 1984). Intravenously injected 1,2,3-trichloropropane

rapidly distributes to many tissues. The major sites of accumulation are

liver, kidney, small and large intestine, adipose tissue, muscle, and skin.

Peak concentrations are achieved within l-2 hours after intravenous injection.

Elimination of 1,2,3-trichloropropane from tissues in the rat is also

rapid and a two-phase process (Volp et al. 1984). Elimination half-times for

greater than 90% of the 1,2,3-trichloropropane in tissues ranged from

20 minutes in kidney to 2 hours in adipose tissue (first phase). A small

fraction of the 1,2,3-trichloropropane in these tissues (less than 10%) was

eliminated more slowly, with half-times ranging from 23 to 45 hours (second

phase). Elimination of total radioactivity from the tissues after intravenous

injection of radiolabeled 1,2,3-trichloropropane (phase one half-times between

2-5 hours, phase two half-time between 87-182 hours) is slower than

elimination of parent 1,2,3-trichloropropane. This suggests that metabolites

of 1,2,3-trichloropropane are eliminated slower than the parent compound.

Based on the results of studies in the rat, it can be concluded that

1,2,3-trichloropropane absorbed by any route is likely to be widely

distributed in the body. Most of the 1,2,3-trichloropropane that enters

tissues is eliminated within hours to days.

2.3.3 Metabolism

No information was located regarding the metabolism of

1,2,3-trichloropropane in humans; however, studies in animals have provided

information about metabolic pathways and rates of metabolism that are likely

to occur in humans. Intravenously injected 1,2,3-trichloropropane is

extensively metabolized within hours in rats. Metabolic products in rats

include carbon dioxide, which is expired, and numerous unidentified
34

2. HEALTH EFFECTS

metabolites that are excreted in urine and enter the bile to be excreted in

feces or absorbed in the intestines (Sipes et al. 1982; Volp et al. 1984).

Although the nonvolatile metabolites of 1,2,3-trichloropropane that are formed

in the rat have not been identified, dehalogenation products, glutathione

conjugates, and subsequent metabolites (e.g., mercapturic acids) can be

anticipated, based on the metabolic pathways that have been identified for

other halogenated alkanes.

Chloroalkanes such as 1,2,3-trichloropropane undergo dehalogenation

reactions catalyzed by cytochrome P-450 (Ivanetich et al. 1978; Salmon et al.

1981; Van Dyke et al. 1971). Depending on the reaction mechanism, highly

reactive intermediates (e.g., radicals) can be formed from these reactions

leading to protein and DNA adducts or lipid peroxidation. Conjugation with

glutathione could result in formation of sulfur mustard-like compounds that

are potential alkylating agents.

2.3.4 Excretion

2.3.4.1 Inhalation Exposure

No information was located regarding the excretion of

1,2,3-trichloropropane in humans or animals following inhalation exposure.

2.3.4.2 Oral Exposure

No information was located regarding the excretion of

1,2,3-trichloropropane in humans following oral exposure.

Studies conducted with rats showed that 1,2,3-trichloropropane and its

metabolites were excreted in urine, feces, and exhaled breath after oral

exposure (Sipes et al. 1982). Excretion was nearly complete (95-96%) within

2 days. Most of the dose was excreted in the urine and feces (up to 56% and

25%, respectively), with the remainder in the breath.

2.3.4.3 Dermal Exposure

No information was located regarding the excretion of

1,2,3-trichloropropane in humans or animals following dermal exposure.

2.3.4.4 Other Routes of Exposure

No information was located regarding the excretion of

1,2,3-trichloropropane in humans following other routes of exposure.

Studies of the excretion of intravenously injected 1,2,3-trichloropropane

in rats have provided a quantitative description of the excretion

kinetics from which predictions can be made about other routes of exposure

(Sipes et al. 1982; Volp et al. 1984). Excretion of intravenously injected
35

2. HEALTH EFFECTS

1,2,3-trichloropropane and metabolites is nearly complete within 2 days.

Unchanged 1,2,3-trichloropropane and its major metabolite, carbon dioxide, are

expired in exhaled breath. Nonvolatile metabolites are excreted in the urine.

Extensive biliary excretion of nonvolatile metabolites also occurs, resulting

in fecal excretion as well as reabsorption of metabolites from the

gastrointestinal tract. Based on the results of studies in rats, exhaled

breath, urine, and feces are likely to be significant routes of excretion of

absorbed 1,2,3-trichloropropane and its metabolites in humans.

2.4 RELEVANCE TO PUBLIC HEALTH

The only information that is available on the health effects of

1,2,3-trichloropropane in humans indicates that exposure to

1,2,3-trichloropropane of unknown purity in air can produce eye and throat

irritation. Effects in the respiratory system, eyes and skin,

gastrointestinal tract, liver, kidneys, blood, and spleen have been observed

in animals exposed to 1,2,3-trichloropropane by air, mouth, and/or skin.

1,2,3-Trichloropropane also induced tumors at multiple sites in animals

exposed orally.

Sufficient information is available on the health effects of

1,2,3-trichloropropane to derive MRLs for acute duration inhalation exposure

and intermediate duration oral exposure. Based on a NOAEL of 1 ppm for

histological changes in the nasal olfactory epithelium of rats (Miller et al.

1986b), an acute inhalation MEL of 0.0003 ppm was calculated by adjusting the

NOAEL for intermittent exposure, converting the adjusted NOAEL to an

equivalent concentration in humans, and dividing the equivalent concentration

by an uncertainty factor of 100 (10 for extrapolation from animals to humans,

and 10 for human variability). The LOAEL for effects on the olfactory

epithelium (decreased thickness) in rats is 3 ppm (Miller et al. 1986b).

Supporting studies show that similar nasal effects occurred in mice at 10 ppm,

and more pronounced changes in nasal tissues occurred in rats and mice at

higher concentrations (Miller et al. 1986a, 1986b). An intermediate duration

inhalation MEL for 1,2,3-trichloropropane cannot be derived due to a lack of

information on effects on the nasal olfactory epithelium which, based on the

acute data, is the critical target of inhalation exposure. A chronic

inhalation MEL is precluded by a lack of data on chronic toxicity.

Insufficient information is available on the systemic effects of acute oral

exposure to 1,2,3-trichloropropane at sublethal doses to derive an acute oral

MEL. Based on a NOAEL of 8 mg/kg/day for hepatic effects in rats (NTP 1983a),

an oral MEL of 0.06 mg/kg/day was calculated for intermediate duration

exposure by dividing the NOAEL by an uncertainty factor of 100 (10 for

extrapolation from animals to humans, and 10 for human variability). The

LOAEL for hepatic effects (increased liver weight, decreased serum

cholinesterase) is 16 mg/kg/day (NTP 1983a). The NOAEL and LOAEL for anemia

in rats are the same as the NOAEL and LOAEL for hepatic effects, but other

data that lend support to the intermediate oral MEL are not available. A

chronic oral MEL is precluded by lack of information on chronic toxicity.
36

2. HEALTH EFFECTS

Acute-duration, intermediate-duration, and chronic duration dermal MRLs were

not derived for 1,2,3-trichloropropane due to the lack of an appropriate

methodology for the development of dermal MRLs.

Death. Information regarding death in humans following exposure to

1,2,3-trichloropropane by any route was not found.

Studies with rats and mice suggest that 1,2,3-trichloropropane is

similarly toxic following acute- and intermediate-duration exposure by either

the inhalation or oral route. Lethal concentrations as low as approximately

300 ppm for inhalation exposure and lethal doses in the range of 125-250 mg/kg

for gavage exposure indicate that the 1,2,3-trichloropropane is likely to be

moderately toxic for humans. However, 1,2,3-trichloropropane may be less

toxic when ingested gradually throughout the day, such as in the drinking

water, than when taken as a bolus. Acute dermal and oral lethal doses of

1,2,3-trichloropropane in animals appear to be similar in magnitude,

suggesting that skin contact with liquid 1,2,3-trichloropropane at waste sites

could be toxic for humans. The dermal doses may actually overestimate

lethality, however, because the testing methods may have prevented evaporation

of 1,2,3-trichloropropane from the skin.

Systemic Effects.

Respiratory Effects. The respiratory tract is a principal target of

inhaled 1,2,3-trichloropropane in studies with humans and animals. Human

subjects experienced objectionable throat and eye irritation at 100 ppm. Some

subjects found 50 ppm unacceptable for an 8-hour day, but information on

irritation in humans at lower concentrations is not available. Rodent data

showing that 1,2,3-trichloropropane causes irritative effects in the

respiratory tract, eyes, and skin following vapor exposure, and in the

gastrointestinal tract following oral exposure support the fact that

1,2,3-trichloropropane is a local irritant in humans. Effects indicative of

local irritation have occurred in rats and mice at air concentrations as low

as 3 ppm (rats); these effects consisted of microscopic alterations in the

nasal cavity (inflammatory and degenerative changes) and bronchi (lymphoid

hyperplasia). The animal evidence suggests that the nasal olfactory

epithelium is more sensitive than the respiratory epithelium to inhaled

1,2,3-trichloropropane, but most inhalation studies, including the only

intermediate-duration study in animals (rats), did not examine the nasal

cavity. Because rodents are obligate nose breathers (Miller et al. 1986a,

1986b), histologicai alterations in rodent olfactory mucosa might be

pronounced in comparison to humans, who are capable of breathing via the

mouth. However, because the effects on the olfactory tissue are progressive

and show the potential for olfactory impairment in humans, they are an

appropriate basis for the acute inhalation MRL.

Histological effects have also been observed in the nasal cavity and

bronchiolar epithelium of rats and/or mice that were exposed to
37

2. HEALTH EFFECTS

1,2,3-trichloropropane for acute and intermediate durations by oral intubation

at doses of 63 mg/kg/day and more. These effects seem to be generally

consistent with those found in the inhalation studies and confirm that

1,2,3-trichloropropane is a probable respiratory tract toxicant in humans.

The nasal effects ranged from inflammation to mucosal necrosis at lethal

doses, but appear to have occurred principally in the dorsal posterior nasal

mucosa rather than the olfactory mucosa. The pathogenesis of the nasal

lesions in orally treated animals is unclear since the principal location of

the nasal effects in these animals (dorsal posterior) may suggest a local

rather than systemic effect. This could possibly result from small amounts of

residual compound in the pharynx after dosing, escape of volatile material

from the stomach into the nasal passages, or elimination of

1,2,3-trichloropropane or metabolites in expired air. Therefore, the

respiratory effects seen in animals after gavage exposure may be relevant to

human exposure to 1,2,3-trichloropropane via drinking water because

1,2,3-trichloropropane could also escape from the pharynx and stomach into the

nasal passages or be eliminated in expired air after exposure by this route.

The relevance of the effects in the bronchiolar epithelium, which were

primarily regenerative changes such as hyperplasia in mice, is uncertain

because it is possible that they were caused by exposure due to improper

gavage treatment. This possibility may be substantive since there were a

number of deaths resulting from faulty intubation techniques in the same

study. Based on the overall evidence from animal studies, it appears that

continued exposure to 1,2,3-trichloropropane in air or water at sufficiently

high levels may be capable of producing adverse changes in nasal tissues of

humans.

Hematological Effects. 1,2,3-Trichloropropane has not been reported to

produce hematological effects in humans. Nonregenerative anemia occurred in

rats orally exposed to 1,2,3-trichloropropane for intermediate durations.

This is one of most sensitive effects of 1,2,3-trichloropropane in animals.

Effects in the spleen (increased hematopoiesis, decreased spleen weight or

lymphoid depletion) in rats and mice exposed orally or by inhalation may

indicate hematological effects of 1,2,3-trichloropropane, but the biological

significance of these changes is uncertain because anemia was the only

abnormal hematology measurement in the rats and hematology was normal in the

mice. Overall, the animal data suggest some potential for adverse

hematological effects in humans exposed to 1,2,3-trichloropropane.

Hepatic Effects. Adverse effects on the liver in humans have not been

reported; however, the liver is a major target organ of 1,2,3-trichloropropane

in animals. 1,2,3-Trichloropropane causes dose-related hepatic toxicity that

is severe enough at high doses to contribute to death in rats and mice

following acute- or intermediate-duration gavage administration.

1,2,3-Trichloropropane appears to be less hepatotoxic when ingested throughout

the day (i.e., in drinking water) than when taken as a bolus. Hepatic effects

other than increased liver weight and hepatocellular hypertrophy have not been

observed in rats and mice exposed by inhalation, but examinations were not
38

2. HEALTH EFFECTS

performed on animals exposed for periods longer than 13 weeks. Gavage studies

show that the changes in the liver are progressive, with increased organ

weights, minimal histological alterations, and/or clinical chemistry

alterations occurring at lower doses. The most sensitive hepatic effect

observed appears to be decreased serum pseudocholinesterase activity which, in

the absence of known inhibitors, suggests depressed synthesis due to

hepatocellular damage (NTP 1983a). The oral MRL for intermediate-duration

exposure is based on this effect. There was macroscopic evidence of liver

damage in rabbits that died following acute dermal exposure to

1,2,3-trichloropropane. Although effects on the liver have not been observed

in humans, the studies in animals indicate that such hepatic effects might

occur in humans at sufficiently high or prolonged exposures.

Renal Effects. Adverse effects on the kidneys in humans have not been

reported, but the kidneys are a major target of 1,2,3-trichloropropane

toxicity in animals. 1,2,3-Trichloropropane causes dose-related renal

toxicity that is severe enough at high doses to contribute to death in rats

and mice following acute- or intermediate-duration gavage administration.

1,2,3-Trichloropropane appears to be less toxic to the kidneys when ingested

throughout the day (i.e., in drinking water) than when taken as a bolus.

Renal effects other than increased kidney weights have not been observed in

rats exposed by inhalation, but examinations were not performed on animals

exposed for longer than 13 weeks. Gavage studies indicate that the renal

effects are progressive, with increased organ weight and clinical chemistry

alterations occurring at lower doses. Macroscopic evidence of kidney damage

was observed in rabbits that died following acute dermal exposure to

1,2,3-trichloropropane. Although effects on kidneys have not been observed in

humans, the studies in animals indicate that renal effects might occur in

humans at sufficiently high or prolonged exposures.

Other Systemic Effects. Other systemic effects observed in rats

following intermediate-duration oral exposure to 1,2,3-trichloropropane

included weight loss, alopecia, and histological changes in the thyroid

(reduced follicular size, increased epithelial height). Insufficient

information is available to determine if 1,2,3-trichloropropane is likely to

produce these effects in exposed humans.

Immunological Effects. Immunological effects of 1,2,3-trichloropropane

have not been reported in humans. Intermediate-duration studies with rats and

mice have shown effects in the spleen and thymus (lymphoid depletion and/or

decreased organ weight) following oral or inhalation exposure. The effects

occurred at high levels of exposure, frequently in the lethal range. These

effects cannot be used to infer immunotoxicity of 1,2,3-trichloropropane in

humans because immune function has not been evaluated.

Neurological Effects. Neurological effects of 1,2,3-trichloropropane

have not been reported in humans. Signs suggestive of CNS impairment occur in

rodents exposed to lethal levels of 1,2,3-trichloropropane by the inhalation,
39

2. HEALTH EFFECTS

oral, and dermal routes, but these effects do not necessarily indicate that

1,2,3-trichloropropane is neurotoxic because they could be due to indirect

causes (e.g., asphyxiation, kidney failure) in dying animals. Brain weights

were reported to have increased in rats that inhaled lethal concentrations of

1,2,3-trichloropropane in an intermediate-duration study, but this could

simply reflect a decrease in body weight (i.e., if relative brain weight was

increased). Since the studies that reported the aforementioned effects did

not perform neurological or behavioral evaluations, insufficient information

is available to determine if 1,2,3-trichloropropane is likely to produce

neurological effects in humans at sublethal levels.

Developmental Effects. Developmental effects of 1,2,3-trichloropropane

have not been reported in humans. 1,2,3-Trichloropropane did not produce

effects on survival or growth during gestation or lactation in offspring of

rats exposed by inhalation, but teratogenicity was not evaluated.

Developmental toxicity of 1,2,3-trichloropropane has not been evaluated in

animals exposed orally or dermally. There was no evidence of teratogenicity

or fetal toxicity in rats treated with a maximum tolerated dose of

1,2,3-trichloropropane (37 mg/kg) by intraperitoneal injection on days l-15 of

gestation (Hardin et al. 1981). Although the available data provide some

assurance that 1,2,3-trichloropropane is not developmentally toxic in animals,

additional information, particularly teratogenicity evaluations in animals by

environmentally relevant routes of exposure, would be needed to prove that

1,2,3-trichloropropane is not a likely developmental toxicant in humans.

Reproductive Effects. Reproductive effects of 1,2,3-trichloropropane in

humans have not been reported. There were no effects on mating performance or

fertility in rats exposed orally for 5 days or by inhalation at relatively low

concentrations (less than or equal to 15 ppm) for 10 weeks. Oral

administration for up to 4 months at lethal levels caused decreased testes and

epididymis weights in rats and mice, but no effects on testicular histology or

sperm. Rats exposed by inhalation for 4 weeks at lethal levels experienced

decreased testes and ovary weights, but histology and sperm were not

evaluated. Although effects of 1,2,3-trichloropropane on reproductive

function have not been evaluated in animals treated at high (near maximum

tolerated) doses or concentrations, the normal testicular histology and sperm

counts and morphology at lethal levels in the 4-week inhalation study are

consistent with normal reproductive function. Overall, the available data

suggest that 1,2,3-trichloropropane will not be a reproductive toxicant in

humans.

Genotoxic Effects. Genotoxic effects of 1,2,3-trichloropropane in

humans have not been reported. 1,2,3-trichloropropane was mutagenic in

certain strains of Salmonella typhimurium when assayed with exogenous

metabolic activation preparation, and it induced sister chromatid exchanges in

cultured hamster cells (Table 2-4). 1,2,3-trichloropropane did not induce

dominant lethal mutations when administered orally to rats (Saito-Suzuki et

al. 1982) (see Section 2.2.2.7). Although only limited data are available,

41

2. HEALTH EFFECTS

this evidence indicates that 1,2,3-trichloropropane is genotoxic in animals

and may be genotoxic in humans.

Cancer. Information regarding the carcinogenicity of 1,2,3-trichloropropane

in humans by any route of exposure was not located. Clear evidence of

carcinogenicity was found for 1,2,3-trichloropropane in male and female rats

at doses of 3 mg/kg/day or more and in male and female mice at doses of

6 mg/kg/day or more in a 2-year gavage study (NTP 1991). Increased incidences

of squamous cell papilloma and/or carcinoma were found in the oral mucosa

and/or the forestomach of both sexes of both species. These tumors were

morphologically similar in the oral mucosa and forestomach, forming a

continuum. Other tumors that were considered to be related to

1,2,3-trichloropropane exposure consisted of pancreatic acinar adenoma, renal

tubule adenoma, adenoma and carcinoma of the preputial gland in male rats;

clitoral gland adenoma and carcinoma, mammary gland adenocarcinoma in female

rats; hepatocellular adenoma and carcinoma and Harderian gland adenoma in male

and female mice; and uterine neoplasms in female mice. Zymbal's gland

carcinoma and intestinal adenocarcinoma also found in the male and female rats

may be related to the 1,2,3-trichloropropane exposure. The carcinogenicity of

1,2,3-trichloropropane is consistent with the positive genotoxicity findings

in the presence of bioactivation (see Table 2-4) and with its metabolism to

reactive intermediates, such as alkylating agents, which can lead to protein

and DNA adducts (see Section 2.3.3). NTP, IARC, and EPA have not yet

classified 1,2,3-trichloropropane with respect to its potential

carcinogenicity for humans, but the evidence in both sexes of two species of

animals strongly suggests a public health concern.

2.5 BIOMARKERS 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

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
42

2. HEALTH EFFECTS

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

and selenium). Biomarkers of exposure to 1,2,3-trichloropropane 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 1,2,3-trichloropropane

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 1,2,3-Trichloropropane

Biomarkers of exposure to 1,2,3-trichloropropane cannot be identified

because information on levels of 1,2,3-trichloropropane or its metabolites in

human tissues, fluids, or excreta or information on effects specific for

1,2,3-trichloropropane is not available. Studies with rats indicate that

excretion of 1,2,3-trichloropropane in the breath or urine may be sufficient

for monitoring purposes (see Section 2.3.4). Mild anemia and serum enzyme

alterations associated with liver toxicity, particularly decreased serum

pseudocholinesterase activity, occurred in rats exposed to

1,2,3-trichloropropane. The enzyme alterations were used as the basis for the

intermediate-duration oral MRL. Although the anemia and enzyme alterations

are sensitive indicators of toxicity in rats, they are not specific indicators

of exposure to 1,2,3-trichloropropane and may not occur in humans.

2.5.2 Biomarkers Used to Characterize Effects Caused by

 1,2,3-Trichloropropane

Effects in humans that are specifically attributable to 1,2,3-

trichloropropane

exposure are not known. Principal targets of 1,2,3-trichloropropane

in animals are the respiratory tract, blood, liver, and kidneys (see

Section 2.4). One study with rats suggests that alterations of serum enzymes

(e.g., decreased serum pseudocholinesterase activity) and anemia might be
43

2. HEALTH EFFECTS

useful biomarkers for hepatic and hematologic effects, respectively, of

1,2,3-trichloropropane. Insufficient data exist, however, to determine

whether 1,2,3-trichloropropane is likely to cause anemia in humans, and

substances other than 1,2,3-trichloropropane could also cause similar

hematologic and hepatic effects.

2.6 INTERACTIONS WITH OTHER CHEMICALS

Rats were exposed by inhalation to 500 ppm 1,2,3-trichloropropane and

1,000 ppm dichloropropane alone and in combination for 4 hours (Drew et al.

1978). Activities of liver-associated serum enzymes (serum glutamicoxaloacetic

transaminase, serum glutamic-pyruvic transaminase, ornithine

carbamyl transferase) were increased 24-48 hours following exposure to each

chemical alone. The combined exposure resulted in higher enzyme activities

than with either chemical alone, but the increases were less than additive.

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

No populations with unusual susceptibility to health effects of

1,2,3-trichloropropane have been identified. The respiratory tract, blood,

liver, and kidneys are principal targets of 1,2,3-trichloropropane in animals

(see Section 2.4). It is therefore possible that people with chronic

respiratory, liver, or kidney disease, or possibly people with compromised

pulmonary, hepatic, or renal function (e.g., alcoholics), might be unusually

susceptible to 1,2,3-trichloropropane.

2.8 MITIGATION OF TOXICOLOGICAL EFFECTS

This section will describe the clinical practice and research methods

for reducing toxic effects of exposure to 1,2,3-trichloropropane. However,

because some the treatments discussed may be experimental and unproven, this

section should not be used as a guide for treatment of exposures to

1,2,3-trichloropropane. When specific exposures have occurred poison control

centers and medical toxicologists should be consulted for medical advice.

Human exposure to 1,2,3-trichloropropane may occur by inhalation,

ingestion, or by dermal contact. Specific information on the management and

treatment of toxicological effects following acute exposure to

1,2,3-trichloropropane were not located in the literature. However, since

effects of 1,2,3-trichloropropane are consistent with those produced by other

halogenated aliphatic hydrocarbons compounds, general information on

mitigation for this chemical class pertains to 1,2,3-trichloropropane (Stutz

and Janusz 1988). Mitigation approaches to reduce absorption of

1,2,3-trichloropropane have included general recommendations of separating

contaminated food, water, air, and clothing from the exposed individual.

Externally, 1,2,3-trichloropropane can produce irritation and injury to the

skin and mucous membranes. Exposed eyes are flushed with a clean neutral
44

2. HEALTH EFFECTS

solution such as water or normal saline. The skin is immediately washed with

large amounts of soapy water.

If oral exposure has occurred, inducing emesis may be indicated within

the first 30 minutes following substantial ingestion unless the patient is or

could rapidly become obtunded, comatose, or convulsing (HSDB 1992). The

victim is then given water or milk to dilute the chemical and activated

charcoal to adsorb the chemical (Stutz and Janusz 1988). Although of unproven

value in all cases of ingestion, administration of a cathartic such as

magnesium sulfate may stimulate fecal excretion of the chemical before it is

completely absorbed by the body (Stutz and Janusz 1988).

Little information specific to enhancing excretion or reducing body

burden of 1,2,3-trichloropropane was available. However, animal data indicate

that once absorbed orally in rats, 95-96% of 1,2,3-trichloropropane is

excreted within 2 days. Most of the dose (56%) was excreted in the urine and

25% in the feces, with the remainder exhaled in the breath. (Sipes et al.

1982). Mitigation strategies to increase urinary output and dilute the

chemical in humans might include flushing the gastrointestinal and circulatory

systems with fluid while carefully monitoring fluid and electrolyte balances.

Muscle, blood, liver, skin, and adipose tissue contained the largest amounts

of radiolabled 1,2,3-trichloropropane following oral exposure in rats (Sipes

et al. 1982).

Based on metabolic pathways for other chloroalkanes, 1,2,3-trichloropropane

probably undergoes dehalogenation reactions via cytochrome P-450

dependent microsomal metabolism, resulting in the formation of highly reactive

intermediates that may lead to protein and DNA adducts or lipid peroxidation

(Ivanetich et al. 1978; Salmon et al. 1981; Van Dyke et al. 1971). If the

mechanism of 1,2,3-trichloropropane induced toxicity involves the action of

reactive intermediates, administration of chemicals that interfere with these

metabolic processes might be effective in reducing adverse health effects.

2.9 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 1,2,3-trichloropropane is available. Where adequate

information is 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

1,2,3-trichloropropane.

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
45

2. HEALTH EFFECTS

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 1,2,3-Trichloropropane

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

exposure of humans and animals to 1,2,3-trichloropropane are summarized in

Figure 2-3. The purpose of this figure is to illustrate the existing

information concerning the health effects of 1,2,3-trichloropropane. 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).

Information on health effects of 1,2,3-trichloropropane in humans is

limited to one report of systemic effects (eye and throat irritation)

resulting from acute vapor exposure (Silverman et al. 1946). As indicated in

Figure 2-3, data are available for the lethality, acute systemic toxicity,

intermediate systemic toxicity, and reproductive effects of 1,2,3-trichloropropane

in animals exposed by the oral and inhalation routes. Limited

information is available for immunologic and neurologic effects by the

inhalation and oral routes, and developmental and genotoxic effects by the

oral route. Information is also available on the carcinogenicity of

1,2,3-trichloropropane in animals exposed by the oral route. Dermal toxicity

studies of 1,2,3-trichloropropane provide acute lethality data and limited

information on acute systemic and neurologic effects.

2.9.2 Data Needs

Acute-Duration Exposure. There is evidence that 1,2,3-trichloropropane

vapor irritates the eyes and throat of humans (Silverman et al. 1946), but

information on other targets of acute 1,2,3-trichloropropane toxicity in

humans is not available. The respiratory tract, liver, and kidneys appear to

be principal targets of 1,2,3-trichloropropane toxicity in rats and mice

following inhalation or oral exposure for approximately 2 weeks (Miller et al.

1986a, 1986b; NTP 1983a, 1983b), and are likely targets of acute exposure in

humans. Sufficient respiratory (nasal) effects data are available on which to

base an acute MRL for inhalation exposure (Miller et al. 1986b). Respiratory

effects of 1,2,3-trichloropropane, however, have been investigated in only two

animal species (rats and mice). Studies with other species could confirm that

the respiratory system is the most sensitive target of acute-duration

inhalation exposure to 1,2,3-trichloropropane. Additional acute oral studies

could help characterize the systemic effects of 1,2,3-trichloropropane at

sublethal doses to enable determination of an acute-duration oral MRL.

Information is available for effects of 1,2,3-trichloropropane on the skin and

47

2. HEALTH EFFECTS

eyes (Alpert 1982; Clark 1977; Gushow and Quast 1984), but not on other

tissues, following acute nonlethal dermal exposure. There are no

pharmacokinetic data available to support the identification of target organs

across routes of exposure. Dermal studies may not be necessary to provide

information on systemic toxicity since it appears, based on inhalation and

oral data, that systemic effects of 1,2,3-trichloropropane, other than

respiratory effects, may not be route-specific.

Intermediate-Duration Exposure. Information is not available on

systemic effects of 1,2,3-trichloropropane in humans following intermediateduration exposure by any route. The respiratory system, blood, liver, and

kidneys appear to be principal targets of 1,2,3-trichloropropane in rats and

mice exposed by inhalation or orally for intermediate durations (Johannsen et

al. 1988; NTP 1983a, 1983b; Villeneuve et al. 1985), but studies longer than

2-4 months have not been performed (inhalation) or are not completed (NTP oral

bioassay; see Section 2.8.3). The spleen and thyroid are less sensitive

targets of intermediate-duration oral exposure in animals (NTP 1983a;

Villeneuve et al. 1985), but the biological significance of effects observed

in these organs is uncertain. Although intermediate-duration inhalation

studies with animals are consistent with acute data in showing the respiratory

system to be a target of 1,2,3-trichloropropane toxicity, intermediateduration exposure levels that do not cause adverse respiratory (nasal) effects

have not been determined. Although the respiratory system does not appear to

be the most sensitive target for intermediate-duration oral exposure, drinking

water studies could help ascertain if the pulmonary effects observed in gavage

studies are a consequence of the method of treatment. Sufficient information

is available from one study (NTP 1983a) to determine a dose that does not

cause adverse hepatic and hematologic effects and to derive an MRL for

intermediate-duration oral exposure based on these effects. Confidence in

this MRL could be strengthened by additional studies. Additional information

would be useful to determine if intermediate-duration exposure to

1,2,3-trichloropropane is capable of causing biologically significant

alterations to the spleen and thyroid, particularly at doses in the range for

nonadverse liver and hematologic effects. Information is not available on

effects of intermediate-duration dermal exposure to 1,2,3-trichloropropane in

animals, and there are no pharmacokinetic data to support the identification

of target organs across routes of exposure. Acute-duration toxicity data,

however, suggest that systemic effects of 1,2,3-trichloropropane, other than

respiratory effects, may not be route-specific.

Chronic-Duration Exposure and Cancer. Information is not available

regarding the chronic toxicity of 1,2,3-trichloropropane in humans or animals

exposed by any route. Chronic studies in animals could provide information on

progression or reversibility of effects caused by subchronic exposure,

particularly respiratory system effects following inhalation exposure and

liver and hematological effects following oral exposure. Chronic studies in

animals also could enable identification of effects produced by low-level

exposure that might not be detected in shorter-duration studies.
48

2. HEALTH EFFECTS

The carcinogenicity of 1,2,3-trichloropropane in humans or animals

exposed by any route has not been evaluated. 1,2,3-trichloropropane induced

multiple site tumors in both sexes of rats and mice exposed orally (NTP 1991).

The most frequently induced tumors were found in the oral and forestomach

mucosa, suggesting local reactivity, in addition to systemic reactivity. As

discussed in Section 2.8.3, there is evidence that 1,2,3-trichloropropane is

metabolized to reactive intermediates that can bind to DNA (Weber and Sipes

1988). Since these intermediates can interact with DNA, and respiratory

effects of inhaled 1,2,3-trichloropropane could be due to local reactivity, it

is reasonable to assume that prolonged inhalation exposure to 1,2,3-

trichloropropane would produce local and systemic tumors. An inhalation bioassay

would be useful to confirm this expectation and to determine the airborne

concentrations necessary to produce a carcinogenic response. 1,2,3-

Trichloropropane could also be tested to determine whether it is carcinogenic by

the dermal route.

Genotoxicity. Information on the genotoxicity of 1,2,3-trichloropropane

in humans is not available. The genotoxicity of 1,2,3-trichloropropane has

been evaluated in several assays that provide limited evidence of mutagenicity

in bacteria and clastogenicity (sister chromatid exchanges) in cultured

hamster cells (Haworth et al. 1983; Ratpan and Plaumann 1988; Stolzenberg and

Hine 1980; Von der Hude et al. 1987). 1,2,3-Trichloropropane did not induce

dominant lethal mutations in rats exposed orally for 5 days (Saito-Suzuki et

al. 1982). Additional studies in mammalian cells in vitro and in animals

would more fully characterize the genotoxicity of 1,2,3-trichloropropane.

Reproductive Toxicity. Information on reproductive effects of

1,2,3-trichloropropane in humans is not available. There were no reproductive

effects in rats exposed to a moderately high oral dose for 5 days or by

inhalation to a relatively low concentration (near the lowest concentrations

producing respiratory effects) for 10 weeks prior to mating (Johannsen et al.

1988; Saito-Suzuki et al. 1982). Oral exposure to lethal doses for 4 months

caused decreased testes and epididymis weights and no effects on testicular

histology or sperm in rats and mice, but reproductive function was not

evaluated (NTP 1983a, 1983b). Inhalation exposure to lethal concentrations of

1,2,3-trichloropropane for 4 weeks caused decreased testes and ovary weights

in rats, but reproductive organ histology and sperm and reproductive function

were not evaluated (Johannsen et al. 1988). Insufficient toxicokinetic data

are available to determine if 1,2,3-trichloropropane is likely to produce

similar reproductive effects by different routes of exposure. Evaluation of

reproductive function in animals following prolonged low dose oral exposure

and inhalation exposure at high (near maximum tolerated) concentrations,

therefore, would more fully assess the potential reproductive toxicity of

1,2,3-trichloropropane. Multigeneration or continuous-breeding studies in

animals would provide a better basis for evaluating reproductive toxicity but

may not be desirable unless other studies indicate that the reproductive
49

2. HEALTH EFFECTS

system is a target organ. Reproductive toxicity data are particularly

desirable prior to developing MRLs.

Developmental Toxicity. Information on the developmental toxicity of

1,2,3-trichloropropane in humans is not available. There were no effects on

growth or viability of offspring of rats exposed by inhalation to low

concentrations of 1,2,3-trichloropropane prior to mating and during gestation,

but teratogenicity was not evaluated (Johannsen et al. 1988). 1,2,3-

Trichloropropane was not teratogenic in rats treated by intraperitoneal

injection (Hardin et al. 1981). Insufficient toxicokinetic data are available

to determine if 1,2,3-trichloropropane is likely to produce similar

developmental effects by different routes of exposure. Additional evaluations

using natural routes of exposure and higher doses, particularly inhalation and

oral teratogenicity studies, would more fully evaluate the developmental

toxicity potential of 1,2,3-trichloropropane. Developmental toxicity data are

particularly desirable prior to developing MRLs.

Immunotoxicity. Information on the immunological effects of

1,2,3-trichloropropane in humans is not available. Effects such as lymphoid

depletion and decreased weight of the spleen of rats and mice exposed orally

and by inhalation to near-lethal levels of 1,2,3-trichloropropane for several

weeks could have immunological significance (Johannsen et al. 1988; NTP

1983a). Limited evidence from one study suggests that 1,2,3-trichloropropane

may be a weak dermal sensitizer in guinea pigs (Clark 1977). The only other

skin sensitization study of 1,2,3-trichloropropane (Alpert 1982), also

performed with guinea pigs, was negative and provides evidence that the

vehicle may have accounted for the effect observed by Clark (1977).

Sensitization by 1,2,3-trichloropropane from other routes of exposure has not

been evaluated. Immunoassays and additional sensitization tests would help

assess the immunotoxic potential of 1,2,3-trichloropropane.

Neurotoxicity. Information on the neurological effects of

1,2,3-trichloropropane in humans is not available. Signs suggestive of CNS

impairment occur only in animals exposed to acute lethal levels of

1,2,3-trichloropropane by the inhalation, oral, and dermal routes (Alpert

1982; Clark 1977; Gushow and Quast 1984; Union Carbide 1958), but these do not

necessarily indicate that 1,2,3-trichloropropane is neurotoxic because they

could be due to other causes in dying animals. There is evidence that

exposure to 1,2,3-trichloropropane does not cause histopathological lesions in

the CNS (Johannsen et al. 1988; Miller et al. 1986a; NTP 1983a, 1983b), but

this does not necessarily indicate that 1,2,3-trichloropropane is

nonneurotoxic because behavioral, neurochemical, and neurophysiological

examinations were not performed. Overall, there is evidence that

neurotoxicity is a critical effect of 1,2,3-trichloropropane.

Epidemiological and Human Dosimetry Studies. Health effects of

1,2,3-trichloropropane in humans have only been described as a consequence of

intentional vapor exposure in a study of sensory response. As indicated in
50

2. HEALTH EFFECTS

Chapter 5, there is probably no identifiable subpopulation with exclusive or

predominant exposure to 1,2,3-trichloropropane in the general populace or

workplace. If such a population is identified, excreted 1,2,3-trichloropropane

or its metabolites could probably be correlated with exposure or health

effects. Metabolites specifically attributable to 1,2,3-trichloropropane,

however, are presently unknown.

Biomarkers of Exposure and Effect. There are no known biomarkers of

exposure for 1,2,3-trichloropropane in humans. Studies with rats suggest that

respiratory or urinary excretion of 1,2,3-trichloropropane may be sufficient

for monitoring purposes (Sipes et al. 1982). Additional studies could help

determine the feasibility of using 1,2,3-trichloropropane in the breath or

urine as a biomarker of exposure. Mild anemia and alterations in liverassociated

serum enzymes occurred in rats treated with 1,2,3-trichloropropane

(NTP 1983a) but are not useful as biomarkers of exposure because they can be

due to many causes and might not occur in humans. Information on effects

specific for 1,2,3-trichloropropane would be helpful for developing a

biomarker of exposure for 1,2,3-trichloropropane.

There are no known biomarkers of effects for 1,2,3-trichloropropane in

humans. One study with rats (NTP 1983a) suggests that anemia and alterations

of serum enzymes (e.g., decreased serum pseudocholinesterase activity) might

be sensitive biomarkers for hematologic and hepatic effects of 1,2,3-

trichloropropane, respectively. Additional animal studies or examination of humans

with known exposure to 1,2,3-trichloropropane would help determine if 1,2,3-

trichloropropane is likely to cause anemia or consistent serum enzyme alterations

in humans.

Absorption, Distribution, Metabolism, and Excretion. There is limited

information on absorption and excretion of single oral doses of

1,2,3-trichloropropane in rats (Sipes et al. 1982; Volp et al. 1984), but no

data are available on the toxicokinetics of 1,2,3-trichloropropane in animals

after inhalation or dermal exposure. Tissue distribution, metabolism, and

excretion of intravenously injected 1,2,3-trichloropropane also have been

investigated in rats (Volp et al. 1984). A physiologically based

pharmacokinetic model describing tissue distribution and excretion was

developed using data from this intravenous study. A more complete oral study

in animals, as well as animal studies using inhalation and dermal exposure,

could provide necessary data (e.g., absorption kinetics) for expanding the

model to include inhalation, oral, and dermal exposure and verifying the

model. It might then be possible to use the model to predict the

pharmacokinetics of 1,2,3-trichloropropane in humans exposed by these routes.

Studies with several dose levels and exposure durations would allow more

accurate comparison between routes (e.g., assessment of relative rates and

extent of absorption, ,distribution, metabolism, and excretion) as well as

detection of saturation effects.
51

2. HEALTH EFFECTS

Comparative Toxicokinetics. The toxicokinetics of 1,2,3-trichloropropane

have been studied only in rats by the oral and intravenous routes (Sipes et al.

1982; Volp et al. 1984). A physiologically based pharmacokinetic model has been

proposed based on the intravenous data. Studies in other species would be useful

for verifying predictions made from the model about other species, including

humans.

Mitigation of Effects. Based on limited toxicokinetic data for

1,2,3-trichloropropane and information on the metabolism of other halogenated

alkanes, it is anticipated that 1,2,3-trichloropropane can undergo

dehalogenation reactions catalyzed by microsomal mixed function oxidases.

Depending on the reaction mechanism(s), reactive intermediates could be

formed. Also it is possible that 1,2,3-trichloropropane itself contributes to

toxicity. Studies elucidating the mechanism of action and identity of

reactive intermediates of 1,2,3-trichloropropane would be useful in planning

research aimed at developing agents that could interfere with the mechanism of

toxicity, thereby mitigating the effects.

2.9.3 On-going Studies

A bioassasy in which rats and mice were treated by gavage for 2 years

has been completed and recently approved (NTP 1991). The doses of 1,2,3-

trichloropropane used in the bioassay were 0, 3, 10, and 30 mg/kg in

rats and 0, 6, 20, and 60 mg/kg in mice (Burka 1990a). Preliminary results

indicate that treatment resulted in increased incidences of tumors in both

species (Mahmood et al. 1988; Weber and Sipes 1988).

The final report of an NTP continuous-breeding study is in preparation

(Burka 1990b).

The results of a metabolism and mutagenicity study of 1,2,3-

trichloropropanehave been reported as an abstract (Mahmood et al. 1988). Rats that

were administered 30 mg/kg of 14C-1,2,3-trichloropropane by gavage excreted

approximately 50%, 20%, and 20% of the radioactivity in the urine, feces, and

as carbon dioxide, respectively, in the following 60 hours. Two urinary

metabolites were identified as N-acetyl-S-(3-chloro-2-hydroxypropyl) cysteine

and 3-chloro-2-hydroxypropyl cysteine. Radioactivity was most concentrated in

the liver, kidney, and forestomach. 1,2,3-Trichloropropane was mutagenic in

Salmonella typhimurium TA100 in the Ames assay only in the presence of S9 or

microsomes, and mutagenicity decreased upon addition of glutathione. The

urine from the treated rats or synthetic N-acetyl-S-(3-chloro-2-hydroxypropyl)

cysteine were not mutagenic in this assay.

Rats were administered a 30 mg/kg dose of 14C-1,2,3-trichloropropane by

intraperitoneal injection in a preliminary investigation into the role of

biotransformation in 1,2,3-trichloropropane-induced tumor formation (Weber and

Sipes 1988). Covalent binding to hepatic protein and DNA was demonstrated,

suggesting that 1,2,3-trichloropropane is genotoxic. In vitro studies,
52

2. HEALTH EFFECTS

however, showed that glutathione decreased protein binding and increased the

formation of water-soluble 14C-1,2,3-trichloropropane equivalents, and that

there was no significant covalent binding of 1,2,3-trichloropropane to DNA.

The in vitro data indicated that the role of biotransformation in

1,2,3-trichloropropane-induced genotoxicity is still unclear.

The results of an investigation of the cardiotoxic and hepatic effects

of 1,2,3-trichloropropane were reported in an abstract (Robinson et al. 1989).

Rats were administered various doses of 1,2,3-trichloropropane by gavage for

durations ranging from 1 to 10 days. Doses of 0.2, 0.4, 0.6, and 0.8 mmol/kg

(29.5-117.9 mg/kg) produced myocardial necrosis in 0%, 0%, 10%, and 80% of the

rats, respectively. This effect was observed after 6 days of treatment at

0.8 mmol/kg (117.9 mg/kg). Doses of 1.6-2.8 mmol/kg (235.9-412.8 mg/kg)

caused increasing hepatotoxicity and eventual death but no myocardial

necrosis. Tissue levels of 1,2,3-trichloropropane were markedly increased

after 10 days compared to l-day exposure, suggesting bioaccumulation.

Peripheral catecholamine depletion with 6-hydroxydopamine reduced myocardial

necrosis from moderate to minimum severity. The results of this study

suggested that dose and time of 1,2,3-trichloropropane exposure determine the

appearance of heart or liver toxicity, and that cardiotoxic effects of

1,2,3-trichloropropane may involve bioaccumulation and sympathoadrenergic

factors.
53

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENTITY

Data pertaining to the chemical identity of 1,2,3-trichloropropane are

listed in Table 3-1.

3.2 PHYSICAL AND CHEMICAL PROPERTIES

The physical and chemical properties of 1,2,3-trichloropropane are

presented in Table 3-2.



57

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

4.1 PRODUCTION

Recent data regarding production volumes for 1,2,3-trichloropropane are

not available. The estimated 1977 production volume for the chemical ranged

from 21 to 110 million pounds (EPA 1989b). Current manufacturers of

1,2,3-trichloropropane include Dow Chemical U.S.A., Freeport, Texas, and Shell

Oil Company, Deer Park, Texas (SRI 1989). In 1977, two additional manufacturing

locations were Dow Chemical U.S.A., a major producer in Midland, Michigan, and

Columbia Organic Chemicals Co., a minor producer in Columbia, South Carolina (EPA

1989b). 1,2,3-Trichloropropane can be produced via the chlorination of propylene

(Hawley 1981). Other reported methods for producing 1,2,3-trichloropropane include

the addition of chlorine to ally1 chloride, reaction of thionyl chloride with

glycerol, and the reaction of phosphorus pentachloride with either 1,3- or 2,3-

dichloropropanol (NIOSH 1981; Williams 1949). 1,2,3-Trichloropropane also may be

produced in potentially significant amounts as a byproduct of processes primarily

used to produce other chemicals, including dichloropropene (a soil fumigant and

nematocide), propylene chlorohydrin, propylene oxide, dichlorohydrin, and glycerol

(Baier et al. 1987; NIOSH 1981). Technical-grade 1,2,3-trichloropropane reportedly

varies between 97.5% and 99.4% purity (Alberti 1982; NTP 1983a). The material

tested by the NTP (1983a) contains the following impurities: 0.066% water, 0.14%

unspecified chlorohexene, two unspecified chlorohexadienes (0.24% and 0.13%),

and total acidity of 48 ppm (as HCl).

4.2 IMPORT/EXPORT

No data concerning the import or export of 1,2,3-trichloropropane were

located.

4.3 USE

1,2,3-Trichloropropane has, in the past, been used mainly as a solvent

and extractive agent. No current information is available that indicates that

the compound is still used for these purposes today. It dissolves a variety

of resins, oils, waxes, and other materials while having a low solubility in

water (Williams 1949). Common uses have included use as a paint- and varnishremover, a cleaning and degreasing agent, and a cleaning and maintenance

reagent (Hawley 1981; NIOSH 1981). Currently, it is used as a chemical

intermediate, for example, in the production of polysulfone liquid polymers

and dichloropropene, synthesis of hexafluoropropylene, and as a crosslinking

agent in the synthesis of polysulfides (Baier et al. 1987; Ellerstein and

Bertozzi 1982; Gangal 1980; HSDB 1989). No data were found concerning the

approximate amounts currently used for particular purposes.

4.4 DISPOSAL

1,2,3-Trichloropropane has been identified as a hazardous waste by the

EPA, and the disposal of this compound is regulated under the Resource
58

4. PRODUCTION, IMPORT, USE, AND DISPOSAL

Conservation and Recovery Act (RCRA). Specific information regarding the

federal regulations of land disposal of 1,2,3-trichloropropane is available

(EPA 1988a). 1,2,3-Trichloropropane can be disposed of via atomization in a

suitable incinerator equipped with appropriate effluent gas scrubbers (HSDB

1989). In case of accidental spills, the chemical may be disposed of by

absorption onto vermiculite, dry sand, earth, or similar material followed by

disposal in a secured landfill (HSDB 1989); however, land disposal may no

longer be allowed by the disposal regulations discussed above. Significant

removal of 1,2,3-trichloropropane from waste water and sewage may be

accomplished through the use of activated sludge treatment processes (Matsui

et al. 1975). No data were found concerning the approximate amounts disposed

by the various methods.
59

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

1,2,3-Trichloropropane is a man-made chemical that is present in the

environment as a result of anthropogenic activity. Releases to the

environment are likely to occur as a result of its manufacture, formulation,

and use as a solvent and extractive agent, paint- and varnish-remover,

cleaning and degreasing agent, cleaning and maintenance reagent, and chemical

intermediate (HSDB 1989). Releases may occur as a result of the disposal of

wastes from production of 1,2,3-trichloropropane and disposal of products that

contain the chemical, especially at hazardous waste sites that received

1,2,3-trichloropropane-containing wastes. Release to soil can occur through

the use of certain soil fumigants and nematocides that are known to contain

1,2,3-trichloropropane as an impurity and through the disposal of

1,2,3-trichloropropane-containing sewage sludge from municipal sewage

treatment plants.

In ambient air, the primary removal process is expected to be the vaporphase

reaction with photochemically generated hydroxyl radicals. In surface

waters, the primary removal process is likely to be volatilization. In soil,

the primary removal processes are volatilization from near-surface soil and

leaching to groundwater. Aerobic biodegradation is probably a slow process in

natural waters and soil. It may persist in groundwater for a relatively long

time.

Data regarding the concentrations of 1,2,3-trichloropropane in the

environment are limited, but concentrations should not be large except in case

of an accidental spill. It has been found at low levels in the United States

in a few rivers and bays, drinking water, groundwater, and hazardous waste

sites. The EPA has identified 1,177 NPL sites. 1,2,3-Trichloropropane has

been found at eight of the sites evaluated for the presence of this chemical.

However, we do not know how many of the 1,177 NPL sites have been evaluated

for this chemical. As more sites are evaluated by EPA, the number may change.

The frequency of these sites within the United States can be seen in

Figure 5.1.

The general population can be exposed to low levels of 1,2,3-

trichloropropane mainly by ingesting contaminated water. Members of the general

population living near waste sites that contain 1,2,3-trichloropropane may be

exposed to low levels of 1,2,3-trichloropropane in their drinking water if they

obtain their household water from a well. Additional exposure may occur through

the inhalation of contaminated air, especially for those who live near facilities

that manufacture or use 1,2,3-trichloropropane or at treatment or disposal

facilities. Inhalation and dermal exposure may occur during the use of consumer

products containing 1,2,3-trichloropropane, such as certain paint removers. It is

difficult to assess the extent of general population and occupational exposure

because data are lacking. However, significant exposure to 1,2,3-trichloropropane

may be unlikely because the compound may no longer be used for purposes other than

a chemical intermediate, and current

61

5. POTENTIAL FOR HUMAN EXPOSURE

manufacturing processes generally occur in closed and tightly sealed systems

(NIOSH 1981). The National Occupational Exposure Survey (NOES) conducted by

NIOSH from 1981 to 1983 statistically estimated that 492 workers are

potentially exposed to 1,2,3-trichloropropane in the United States. The NOES

database does not contain information on the frequency, concentration, or

duration of exposure of workers to any of the chemicals listed therein. This

summary provides only estimates of the number of workers potentially exposed

to chemicals in the workplace. Occupational exposure probably results from

inhalation and dermal contact.

5.2 RELEASES TO THE ENVIRONMENT

5.2.1 Air

Data on releases of 1,2,3-trichloropropane to the atmosphere are

lacking. Based on the few data available, current releases to the air are

expected to be relatively small. Minor releases may have occurred as exhaust,

stack, and fugitive emissions from its manufacture, formulation, and use as a

solvent (HSDB 1989). 1,2,3-Trichloropropane may have been released in the

past into the air as a result of its use as a paint- and varnish-remover, a

degreasing agent, and a cleaning and maintenance reagent (Hawley 1981; NIOSH

1981). No information was found that indicates that 1,2,3-trichloropropane is

still used for these purposes today. Very small amounts may be released

during its use as a chemical intermediate and as a result of its formation

during the synthesis of other organic chemicals (see Section 4.1).

Volatilization from contaminated surface waters, effluent waters, and nearsurface soils may also be minor atmospheric sources of this compound. This

includes volatilization from identified and unidentified hazardous waste dumps

that contain 1,2,3-trichloropropane and from farmland treated with

1,2,3-trichloropropane-contaminated fumigants and nematocides (no information

is available to determine whether or not the soil fumigants and nematocides

currently manufactured contain 1,2,3-trichloropropane). Small amounts may be

released to the air during treatment of water containing

1,2,3-trichloropropane, because some of the chemical may be removed via

evaporative stripping from the water.

5.2.2 Water

Data on the release of 1,2,3-trichloropropane to environmental waters

are lacking. Based on the few data available, current releases to

environmental waters are expected to be relatively small. Releases to surface

water may have occurred through runoff of waste water from hazardous waste

sites containing 1,2,3-trichloropropane and runoff from farmland treated with

certain soil fumigants and nematocides that contain 1,2,3-trichloropropane.

Releases to surface and groundwater may have occurred as a result of the

improper disposal of 1,2,3-trichloropropane-containing industrial wastes or

wastes from its use in paint- and varnish-removers, cleaning and degreasing

agents, and maintenance reagents. Releases to groundwater may have occurred
62

5. POTENTIAL FOR HUMAN EXPOSURE

as a result of the chemical leaching through soil at waste sites and

agricultural soil treated with fumigants that contain the chemical. Small

amounts of the chemical may have entered surface waters as a result of washout

from 1,2,3-trichloropropane-contaminated air; however, some of the

1,2,3-trichloropropane removed from the atmosphere by washout is likely to

have re-entered the atmosphere by volatilization. The chemical was found in

groundwater at 0.71% of the sites in the Contract Laboratory Program

Statistical Database (CLPSD) at a geometric mean concentration of 57.3 μg/L

(CLPSD 1989). Note that the CLPSD includes data from both NPL and non-NPL

sites.

5.2.3 Soil

Data on releases of 1,2,3-trichloropropane to soils are sparse, which

makes a quantitative estimation of the magnitude of such releases impossible.

However, releases to soils are expected to be relatively small based upon the

available data. Releases to farmland soil have occurred as a result of the

use of certain soil fumigants and nematocides known to contain

1,2,3-trichloropropane as an impurity. No current information is available,

however, that indicates that these soil fumigants and nematocides still

contain 1,2,3-trichloropropane. Releases of the chemical to soil may have

occurred as a result of disposal of 1,2,3-trichloropropane-containing sewage

sludge from municipal sewage treatment plants (Jacobs and Zabik 1983). Very

small amounts of the chemical may be brought to the surface of the earth as a

result of washout from 1,2,3-trichloropropane-containing air; however, much of

the 1,2,3-trichloropropane removed from the atmosphere by washout may re-enter

the atmosphere by volatilization from near-surface soil. Land disposal of

wastes from its use in paint- and varnish-removers, cleaning and degreasing

agents, and cleaning and maintenance reagents may have released

1,2,3-trichloropropane to soil. The chemical was found in soil at 0.71% of

the sites in the CLPSD at a geometric mean concentration of 204 μg/kg (CLPSD

1989). Note that the CLPSD includes data from both NPL and non-NPL sites.

5.3 ENVIRONMENTAL FATE

5.3.1 Transport and Partitioning

No experimental or predictive data were located in the literature

regarding the transport of 1,2,3-trichloropropane in the atmosphere.

1,2,3-Trichloropropane is expected to exist in the atmosphere predominantly in

the vapor phase, based on its vapor pressure (Table 3-2) (Eisenreich et al.

1981; MacKay et al. 1982). The speculation that substantial amounts of

1,2,3-trichloropropane are not likely to be present in the particulate phase

indicates that dry deposition to the earth's surface will not be an important

removal process. Based upon its low water solubility and moderate vapor

pressure (Table 3-2), very small amounts of 1,2,3-trichloropropane present in
63

5. POTENTIAL FOR HUMAN EXPOSURE

air may be removed by wet deposition; however, much of the 1,2,3-trichloropropane

removed from the atmosphere by washout is likely to re-enter the

atmosphere by volatilization.

Based upon an estimated soil organic carbon partition coefficient (Koc)

of 98 (calculated from water solubility) (Lyman et al. 1982; Riddick et al.

1986), 1,2,3-trichloropropane is expected to display high mobility in soil

(Swann et al. 1983); therefore, it has the potential to leach into

groundwater. This predicted mobility is confirmed by the detection of

1,2,3-trichloropropane in groundwater from various locations (see

Section 5.4.2). The vapor pressure of 1,2,3-trichloropropane (3.1 mmHg at

25°C) (MacKay et al. 1982), and the calculated Henry's law constant

(3.17x10-4 atm-m3

/mol at 25°C) (Lyman et al. 1982) suggest that volatilization

from either dry or moist soil to the atmosphere will be a significant

environmental process.

1,2,3-Trichloropropane in surface water is expected to volatilize

rapidly to the atmosphere. An experimental half-life of 56.1 minutes has been

measured for evaporation of 1,2,3-trichloropropane from a 1 ppm solution, with

a depth of 6.5 cm, stirred with a shallow pitch propeller at 200 rpm at 25°C

under still air (less than 0.2 mph air currents) (Dilling 1977). Using the

Henry's law constant, a half-life of 6.9 hours was calculated for evaporation

from a model river 1 m deep, flowing at 1 m/set, with a wind velocity of

3 m/set, and neglecting adsorption to sediment (Lyman et al. 1982). A

volatilization half-life of 3.5 days from a model pond can be estimated (EPA

1985). 1,2,3-Trichloropropane is not expected to significantly adsorb to

sediment and suspended organic matter based upon the estimated Koc of 98

(calculated from water solubility) (Lyman et al. 1982; Riddick et al. 1986).

It is also not expected to significantly bioconcentrate in fish and aquatic

organisms based upon an estimated bioconcentration factor (BCF) of 9.2

(calculated from log octanol-water partition coefficient (Kow) (EPA 1988b;

Lyman et al. 1982). No data were located to indicate a potential for

1,2,3-trichloropropane to biomagnify from lower to higher trophic states of

the food chain, but based upon the estimated BCF, this is not likely.

5.3.2 Transformation and Degradation

5.3.2.1 Air

The primary degradation process for 1,2,3-trichloropropane in the

atmosphere is expected to occur via gas-phase reaction with photochemically

produced hydroxyl radicals. The rate constant for this process is an

estimated 1.0475x10-12 cm3

/molecule-sec (Atkinson 1987). This corresponds to a

half-life of 15.3 days at an estimated atmospheric concentration of 5x105

hydroxyl radicals/cm3. Direct photolysis of 1,2,3-trichloropropane is not
64

5. POTENTIAL FOR HUMAN EXPOSURE

expected to occur in the atmosphere because the chemical lacks a chromophore

that absorbs light at environmentally significant wavelengths (greater than

290 nm) (Silverstein et al. 1974).

5.3.2.2 Water

Degradation of 1,2,3-trichloropropane in natural waters is expected to

be a slow process. The chemical should volatilize from surface waters before

significant degradation can occur. Hydrolysis of 1,2,3-trichloropropane in

natural waters is not expected to be a significant removal process. The

measured neutral and base hydrolysis rate constants at 25°C are 1.8x10-6 hour-l

and 9.9x10-4 M-1 hour-l, respectively (EPA 1988c). These rate constants

correspond to a hydrolysis half-life of 44 years over a pH range of 5-9.

Direct photolysis of 1,2,3-trichloropropane is not expected to occur in

environmental waters because the chemical lacks a chromophore that absorbs

light at environmentally significant wavelengths (greater than 290 nm)

(Silverstein et al. 1974).

No studies were located regarding the biodegradation of

1,2,3-trichloropropane in natural waters. An aqueous screening study with

activated sewage sludge has indicated that 1,2,3-trichloropropane can be

removed by biological treatment processes and that at least part of the

removal was due to volatilization. However, this study cannot be used to

predict the biodegradability of this compound under natural conditions. Other

authors have observed that halogenated hydrocarbons, in general, and

especially those with multiple chlorine substitution, such as

1,1,2-trichloroethane and 1,1,2,2-tetrachloroethane, are recalcitrant towards

biodegradation (Kawasaki 1980; Tabak et al. 1981). No data concerning the

potential for anaerobic aqueous biodegradation of 1,2,3-trichloropropane were

found.

5.3.2.3 Soil

No data specifically regarding the degradation of 1,2,3-trichloropropane

in soil were found. However, it has been observed that 1,2-dichloropropane

will not significantly biodegrade in soil (Roberts and Stoydin 1976).

Therefore, 1,2,3-trichloropropane is expected to be even less biodegradable

because it contains an additional chlorine. The rate of 1,2,3-trichloropropane

loss from soil due to biodegradation may not be significant when compared with its

loss by volatilization and leaching from soil. 1,2,3-Trichloropropane will be lost

from the soil by evaporation (from both moist and dry near-surface soil) and by

leaching to groundwater before 1,2,3-trichloropropane will hydrolyze in soil.

Direct photolysis on the surface of soil will not occur.
65

5. POTENTIAL FOR HUMAN EXPOSURE

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

5.4.1 Air

No data were located regarding the detection of 1,2,3-trichloropropane

in ambient air in the United States. Therefore, no estimate of U.S.

atmospheric levels of the chemical, including background levels, is possible.

5.4.2 Water

Limited data are available regarding the detection of

1,2,3-trichloropropane in environmental waters. It has been detected by one

of the sampling techniques at less than 0.2 μg/L in drinking water from the

Carrollton Water Plant in New Orleans, Louisiana, sampled during August, 1974;

however, since two of the three sampling techniques failed to detect the

compound, the significance of this detection is in question (Keith et al.

1976). 1,2,3-Trichloropropane has been qualitatively detected in the drinking

water of Cincinnati, Ohio, sampled during 1978 (EPA 1984), and Ames, Iowa, on

an unspecified date (EPA 1987). Data from the EPA STORET Data Base indicate

that 1,2,3-trichloropropane was found in 39% of 941 samples of groundwater at

a median concentration of 0.69 μg/L, at an average concentration of 1.0 μg/L,

and a range of trace (below unspecified detection limit) to 2.5 μg/L (STORET

1989). It has been found at concentrations ranging from 0.1 to 5.0 μg/L in

groundwater samples from California and Hawaii during small- and large-scale

retrospective studies of farmlands possibly treated with fumigants and

nematocides that contained 1,2,3-trichloropropane as an impurity (Cohen et al.

1986, 1987). The locations that had 1,2,3-trichloropropane-contaminated wells

included the island of Oahu, Hawaii, and the Central Valley of California.

Typical concentrations ranged from 0.2 to 2 μg/L. 1,2,3-Trichloropropane was

found in water from nine of nine wells in Oahu, Hawaii, sampled in 1983 and

1984 at maximum concentrations ranging from 0.30 to 2.8 μg/L (Oki and

Giambelluca 1987). The wells had been closed previously to drinking water use

due to contamination with other halogenated hydrocarbons.1,2,3-

Trichloropropane has been detected in groundwater from 2 of 10 sites in

an agricultural community in Suffolk County, New York, at concentrations of 6

and 10 μg /L (Lykins and Baier 1985).

1,2,3-Trichloropropane was qualitatively found in 1 of 30 water samples

from the Delaware, Schuylkill, and Lehigh Rivers, taken February 17-20, 1976

(DeWalle and Chian 1978). 1,2,3-Trichloropropane was qualitatively found in

water from Narragansett Bay, Rhode Island, sampled during the summers of 1979

and 1980, and the winters of 1980 and 1981 (Wakeham et al. 1983). Some

samples reportedly contained significant levels of the chemical. The chemical

was qualitatively detected in effluent from an advanced waste treatment plant

in Lake Tahoe, California, in 1974 (EPA 1984). The chemical was found in

groundwater at 0.71% of the sites in the CLPSD, which includes data from both

NPL and non-NPL sites, at a geometric mean concentration of 57.3 μg/L (CLPSD

1989). 1,2,3-Trichloropropane was found in 69 of 141 samples of sewage
66

5. POTENTIAL FOR HUMAN EXPOSURE

sludges from municipal sewage treatment plants in Michigan in 1980 (Jacobs and

Zabik 1983). The median and average concentrations of 1,2,3-trichloropropane

in the sludges were 0.352 and 1.07 mg/kg, respectively, and the range was

0.00459-19.5 mg/kg on a dry-weight basis.

5.4.3 Soil

Limited data are available regarding the detection of 1,2,3-trichloropropane

in soil samples. It has been found in soil samples from California and Hawaii

during small- and large-scale retrospective studies at levels typically ranging

from 0.2 to 2 ppb (Cohen et al. 1987). It was found at least 10 feet down in the

soil profiles in Hawaii. 1,2,3-Trichloropropane may be present in these soils as a

result of the use of dichloropropene (a soil fumigant and nematocide). 1,2,3-

Trichloropropane is used in the preparation of this nematocide and is an impurity

in the formulation of it (Baier et al. 1987). 1,2,3-Trichloropropane was not found

in any of the soil samples from the sites in the CLPSD (1988). The detection

of the chemical in the groundwater of hazardous waste sites, however, suggests

that it is released to soil at these sites. The chemical was found in soil at

0.71% of the sites of the CLPSD at a geometric mean concentration of 204 pg/L

(CLPSD 1989); the CLPSD includes data from both NPL and non-NPL sites.

5.4.4 Other Environmental Media

1,2,3-Trichloropropane has been qualitatively identified as a component

of ethylene dichloride-tar, a tarlike, oily waste byproduct of vinyl chloride

production that had been disposed of by dumping into the sea (Jensen et al.

1975). The chemical has been found in the volatile products from the thermal

oxidative degradation of the flame-retardant plasticizer, tris(dichloropropy1)

phosphate (Christos et al. 1977). No information was found that indicated

that 1,2,3-trichloropropane has been found in food. Because of the lack of

recent comprehensive monitoring data, the average daily intake of

i,2,3-trichloropropane and the relative significance of each source of

exposure cannot be determined.

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

There are not enough measured data to assess the general population's

exposure to this compound. The paucity of data may be the result of either a

lack of 1,2,3-trichloropropane contamination in the environment or a lack of

studies that attempt to identify and quantify the compound in the environment

using sufficiently sensitive techniques. Based upon the few data available,

the estimated transport and partitioning properties of the compound, and

information on production and use, the following estimations concerning

exposure can be made. A small part of the population may be exposed to very

low levels of 1,2,3-trichloropropane through the ingestion of contaminated

drinking water. Exposure to very low levels of 1,2,3-trichloropropane also

may occur through the inhalation of contaminated air; however, no monitoring
67

5. POTENTIAL FOR HUMAN EXPOSURE

data regarding the presence of 1,2,3-trichloropropane in the atmosphere in the

United States were located. General exposure to air containing low levels may

occur near chemical manufacturing facilities that produce 1,2,3-trichloropropane

and certain other chemicals, near 1,2,3-trichloropropane-containing

hazardous waste dumps, and farmlands treated with fumigants and nematocides

that contain 1,2,3-trichloropropane. No current information is available,

however, that indicates that 1,2,3-trichloropropane is still present in soil

fumigant formulations, and commercial manufacturing processes generally occur

in closed and tightly sealed systems (NIOSH 1981). Inhalation and dermal

exposure may occur during the use of 1,2,3-trichloropropane as a solvent and

extractive agent, in paint- and varnish-removers, in cleaning and degreasing

agents, and in cleaning and maintenance reagents, although there is no current

information that indicates that the compound is still used for these purposes

(Hawley 1981; NIOSH 1981). No data regarding the detection of

1,2,3-trichloropropane in humans in the United States were located.

According to the NOES conducted by NIOSH from 1981 to 1983, 492 workers

(of which 9 were women) were potentially exposed to 1,2,3-trichloropropane in

the workplace in 1980 (NIOSH 1989); however, no report of actual measured

exposure levels in any occupational situation in the United States was

located. The NOES database does not contain information on the frequency,

concentration, or duration of exposure of workers to any of the chemicals

therein. This survey provides only an estimate of the number of workers

potentially exposed to chemicals in the workplace. Occupational exposure to

1,2,3-trichloropropane is expected to be higher in facilities where the

chemical or products containing the chemical are used than in facilities that

produce 1,2,3-trichloropropane either directly or as a byproduct, since the

commercial manufacturing processes generally occur in closed and tightly

sealed systems (NIOSH 1981). Furthermore, exposure may result from procedures

that require direct handling of the material; these include purification,

formulation of products, sampling and quality control, packaging and storage,

leakage of equipment, startup and shutdown procedures, maintenance, cleanup,

spills, and other plant emergencies (NIOSH 1981).

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Data regarding the presence of 1,2,3-trichloropropane in the environment

are lacking, which prevents the thorough assessment of the potential for high

exposure in various populations. Populations with potentially high exposure

to 1,2,3-trichloropropane will generally include those that may be exposed to

environmental contamination over long periods of time. These may include

populations exposed to low levels of 1,2,3-trichloropropane via inhalation of

contaminated air at or near both identified and unidentified

1,2,3-trichloropropane-containing waste disposal sites and landfills.

Children playing in and around these sites may also be dermally exposed to

soil containing 1,2,3-trichloropropane, although any 1,2,3-trichloropropane il

surface soil would be expected to volatilize or leach through the soil.
68

5. POTENTIAL FOR HUMAN EXPOSURE

Persons whose drinking water is derived from 1,2,3-trichloropropanecontaminated

groundwater or surface water for a long period of time may be

exposed to relatively high levels of 1,2,3-trichloropropane. Workers involved

in the manufacture or use of 1,2,3-trichloropropane or 1,2,3-

trichloropropanecontaining products may have the highest potential for exposure to

1,2,3-trichloropropane. Potentially high general population exposure may

occur during the use of 1,2,3-trichloropropane-containing products, such as

paint- and varnish-removers and cleaners, especially when they are used in

poorly ventilated areas such as in the cleaning of reactors. Exposure through

the manufacture or use of 1,2,3-trichloropropane-containing products may not

be significant, however, since current manufacturing processes generally occur

in closed and tightly sealed systems (NIOSH 1981) and no current information

indicates that 1,2,3-trichloropropane is still used for those purposes listed.

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 1,2,3-trichloropropane 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 1,2,3-trichloropropane. 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 substancespecific research agenda will be proposed.

5.7.1 Data Needs

Physical and Chemical Properties. Physical and chemical property data

are essential for estimating the transport and partitioning of a chemical in

the environment. Many of the physical and chemical properties of

1,2,3-trichloropropane are available (Table 3-2) (Hawley 1981; HSDB 1989;

Mackay et al. 1982; McNeil1 1979; Riddick et al. 1986; Ruth 1986; Weast 1985;

Williams 1949). However, only estimated values are listed for the log Kow,

Koc, and BCF (Lyman et al. 1982). Since the log Kow was used to estimate the

Koc and BCF, an experimentally determined log Kow would lead to less

uncertainty in those estimated properties. Experimentally determined values

would remove any doubt regarding the reliability of these data, although the

techniques used for the estimations appear to be accurate.

Production, Import/Export, Use, and Disposal. Data regarding the

production methods for 1,2,3-trichloropropane are available (Bauer et al.
69

5. POTENTIAL FOR HUMAN EXPOSURE

1987; Hawley 1981; NIOSH 1981; SRI 1989; Williams 1949); however, data

regarding current production, import, and export volumes, and use patterns are

lacking. We do know that the chemical is currently produced (SRI 1989), but

not in what quantities or whether future production levels will increase, We

do not know if the chemical is widely used in the home, the environment, or in

the workplace, but it does not appear that such widespread use is likely. It

has not been found in food although foods may not have been tested for its

presence. Use, release, and disposal information is useful for determining

where environmental exposure to 1,2,3-trichloropropane may be high, and may

help in estimating whether exposure is likely, and therefore may help to

determine whether further toxicological studies are warranted. General data

are available regarding the methods of disposal of 1,2,3-trichloropropane

(HSDB 1989; Matsui et al. 1975), but information concerning the efficiencies

of these methods, as well as the amount disposed of by each method is lacking.

Specific disposal information, obtainable by polling industries or industry

organizations, may be useful for determining environmental burden and

potential concentrations where environmental exposures may be high. Rules and

regulations governing land disposal of 1,2,3-trichloropropane are known (EPA

1988a).

Environmental Fate. The environmental fate of 1,2,3-trichloropropane

remains unclear due to a lack of experimental data. We do not know where the

chemical partitions in the environment. However, based upon estimated

physical properties (Lyman et al. 1982), the chemical is expected to partition

into the atmosphere and groundwater (Swann et al. 1983). It has been shown

that the chemical leaches through soil (Cohen et al. 1986, 1987; Lykins and

Baier 1985; Oki and Giamelluca 1987; STORET 1989). It is estimated that it

can volatilize ,through near-surface soil and water to the atmosphere (EPA

1985; Lyman et al. 1982). Nothing definitive is known about the

biodegradability of the compound. The rate constant for reaction with

hydroxyl radicals in the atmosphere is an estimated value (Atkinson 1987), as

are significant partition coefficient values used in predicting the

environmental fate of the compound (EPA 1988b). Experimental data in these

areas would aid in assessing the ultimate environmental fate of

1,2,3-trichloropropane, which would, in turn aid in assessing its background

levels in the environment and levels of human exposure.

Bioavailability from Environmental Media. Studies have shown that

1,2,3-trichloropropane is absorbed through the lungs, gastrointestinal tract,

and skin of animals (see Section 2.3.1) (Alpert 1982; Clark 1977; Johannsen

et al. 1988; Sipes et al. 1982; Union Carbide 1958; Volp et al. 1984). This

indicates that it may be absorbed through the inhalation of contaminated air,

ingestion of contaminated water, food, and soil, and through dermal contact.

The amount of 1,2,3-trichloropropane that is bioavailable from each route is

not well documented, and no data were found for humans. Data on the

bioavailability of 1,2,3-trichloropropane would be helpful in assessing the

importance of environmental exposure levels.
70

5. POTENTIAL FOR HUMAN EXPOSURE

Food Chain Bioaccumulation. The estimated BCF for 1,2,3-trichloropropane

(EPA 1988b; Lyman et al. 1982) indicates that this compound would not

significantly bioconcentrate in plants, aquatic organisms, or animals. No

experimental data were found to support this conclusion. Information was

unavailable on the biomagnification of 1,2,3-trichloropropane in food chains.

Additional information on bioconcentration by plants, aquatic organisms, and

animals and biomagnification in terrestrial and aquatic food chains could be

helpful because it might help to indicate whether the chemical biomagnifies in

food chains and thereby poses a potential for significant exposure.

Biomagnification is not likely, however, based upon the estimated BCF.

Exposure Levels in Environmental Media. Limited data were available

regarding the levels of 1,2,3-trichloropropane in the environment (Baier et

al. 1987; CLPSD 1989; Cohen et al. 1986, 1987; Dewalle and Chian 1978; EPA

1984, 1987; Jacobs and Zabik 1983; Keith et al. 1976; Lykins and Baier 1985;

Oki and Giambelluca 1987; STORET 1989; Wakeham et al. 1983). Information on

exposure to 1,2,3-trichloropropane from environmental media would be useful,

especially from drinking water derived from groundwater downgradient from

1,2,3-trichloropropane-containing hazardous waste disposal sites and other

contaminated surface waters, air near facilities that make or use products

containing the compound, and soil at waste disposal sites. Data concerning

the presence of 1,2,3-trichloropropane in foods would also be useful in

assessing potential exposure.

Exposure Levels in Humans. No data have been found that indicate that

1,2,3-trichloropropane has been found in human samples of blood, urine, fat,

or breast milk. Furthermore, no biomarkers of exposure or effect have been

identified. Data on both workplace exposure and ambient environmental

exposure are sparse and outdated (NIOSH 1981; 1989). A detailed, recent

database of exposure would be helpful in determining the current exposure

levels, thus allowing estimation of the average daily dose associated with

various scenarios such as living near a hazardous waste disposal site,

drinking contaminated drinking water, or working in a contaminated workplace.

This database of exposure may be very useful if current use patterns, for

which information is not available, warrant it.

Exposure Registries. No exposure registries for 1,2,3-trichloropropane

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.
71

5. POTENTIAL FOR HUMAN EXPOSURE

5.7.2 On-going Studies

Remedial investigations and feasibility studies conducted at the eight

NPL sites known to be contaminated with 1,2,3-trichloropropane will add to the

available database on exposure levels in environmental media, exposure levels

in humans, and exposure registries and will increase the current knowledge

regarding transport and transformation of 1,2,3-trichloropropane in the

environment.

As part of the Third National Health and Nutrition Evaluation Survey

(NHANES III), the Environmental Health Laboratory Sciences Division of the

Center for Environmental Health and Injury Control, Centers for Disease

Control, will be analyzing human blood samples for 1,2,3-trichloropropane and

other volatile organic compounds. These data will indicate the frequency of

occurrence and background levels of these compounds in the general population.

No other on-going studies were located.

73

6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that

are available for detecting and/or measuring and monitoring 1,2,3-trichloropropane

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 1,2,3-trichloropropane. Rather, the intention is to

identify well-established methods that are used as the standard methods of

analysis. Many of the analytical methods used to detect 1,2,3-trichloropropane

in environmental samples are the methods approved by federal agencies

such as EPA and the National Institute for Occupational Safety and Health

(NIOSH). Other methods presented in this chapter are those that are approved

by groups such as the Association of Official Analytical Chemists (AOAC) and

the American Public Health Association (APHA). Additionally, analytical

methods are included that refine previously used methods to obtain lower

detection limits, and/or to improve accuracy and precision.

6.1 BIOLOGICAL MATERIALS

No completed studies were located in the literature that reported the

analysis of 1,2,3-trichloropropane in human biological matrices. Methods were

located, however, for the analysis of the compound in rat biological matrices.

These methods are listed in Table 6-l. With suitable modifications, the

methods used to detect this chemical in animal samples may apply generally to

its determination in human biological samples. Section 6.2 includes a

discussion of the methods that may be most sensitive for the determination of

1,2,3-trichloropropane concentrations in environmental samples, including

advantages and disadvantages of the commonly used methods. Initial testing to

determine minimum detection limits, recovery, accuracy, and precision of the

particular, suitably modified methods is necessary to gauge the applicability

of the methods used to detect 1,2,3-trichloropropane in animal biological

samples for the chemical's determination in human biological samples.

6.2 ENVIRONMENTAL SAMPLES

Methods for analyzing 1,2,3-trichloropropane in environmental samples

are presented in Table 6-2. All of the methods listed use either adsorption

on a sorption column (air samples) or purge-and-trap methods (solid and liquid

samples), followed by thermal desorption and some form of gas chromatography

(GC) with an appropriate detector as the analytical quantification technique.

Purge-and-trap methods involve the purging of the vapor from the sample or its

suspension in water with an inert gas and the trapping of the desorbed vapors

in a sorbent trap. Particular care must be taken in sampling and storage of

samples in view of the compound's high volatility. Although 1,2,3-trichloropropane

was listed as a chemical that could be determined using the listed techniques,

significant factors such as the detection limit and percent recovery were not

reported for this chemical. Both halogen-specific detection (e.g., Hall

electrolytic conductivity detectors) and mass spectrometry (MS) provide excellent

detection limits (EPA 1986a; Ho 1989;


76

6. ANALYTICAL METHODS

Lopez-Avila et al. 1987; Ramus et al. 1984). An advantage of halogenspecific

detectors is that they are very sensitive and specific to halogen

compounds. MS, on the other hand, provides additional confirmation of the

identity of a compound through its ion fragment patterns. High-resolution gas

chromatography (HRGC) with capillary columns coupled with MS provides better

resolution and increased sensitivity for volatile compounds than packed

columns. In this method, desorbed compounds are cryogenically trapped onto

the head of the capillary column. This HRGC-MS method overcomes some common

problems involved in analyses of excessively complex samples, samples with

large ranges of concentrations, and samples that also contain nonvolatile

compounds (Dreisch and Munson 1983; EPA 1986a).

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 1,2,3-trichloropropane 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 1,2,3-trichloropropane.

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. No

biomarker, other than possibly 1,2,3-trichloropropane itself, that can be

associated quantitatively with exposure to 1,2,3-trichloropropane has been

identified (see Section 2.5). Even the compound itself may not be a

quantitative biomarker of exposure because the levels found have not been

proven to qualitatively reflect exposure levels. Nevertheless, there are

methods for analyzing 1,2,3-trichloropropane in most of the biological

matrices for the rat, although important information such as detection limits

and recoveries was not reported (Sipes et al. 1982). These methods may be

sufficient for the analysis of human biological matrices.

No biomarkers have been identified that can be associated quantitatively

with effects caused by exposure to 1,2,3-trichloropropane. Therefore, methods

for biomarkers of effects are not currently available.
77

6. ANALYTICAL METHODS

Methods for Determining Parent Compounds and Degradation Products in

Environmental Media. Analytical methods for determining 1,2,3-trichloropropane in

contaminated air, water, soil, liquid and solid waste, sewage sludge, and citrus

fruits are available (EPA 1986a, 1986b; Ho 1989; Lopez-Avila et al. 1987; NIOSH

1987; Tonogai et al. 1986). No methods were found for the determination of 1,2,3-

trichloropropane in sediments. Most of the methods used for environmental samples,

however, did not report detection limits, recovery, accuracy, and precision for

1,2,3-trichloropropane. Knowledge of these factors, as well as the

development of alternative methods of analysis, would help in estimating the

potential for human exposure to 1,2,3-trichloropropane. No information was

found regarding degradation products of 1,2,3-trichloropropane. Consequently,

no comment regarding the availability of analytical methods for determining

degradation products can be made.

6.3.2 On-going Studies

The Environmental Health Laboratory Sciences Division of the Center for

Environmental Health and Injury Control, Centers for Disease Control, is

developing methods for analyzing 1,2,3-trichloropropane and other volatile

organic compounds in blood. These methods use high resolution gas

chromatography and magnetic sector mass spectrometry, which gives detection

limits in the low ppt (parts per trillion) range.

79

7. REGULATIONS AND ADVISORIES

National regulations and guidelines pertinent to human exposure to

1,2,3-trichloropropane are summarized in Table 7-l. Guidance from the World

Health Organization and the International Agency for Research on Cancer is not

available.

81

8. REFERENCES

*ACGIH. 1989. Threshold limit values and biological exposure indices for

19894990. American Conference of Governmental Industrial Hygenists,

Cincinnati, OH, 41.

Albrecht WN. 1987. Central nervous system toxicity of some common

environmental residues in the mouse. J Toxicol Environ Health 21(4):405-421.

*Alpert JR. 1982. Acute toxicity studies with 1,2,3-trichloropropane.

Report to Shell Oil Co. OTS 0515726. [Unpublished study]

*Atkinson R. 1987. A structure-activity relationship for the estimation of

rate constants for the gas-phase reactions of OH radicals with organic

compounds. J Chem Kinet 19:799-828.

*Baier JH, Lykins BW Jr., Fronk CA, et al. 1987. Using reverse osmosis to

remove agricultural chemicals from groundwater. Am Water Works Assoc J

79(8):55-60.

*Barnes D, Bellin J, DeRosa C, et al. 1988. Reference dose (RfD) description

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

information system supportive documentation. Washington, DC; US Environmental

Protection Agency, Office of Health and Environmental Assessment. EPA/600/8-

86/032a.

*Burka L. 1990a. Personal communication (telephone conversation) from Dr. L.

Burka, Staff Scientist, National Toxicology Program, Division of Toxicology

Research and Testing, to Stephen J. Bosch, Syracuse Research Corporation.

March 12, 1990.

*Burka L. 1990b. Memo to Dr. Terri Damstra on ATSDR document on

1,2,3-trichloropropane. March 29, 1990.

*CAS. 1989. Chemical Abstracts Service, American Chemical Society, Chemical

Abstracts Registry File. [Database] September 8, 1989.

*CHEMLINE. 1989. National Library of Medicine Chemline [Database].

*Christos T, Forshey DR, Hartstein AM. 1977. Coal mine combustion products:

Ingredients of conveyor belts. U.S. Bur Mines Rep Invest, (RI):8235

*Clark DG. 1977. Acute toxicity, skin and eye irritancy and skin sensitizing

potential of 1,2,3-trichloropropane. Report to Shell Oil Co. OTS 0515731.

[Unpublished study]

____________________

*Cited in text.
82

8. REFERENCES

CLPSD. 1989. Contract Laboratory Program Statistical Database. Viar and

Company, Alexandria, VA, July 12, 1989.

*Cohen SZ, Eiden C, Lorber MN. 1986. Monitoring ground water for pesticides.

In: Garner WY et al., ed. ACS Symp Ser, Washington, DC. 315:170-196.

*Cohen SZ, Eiden C, Lorber MN. 1987. Monitoring ground water for pesticides

in the U.S.A. Schriftenr Ver Wasser-, Bodenlufthyg 68:265-294.

*DeWalle FB, Chian ESK. 1978. Presence of trace organics in the Delaware

River and their discharge by municipal and industrial sources. Proc Ind Waste

Conf 32:908-919.

*Dilling WL. 1977. Interphase transfer process. II. Evaporation rates of

chloromethanes, ethanes, ethylenes, propanes, and propylenes from dilute

aqueous solutions. Comparisons with theoretical predictions. Environ Sci

Technol 11:405-409.

*Dix KM. 1979. Toxicity of fine chemicals: preliminary studies for the

detection of testicular changes in rats. Report to Shell Oil Co. OTS

0510352. [Unpublished study]

*Dreisch FA, Munson TO. 1983. Purge-and-trap analysis using fused silica

capillary column gas chromatography-mass spectrometry. J Chromatogr Sci

21(3):111-118.

Drew RT, Pate1 JM, Lin FN. 1978. Changes in serum enzymes in rats after

inhalation of organic solvents singly and in combination. Toxicol Appl

Pharmacol 45(3):809-819.

*Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants

in the Great Lakes ecosystem. Environ Sci Technol 15(1):30-38.

*Ellerstein SM, Bertozzi ER. 1982. Polysulfides. In: Kirk-Othmer

encyclopedia of chemical technology. 3rd ed. New York, NY: John Wiley and

Sons, 11:814-815.

*EPA. 1984. GC/MS analysis of organics in drinking water concentrates and

advanced waste treatment concentrates. Vol. 2. Computer-printed tabulations

of compound identification results for large-volume concentrates. Columbus

Labs, Health Effects Research Lab, Columbus, OH. EPA/600/i-84-020B. NTIS

PB85-128239.

*EPA. 1985. Exposure analysis modeling system: reference manual for EXAMS

II. U.S. Environmental Protection Agency, Environmental Research Lab, Athens,

GA. EPA/600/3-85/038.
83

8. REFERENCES

*EPA. 1986a. Method for the determination of organic compounds in finished

drinking water and raw source water. Method Nos. 502.1, 524.1 and 524.2.

U.S. Environmental Protection Agency, Environmental Monitoring and Support

Laboratory, Cincinnati, OH.

*EPA. 1986b. Test method for evaluating solid waste, physical/chemical

methods, SW-846, Methods No. 5030 and 8010. U.S. Environmental Protection

Agency, Office of Solid Waste and Emergency Response, Washington, DC.

*EPA. 1987. Health and environmental effects document for trichloropropanes.

Prepared by the Environmental Criteria and Assessment Office, Office of Health

and Environmental Assessment, U.S. Environmental Protection Agency,

Cincinnati, OH for the Office of Solid Waste and Emergency Response.

*EPA. 1988a. List of halogenated organic compounds regulated under 268.32.

40 CFR 268, Appendix III. July 1, 1988.

*EPA. 1988b. PC Gems CLOGP3 (Octanol/Water Partition Coefficient).

Graphical Exposure Modeling Systems. U.S. Environmental Protection Agency,

Washington, DC.

*EPA. 1988c. Measurement of hydrolysis rate constants for evaluation of

hazardous waste land disposal: Volume 3. Data on 70 chemicals. U.S.

Environmental Protection Agency, Washington, DC. NTIS PB88-234 042/AS.

EPA/600/S3-88/028.

*EPA. 1989a. Interim methods for development of inhalation reference doses.

U.S. Environmental Protection Agency, Office of Health and Environmental

Assessment. Washington, DC. EPA 600/8-88-066F.

*EPA. 1989b. CIS computer printout: 1977 Non-confidential production data

from TSCA inventory. OPTS, CID, U.S. Environmental Protection Agency,

Washington, DC. September 1, 1989.

*Gangal SV. 1980. Fluorinated ethylene-propylene copolymers. In: KirkOthmer Encyclopedia of Chemical Technology. 3rd ed. New York, NY: John Wiley

and Sons, 11:24-25.

*Gushow TS, Quast JF. 1984. 1,2,3-Trichloropropane: Acute inhalation

toxicity evaluation in male rats and mice. Report to Dow Chemical Co. OTS

0510175. [Unpublished study]

*Hardin BD, Bond GP, Sikov MR, et al. 1981. Testing of selected workplace

chemicals for teratogenic potential. Stand J Work Environ Health 7(Suppl

4):66-75.

*Hawley GG. 1981. The condensed chemical dictionary. 10th ed. New York, NY:

Van Nostrand Reinhold Co., 1043.
84

8. REFERENCES

*Haworth S, Lawlor T, Mortelmas K, et al. 1983. Salmonella mutagenicity test

results for 250 chemicals. Environ Mutagen Supplement 5(1):3-142.

*Ho JSY. 1989. A sequential analysis for volatile organics in water by

purge-and-trap capillary column gas chromatography with photoionization and

electrolytic conductivity detectors in a series. J Chromatogr Sci 27:91-98.

*HSDB. 1989. Hazardous Substance Data Bank. National Library of Medicine,

National Toxicology Information Program, Bethesda, MD. Profile No. 1340.

September 8, 1989.

*IRIS. 1991. Integrated Risk Information System (IRIS). Online.

Cincinnati, OH: Office of Health and Environmental Assessment, Environmental

Criteria and Assessment Office, U.S. Environmental Protection Agency.

*Ivanetich KM, Lucas S, Marsh JA, et al. 1978. Organic compounds: Their

interaction with and degradation of hepatic microsomal drug -- Metabolizing

enzymes in vitro. Drug Metab Dispos 6(3):218-225.

*Jacobs LW, Zabik MJ. 1983. Importance of sludge-borne organic chemicals for

land application programs. Sixth annual Madison waste conference municipal

and industrial waste, September 14-15, 1983. 418-426.

*Jensen S, Lange R, Berge G, et al. 1975. Chemistry of EDC-tar and its

biological significance in the sea. Proc. R. Sot. London, Ser B,

189(1096):33-46.

*Johannsen FR, Levinskas GJ, Rusch GM, et al. 1988. Evaluation of the

subchronic and reproductive effects of a series of chlorinated propanes in the

rat. I. Toxicity of the 1,2,3-trichloropropane. J Toxicol Environ Health

25(3):299-315.

*Kawasaki M. 1980. Experience with the test scheme under the chemical

control law of Japan: An approach to structure-activity correlations. Ecotox

Environ Safety 4:444-454.

*Keith LH, Garrison AW, Allen FR, et al. 1976. Identification of organic

compounds in drinking water from thirteen U.S. cities. In: Keith LH, ed.

Ident Anal Organic Pollut Water. Ann Arbor, MI: Ann Arbor press, 329-373.

*Lopez-Avila V, Heath N, Hu A. 1987. Determination of purgeable halocarbons

and aromatics by photoionization and Hall electrolytic conductivity detectors

connected in series. J Chromatogr Sci 25(8):356-363.

*Lykins BW Jr., Baier JH. 1985. Removal of agricultural contaminants from

ground water. U.S. Environmental Protection Agency, Washington, DC.

EPA/600/D-85/136.
85

8. REFERENCES

*Lyman WJ, Reehl WF, Rosenblatt DH. 1982. Handbook of chemical property

estimation methods. Environmental behavior of organic compounds. New York,

NY: McGraw-Hill Book Co., 4-9, 5-5, 15-9 to 15-31.

*MacKay D, Bobra A, Chan DW, et al. 1982. Vapor pressure correlations for

low-volatility environmental chemicals. Environ Sci Technol 16:645-649.

*Mahmood NA, Burka LT, Cunningham ML. 1988. Metabolism and mutagenicity of

1,2,3-trichloropropane. Pharmacologist. 30:A8.

*Matsui S, Murakami T, Sasaki T, et al. 1975. Activated sludge degradability

of organic substances in the waste water of the Kashima petroleum and

petrochemical industrial complex in Japan. Prog Water Technol 7:645-659.

*McNeil1 WC Jr. 1979. Trichloroethylene. In: Kirk-Othmer encyclopedia of

chemical technology, 3rd ed. New York, NY: John Wiley and Sons, 5:745.

*McOmie WA, Barnes TR. 1949. Acute and subacute toxicity of

1,2,3-trichloropropane in mice and rabbits. Fed Proc 8:319.

*Miller RR, Quast JF, Gushow TS. 1986a. 1,2,3-Trichloropropane: 2-Week vapor

inhalation study in rats and mice. Report to Dow Chemical Co. OTS 0517050.

[Unpublished study]

Miller RR, Quast JF, Momany-Pfruender JJ. 1986b. 1,2,3-Trichloropropane: 2-

Week vapor inhalation study to determine the no-adverse-effect level in rats

and mice. Report to Dow Chemical Co. OTS 0517055. [Unpublished study]

Moody DE, James JL, Clawson GA, et al. 1981. Correlation among the changes

in hepatic microsomal components after intoxication with alkyl halides and

other hepatotoxins. Mol Pharmacol 20(3):685-693.

*NAS/NRC. 1989. Biologic markers in reproductive toxicology. National

Academy of Sciences/National Research Council. Washington, DC: National

Academy Press, 15-35.

*NATICH. 1988. National Air Toxics Information Clearinghouse. July 1988.

*NIOSH. 1975. NIOSH Analytical Method 1,2,3-Trichloropropane S126. National

Institute for Occupational Safety and Health, Rockville, MD.

*NIOSH. 1981. Trichloropropanes. Report 4. Report to National Institute

for Occupational Safety and Health, Cincinnati, OH by Franklin Research

Center, Silver Springs, MD.
86

8. REFERENCES

*NIOSH. 1987. Manual of analytical methods. Vol. 1, 3rd ed. U.S.

Department of Health and Human Services, Centers for Disease Control, National

Institute for Occupational Safety and Health, Cincinnati, OH.

*NIOSH. 1989. National Occupational Exposure Survey (NOES) as of March 29,

1989. National Institute for Occupational Safety and Health. Cincinnati, OH.

*NTP. 1983a. Final report. 120-Day toxicity gavage study of

1,2,3-trichloropropane in Fischer 344 rats. Report to the National Toxicology

Program by Hazelton Laboratories, [Unpublished study]

*NTP. 1983b. Final report. 120-Day gavage toxicity study in B6C3Fl mice.

1,2,3-Trichloropropane. Report to the National Toxicology Program by Hazelton

Laboratories. [Unpublished study]

*NTP. 1991. National Toxicology Program -- technical report series no. 384.

Toxicology and carcinogenesis studies of 1,2,3-trichloropropane (CAS no. 96-

18-4) in F344/N rats and B6C3Fl mice (gavage studies). Research triangle

Park, NC: Department of Health and Human Services, National Institute of

Health. NTH publ. no. 91-2839.

*Oki DS, Giambelluca TW. 1987. DBCP, EDB, and TCP contamination of ground

water in Hawaii. Ground Water 25:693-702.

Olson KS. 1975. Results of range finding toxicological tests on

1,2,3-trichloropropane. Report to Dow Chemical Company. OTS 0510177.

[Unpublished study]

*OSHA. 1989. U.S. Department of Labor. Occupational Safety and Health

Administration. Air contaminants; final rule. 29 CFR 1910. Federal Register

54:2955 (January 19, 1989).

Pinkerton MN, Schwebel RL. 1975. Acute toxicological properties and

industrial handling hazards of crude 1,2,3-trichloropropane. Report to Dow

Chemical Company. OTS 0510173. [Unpublished study]

Pullin TG, Schwebel RL. 1958. Acute toxicological properties and industrial

handling hazards of 1,2,3-trichloropropane, crude. Report to Dow Chemical

Company. OTS 0510174. [Unpublished study]

*Ramus TL, Hein SJ, Thomas LC. 1984. Determinations of chlorinated

hydrocarbons by gas chromatography using response factor calibration. 3

Chromatogr 314:243-251.

*Ratpan F, Plaurnann H. 1988. Mutagenicity of halogenated propanes and their

methylated derivatives. Environ Mol Mutagen 12(2):253-260.
87

8. REFERENCES

*Riddick JA, Bunger WB, Sakano TK. 1986. Organic solvents: Physical

properties and methods of purification. Techniques of chemistry. 4th ed.

New York, NY: Wiley-Interscience, 524.

*Roberts TR, Stoydin G. 1976. The degradation of (Z)- and (E)-,1,3-

dichloropropenes and 1,2-dichloropropane in soil. Pestic Sci 7:325-335.

*Robinson M, McKean DL, Condie LW et al. 1989. 1,2,3-Trichloropropane (TCP)

induced heart and liver toxicity. Toxicologist 9:278.

*RTECS. 1989. Registry of Toxic Effects of Chemical Substances on-line

database. U.S. Department of Health and Human Service, Public Health Service,

Center for Disease Control, National Institute of Occupational Safety and

Health, Research Triangle Park, NC. September 8, 1989.

*Ruth JH. 1986. Odor thresholds and irritation levels of several chemical

substances. A review. Am Ind Hyg Assoc J 47:A142-A151.

*Saito-Suzuki R, Teramoto S, Shirasu Y. 1982. Dominant-lethal studies in

rats with 1,2-dibromo-3-chloropropane and its structurally related compounds.

Mutat Res 101(4):321-328.

*Salmon AG, Jones RB, Mackrodt WC. 1981. Microsomal dechlorination of

chloroethanes: Structure-reactivity relationships. Xenobiotica. 11(11):723-

734.

*Silverman L, Schulte HF, First MW. 1946. Further studies on sensory

response to certain industrial solvent vapors. J Ind Hyg Toxicol 28: 262-

266.

*Silverstein RM, Bassler GC, Merrill TC. 1974. Spectrometric identification

of organic compounds. 3rd ed. New York, NY: John Wiley and Sons, 239.

*Sipes IG, Carter DE, Volp RF. 1982. Pharmacokinetics of xenobiotics:

1,2,3-Trichloropropane. Study performed for N.I.E.H.S. under Contract No.

NOl-ES-8-2130. [Unpublished study]

*Smyth HF, Carpenter CP, Weil CS, et al. 1962. Range-finding toxicity data:

List VI. Ind Hyg J 23:95-107.

*SRI. 1989. 1989 Directory of chemical producers. United States of America.

Standard Research International, Menlo Park, CA. 1042,

*Stolzenberg SJ, Hine CH. 1980. Mutagenicity of 2- and 3- carbon halogenated

compounds in the Salmonella/mammalian-microsome test. Environ Mutagen

2(1):59-66.
88

8. REFERENCES

*STORET. 1989. STORET database. U.S. Environmental Protection Agency,

Washington, D.C. September 13, 1989.

*Stutz DR, Janusz SJ. 1988. Hazardous materials injuries. A handbook for

pre-hospital care. 2nd ed. Beltsville, MD: Bradford Communications

Corporation. p. 300-301.

*Swarm RL, Laskowski DA, McCall PJ, et al. 1983. A rapid method for the

estimation of the environmental parameters octanol/water partition

coefficient, soil sorption constant, water to air ratio and water solubility.

Res Rev 85:17-28.

*Tabak HK, Quave SA, Mashin CI, et al. 1981. Biodegradability studies with

organic priority pollutant compounds. J Water Pollut Contr Fed 53:1503-1517.

*Tonogai Y, Ito Y, Ogawa S, et al. 1986. Determination of

dibromochloropropane and related fumigants in citrus fruit. J Food Prot

49(11):909-913.

Tsulaya VR, Bonashevskaya TI, Zykova VV. 1977. [Toxicological

characteristics of some chlorinated hydrocarbons.] Gig Sanit 8:50-53.

(Russian)

*Union Carbide Company. 1958. Range finding tests on 1,2,3-trichloropropane.

OTS 0515585. [Unpublished study]

*Van Dyke RA, Wineman CG. 1971. Enzymic dechlorination. Dechlorination of

chloroethanes and propanes in vitro. Biochem Pharmacol 20(2):463-470.

*View Database. 1989. Agency for Toxic Substances and Disease Registry

(ATSDR), Office of External Affairs, Exposure and Disease Registry Branch,

Atlanta, GA, September 25, 1989.

*Villeneuve DC, Chu I, Secours VE, et al. 1985. Results of a go-day toxicity

study on 1,2,3- and 1,1,2-trichloropropane administered via the drinking

water. Sci Total Environ 47:421-426.

*Volp RF, Sipes IG, Falcoz DE, et al. 1984. Disposition of

1,2,3-trichloropropane in the Fischer-344 rat: Conventional and physiological

pharmacokinetics. Toxicol Appl Pharmacol 75(1):8-17.

*Von Der Hude W, Scheutwinkel M, Gramlich U, et al. 1987. Genotoxicity of

three-carbon compounds evaluated in the SCE test In vitro. Environ Mutagen

9(4):401-410.

*Wakeham SG, Goodwin JT, Davis AC. 1983. Distributions and fate of volatile

organic compounds in Narragansett Bay, Rhode Island. Can J Fish Aquat Sci

40:304-321.
89

8. REFERENCES

*Weast RC. 1985. CRC handbook of chemistry and physics. 66th ed. Boca

Raton, FL: CRC Press, Inc., C-444.

*Weber GL, Sipes IG. 1988. Investigations into the role of biotransformation

in the covalent binding of 1,2,3-trichloropropane (TCP) to hepatic protein and

DNA. Toxicologist. 8:51.

*Williams PH. 1949. Chlorine compounds, organic. In: Kirk-Othmer

encyclopedia of chemical technology. 1st ed. Kirk RE, Othmer DF, ed. New

York, NY: Interscience Encyclopedia, Inc., 3:775-776, 838.

Wright WH, Schaffer JM. 1932. Critical anthelmintic tests of chlorinated

alkyl hydrocarbons and a correlation between the anthelmintic efficacy,

chemical structure and physical properties. Am J Hyg 16:325-428.
89

8. REFERENCES

*Weast RC. 1985. CRC handbook of chemistry and physics. 66th ed. Boca

Raton, FL: CRC Press, Inc., C-444.

*Weber GL, Sipes IG. 1988. Investigations into the role of biotransformation

in the covalent binding of 1,2,3-trichloropropane (TCP) to hepatic protein and

DNA. Toxicologist. 8:51.

*Williams PH. 1949. Chlorine compounds, organic. In: Kirk-Othmer

encyclopedia of chemical technology. 1st ed. Kirk RE, Othmer DF, ed. New

York, NY: Interscience Encyclopedia, Inc., 3:775-776, 838.

Wright WH, Schaffer JM. 1932. Critical anthelmintic tests of chlorinated

alkyl hydrocarbons and a correlation between the anthelmintic efficacy,

chemical structure and physical properties. Am J Hyg 16:325-428.
91

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.
92

9. GLOSSARY

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

concentration of a contaminant from which one could escape within 30 min

without any escape-impairing symptoms or irreversible health effects.

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days

as specified in the Toxicological Profiles.

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

that may result from exposure to environmental agents such as chemicals.

In vitro -- Isolated from the living organism and artificially maintained, as

in a test tube.

In vivo -- Occurring within the living organism.

Lethal Concentration(Lo) (LCLo) -- The lowest concentration of a chemical in

air which has been reported to have caused death in humans or animals.

Lethal Concentration(50) (LC50) -- A calculated concentration of a chemical in

air to which exposure for a specific length of time is expected to cause death

in 50% of a defined experimental animal population.

Lethal Dose(Lo) (LDLo) -- The lowest dose of a chemical introduced by a route

other than inhalation that is expected to have caused death in humans or

animals.

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

cause death in 50% of a defined experimental animal population.

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.
94

9. GLOSSARY

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.

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 2-1 and Figure 2-1 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
A-3

APPENDIX A

adverse health effects first appear and the gradation of effects with

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 2-1

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 in10,000,000. 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 continous 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.




C-l

APPENDIX C

PEER REVIEW

A peer review panel was assembled for 1,2,3-trichloropropane. The panel

consisted of the following members: Dr. Hugh Farber, Private Consultant,

Midland, MI; Dr. I.G. Sipes, Professor and Head, Department of Toxicology,

University of Arizona, Tucson, AZ; and Dr. Shane Que Hee, Associate Professor,

School of Public Health, University of California, Los Angeles, CA. These

experts collectively have knowledge of 1,2,3-trichloropropane's physical and

chemical properties, toxicokinetics, key health end points, mechanisms of

action, human and animal exposure, and quantification of risk to humans. All

reviewers were selected in conformity with the conditions for peer review

specified in the Comprehensive Environmental Response, Compensation, and

Liability Act of 1986, Section 104.

Scientists from the Agency for Toxic Substances and Disease Registry

(ATSDR) have reviewed the peer reviewers' comments and determined which

comments will be included in the profile. A listing of the peer reviewers'

comments not incorporated in the profile, with a brief explanation of the

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

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

documents cited are also included in the administrative record.

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

its approval of the profile's final content. The responsibility for the

content of this profile lies with the ATSDR.

*U.S. Government Printing Office: 1992-638-236.