Toxicological
Profile
for
ISOPHORONE
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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TOXICOLOGICAL PROFILE FOR
ISOPHORONE
Prepared by:
Syracuse Research Corporation
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
In collaboration with
U.S. Environmental Protection Agency (EPA)
December 1989
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ii
DISCLAIMER
Mention of company name or product does not constitute endorsement
the Agency for Toxic Substances and Disease Registry.
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iii
FOREWORD
The Superfund Amendments and Reauthorization Act 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 (also known as SARA) 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 most significant hazardous substances were published in the Federal
Register on April 17, 1987, and on October 20, 1988.
Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a
toxicological profile for each substance on the list. 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, or chronic
health effects, and
(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, but no less often than every 3 years, as required
by SARA.
The ATSDR toxicological profile is intended to characterize succinctly
the toxicological and health effects information for the hazardous substance
being described. Each profile identifies and reviews the key literature that
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iv
describes a hazardous substance's toxicological properties. Other literature
is 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.
Each toxicological profile begins with a public health statement, which
describes in nontechnical language a substance's relevant toxicological
properties. Following the statement is material that presents levels of
significant human exposure and, where known, significant health effects. The
adequacy of information to determine a substance's health effects is described
in a health effects summary. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of the
profiles is on health and toxicological information; therefore, we have
included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public. We plan to revise
these documents as additional data become available.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed by
scientists from ATSDR, EPA, the Centers for Disease Control, and the National
Toxicology Program. It has also been reviewed by a panel of nongovernment
peer reviewers and was made available for public review. Final responsibility
for the contents and views expressed in this toxicological profile resides
with ATSDR.
Wi »h.D.
Acting Administrator
Agency for Toxic Substances and
Disease Registry
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V
CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS ISOPHORONE? 1
1.2 HOW MIGHT I BE EXPOSED TO ISOPHORONE? 1
1.3 HOW CAN ISOPHORONE ENTER AND LEAVE MY BODY? 1
1.4 HOW CAN ISOPHORONE AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO ISOPHORONE? 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH
EFFECTS? 2
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? 7
1.8 WHERE CAN I GET MORE INFORMATION? 7
2. HEALTH EFFECTS 9
2.1 INTRODUCTION 9
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 9
2.2.1 Inhalation Exposure 10
2.2.1.1 Death 10
2.2.1.2 Systemic Effects 15
2.2.1.3 Immunological Effects 19
2.2.1.4 Neurological Effects 19
2.2.1.5 Developmental Effects 20
2.2.1.6 Reproductive Effects 21
2.2.1.7 Genotoxic Effects 22
2.2.1.8 Cancer 22
2.2.2 Oral Exposure 22
2.2.2.1 Death 22
2.2.2.2 Systemic Effects 28
2.2.2.3 Immunological Effects 31
2.2.2.4 Neurological Effects 32
2.2.2.5 Developmental Effects 32
2.2.2.6 Reproductive Effects 32
2.2.2.7 Genotoxic Effects 33
2.2.2.8 Cancer 33
2.2.3 Dermal/Ocular Exposure 33
2.2.3.1 Death 33
2.2.3.2 Systemic Effects 36
2.2.3.3 Immunological Effects 36
2.2.3.4 Neurological Effects 36
2.2.3.5 Developmental Effects 37
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vi
2.2.3.6 Reproductive Effects 37
2.2.3.7 Genotoxic Effects 37
2.2.3.8 Cancer 37
2.3 RELEVANCE TO PUBLIC HEALTH 37
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH
EFFECTS 44
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN
TISSUES AND/OR HEALTH EFFECTS 44
2.6 TOXICOKINETICS 45
2.6.1 Absorption 45
2.6.1.1 Inhalation Exposure 45
2.6.1.2 Oral Exposure. . 45
2.6.1.3 Dermal Exposure 45
2.6.2 Distribution 46
2.6.2.1 Inhalation Exposure 46
2.6.2.2 Oral Exposure 46
2.6.2.3 Dermal Exposure. . 46
2.6.3 Metabolism 46
2.6.4 Excretion 47
2.6.4.1 Inhalation Exposure 47
2.6.4.2 Oral Exposure 47
2.6.4.3 Dermal Exposure 47
2.7 INTERACTIONS WITH OTHER CHEMICALS 47
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 49
2.9 ADEQUACY OF THE DATABASE „ 49
2.9.1 Existing Information on Health Effects of Isophorone . 49
2.9.2 Data Needs 51
2.9.3 On-going Studies 56
3. CHEMICAL AND PHYSICAL INFORMATION 57
3.1 CHEMICAL IDENTITY 57
3.2 PHYSICAL AND CHEMICAL PROPERTIES 57
4. PRODUCTION, IMPORT, USE, AND DISPOSAL 61
4.1 PRODUCTION 61
4.2 IMPORT 61
4.3 USE 61
4.4 DISPOSAL 62
4.5 ADEQUACY OF THE DATABASE 62
4.5.1 Data Needs 62
5. POTENTIAL FOR HUMAN EXPOSURE 63
5.1 OVERVIEW 63
5.2 RELEASES TO THE ENVIRONMENT 63
5.2.1 Air 63
5.2.2 Water 64
5.2.3 Soil 64
5.3 ENVIRONMENTAL FATE 64
5.3.1 Transport and Partitioning 64
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vli
5.3.2 Transformation and Degradation 66
5.3.2.1 Air 66
5.3.2.2 Water 66
5.3.2.3 Soil 67
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 67
5.4.1 Air 67
5.4.2 Water 67
5.4.3 Soil 70
5.4.4 Other Media . 71
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 71
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE 74
5.7 ADEQUACY OF THE DATABASE 74
5.7.1 Data Needs 76
5.7.2 On-going Studies 77
6. ANALYTICAL METHODS 79
6.1 BIOLOGICAL MATERIALS 79
6.2 ENVIRONMENTAL SAMPLES 79
6.3 ADEQUACY OF THE DATABASE 81
6.3.1 Data. Needs SI
6.3.2 On-going Studies 82
7. REGULATIONS AND ADVISORIES 83
8. REFERENCES 87
9. GLOSSARY 99
APPENDIX 103
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ix
LIST OF FIGURES
2-1 Levels of Significant Exposure to Isophorone - Inhalation 14
2-2 Levels of Significant Exposure to Isophorone - Oral 27
2-3 Metabolic Scheme for Isophorone 48
2-4 Existing Information on Health Effects of Isophorone 50
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1
2
3
4
1
2
3
4
1
2
1
2
3
1
1
3
4
5
6
11
23
34
42
58
59
68
72
75
80
84
xi
LIST OF TABLES
Human Health Effects from Breathing Isophorone
Animal Health Effects from Breathing Isophorone
Human Health Effects from Eating or Drinking Isophorone .
Animal Health Effects from Eating or Drinking Isophorone.
Levels of Significant Exposure to Isophorone - Inhalation
Levels of Significant Exposure to Isophorone - Oral . . .
Levels of Significant Exposure to Isophorone - Dermal . .
Genotoxicity of Isophorone In Vitro and In Vivo
Chemical Identity of Isophorone
Physical and Chemical Properties of Isophorone
Detection of Isophorone in Water
Detection of Isophorone in Fish Hear Lake Michigan . . .
Occupational Monitoring of Isophorone
Analytical Methods for Isophorone
Regulations and Guidelines Applicable to Isophorone . . .
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1
1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS ISOPHORONE?
Isophorone is a clear liquid with a peppermint-like odor. It
evaporates faster than water but slower than charcoal starter or paint
thinner, and it will not mix completely with water. Isophorone is a man-
made chemical for use commercially, but it has been found to occur
naturally in cranberries. It is used as a solvent in some printing inks,
paints, lacquers, and adhesives. Isophorone does not remain in the air very
long, but can remain in water for possibly more than 20 days. The length of
time that isophorone will remain in soil is not known, but it probably is
about the same as the length of time it remains in water. More information
can be found in Chapters 3 and 4.
1.2 HOW MIGHT I BE EXPOSED TO ISOPHORONE?
Exposure to isophorone may take place where you work or in very low
concentrations at home. Because it is used in some inks, paints, lacquers,
and adhesives, people who work with these products may be exposed to
isophorone. Isophorone has been found in the drinking water of Cincinnati,
Philadelphia, and New Orleans at amounts less than 10 parts of isophorone in
1 billion parts of water (10 ppb). In one instance (a screen print shop),
isophorone was found in amounts as high as 26 parts in 1 million parts of
air (26 ppm), but the usual amounts in the workplace are much lower. At
this time, isophorone has been found in at least 9 out of 1177 National
Priorities List (NPL) hazardous waste sites in the United States. Exposure
to isophorone at these sites may occur by touching contaminated soil,
water, or sediment. For more information please read Chapter 5.
1.3 HOW CAN ISOPHORONE ENTER AND LEAVE MY BODY?
Isophorone can enter your body if you breathe its vapor, have skin
contact with it, drink contaminated water, or eat contaminated food. If
isophorone is present at a waste site near homes that use local wells as a
source of water, the well water could be contaminated with isophorone.
Experiments in animals show that after doses by mouth, isophorone enters
easily and spreads to many organs of the body, but most of it leaves the
body within 24 hours in the breath and in urine. Isophorone may enter the
lungs of workers exposed to isophorone where it is used indoors as a
solvent. Isophorone disappears quickly from outside air, so the chance of
breathing outdoor air contaminated with isophorone is small. If isophorone
is spilled at a waste site and evaporates, however, a person nearby may
breathe isophorone before it disappears from the air. In addition, soil
around waste sites may contain isophorone, and a person, such as a child
playing in the dirt, may eat or have skin contact with the contaminated
soil. How much isophorone enters the body through the skin is not known.
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2
1. PUBLIC HEALTH STATEMENT
More information on how isophorone can enter and leave the body can be found
in Chapter 2.
1.4 HOW CAN ISOPHORONE AFFECT MY HEALTH?
The only effects of isophorone reported in humans are irritation of the
skin, eyes, nose, and throat, and possibly dizziness and fatigue. These
effects have occurred in workers who breathe vapors of isophorone and other
solvents during use in the printing industry. Short-terra exposure of
animals to high vapor amounts and short- or long-term exposure of animals to
high doses by mouth cause death or a shortened lifespan. Short-term
exposure to high amounts of vapors or high doses by mouth has caused
inactivity and coma in animals. Inconclusive studies suggested that
Isophorone may have caused birth defects and growth retardation in the
offspring of rats and mice that breathed the vapors during pregnancy. Some
harmful health effects were seen In adult female animals in these studies.
It is not known whether isophorone could cause birth defects in humans. In
a long-term study in which rats and mice were given high doses of
isophorone by mouth, the male rats developed kidney disease and kidney
tumors. Male rats also developed tumors in a reproductive gland. Some male
mice developed tumors in the liver, in connective tissue, and in lymph
glands (tissues of the body that help fight disease), but the evidence was
not strong. It is not known whether isophorone causes cancer in humans.
More information on the health effects of isophorone in animals and humans
can be found in Chapter 2.
1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
ISOPHORONE?
No medical test is known to determine human exposure to isophorone. A
few studies in rats and rabbits have shown that isophorone and its
metabolites can be found in the urine of these animals, so it may be
possible to find a method for testing the urine of humans to determine
exposure to isophorone. It is not known, however, whether such a
measurement would predict how much exposure had occurred or the possible
health effects. For more information see Chapter 2.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Tables 1-1 through 1-4 show the link between exposure to isophorone and
known health effects. A Minimal Risk Level (MRL) is also included in Table
1-3. This MRL was derived from animal data for long-term exposure, as
described in Chapter 2 and in Table 2-2. The MRL provides a basis for
comparison with levels that people might encounter in food. If a person is
exposed to isophorone at an amount below the MRL, it is not expected that
harmful (noncancer) health effects will occur. Because this level is based
on information that Is currently available, some uncertainty is always
associated with it. Also, because the method for deriving MRLs does not use
any Information about cancer, a MRL does not imply anything about the
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3
1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing Isophorone*
Short-term Exposure
(less than or equal to
14 days)
Levels
in Air
(ppm)
Length of Exposure
Description of Effects**
25
4 minutes
Eye, nose, throat irritation
Long-term Exposure
(greater than 14 days)
Levels
in Air
(dduO
Leneth of ExDosure
Description of Effects**
5
1 month
Fatigue, depression
*See Section 1.2 for a discussion of exposures encountered in
daily life.
**These effects are listed at the lowest level at which they were
first observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing Isophorone
Short-term Exposure
(less than or equal to 14 days)
Levels
in Air
(Dpm)
Leneth of Exposure
Description of Effects*
28
5 minutes
Lung irritation in mice
89
4 hours
Behavior problems in mice
620
6 hours
Lung congestion in rats
and mice
885
6 hours
Death in rats
Long-term Exposure
(greater than 14
days)
Levels
in Air
(ddiiO
Length of ExDosure
DescriDtion of Effects*
37
4 weeks
Poor weight gain in rats
250
18 months
Slight liver effects, eye
and nose irritation in
rats and rabbits
500
4-6 months
Death in rats
*These effects are listed at the lowest level at which they were
first observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or Drinking Isophorone*
1
Short-term Exposure j
(less than or equal to 14 days) j
i
Levels
in
Food
(ddih)
Length of ExDosure Description of Effects
The health effects resulting
from short-term human
exposure to food containing
specific levels of isophorone
are not known.
Levels
in
Water
(Dtjm)
The health effects resulting
from short-term human
exposure to water containing
specific levels of isophorone
are not known.
Long-term Exposure
(greater than 14 days)
Levels
in
Food
(ppm)
Leneth of Exnosure DescriDtion of Effects
7
Minimal risk level (based
on animal data, see Section
1.6 for discussion)
Levels
Water
(otmi)
The health effects resulting
from long-term human
exposure to water containing
specific levels of isophorone
are not known.
*See Section 1.2 for a discussion of exposures encountered in daily life.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or Drinking Isophorone
Short-tern Exposure
(less than or equal to 14 days)
Length of Exposure Description of Effects*
1 day Fatigue, staggering in mice
1 day Death in mice
1 day Death in rats
Long-term Exposure
(greater than 14 days)
in Food fpnm) T^nyth of Exposure Description of Effects*
1900
2 years
Liver disease, stomach
irritation in mice
5000
2 years
Kidney disease in rats
8000
13 weeks
Death in mice
15,000
16 days
Death in mice
in Water (PPm)
The health effects resulting
from long term animal exposure
to drinking water containing
specific levels of isophorone
are not known.
Levels in Food (PPm)
8000
Levels in Water (ppnn
11,000
15,000
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
presence, absence, or level of risk of cancer. The information on health
effects in humans or animals for short-term or long-term exposure to
isophorone in air, for short-term exposure in food or water, and for long-
term exposure in water was either not available or not suitable to derive
MRLs.
The amounts listed in Table 1-1 that cause eye, nose, and throat
irritation (25 ppm) with short-term exposure and fatigue and depression (5
ppm) with long-term exposure are much higher than the amount at which the
odor is first noticed, which is about 0.2 ppm. This means that you can
probably smell isophorone before you would have harmful health effects. The
levels of isophorone in air that cause death and lung congestion in animals
are much higher than the amounts that workers breathe in industry when using
isophorone as a solvent. The amount that causes lung irritation in animals
is about the same as the amount that causes eye, nose, and throat irritation
in humans.
Besides the harmful health effects from exposure to isophorone in air,
food, and water, skin irritation or eye damage occurred in animals after a
few drops of isophorone had been applied directly to the skin or eyes.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
HEALTH?
The Environmental Protection Agency (EPA) has determined that the level
of isophorone in natural waters (lakes, streams) should be limited to 5.2
parts isophorone per million parts of water (5.2 ppm) to protect human
health from the harmful effects of isophorone from drinking the water and
from eating contaminated fish and other animals found in the water. The
Occupational Safety and Health Administration (OSHA) has set a permissible
exposure limit of 4 parts of isophorone per million parts of workroom air
(4 ppm) during an 8-hour work shift to protect workers. The National
Institute for Occupational Safety and Health (NIOSH) recommends that the
amount in workroom air be limited to 4 ppm averaged over a 10-hour work
shift. Further information on government recommendations can be found in
Chapter 7.
1.8 WHERE CAN I GET MORE INFORMATION?
If you have more questions or concerns, please contact your State
Health or Environmental Department or:
Agency for Toxic Substances and Disease Registry
Division of Toxicology
1600 Clifton Road, E-29
Atlanta, Georgia 30333
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and evaluations of studies and
interpretation of data on the health effects associated with exposure to
isophorone. Its purpose is to present levels of significant exposure for
isophorone based on toxicological studies, epidemiological investigations,
and environmental exposure data. This information is presented to provide
public health officials, physicians, toxicologists, and other interested
individuals and groups with (1) an overall perspective of the toxicology of
isophorone and (2) a depiction of significant exposure levels associated
with various adverse health effects.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the data in this section are
organized first by route of exposure -- inhalation, oral, and dermal --and
then by health effect -- death, systemic, immunological, neurological,
developmental, reproductive, genotoxic, and carcinogenic effects. These
data are discussed in terms of three exposure periods -- acute,
intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in figures.
The points in the figures showing no-observed-adverse-effect levels (NOAELs)
or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses
(levels of exposure) used in the studies. LOAELs have been classified into
"less serious" or "serious" effects. These distinctions are intended to
help the users of the document identify the levels of exposure at which
adverse health effects start to appear, determine whether or not the
intensity of the effects varies with dose and/or duration, and place into
perspective the possible significance of these effects to human health.
The significance of the exposure levels shown on the tables and graphs
may differ depending on the user's perspective. For example, physicians
concerned with the interpretation of clinical findings in exposed persons or
with the identification of persons with the potential to develop such
disease may be interested in levels of exposure associated with "serious
effects." Public health officials and project managers concerned with
response actions at Superfund sites may want information on levels of
exposure associated with more subtle effects in humans or animals (LOAEL) or
exposure levels below which no adverse effects (NOAEL) have been observed.
Estimates of levels posing minimal risk to humans (minimal risk levels,
MRLs) are of interest to health professionals and citizens alike.
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2. HEALTH EFFECTS
For certain chemicals, levels of exposure associated with carcinogenic
effects may be indicated in the figures. These levels reflect the actual
doses associated with the tumor incidences reported in the studies cited.
Because cancer effects could occur at lower exposure levels, the figures
also show estimated excess risks, ranging from a risk of one in 10,000 to
one in 10,000,000 (10~^ to 10"^), as developed by EPA.
Estimates of exposure levels posing minimal risk to humans (MRLs) have
been made, where data were believed reliable, for the most sensitive
noncancer end point for each exposure duration. MRLs include adjustments to
reflect human variability and, where appropriate, the uncertainty of
extrapolating from laboratory animal data to humans. Although methods have
been established to derive these levels (Barnes et al. 1987; EPA 1980a),
uncertainties are associated with the techniques.
2.2.1 Inhalation Exposure
2.2.1.1 Death
No studies were located regarding death of humans following inhalation
exposure to isophorone.
Acute inhalation exposure of rats, guinea pigs, or mice to isophorone
at a concentration of 619 ppm for 6 hours caused slight lacrimation during
exposure but did not result in any deaths (Hazleton Labs 1964).' Although
this study used few animals and did not report the use of controls, the
acute exposure level of 619 ppm probably can be considered a NOAEL for
lethality because none of the animals of the three species tested died
(Table 2-1 and Figure 2-1). Hazleton Labs (1965a) statistically determined
the 4-hour LC50 in rats to be 1238 ppm, with 95X confidence limits of 1008-
1531 ppm. The LC50 is indicated in Table 2-1 and Figure 2-1. Exposure to
885 ppm for 6 hours resulted in the death of 1/10 rats (Hazleton Labs
1965a); the exposure of 885 ppm is considered the acute inhalation LOAEL for
lethality of isophorone (see Table 2-1 and Figure 2-1). The concentration
of 885 ppm in air (Hazleton Labs 1965a) is also presented in Table 1-2. The
cause of death of the rats was not stated, but marked pulmonary congestion
was observed. Dutertre-Catella (1976) attempted to determine the LC50 of
isophorone in rats and rabbits, but saturation of the air at a concentration
up to 7000 ppm for 5 hours produced mortality in only 10% of the rats and
30% of the rabbits. The animals became comatose before death and had
hemorrhagic lungs, vascular dilation of the alveolar capillaries and
peribronchial vessels. Dutertre-Catella (1976) noted that at high
concentrations of vapor, which were attained by heating isophorone, an
appreciable quantity of the solvent remained suspended as an aerosol in the
exposure chamber due to condensation. As the concentrations at which the
animals began to die could not be determined from the report, the LOAELs are
not known.
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TABLE 2-1. Levels of Significant Exposure to Isophorone - Inhalation
Exposure
Graph Frequency/ LOAEL8 (Effect)
Key Species Duration Effect NQAEL Less Serious Serious Reference
(ppm) (ppm) (ppm)
ACUTE EXPOSURE
Death
rat
rat
Systolic
6.7
8.9
10
11
12
Neurological
13
14
15
guinea
pig
hunn
huaan
rat
rat
once
6 hr
once
4 hr
once
6 hr
once
6 hr
IS ain
7 ain
once
6 hr
5 ain
once
6 hr
once
4 hr
4 hr
once
4 hr
619
619
619
Deraal/ 10
Ocular
Derael/
Ocular
Respi ratory
Respi ratory
Respi ratory
18
25 (irritation)
35 (eye irritation)
(throat irritation)
619 (congestion)
27.8 (RD50)
619 (congestion)
89 (behavioral
test)
131 (CNS
depression)
1238 (LC50)
885 (1/10 died)
1238 (comatose)
Hazleton Labs
1964
Hazleton Labs
1965a
Hazleton Labs
1964
Hazleton Labs
1964
Si Ivemn
etal. 1946
Hazleton Labs
1965b
Hazleton Labs
1964
DeCeaurriz et
al. 1981a
Hazleton Labs
1964
Hazleton Labs
1965a
De Ceaurriz et
al. 1984
De Ceaurriz et
al. 1981b
£
X
•n
TJ
m
o
H
C/3
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TABLE 2-1 (continued)
Exposure
Graph Frequency/ LQftEL3 (Effect)
Key Species Duration Effect NCMEL Less Serious Serious Reference
(ppm) (ppm) (ppm)
Developmental
16
17
18
19,20
rat
aiouse
9 d
d 6-15gestation
6 hr/d
9 d
d 6-15gestation
6 hr/d
100
115
115 (growth
retardation)
150 (exencephaly)
150 (exencephaly)
Bio/dynamics
1984a,b
Bio/dynamics
1984a,b
INTERMEDIATE EXPOSURE
Death
21
Systeaic
22
23
24
25
26
27
rat
rat
rat
4-6 mo
6 hr/d
5 d/wk
4 wk
6 hr/d
5 d/wk
4-6 mo
6 hr/d
5 d/wk
Hematological 37
Renal 37
Other
Respi ratory 500
Hepatic 500
Dermal/
Ocular
500 (1/10 F,
3/10 M died)
37 (decreased body
weight gain)
500 (ocular and nasal
irritation)
Dutertre-
Catella 1976
Hazleton Labs
1968
Dutertre-
Catella 1976
EC
5
ac
M
M
n
H
w
Neurological
28,29 hunan
1 no
1-4
5-8 (fatigue)
(malaise)
Ware 1973
CHRONIC EXPSOSURE
Death
30
rat
18 mo
6 hr/d
5 d/wk
250
Dutertre-
Catella 1976
-------
TABLE 2-1 (continued)
Exposure
Graph Frequency/ LOAELa (Effect?
Key Species Duration Effect NQAEL Less Serious Serious Reference
(ppm) (ppm) (ppm)
31
rabbit
18 no
6 hr/d
5 d/wk
250
Dutertre-
Catella 1976
Systemic
32
rat
18 no
Respi ratory
250
Dutertre-
33
6 hr/d
Hematological
250
Catella 1976
34
5 d/wk
Hepatic
250 (microvacuolization)
35
Renal
250
36
Dermal/
(irritation of nasal
Ocular
mucosa)
37
rabbit
18 mo
Respi ratory
250
Dutertre-
38
6 hr/d
Hematological
250
Catella 1976
39
5 d/wk
Hepatic
250 (microvacuolization)
40
Renal
250
41
Dermal/
250 (irritation of
Ocular
nasal mucosa)
X
£
5
se
m
"d
m
o
H
CO
®LOAEL - Lowest Observed Adverse Effect Level
nWMEL - No Observed Adverse Effect Level
-------
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ACUTE INTERMEDIATE
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A MOAEL (human*)
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FIGURE 2-1. Levels of Significant Exposure to Isophorone - Inhalat on
-------
15
2. HEALTH EFFECTS
In an intermediate duration study, 1/10 female rats and 3/10 male rats
died after being exposed to 500 ppm isophorone for 6 hours/day for up to 6
months (Dutertre-Catella 1976). The 500 ppm concentration is presented in
Table 2-1 and plotted in Figure 2-1 as the intermediate duration LOAEL for
lethality. The concentration of 500 ppm (Dutertre-Catella 1976) is also
presented in Table 1-2. No differences in mortality were observed in rats
compared with controls, and no deaths occurred in rabbits exposed to 250 ppm
isophorone, 6 hours/day for 18 months (Dutertre-Catella 1976). The 250 ppm
concentration is a chronic inhalation NOAEL for lethality in both rats and
rabbits (see Table 2-1 and Figure 2-1).
2.2.1.2 Systemic Effects
Respiratory Effects. Lee and Frederick (1981) found that eye,
respiratory, and skin irritation were among the complaints of 27/35 workers
in a printing plant. Two of the workers (screen printers) were exposed to
8-hour TWA concentrations of isophorone of 0.7 and 14 ppm, but it was not
clear whether these two individuals were among those who complained of
respiratory irritation. Lee and Frederick (1981) concluded that screen
printers are exposed to hazardous concentrations of isophorone and other
solvents (xylene, methylene chloride, and toluene).
Very little information is available concerning the systemic effects on
the respiratory system of animals due to inhalation exposure to isophorone.
Isophorone is irritating to the respiratory tract of animals. DeCeaurriz et
al. (1981a) reported that a concentration of 27.8 ppm for 5 minutes caused a
50% decrease (RD50) in the reflex respiratory rate of mice, an indication
of respiratory irritation. Because the lowest concentration resulting in a
decreased respiratory rate was not indicated clearly in the study, the 27.8
ppm level is indicated as a LOAEL for less serious respiratory effects in
mice due to acute inhalation exposure to isophorone (see Table 2-1 and
Figure 2-1).
Slight lung congestion was observed In rats and mice sacrificed
immediately after exposure to 619 ppm isophorone for 6 hours, but not in
rats or mice sacrificed 14 days after the exposure (Hazleton Labs 1964),
suggesting reversibility of the lesion. This study used only one
concentration (619 ppm) and did not report the use of controls.
Nevertheless, isophorone is known to be irritating to mucous membranes (see
Dermal/Ocular effects below), so it is reasonable to attribute the lung
congestion to exposure to isophorone. As the congestion was not a permanent
condition, it is not a serious adverse effect; therefore, the 619 ppm level
is indicated in Table 2-1 and Figure 2-1 as a LOAEL for less serious effects
on the respiratory system due to acute inhalation exposure to isophorone.
Rats and rabbits that were exposed to isophorone at concentrations up to
7000 ppm for 5 hours died and had hemorrhagic lungs with vascular dilation
of the alveolar capillaries and peribronchial vessels (Dutertre-Catella
1976). The concentration of 7000 ppm cannot be considered a LOAEL because
it was not clear from the report if the animals started dying at
-------
16
2. HEALTH EFFECTS
concentrations less than 7000 ppm. Moreover, Dutertre-Cate1 La (1976) noted
that at 7000 ppm, a considerable quantity of the isophorone was present in
the exposure atmosphere as an aerosol rather than as a vapor. The
concentration of 27.8 ppm in air (DeCeaurriz et al. 1981a) was rounded to 28
ppm, and the concentration of 619 ppm in air was rounded to 620 ppm
(Hazleton Labs 1964) for presentation in Table 1-2.
Severe lung injury consisting of congestion, necrosis, and
degeneration was reported in rats and guinea pigs exposed intermittently to
100 ppm, but not to 25 ppm, isophorone for 6 weeks (Smyth et al. 1942).
According to Rowe and Wolf (1963), however, later investigation led to the
conclusion that the isophorone used by Smyth et al. (1942) contained several
highly volatile impurities, a fact unknown to the investigators at the time.
These impurities could have contributed to the severity of the observed
effects. Moreover, Rowe and Wolf (1963) argued that some of the vapor
concentrations reported by Smyth et al. (1942) were higher than could
possibly be achieved under the conditions employed and some were
overestimated because the vapor concentrations of the impure commercial
product within the exposure chamber were determined using an interferometer
that had been calibrated against pure isophorone.
These criticisms of the Smyth et al. (1942) study have also been noted
by NTP (1986) and ACGIH (1986). Given the uncertainty regarding the results
and the exposure levels reported by Smyth et al. (1942), it is
inappropriate to consider this study for the determination of levels of
significant exposure.
Hazleton Labs (1968) found no treatment-related histopathological
lesions in lungs of rats exposed intermittently to 37 ppm for 4 weeks
compared with controls. The 37 ppm concentration was the only one tested,
and histological examination was limited to 30% of the control and treated
rats. Although the limited histological examination could have missed lung
lesions in the rats that were not examined (70%), no exposure - related
histopathological lesions were observed in the lungs of rats exposed to 500
ppm isophorone for up to 6 months or in rats and rabbits exposed to 250 ppm
for 18 months (Dutertre-Catella 1976). The NOAELs for respiratory effects
of 500 ppm in rats for intermediate duration exposure and 2.50 ppm in rats
and rabbits for chronic exposure are presented in Table 2-1 and Figure 2-1.
Hematological Effects. No studies were located regarding
hematological effects in humans following inhalation exposure to
isophorone.
Hematological effects of inhalation exposure of animals to isophorone
are not well documented. No studies were located regarding hematological
effects in animals following acute inhalation exposure to isophorone.
Hazleton Labs (1968) compared the hematological effects of inhalation
exposure to isophorone with those of three other ketones in rats. The post-
exposure values in the treated and control groups were compared with the
-------
17
2. HEALTH EFFECTS
pre-exposure values. No extreme variations occurred in any group, but the
isophorone-exposed group (37 ppm for 4 weeks) had an increased percentage of
lymphocytes (3% in males, 5.8% in females), decreased percentage of
neutrophils (2.8% in males, 5.OX in females), and increased hemoglobin
content (1.2-1.4 g/100 ml) compared with the pre-exposure values. Since
statistical analysis was not performed, the significance of these findings
is not known. The control males also displayed this trend. Because the
variations in the isophorone-treated group were slight, and similar to those
observed in the unexposed animals, the 37 ppm concentration can be
considered a NOAEL for hematological effects of intermediate duration
inhalation exposure to isophorone. No exposure-related hematological
effects were observed in rats or rabbits exposed to 250 ppm isophorone for
18 months (Dutertre-Catella 1976), which is a NOAEL for chronic exposure.
The NOAELs are presented in Table 2-1 and Figure 2-1.
Hepatic Effects. No studies were located regarding hepatic effects in
humans following inhalation exposure to isophorone.
No studies were located regarding hepatic effects in animals following
acute inhalation exposure to isophorone. In the Hazleton Labs (1968) 4~weelc
study, rats exposed to 37 ppm had statistically significant decreased mean
absolute liver weights and statistically significant decreased mean liver-
to-body weight ratios compared with controls. Histological examination of
the livers of 30% of the rats revealed no treatment-related liver lesions;
therefore, the toxicological significance of the decreased liver weight is
probably minimal. As 70% of the rats in each group were not examined
histologically, however, the possibility exists that histopathologlcal liver
lesions were missed. No exposure-related histopathologlcal liver lesions
occurred in rats exposed to 500 ppm isophorone for up to 6 months, but
cytoplasmic microvacuolization of hepatocytes was observed in rats and
rabbits exposed to 250 ppm isophorone for 18 months (Dutertre-Catella 1976).
The NOAEL of 500 ppm for intermediate duration exposure and the LOAEL of 250
ppm for chronic exposure are presented in Table 2-1 and Figure 2-1. The
concentration of 500 ppm in air (Dutertre-Catella 1976) is also presented In
Table 1-2.
Renal Effects. No studies were located regarding renal effects in
humans following inhalation exposure to isophorone.
No studies were located regarding kidney effects in animals following
acute inhalation exposure to isophorone. Smyth et al. (1942) found severe
kidney damage, consisting of congestion, necrosis, and degeneration, in rats
and guinea pigs exposed intermittently to 100 ppm isophorone for 6 weeks.
As noted, however, Rowe and Wolf (1963) criticized this study for using
impure isophorone and overestimating the exposure concentrations. Therefore
the 100 ppm level cannot be considered the LOAEL for serious effects on the
kidney due to inhalation exposure to Isophorone.
-------
18
2. HEALTH EFFECTS
In the Hazleton Labs (1968) 4-week study, no treatment-related
histopathological effects on the kidney were found in rats exposed to 37
ppm. Because the histological examination was performed on only 30% of the
treated and control rats, however, the possibility exists that renal lesions
were missed. The 37 ppm concentration can be considered an intermediate
duration NOAEL for kidney effects, however, because no exposure-related
renal effects were detected upon urinalysis and histological examination of
rats and rabbits that were exposed to isophorone in air at a concentration
of 250 ppm for 18 months (Dutertre-Catella 1976). The NOAELs of 37 ppm for
intermediate duration and 250 ppm for chronic exposure are presented in
Table 2-1 and Figure 2-1.
Dermal/Ocular Effects. Isophorone is irritating to the eyes and
mucous membranes of humans. Several studies have attempted to determine the
thresholds for eye, nose, and throat irritation for isophorone in humans.
As seen from Table 2-1, when the exposure duration was 15 minutes, 10 ppm
was tolerated, while 25 ppm produced irritation to the eye, nose, and throat
(Silverman et al. 1946). NIOSH (1978a) noted that Silverman et al. (1946)
did not discuss acclimatization. In another study, when the exposure
duration was 7 minutes, no irritation was reported at 18 ppm, but the
threshold for throat irritation was 35 ppm. Eye and nose irritation
occurred at 65 ppm, but not at 35 ppm (Hazleton Labs 1965b). Since no
exposure concentrations between 35 and 65 ppm were tested, the threshold for
eye and nose irritation falls between these concentrations. The subjects
were retested after 2 weeks, with no significant difference between the
trials. Thus, these thresholds appear to be reliable, although there was
some concern that the concentrations were slightly overestimated because the
isophorone may not have vaporized completely. Furthermore, only six
subjects per group were tested, and there was substantial individual
variability in response. Smyth and Seaton (1940) reported that exposure of
humans for a few minutes to 40-400 ppm resulted in eye, nose, and throat
irritation at all exposures, but Rowe and Wolf (1963) criticized this study
for using impure isophorone and overestimating the exposure concentrations.
The NOAELs and LOAELs for irritation due to 7 and 15 minutes of exposure in
the studies by Silverman et al. (1946) and Hazleton Labs (1965b) are
indicated in Table 2-1 and Figure 2-1. The concentration of 25 ppm in air
(Silverman et al. 1946) is presented in Table 1-1.
The irritancy properties of isophorone have also been observed in
humans exposed occupationally to isophorone. In an industrial hygiene
survey, Kominsky (1981) reported that the eye and nose irritation
complained of by a screen printer could have been caused by 4-minute
exposure to 25.7 ppm isophorone, which was measured in the personal
breathing zone while the worker was washing a screen. Lee and Frederick
(1981) found that eye, respiratory, and skin irritation were among the
complaints of 27/35 workers in a printing plant where isophorone and other
solvents (xylene, methylene chloride, and toluene) were used. On the day of
measurement, two of the screen printers were found to be exposed to 8-hour
TWA concentrations of isophorone of 0.7 and 14 ppm, but it was not clear
-------
19
2. HEALTH EFFECTS
whether these two individuals were among the worker* complaining of
Irritation. The odor threshold for isophorone in air has been reported to
be 0.2 ppm (v/v) (Amoore and Hautala 1983).
Isophorone is also irritating to animals. Smyth et al. (1942)
reported conjunctivitis and skin irritation in rats and guinea pigs exposed
to Isophorone at high concentrations; as discussed above, however, Rowe and
Wolf (1963) criticized this study for using impure isophorone and for
overestimating the exposure concentrations. As discussed above for
respiratory effects, a concentration of 27.8 ppm for 5 minutes caused a 50*
decrease (RD50) in the reflex respiratory rate of mica, which indicated
sensory irritation rather than a neurological efface (DeCeaurriz et al.
1981a). Irritation of the eyes and nasal mucosa was observed in rats
exposed to 500 ppm isophorone in air for up to 6 months and rats and rabbits
exposed to 250 ppm for 18 months (Dutertre-Catella 1976). These LOAELs for
intermediate and chronic duration exposure are presented in Table 2-1 and
Figure 2-1. The 250 ppm concentration is also presented in Table 1-2.
Other Systemic Effects. In the 4-week Hazleton Labs (1968) study,
exposure of rats to 37 ppm resulted in statistically significant decreased
body weight gain. The 37 ppm level can be considered a L0AEL for less
serious effects for intermediate inhalation exposure to isophorone (see
Table 2-1 and Figure 2-1). The concentration of 37 ppm in air is presented
in Table 1-2.
2.2.1.3 Immunological Effects
No studies were located regarding immunological effects in humans or
animals following inhalation exposure to isophorone.
2.2.1.4 Neurological Effects
Isophorone affects the central nervous system. In an industrial
hygiene survey report, Lee and Frederick (1981) attributed dizziness
complained of by workers to exposure to isophorone and other solvents
(xylene, toluene, methylene chloride). In a communication to the American
Conference of Governmental Industrial Hygienists, Ware (1973) reported that
employees exposed for 1 month to 5-8 ppm isophorone complained of fatigue
and malaise. Complaints stopped when workroom exposure levels of isophorone
were lowered to 1-4 ppm. This communication formed the basis for
establishing the ACGIH Ceiling Limit of 5 ppm for isophorone (ACGIH 1986).
Thus, 5 ppm can be considered a LOAEL and the range of 1-4 ppm a NOAEL for
neurological effects in humans due to intermediate inhalation exposure to
isophorone (see Table 2-1 and Figure 2-1), The concentration of 5 ppm in
air (Ware 1973) is presented in Table 1-1,
Neurological effects of inhalation exposure Co Isophorone also have
been reported in animals. Narcosis and ataxia occurred in rats and guinea
pigs at high exposure concentrations fox 6-24 hours (Smyth and Seaton 1940),
-------
20
2. HEALTH EFFECTS
but Rowe and Wolf (1963) noted that this study used impure isophorone and
overestimated the concentrations. DeCeaurriz et al. (1984) found dose-
related neurobehavioral effects (decreased immobility in a behavioral
despair swimming test) in mice exposed for 4 hours. The lowest
concentration resulting in the behavioral effects was 89 ppm, which is
indicated as a less serious LOAEL in Table 2-1 and Figure 2-1. The
concentration of 89 ppm in air (DeCeaurriz et al. 1984) is presented in
Table 1-2.
DeCeaurriz et al. (1981b) also reported that inhalation of isophorone
for 4 hours by mice increased the threshold for onset of seizures produced
by intravenous administration of pentrazole, indicating that isophorone
depressed the central nervous system. The concentration of isophorone that
resulted in a 50% increase in the seizure threshold (STI50) was 131 ppm
(LOAEL for less serious effects on Table 2-1 and Figure 2-1), with 95%
confidence intervals of 113-145 ppm. At the 4-hour LC50 of 1238 ppm and
higher, rats were ataxic and comatose during exposure, after which they
displayed depression and inactivity (Hazleton Labs 1965a). The 1238 ppm
concentration is indicated as a LOAEL for serious effects in Table 2-1 and
Figure 2-1. These effects were not noted at 885 ppm. Although the
exposure concentration of 885 ppm did not result in overt signs of
neurotoxicity, more sensitive tests for neurotoxicity (e.g., operant
performance, motor activity, electrophysiology), which may have revealed
neurobehavioral effects at this level, were not performed. Therefore, the
concentration of 885 ppm should not be considered a NOAEL for neurotoxicity
for acute inhalation exposure. Rats and rabbits that were exposed to
isophorone for 5 hours at concentrations up to 7000 ppm became comatose and
died (Dutertre-Catella 1976) . The concentration of 7000 ppm cannot be
considered a LOAEL because it was not clear from the report whether the
animals became comatose at concentrations less than 7000 ppm. Furthermore,
at high concentrations, a considerable amount of isophorone was present in
the exposure atmosphere as an aerosol rather than as a vapor (Dutertre-
Catella 1976).
2.2.1.5 Developmental Effects
No studies we*e located regarding developmental effects in humans
following inhalation exposure to isophorone.
As part of ati intermediate duration study, in which rats were exposed
to 500 ppm isophorone air> Dutertre-Catella (1976) mated exposed males
with exposed femaleS> Control males with exposed females, exposed males with
control females, and Control males with control females after 3 months of
exposure. Exposu^® females continued throughout gestation, and they were
allowed to deliver. N0 differences in pregnancy rate or litter size and no
abnormalities in puPs Were found. The pups were not examined for internal
malformations; theref°re, this study was inadequate to determine
developmental eff®cts of isophorone.
-------
21
2. HEALTH EFFECTS
In a pilot developmental toxicity study, pregnant rats and mice were
exposed by inhalation to isophorone at concentrations up to 150 ppm on days
6-15 of gestation (Bio/dynamics 1984a). Dose-related mild maternal toxicity
(increased liver weight and clinical signs) occurred at all concentrations
(>50 ppm) in rats, but there was no clear indication of maternal toxicity in
mice. Exencephaly was observed in one late resorption in one litter in the
high-concentration group of rats, and in one late resorption in one litter
and in two live fetuses in another litter in the high-concentration group of
mice. Because this was a pilot study, only 12 female rats and 12 female
mice were used, and the fetuses were examined only for gross abnormalities.
A second, more complete developmental toxicity study was also performed in
two species. Groups of 22 female rats and 22 female mice were exposed on
gestation days 6-15 to concentrations of isophorone up to 115 ppm
(Bio/dynamics 1984b). In rats, dose-related maternal toxicity (alopecia)
was seen at all concentrations (>25 ppm). In addition, rat dams exposed to
115 ppm had lower body weights than controls on some days. No other
indications of maternal toxicity were noted. There was a statistically
significant reduction in mean crown-rump length among rat fetuses, but not
among litters, in the group exposed to 115 ppm. In mice, the only effect
noted was that the mean body weight of dams exposed to 115 ppm isophorone
was decreased during one day of the treatment period. Bio/dynamics (1984b)
concluded that isophorone was not teratogenic or fetotoxic in rats or mice
at concentrations up to 115 ppm. This conclusion is not supported by the
results. Although significance across litters was not reached, the
reduction in crown-rump length in the offspring of rats exposed to 115 ppm
is evidence of growth retardation. Several deviations from the protocol
resulted in the failure to perform some of the scheduled fetal examinations.
Bio/dynamics (1984b) stated that these deviations did not alter the
conclusions. Based on the findings of the second study, Bio/dynamics
(1984b) did not regard the occurrences of exencephaly in the pilot study to
be treatment-related. This conclusion is untenable because the second study
did not test isophorone at 150 ppm, the exposure level at which the
exencephaly was observed. Thus, the findings in the pilot study are
difficult to interpret; the incidences of exencephaly/litter at the 150 ppm
exposure were not significantly different from controls, but this
malformation was observed only at the 150 ppm exposure level. Furthermore,
the malformation was seen in both species. Although these results are
inconclusive, 150 ppm may be a serious LOAEL for malformations in rats and
mice, and 115 ppm may be a NOAEL in mice. The concentration of 115 ppm in
rats, however, was associated with growth retardation and represents a
serious LOAEL for developmental effects of inhalation exposure. The NOAEL
for rats is 100 ppm, which was the next lower dose in the Bio/dynamics
(1984a,b) studies. The NOAELs and LOAELs are indicated in Table 2-1 and
Figure 2-1.
2.2.1.6 Reproductive Effects
As discussed above in Section 2.2.1.5, no differences In pregnancy rate
or litter size were observed in rats exposed to isophorone in air at 500 ppm
-------
22
2. HEALTH EFFECTS
for 3 months before mating (Dutertre-Catella 1976). Since this study did
not examine other parameters of reproductive toxicity, 500 ppm cannot be
considered a NOAEL for reproductive effects.
2.2.1.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans or
animals following inhalation exposure to isophorone.
2.2.1.8 Cancer
No studies were located regarding cancer in humans or animals following
inhalation exposure to isophorone.
2.2.2 Oral Exposure
No studies were located regarding health effects in humans following
oral exposure to isophorone.
2.2.2.1 Death
The oral LD50 of isophorone was reported as 3450 mg/kg in male rats
(Hazleton Labs 1964) and 2104-2150 mg/kg in female rats (Smyth et al. 1969
1970). LD50 values of 2700 ± 200 mg/kg for male rats, 2100 ± 200 mg/kg for
female rats, and 2200 ± 200 mg/kg for male mice also were reported by
Dutertre-Catella (1976). The value reported by Hazleton Labs (1964) was
estimated because the mortality data did not lend itself to statistical
analysis. Furthermore, the doses were widely spaced, and the animals were
fasted for only 3-4 hours before dosing, which could have interfered with
gastrointestinal absorption of isophorone. Necropsy of rats that died
revealed congestion of the lungs, kidneys, adrenals, and pancreas, and
gastrointestinal inflammation. Necropsy of rats that survived the 14-day
observation period revealed no effects. The studies by Smyth et al. (1969
1970) were determinations of the joint toxic action of 27 pairs of
industrial solvents (see Section 2.7 on Interactions with other chemicals)
but the details of the individual LD50 determinations and the cause of death
were not provided. Nevertheless, the values for isophorone were
reproducible in the two studies by Smyth et al. (1969, 1970). The reason
for the sex difference is not apparent. The LD50S are indicated in Table
2-2 and Figure 2-2. No short-term studies of isophorone administered in
food or drinking water were located. The LD50 of <*2100 mg/kg, which was
determined using liquid isophorone by gavage (Smyth et al. 1969, 1970), was
converted to an equivalent concentration of 15,000 ppm in water for
presentation in Table 1-4.
Lethality data for intermediate duration oral exposure to isophorone
are provided for 16 days and for 13 weeks of exposure in the NTP (1986)
study. For the 16-day experiment, Table 2-2 and Figure 2-2 indicate 2000
mg/kg/day as a LOAEL for lethality and 1000 mg/kg/day as a NOAEL for
-------
Table 2-2. Levels of Significant Exposure to Isophorone - Oral
Exposure
Graph Frequency/ LOAELc(Effeet)
Key Species Route3 Duration Effect NOAEL Less Serious Serious Reference
(mg/kg/day)
ACUTE EXPOSURE
Death
1 rat
2.3
rat
(G)
(G)
mouse (G)
Neurological
5,6 rat (G)
INTERMEDIATE EXPOSURE
Death
7,8 rat (G)
9,10 mouse (G)
11,12 mouse (G)
16 d
5 d/wk
(12 doses
in 16 d)
16 d
5 d/wk
(12 doses
in 16 d)
13 wk
5 d/wk
1450
1450 (depression)
1000
1000
500
2104- (LD50)
2150
3450 (estimated
ld50)
2200 (LD50)
5000 (pros-
tration)
2000 (4/5F died)
(1/5M died)
Smyth et al.
1969,1970
Hazleton Labs
1964
Dutertre-
Catella 1976
Hazleton Labs
1964
NTP 1986
ZOOO (100% mort) NTP 1986
1000 (3/10F died) NTP 1986
sc
M
>
r
H
K
W
•n
TO
o
H
w
ho
OJ
-------
Graph
Key
Exposure
Frequency/
Species Route8 Duration Effect
Systemic
13 rat (F> 90 d
14 rat (G) 13 wk
5 d/wk
15 mouse (G) 13 wk
5 d/wk
16 dog (C) 90 d
Resp
Cardio
Gastro
Hemato
Husc/Skel
Hepatic
Renal
Derai/Oc
Other
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Derm/Oc
Other
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Oerm/Oc
Other
Resp
Cardio
Gastro
Hemato
Nusc/skel
Hepatic
Renal
Derm/Oc
Other
Table 2-2 (continued)
L0AELc(Effeet)
NOAEL Less Serious Serious Reference
(mg/kg/day)
311.8 AME Inc 1972a
311.8
311.8
311.8
311.8
311.8
311.8
311.8
311.8®
X
1000 NTP 1986 W
1000 £
1000 H
1000
2C
1000 m
1000
1000
1000
1000 NTP 1986
1000
1000
1000
1000
1000
1000
1000
150 AME Inc 1972b
150
150
150
150
150
150
150
150
•n
**3
-------
Graph
Key
Exposure
Frequency/
Species Route8 Duration Effect
Neurological
17 rat (G) 13 wk
5 d/wk
18 mouse (G) 16 d
5 d/wk
(12 doses
16 d)
CHRONIC EXPOSURE
Death
19,20 rat (G) 103 wk
5 d/wk
Systemic
21
22
23
rat (G) 103 wk
5 d/wk
mouse (G) 103 wk
5 d/wk
24
25
26
Resp
Cardio
Gastro
Hemato
Renal
Derm/Oc
Other
Resp
Cardio
Gastro
Hemato
Hepatic
Renal
Other
Table 2-2 (continued)
NOAEL
Less Serious
(mg/kg/day)
LOAEL (Effect)
Serious
Reference
1000 (lethargy)
1000 (stagger)
NTP 1986
NTP 1986
250
500
500
500
500
500
500
500
500
500
500
250 (nephropathy)
250 (hyperkeratosis)
250* (necrosis)
500 (inflammation)
500(increased
mortality)
NTP 1986
NTP 1986
NTP 1986
5C
M
>
f
H
5C
M
•Tl
M
O
H
w
ro
U1
-------
Table 2-2 (continued)
Exposure
Graph Frequency/ lOAELc(EffecO
Key Species Route8 Duration Effect NQAEL Less Serious Serious Reference
(mg/kg/day)
Cancer
27
28
29
30
rat
mouse
(G)
(G)
103 uk
5 d/wk
103 uk
5 d/wk
250 (CEL9- NTP 1986
kidney tunors)
500 (CEL9-preputial
gland tumors)
250 (CEL9- NTP 1986
lymphoma)
500 (CEL9-liver,
integunentary
system tunors)
?G * Gavage, F - feed, C - capsule
^KMEL - No Observed Adverse Effect Level
^LOAEL - Lowest Observed Adverse Effect Level
t-1
H
EC
PI
T)
PJ
O
H
tn
ro
-------
ACUTE
fc 14 Days)
INTERMEDIATE
(15-364 Days)
(mg/kg/day) ^
10.000
I
1,000
100
„ 4m • *
*mf%
* Jr.®,
Olt Ol* O'Sm
011m
Ql3r
10
v»
Ol9r
Ol«d
NX/
0.1
CHRONIC
(> 365 Days)
j?
~
~
^
y
o*
979m 0» 0»« ~ » ~ 30rn
dam (^24m 3?1r ~ 27» ~ Mm
5
EC
M
"d
m
o
H
CA
fO
Kev
r U
¦ UDS0
•
Minimal risk lawt for
m Moum
9 LOAEL far aarious affacb (ankmta)
i dlicliflfwfiincvMf
d Dog
9 LOAEl. lor ton aartous aflacfe (animals)
»
O NOAEL (animah)
V/
+ CEL- Cancar E«KltM*l
H#wuWbn)OfldiiptflitelnfinoBWBpin|ifcnMbli.
FIGURE 2-2. Levels of Significant Exposure to Isophorone - Oral
-------
28
2. HEALTH EFFECTS
lethality in rats and mice. For the 13-week study, 1000 mg/kg/day is the
LOAEL for lethality and 500 mg/kg/day is the NOAEL for lethality in mice
(see Table 2-2 and Figure 2-2). Although the deaths were considered to be
related to isophorone exposure, NTP (1986) did not comment on the cause of
death. At 1000 mg/kg/day in the 13-week study, one female rat died during
week 5, but NTP (1986) did not comment on whether this death was considered
to be related to isophorone exposure.
In the chronic exposure experiment by NTP (1986), male rats treated
with 500 mg/kg/day (LOAEL for lethality due to chronic oral exposure on
Table 2-2 and Figure 2-2) showed increased mortality, while no increased
mortality was observed at 250 mg/kg/day (NOAEL on Table 2-2 and Figure 2-2)
NTP (1986) regarded the increased mortality in the male rats to be related
to treatment with isophorone, but the cause was not attributed to lesions In
any one particular organ system. The increased mortality occurred late in
the study (after 96 weeks). No long-term studies of isophorone administered
in food or drinking water demonstrating increased mortality were located.
The dose levels of 1000 and 2000 mg/kg/day, which were administered to mice
by gavage in corn oil for 16 days and 13 weeks (NTP 1986), respectively,
were converted to equivalent concentrations of 8000 and 15,000 ppm in food
for presentation in Table 1-4.
2.2.2.2 Systemic Effects
No reliable studies were located regarding the systemic effects in
animals following acute oral exposure to isophorone.
Gastrointestinal Effects. In generally well-conducted, comprehensive
90-day studies, no treatment-related grossly or histologically observable
lesions were found in the gastrointestinal tract of rats and mice dosed by
gavage with isophorone (NTP 1986), rats exposed to isophorone in the diet
(AME Inc 1972a), or dogs treated with isophorone in gelatine capsules (AME
Inc 1972b). The studies by AME Inc (1972a,b) had several limitations, which
include lack of reporting of chemical analysis of feed formulations and
statistical methods in the rat study, and failure to examine all animals
histologically in both studies. Despite the limitations, the results
reported for gastrointestinal effects, as well as for other endpoints, are
probably valid because the doses are lower than the NOAELs for the same
endpoints in the NTP (1986) 90-day (13-week) study. The highest doses
administered in these studies were 311.8 mg/kg/day in the diet in rats (AME
Inc 1972a), 1000 mg/kg/day by gavage in rats and mice (NTP 1986), and 150
mg/kg/day in dogs (AME Inc 1972b), which are indicated as NOAELs for
systemic toxicity due to intermediate oral exposure in Table 2-2 and Figure
2-2.
In the chronic gavage study by NTP (1986), hyperkeratosis of the
forestomach was observed in isophorone-treated mice at both doses (Table 2-2
and Figure 2-2), but not in rats. The lowest dose of 250 mg/kg/day is
indicated as a LOAEL for less serious gastrointestinal effects due to
-------
29
2. HEALTH EFFECTS
chronic oral exposure to isophorone. No long-terra studies of isophorone
administered in food or drinking water demonstrating gastrointestinal
effects were located. The dose level of 250 mg/kg/day, which was
administered by gavage in corn oil (NTP 1986) , was converted to an
equivalent concentration of 1900 ppm in food for presentation in Table 1-4.
Hepatic Effects. No significant differences between pre-exposure and
post-exposure levels of serum electrolytes, blood glucose and sulfhydride
radicals, SGOT, SGPT, serum creatine phosphokinase, or serum lactic
dehydrogenase were found in rabbits treated by gavage with isophorone at a
dose of 1000 mg/kg/day, 2 days/week for 2 weeks (Dutertre-Catella 1976). No
other indices of liver toxicity were examined; therefore, the dose of 1000
mg/kg/day cannot be considered a N0AEL for liver effects. In the 90-day
studies conducted by NTP (1986) and AME Inc (1972a,b), no treatment-related
grossly or histologically observable lesions were found in the livers of
rats and mice dosed by gavage with isophorone (NTP 1986), rats treated with
isophorone in the diet (AME Inc 1972a), or dogs treated with isophorone in
gelatine capsules (AME Inc 1972b). These studies were comprehensive and
generally well-conducted. The highest doses administered in these studies
were 311.8 mg/kg/day in the diet in rats (AME Inc 1972a), 1000 mg/kg/day by
gavage in rats and mice (NTP 1986), and 150 mg/kg/day in dogs (AME Inc
1972b) , which are indicated as NOAELs for systemic effects due to
intermediate oral exposure in Table 2-2 and Figure 2-2.
No treatment-related gross or histopathological lesions in the liver
were observed in rats in the chronic experiment by NTP (1986), but dosed
male mice had increased coagulative necrosis and hepatocytomegaly, along
with increased incidences of hepatocellular adenomas and carcinomas (see
Section 2.2.2.8 on carcinogenicity). Female mice, however, did not have
treatment-related lesions in the liver. The highest dose (500 mg/kg/day) is
indicated as a NOAEL for liver effects in rats, while the low dose (250
mg/kg/day) is indicated as a LOAEL for non-neoplastic liver lesions in mice
due to chronic oral exposure to isophorone (see Table 2-2 and Figure 2-2).
No long-term studies of isophorone administered in food or drinking water
demonstrating hepatic effects were located. The dose level of 250
mg/kg/day, which was administered by gavage in corn oil (NTP 1986), was
converted to an equivalent concentration of 1900 ppm in food for
presentation in Table 1-4.
Renal Effects. Gross and histological examination of the kidneys of
rats and mice treated with isophorone by gavage (NTP 1986), rats fed diets
containing isophorone (AME Inc 1972a), or dogs treated with isophorone in
gelatine capsules (AME Inc 1972b) for 90 days revealed no treatment-
related lesions. In the NTP (1986) 90-day studies, recuts and special
stains of kidney tissues were performed to confirm the lack of response on
the kidney. Thus, the highest doses administered in these studies (311.8
mg/kg/day in the diet in rats, 1000 mg/kg/day by gavage in rats and mice,
and 150 mg/kg/day in dogs (AME Inc 1972b) are NOAELs for systemic effects
due to intermediate oral exposure (see Table 2-2 and Figure 2-2).
-------
30
2. HEALTH EFFECTS
The kidney is a target organ for chronic oral exposure to isophorone.
Tn the NTP (1986) study, dosed male mice, but not female mice, had increased
incidences of chronic focal inflammation of the kidney, but no other
incid n me/ke/day dose is indicated as a LOAEL tor less serious
^Hffe^s 1° »tce due L chronic oral exposure In Table 2-2 and Figure
I7 Dosed male rats had Increased Incidences of tubular cell hyperplasia
(possibly pre-neoplasttc), epithelial cell hyperplasia of the renal pelvis,
and tubular mineralization at both doses. The incidence of tubular
mineralizacion was higher In low dose males than in high dose males, and was
coincident with chronic nephropathy, the incidence of which was also higher
' L l0„ dose For this reason, NTP (1986) stated that the nephropathy
™s probably not the cause of the Increased mortality in the high dose
™!es Male rats also had Increased incidences of tubular cell adenomas and
carcinomas (see Section 2.2.2.8 on carcinogenicity . As discussed in
Section 2 3 (Relevance to Public Health), the tubular eel lesions may be
secuioi . v female rats had increased incidences of
hrLathv which may have been related to isophorone exposure. The dose
"f^ocQmo/Vg/day is indicated as a LOAEL for less serious effects on the
of 250 Ȥ/ 8/ y chronic oral exposure to Isophorone in Table 2-2 and
kidney in r tSirm stu(Jies of isophorone administered In food or
d fring'water dJZstrating renal effects were located. The dose level of
o™ nWWdav which was administered by gavage in com oil (NTP 1986) , was
S^S^Svlent concentration of 5000 PPm in food for
presentation in Table 1-4,
nt-Vi*»r Svstemic Effects. Mean body weight gain was decreased in rats
t- rthv elvaee with isophorone at 1000 mg/kg/day, but not at 500
/Wdav in a 16-day experiment by NTP (1986). The mice in the 16-day
mg/kg/day in a ,Z_r PAced growth Body weight changes were not
study did not have ^reased^growth^ o/mice treated with up to 1000
C°/Wdav in the 13-week experiment or up to 500 mg/kg/day in the 103-week
mg/kg/day in treated with 233.8 mg/kg/day had transient
experiment (N . the 9Q day feedlng study by ame Inc
bit body weights were not significantly different from controls at
nd of the study As 1000 mg/kg/day was a NOAEL for body weight changes
the end of yi3.week experiments, the decreased mean body weight at
in rats and mic 16_d study cannot be considered an adverse effect.
Therefore^°1000 mg/kg/day is a NOAEL for body weight changes in rats and
mice for intermediate duration exposure.
in the well-conducted, comprehensive 90-day studies, no treatment-
in trie wei histoiORically observable lesions were found in the
related grossly _,-000ietic tissues, or in the skin or eyes of rats and
lungs, hearts, hem p isoD^orone (NTP 1986), rats treated with
mice dosed by 8*™*® (AM£ Inc 1972a) , or dogs treated with isophorone in
isophorone in the 1972b). Furthermore, no changes in
gelatine capsules (AM histopathological lesions in the skeletal
hematological indices ana * by ^ Inc (1972a>b)
muscle were found in rats or
-------
31
2. HEALTH EFFECTS
highest doses administered in these studies were 311,8 mg/kg/day in the diet
in rats (AME Inc 1972a), 1000 mg/kg/day by gavage in rats and mice (NTP
1986), and 150 rag/kg/day in dogs (AME Inc 1972b), which are indicated as
NOAELs for systemic effects due to intermediate oral exposure in Table 2-2
and Figure 2-2.
A minimal risk level (MRL) for intermediate oral exposure can be
derived from the NOAELs for systemic endpoints. The highest NOAELs for
systemic effects of intermediate oral exposure were the 1000 mg/kg/day
doses in rats and mice in the 13-week (NTP 1986) study. Increased
mortality was observed in mice at 1000 mg/kg/day, however, precluding the
use of this dose. Based on the dose of 311.8 mg/kg/day in rats (AME Inc
1972a), an intermediate duration oral MRL of 3 mg/kg/day was calculated, as
described in the footnote in Table 2-2. The MRL for intermediate exposure
can be compared to existing State and Federal criteria levels (see Chapter
7) or to amounts of the chemical encountered in environmental or
occupational situations (see Chapter 5).
Other than the gastrointestinal, hepatic, and renal lesions described
above, no treatment-related gross or histopathological lesions were observed
in the lungs, heart, hematopoietic organs, skin, or other organs and tissues
of rats and mice in the chronic experiment by NTP (1986) . There was a dose-
related increased incidence of fatty metamorphosis of the adrenal cortex in
the male rats, but NTP (1986) stated that the biological significance of
this observation is not known. The highest dose (500 mg/kg/day) is
indicated as a NOAEL for systemic effects other than gastrointestinal,
hepatic, and renal toxicity due to chronic oral exposure to isophorone
(Table 2-2 and Figure 2-2). As discussed above under these endpoints, the
LOAEL for gastrointestinal, hepatic, and renal effects is 250 mg/kg/day, (as
the dose was given 5 days/week, it is equivalent to 179 mg/kg/day). A MRL
for chronic oral exposure can be derived from the LOAELs for systemic
effects. Based on the dose of 179 mg/kg/day, a chronic oral MRL of 0.2
mg/kg/day was calculated as described in the footnote to Table 2-2. The MRL
has been converted to an equivalent concentration in food (7 ppm) for
presentation in Table 1-3.
2.2.2.3 Immunological Effects
No studies were located regarding immunological effects in animals
following acute oral exposure to isophorone.
Histological examination of organs and tissues of the immune system did
not reveal any effects in rats or mice treated by gavage with isophorone for
13 or 103 weeks (NTP 1986), in rats treated with isophorone in the diet for
13 weeks (AME Inc 1972a), or in dogs treated with isophorone in gelatine
capsules for 13 weeks (AME Inc 1972b). In none of these studies, however,
were specific tests of immune function performed. Such tests of immune
function are more likely to detect immunological effects than are
-------
32
2. HEALTH EFFECTS
histological examinations. Therefore, the doses used in these studies
cannot be considered NOAELs for effects on the immune system.
2.2.2.4 Neurological Effects
Neurological effects of isophorone have been observed in animals aftei
oral dosing. In an acute study, rats treated by gavage with isophorone at
5000 mg/kg displayed depression, ptosis, absence of righting reflex, and
prostration (LOAEL for serious effects due to acute oral exposure on Table
5 7 and Fieure 2-2)" 4/5 died within 2 days after dosing (Hazleton Labs
1964) At 1450 mg/kg, depression was observed but the rats recovered with!
2 davs (LOAEL for less serious effects for acute oral exposure in Table 2-2
and Figure 2-2). No signs of neurotoxicity occurred at 417 mg/kg. In the
16 dav NTP (1986) study, mice treated by gavage at 1000 mg/kg/day, but not
at 500 me/kg/day, staggered after dosing, indicating an acute response to
the high dose. Similarly, in the 13-week NTP (1986) study, rats given 1000
ms/kE/dav but not 500 mg/kg/day, were sluggish and lethargic after dosing,
I!^n2[^in6« « *•
Is the acute LOAEL for less serious neurological effects (Table 2-2 and
Fieure 2-2) Although the doses of 417 mg/kg and 500 mg/kg did not result
in overt signs of neurotoxicity, more sensitive tests for neurotoxicity
Ce £ operant performance, motor activity, electrophysiology), which may
have revealed neurobehavioral effects at these doses, were not performed.
Therefore, these doses should not be considered NOAELs for neurotoxicity fOJ
oral exposure No short-term studies of isophorone administered in food or
drinking water were located. The dose level of 1000 mg/kg in mice, which
administered by gavage in com oil (NTP 1986), was converted to an
"quivflent concentration o{ 8000 ppm in food for presentation in Table 1-4.
2.2.2.5 Developmental Effects
No studies were located regarding developmental effects in humans or
animals following oral exposure to isophorone.
2.2.2.6 Reproductive Effects
Ro studies were located regarding reproductive effects in animals
following acute oral exposure to isophorone.
Histological examination of reproductive organs did not reveal any
effects in rfts or mice treated by gavage with isophorone for 13 or 103
weeks (NTP 1986), in rats treated with isophorone in the diet for 13 weeks
7am Tne1972a) or in dogs treated with isophorone in gelatin, capsules foi
i fAME Inc 1972b). In none of these studies, however, were specific
t at X reproductive function performed, which would be necessary to rule
out an effect. Therefore, the doses used in these studies cannot be
considered NOAELs for effects on reproduction.
-------
33
2. HEALTH EFFECTS
2.2.2.7 Genotoxic Effects
No studies were located regarding genotoxic effects in humans or
animals following oral exposure to isophorone.
2.2.2.8 Cancer
In the chronic gavage study, NTP (1986) concluded that there is "some
evidence of carcinogenicity" in male rats due to an increased incidence of
relatively rare renal tubular cell adenomas and adenocarcinomas at 250 and
500 mg/kg/day and rare preputial gland carcinomas at 500 mg/kg/day.
According to the strict criteria of NTP, "some evidence" in this case means
that the study showed a slight increase in uncommon malignant or benign
neoplasms. The 250 and 500 mg/kg/day doses are indicated in Table 2-2 and
Figure 2-2 as effect levels for carcinogenicity (Cancer Effect Levels, CELs)
in rats due to oral exposure to isophorone. Based on the combined
incidences of renal tubular cell tumors and preputial gland tumors, EPA
(1986, 1987b) proposed an oral qi£ of 4.1 x 10"^ (mg/kg/day)"-^ for
isophorone, but this analysis is under review by the EPA.
In the NTP (1986) study, male mice had marginally increased
incidences of hepatocellular tumors and mesenchymal tumors of the
integumentary system at 500 mg/kg/day and of malignant lymphomas at 250
mg/kg/day. NTP (1986) considered this evidence to be equivocal because the
study showed marginal increases in neoplasms related to isophorone
exposure. The doses of 250 and 500 mg/kg/day are indicated in Table 2-2 and
Figure 2-2 as CELs for carcinogenicity in mice. There was no evidence of
carcinogenicity in female rats or mice.
2.2.3 Dermal/Ocular Exposure
No studies were located regarding health effects in humans following
dermal or ocular exposure to isophorone.
2.2.3.1 Death
Hazleton Labs (1964) reported that the dermal LD50 of isophorone in
rabbits was greater than 3160 mg/kg, the highest dose tested. In this study,
the area of application was occluded for 24 hours. Union Carbide (1968),
however, reported 1.5 mL/kg (1384 mg/kg) as the dermal LD50 in rabbits, but
no details of the determination were provided. Therefore, it is not
possible to reconcile these contradictory reports. Dutertre-Catella (1976)
estimated a dermal LD50 of 1200 mg/kg in rabbits. The LD50 was difficult to
determine with precision because some rabbits died within 6 hours of
application and the method requires that the chemical remain on the skin for
24 hours. The rabbits that did not die within 6 hours recovered and were
not harmed by doses up to 4000 mg/kg. The dermal LD50 is Indicated on
Table 2-3. When 0.1 or 0.2 mL isophorone was applied to the shaved skin of
-------
Table 2-3. Levels of Significant Exposure to Isophorone - Dermal3
Spec i es
Exposure
Frequeny/
Duration Effect
NQAELl
Less Serious
LOAEL (Effect)
Serious
Reference
ACUTE EXPOSURE
Death
Systemic
rabbit
guinea
pi 9
rabbit
rabbit
rabbit
rabbit
rabbit
once Dermal
24 hr
Dermal
Ocular
30 sec Ocular
once
24 hr
once
1 or 4 h
Dermal 50 rog/kg
Dermal
dose not (irritation)
specified
0.5 ml (irritation)
200 mg/kg
(desquamation)
0.5 ml (irritation)
1200 mg/kg (LDcn) Dutertre-
Catella 1976
Eastman Kodak
1967
Triiiaut et al.
1972
0.02 ml (eye
necrosis)
0.1 ml (corneal
opaci ty)
Carpenter and
Smyth 1946
Hazleton Labs
1964
Hazleton Labs
1964
Potokar et al.
1985
X
m
>
ae
•"i
m
o
<-3
C/i
U3
rabbi t
Ocular
0.1 ml (eye
i nj ury)
Triiiaut et al.
1972
Neurological
rabbit
once
24 hr
794 mg/kg
3160 mg/kg (CMS
depression)
Hazleton Labs
1964
-------
Table 2-3 (continued)
Exposure
Frequery/ LOAEL (Effect)
Species Duration Effect NQAELC Less Serious Serious Reference
INTERMEDIATE EXPOSURE
Death
rat
8 wk
7 d/wk
0.1 ml (death
of 20X males)
Dutertre-
Catella 1976
Systemic
rat
8 wk
7 d/uk
0.1 ml (erythema
and scar tissue)
Dutertre-
Catella 1976
aThese levels are got displayed graphically because none of the studies used doses expressed
in units of mg/cnr/day
\oA£l - Lowest Observed Adverse Effect Level
cMOA£L - No Observed Adverse Effect Level
-------
36
2. HEALTH EFFECTS
rats for 8 weeks, 20% of the males but none of the females died (Dutertre.
Catella 1976) (Table 2-3). No studies were located regarding death of
animals following chronic duration exposure to isophorone.
2.2.3.2 Systemic Effects
Dermal/Ocular Effects. Skin Irritation was observed In rabbits and
guinea Pif «onowm, ,-a! application «*»»«
studies" undiluted' isophorone generally In a volume of 0.(Tab,e 2-3)
was applied to the clipped skin of the animals and held under an occlusive
coverinR Hazleton Labs (1964) reported doses n units of „,,,/k« and found
that >200 BE/kE (LOAEL for less serious effects) resulted in desquamation
and erythema, while 50 mgAg C^L) without effect. Application of 0.1
' o ,ymL ts0phorone to the shaved skin of rats for 8 week, resulted In
erythema and scar tissue formation (Dutertre.Catella 1976). These effects
disappeared rapidly after exposure ceased. These doses are dieted in
Table 2-3.
Isophorone is also irritating to the eyes of rabbits. Application of
0 09 0 1 ml of undiluted isophorone directly to the eye caused severe
-i 4 <-v and necrosis (Carpenter and Smyth 1946; Hazleton
^IkTTALTll ai.'^972, (see Table 2-3) . HaZle,:o„ Labs (1964, found
rha? the corneal damage was no longer present 14 days after exposure . No
studies were located regarding dermal/ocular effects in animals following
intermediate or chronic duration exposure to isophorone.
Other Systemic Effects. In rabbits exposed dermally to Isophorone at
doses up to 3160 mg/kg, no systemic pathological effects were found by gross
necropsy (Hazleton Labs 1964), but histological examinations wore not
necropsy*, study, the site of application was occluded for 24 hours
Torment eiaporlti^ o'f' isophorone from the skin No .Ignif leant
to preveu f rp anci Cost-exposure levels of serum
differences be£ween p ' P and sulfhydride radicals, SG0T, SGPT, serum
electrolytes, b oo g serum lactic dehydrogenase were found in rabbits
creatine phosphokxnase, ^ horone (Dutertre-Catella 1976). No other
indices 0""^ toxicity were examined; therefore, the 20 mL dose cannot be
considered a NOAEL for liver effects.
2.2.3.3 Immunological Effects
No studies were located regarding Immunological effects in humans or
animals following dermal or ocular exposure to isophorone.
2.2.3.4 Neurological Effects
In the study by Hazleton Labs (1964), 1/4 rabbits exposed dermally to
3160 S/S under an occlusive bandage for 24 hours displayed marked
d p^esfion, labored respiration, sprawling, and depressed reflexes (see
-------
37
2. HEALTH EFFECTS
Table 2-3). The other three rabbits at this dosage and at <794 mg/kg did
not display any signs of toxicity.
No studies were located regarding the following effects in humans or
animals following dermal or ocular exposure to isophorone:
2.2.3.5 Developmental Effects
2.2.3.6 Reproductive Effects
2.2.3.7 Genotoxic Effects
2.2.3.8 Cancer
2.3 RELEVANCE TO PUBLIC HEALTH
Death. No information was located regarding death of humans following
inhalation, oral, or dermal exposure to isophorone. Concentrations and
doses causing death in animals have been reported for acute and intermediate
duration inhalation exposures, for acute, intermediate duration, and
chronic oral exposures, and for acute and intermediate duration dermal
exposure. The acute lethality of isophorone in animals may be due to its
effects on the central, nervous system. Hazleton Labs (1964) found that rats
exposed by inhalation to the LC50 were comatose, and rats treated orally
with lethal doses displayed depression, absence of righting reflex, and
prostration. In the gavage NTP (1986) studies, rats and mice displayed
lethargy and staggering after dosing with 1000 mg/kg. The highest dose in
the 16-day study (2000 mg/kg/day) was fatal to all the mice and 5/10 of the
rats. NTP (1986) did not comment on the cause of death. In the chronic
study, high-dose (500 mg/kg/day) male rats had increased mortality (NTP
1986). The increased mortality, which occurred late in the study (after 96
weeks), was considered to be related to isophorone exposure, but NTP (1986)
could not relate the cause with effects In any specific organ system. The
concentrations or doses of isophorone that would be required to result in
the death of humans are not known. As mild neurological effects have been
observed in humans exposed to relatively low levels of Isophorone, it is
likely that if humans were to be exposed to levels high enough to result in
death, the cause may be related to more severe CNS effects.
Systemic Effects. The only known effects of isophorone exposure in
humans are eye, nose, and throat irritation, and fatigue and malaise.
Studies were conducted in humans to determine the thresholds for eye, nose,
and throat irritation (25-35 ppm) (Hazleton Labs 1965b; Silverman et al.
1946). The thresholds agree reasonably well with exposure concentrations
(°«25 ppm) associated with eye, nose, and skin irritation in occupational
settings (Kominsky 1981; Lee and Frederick 1981). The thresholds for
irritation are near the OSHA (1989) Permissible Exposure Limit of 25 ppm,
and higher than the ACGIH (1988) Celling Limit of 5 ppm, which Is based on
worker complaints of fatigue and malaise (ACGIH 1986).
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38
2. HEALTH EFFECTS
Systemic effects of isophorone observed in animals include pulmonary
congestion and hemorrhage, hyperkeratosis of the forestomach, irritation to
the skin, eye, and mucous membranes, hematological effects, liver damage,
and kidney damage.
The hemorrhaging observed in rats and rabbits (Dutertre-Catella 1976)
and the pulmonary congestion observed in rats and mice following acute
inhalation exposure to isophorone (Hazleton Labs 1964) is probably related
to irritation of mucous membranes. DeCeaurriz et al. (1981a) assessed the
sensory irritation of isophorone in mice by measuring the decrease in the
respiratory rates, also indicating that isophorone is irritating to the
respiratory system. Ocular and nasal irritation also occurred in rats
exposed to isophorone in air at 500 ppm for up to 6 months and in rats and
rabbits exposed to 250 ppm for 18 months (Dutertre-Catella 1976). Since
isophorone is known to be irritating to mucous membranes of humans,
inhalation exposure probably could result in pulmonary congestion in
humans. The highest inhalation exposures occur in occupational settings,
however, where respiratory irritation has been reported in humans exposed to
isophorone and other solvents.
Chronic exposure of mice by gavage to isophorone at 250 mg/kg/day
resulted in hyperkeratosis of the forestomach (NTP 1986), an effect that may
also be related to the irritating effect on mucous membranes. Although
there is no tissue in man that is precisely analogous to the mouse
forestomach and the effects of oral exposure of humans to isophorone are not
known, ingestion of isophorone could result in gastrointestinal irritation.
The minimum concentration of isophorone in water or food necessary to
produce the irritation cannot be determined from the available data in
animals.
Dermal exposure of rats, rabbits, and guinea pigs results in skin
irritation (Dutertre-Catella 1976; Eastman Kodak 1967; Hazleton Labs 196-4;
Potokar et al. 1985; Truhaut et al 1972). In these studies, liquid
isophorone was applied to the skin and the area of application was occluded
for 24 hours to prevent evaporation, or to the shaved skin for 8 weeks.
While it is unlikely that a human would be exposed in such a manner, screen
printers are exposed dermally to both the vapor and the liquid forms of
isophorone, which could result in irritation of unprotected skin,
Application of undiluted isophorone to the eyes of rabbits results in
severe eye injury (Carpenter and Smyth 1946; Hazleton Labs 1964; Truhaut et
al. 1972), which appears to be reversible with time (Hazleton Labs 1964).
Isophorone is known to be irritating to the eyes of humans exposed to the
vapors (Hazleton Labs 1968; Silverman et al. 1946), it is reasonable to
conclude that liquid isophorone splashed directly into the eyes of humans
could cause severe eye injury.
-------
39
2. HEALTH EFFECTS
When post-exposure values were compared with pre-exposure values,
slight changes in the percentage of white blood cells and slightly increased
hemoglobin content were observed in rats exposed to isophorone by inhalation
(Hazleton Labs 1964), but similar changes also occurred in controls.
Therefore, toxicological significance of this finding is minimal and the
relevance to humans is not known.
Reported effects on the liver include decreased liver weight in rats
exposed subchronically by inhalation (Hazleton Labs 1968), cytoplasmic
microvacuolization in rats exposed chronically by inhalation (Dutertre-
Catella 1976), and increased incidence of coagulative necrosis and
hepatocytomegaly in male mice exposed chronically by gavage at 250 and 500
mg/kg/day (NTP 1986). The decreased liver weight in rats exposed by
inhalation is of questionable toxicological significance because
histological examination of a limited number of rats in the study did not
reveal treatment - related liver lesions. The toxicological significance of
the microvacuolization observed in liver cells of rats and rabbits is also
unknown. The liver lesions observed in male mice in the oral study were not
observed in female mice, but the reason for the sex difference is not known.
The mechanism by which isophorone produces liver lesions in male mice is not
known, but liver lesions are common in aged mice; isophorone may enhance an
age-related process. It is not known whether isophorone causes liver
effects or enhances age-related processes in humans.
Subchronic inhalation studies of isophorone (Smyth and Seaton 1940;
Smyth et al. 1942) reported severe kidney damage in rats and guinea pigs,
but these studies have been criticized for using impure isophorone and for
overestimating the exposure concentration (Rowe and Wolf 1963). Because of
these reports, however, NTP (1986) examined the kidneys twice and used
special staining techniques to confirm the lack of histopathological lesions
and protein droplets in the kidneys of rats and mice exposed subchronically
to isophorone by gavage. Although the NTP (1986) study did not detect
protein droplet formation in the kidneys of rats or mice treated with
isophorone (Bucher 1988), protein droplets were found in the kidneys of male
rats exposed by inhalation to dihydroisophorone (Hazleton Labs 1968) , a
metabolite of isophorone. Furthermore, Strasser (1988) found that
isophorone and its metabolites, dihydroisophorone and isophorol, induced
significant protein droplet formation in the kidneys of male rats treated
acutely by gavage. It was not clear if the response was dose-related.
Isolation and analysis of c*2^-globulin from the kidney cytosol of rats
treated with isophorone or dihydroisophorone positively identified
isophorone or dihydroisophorone, respectively, in the o^-globulin samples.
Following treatment with isophorol, isophorone was found in the a2p~globulin
samples, indicating that isophorol was metabolized to isophorone. The
results of Strasser (1988) are preliminary and require confirmation, but the
data suggest that isophorone and its metabolites bind to
-------
40
2. HEALTH EFFECTS
a^-Globulin is a low molecular weight protein synthesized in large
quantities in the male rat liver, secreted into the blood under the
influence of testosterone (Alden 1986), and filtered through the glomerulus
The o^-globulin is reabsorbed by the tubule cells and sequestered into
lysosomes, where it is catabolized into amino acids and peptides. In the
normal rat kidney, the rate of catabolism of (*2^ "globulin is relatively slow
compared with that of other proteins (Swenberg et al. 1989). In the male
F344 rat, protein droplet nephropathy is characterized by accumulation of
«2^-globulin in lysosomes, degeneration and necrosis of tubular cells,
formation of granular casts, and regeneration (proliferation) of the tubular
epithelium (Swenberg et al. 1989). Chemicals that are known to induce
protein droplet nephropathy bind to a2^"Slobul-i-n. yielding a complex that
may be more resistant to the proteolytic enzymes in the lysosomes, which
leads to the accumulation of the complex in the tubule cells.
o^-Globulin has not been found in immature male rats, female rats, or
humans (Alden 1986). In adult male rats, the protein may function as a
pheromone carrier (Alden 1986). If isophorone induces nephropathy by the
suggested mechanism, the absence of aj/i'Slobulin in humans raises the
question of the relevance to humans of the isophorone- induced kidney lesions
in male rats. a^-Globulin is related to other low molecular weight
transport proteins that have been detected in humans (Swenberg et al. 1989)
but it is not known whether chemicals that are nephrotoxic to the rat will
bind to the human proteins or produce similar effects in humans.
In the chronic gavage study by NTP (1986), dosed male rats had
increased incidences of renal tubular cell hyperplasia, epithelial cell
hyperplasia of the renal pelvis, and tubular mineralization. The male rats
also had increased incidences of renal tubular cell tumors. The hyperplasia
of the tubular cells, therefore, may represent a preneoplastic response (see
discussion of cancer below). These proliferative kidney lesions were not
observed in male or female mice or In female rats. The mechanism for the
induction of proliferative kidney lesions may also be related to c*2/i*
globulin-induced nephropathy (see discussion of cancer below), again raising
the question of the relevance of the proliferative kidney lesions in male
rats to humans. This issue is presently the subject of scientific
investigation.
Female rats had Increased incidences of age-related nephropathy (NTP
1986). The tubular mineralization in the male rats was coincident with
age-related nephropathies, which were more severe in the low-dose males. It
is possible, therefore, that isophorone treatment enhanced the age-related
nephropathies commonly seen in rats, but it is not known if isophorone could
enhance age-related processes in humans.
Neurological Effects. Humans occupationally exposed to isophorone at
levels as low as 5-8 ppm have complained of fatigue and malaise (Ware 1973).
When workroom levels were lowered to 1-4 ppm, complaints ceased.
Neurological effects of oral or dermal exposure of humans to isophorone are
-------
41
2. HEALTH EFFECTS
not known. Acute exposure of animals to high inhalation concentrations and
oral and dermal doses affects the central nervous system as evidenced by
such effects as narcosis, staggering, depression, ataxia, lethargy, and
prostration and coma. No histologically detectable lesions have been found
in the brain, sciatic nerve, or spinal cord of animals exposed to isophorone
by any route for any duration. Although not precisely known, the mechanism
by which isophorone induces its neurological effects may involve
interference with neuronal impulse transmissions via physical interaction of
isophorone with nerve membrane components, as is seen with many organic
solvents. The effects in animals at high exposures and the malaise and
fatigue in humans at relatively low workroom concentrations of isophorone
predict that exposure of humans to high air concentrations or high oral
doses could result in severe central nervous system depression.
Developmental Effects. Isophorone has been tested by inhalation for
developmental effects in rats and mice. Evidence for intrauterine growth
retardation was seen at an exposure concentration of 115 ppm (Bio/dynamics
1984a,b). At 150 ppm, exencephaly was seen in several fetuses. While the
incidence of this malformation was not statistically significant, it was
seen in both species and only in treated animals. Dose-related maternal
toxicity was evident in all treatment groups. Isophorone has not been
tested for developmental effects by the oral or dermal route. No studies
were located demonstrating that isophorone crosses the placenta in animals
or in humans, but there is no reason to assume that it does not do so. It
is not known whether isophorone could cause developmental effects in humans.
Genotoxic Effects. No studies were located regarding the genotoxicity
of isophorone in humans or animals by the inhalation, oral, or dermal
routes. Isophorone has been tested for genotoxic effects in vitro and in
mice treated intraperitoneally (Table 2-4). Isophorone was negative for
reverse mutations with and without metabolic activation with S9 prepared
from rat or hamster livers (NTP 1986). CMA (1984) reported that isophorone
was negative both with and without metabolic activation in mouse lymphoma
cells, while NTP (1986) found a weakly positive effect without activation In
the same cell system. The concentrations of isophorone used by NTP (1986)
were at least 60 times higher than those used by CMA (1984) . Negative
results were found for unscheduled DNA synthesis in rat hepatocytes, for
chromosome aberrations in Chinese hamster ovary cells, and in the
micronucleus test In mice (CMA 1984; NTP 1986). NTP (1986) found a positive
response for sister chromatid exchange in Chinese hamster ovary cells in the
absence, but not in the presence, of a metabolic activating system.
In assessing the potential for a chemical to produce heritable
mutations in humans, it is necessary to examine the weight of evidence
obtained from in vitro tests for mutations in microorganisms and cultured
mammalian cells, from in vivo tests of mutations in animals, and from in
vitro and In vivo tests for chromosome aberrations in mammalian cells. The
strongest evidence would come from the demonstration that a chemical causes
mutations or chromosome aberrations in human cells. As no studies were
-------
TABLE 2-4. Genotoxicity of Isophorone In Vitro and In Vivo
End Point
Species (test system)
Result
Without With
activation activation
References
Reverse mutation
Forward nutation
UDSb
SCEd
Chromosome
aberrations
Nicronucleus
test
Salmonella typhimuriun
L5178Y/TIC+/- mouse
lymphoma cell
Rat primary hepatocyte
Chinese hamster ovary
cells
Chinese hamster ovary
cells
Mouse erythrocytes
(mice treated i.p. >
NT
NA
NTP 1986
NTP 1986
CMA 1984; McKee
et al. 1987
CMA 1984; McKee
et al. 1987
NTP 1986
NTP 1986
CMA 1984; HcKee
et al. 1967
a
w
>
r
H
S
PI
PJ
O
H
CO
¦C-
ro
?Not tested.
Unscheduled DNA synthesis,
ot applicable,
ister chromatid exchange.
-------
43
2. HEALTH EFFECTS
located that tested isophorone in cultured human cells or examined the cells
of people with known exposure, this evidence is lacking. Of the five
experiments that tested whether isophorone caused mutations or chromosome
aberration in cultured mammalian cells, only two were positive: a weak
mutagenic response in mouse lymphoma cells and a positive test for sister
chromatid exchange in Chinese hamster ovary cells in the absence, but not
in the presence, of metabolic activation were obtained by NTP (1986).
Isophorone was not mutagenic in the Salmonella/microsome assay (NTP 1986) .
The only in vivo test was the micronucleus test in mice, which was negative
(CMA 1984). Therefore, isophorone may be weakly genotoxic in mammalian
cells, but the evidence is insufficient to predict that isophorone poses a
genotoxic threat to humans.
Cancer. Increased incidences of relatively rare renal tubular cell
adenomas and carcinomas were observed in male rats, but the increases were
not statistically significant by the Fisher Exact test or the Cochran-
Armitage test (NTP 1986). When adjusted for mortality, however, the
increased incidences were significantly different from control in the high-
dose males when analyzed by the Lifetable test and significant for dose-
related trend by the Lifetable and the Incidental Tumor tests. As the
kidney tumors were not fatal, the appropriateness of Lifetable test for the
analysis of these tumors is questionable. The overall unadjusted incidences
were significantly different from the historical control incidence by the
Fisher Exact test. The kidney tumors were not observed in female rats or in
male or female mice.
Isophorone is one of several diverse chemicals that have been found to
induce kidney tubular cell tumors in male rats, but not in female rats, male
or female mice, hamsters, guinea pigs, dogs, and nonhuman primates (Alden
1986; Swenberg et al. 1989). These chemicals include 1,4-dichlorobenzene,
dimethymethylphosphonate, JP-5 jet fuel; d-limonene, pentachloroethane,
tetrachloroethylene, and unleaded gasoline, which have also been found to
cause protein droplet nephropathy in male rats. As discussed above for
systemic renal effects, binding of these chemicals to a^/i'S^bulin, a
protein that appears to be unique to male rats, is believed to be involved
in the protein droplet nephropathy. Based on tumor initiation-promotion
studies of trimethylpentane, an globulin binding component of unleaded
gasoline, and the body of data on a2^-gl°buH-n"induced protein droplet
nephropathy, the following mechanism has been proposed for the formation of
tumors in the male rat kidney (Swenberg et al. 1988). Accumulation of the
chemical-a2^-globulin complex causes lysosomal protein overload and necrosis
of the cells, with subsequent cellular regeneration that continues as long
as the rat is exposed to the chemical and produces ot2/i"6l°frulin.
increased cellular proliferation may promote tumorigenesis by increasing
the number of cells in the kidney that have undergone spontaneous
initiation. Given the findings of Strasser (1988) that isophorone was
associated with a^-globulin and induced protein droplet formation in the
kidneys of male rats and that cell proliferation may be involved in the
mechanism of male rat kidney tumorigenesis, the finding in the NTP (1986)
-------
44
2. HEALTH EFFECTS
study of increased incidences of tubular epithelial hyperplasia in addition
to the increased incidences of tubular cell tumors is consistent with the
mechanism proposed by Swenberg et al. (1989).
As discussed above, <*2^-globulin appears to be unique to male rats. If
isophorone induces kidney tumors solely by the suggested mechanism, the
absence of c^/i'globulin i-n humans raises the question of the relevance to
humans of the isophorone-induced kidney tumors in male rats. ALthough ai -
globulin is related to other low molecular weight transport proteins that^
have been detected in humans (Swenberg et al. 1989), it is not known whether
chemicals that produce kidney tumors in male rats bind to the human proteins
or produce similar effects in humans. This issue is currently being
reviewed by the EPA.
Male rats treated with isophorone in the NTP (1986) study also had
preputial gland carcinomas, an extremely rare finding. Analogous tissues
in humans are modified sebaceous glands in the prepuce (foreskin of the
penis) , but it is not known whether isophorone could cau.se tumors in these
glands or other glandular tissues in humans.
In male mice, significant dose-related trends by the Cochran-Armitage
test were found for hepatocellular adenoma and carcinoma (combined) and for
fibromas, sarcomas, fibrosarcomas, and neurofibrosarcomas (combined) of the
integumentary system. These incidences were increased significantly above
control rates in the high-dose males by the Incidental Tumor and Fisher
Exact tests. Low-dose male mice had significantly increased incidences of
lymphoma compared with controls by the Life Table test and Fisher Exact
test, but the tests for dose-related trend were not significant because the
incidence in high-dose male mice was lower than the incidence in low-dose
male mice. This evidence was considered equivocal by NTP (1986), and it is
not known whether exposure to isophorone would cause cancer in human.
2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS
No studies were located regarding levels of isophorone or its
metabolites in human tissues and fluids associated with effects.
Furthermore, no studies were located describing methods for detecting
isophorone or its metabolites in human tissues and fluids.
2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES
AND/OR HEALTH EFFECTS
Although isophorone has been detected in environmental media (see
Chapter 5), no data were located allowing associations of effects of
isophorone In humans or levels of isophorone or its metabolites in human
tissues and fluids with environmental levels of isophorone.
-------
45
2. HEALTH EFFECTS
2.6 TOXICOKINETICS
2.6.1 Absorption
2.6.1.1 Inhalation Exposure
No studies were located regarding the rate and extent of absorption of
isophorone following inhalation exposure of humans or animals to isophorone.
Isophorone was widely distributed to the organs of rats exposed for 4 hours
to a concentration of 400 ppm isophorone (Dutertre-Catella 1976),
indicating that isophorone is absorbed after inhalation exposure. That
isophorone is absorbed by the lungs can also be inferred from the systemic
toxicity observed In animals following inhalation exposure (see Section
2.2.1.2 on systemic effects following inhalation exposure). Imbriani et al.
(1985) measured a blood/air partition coefficient of 2349 for isophorone,
Indicating that isophorone is absorbed readily from the lungs.
2.6.1.2 Oral Exposure
No studies were located regarding the absorption of isophorone in
humans following oral exposure.
Preliminary results of a pharmacokinetic study indicate that rats
treated orally with ^-^C-isophorone excreted 93% of the radiolabel in the
urine, expired air, and feces in 24 hours (Strasser 1988). The majority was
found in the urine indicating that isophorone was well absorbed. The wide
distribution of isophorone in the organs of rats and a rabbit 1-5 hours
after dosing by gavage with 4000 mg/kg (Dutertre-Catella 1976) Indicates
rapid gastrointestinal absorption. In two rabbits given a gavage dose of
1000 mg/kg isophorone, a blood level of isophorone of 102 /ig/L was found
within 10 minutes. The level increased to 141 ng/h in 30 minutes and
declined to <0.05 /ig/L in 21 hours. The results indicate rapid absorption
and elimination. The detection of unchanged isophorone and its metabolites
(see Section 2.6.3 on Metabolism) in the urine and the observations of
systemic toxicity and carcinogenicity (see Section 2.2.2 on effects of oral
exposure) in animals exposed orally to isophorone provide qualitative
evidence that isophorone Is absorbed after oral exposure.
2.6.1.3 Dermal Exposure
No studies were located regarding the absorption of isophorone
following dermal exposure of humans or animals. A report that a high dermal
dose resulted in signs of CNS depression in 1/4 rabbits suggests that
isophorone is absorbed dermalLy (Hazleton Labs 1964) , but other systemic
effects have not been described.
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46
2. HEALTH EFFECTS
2.6.2 Distribution
2.6.2.1 Inhalation Exposure
No studies were located regarding the distribution of isophorone
following inhalation exposure of humans.
In rats exposed to 400 ppm isophorone for 4 hours and sacrificed
immediately after exposure or 1.5 or 3 hours after exposure, levels of
isophorone were highest in all tissues examined (brain, lungs, heart
stomach, liver, spleen, pancreas, kidney, adrenals, testicles! and ovaries)
immediately after exposure (Dutertre-Catella 1976). Levels ranged from 1.5
to 74 pg/g tissue wet weight. The levels declined rapidly in males but
declined very little in females by 3 hours after exposure.
2.6.2.2 Oral Exposure
No studies were located regarding the distribution of isophorone in
humans following oral exposure.
Radiolabel was widely distributed in male rats 24 hours after an oral
dose of ^C-isophorone in corn oil, with highest levels in the liver
kidney, preputial gland, testes, brain, and lungs (Strasser 1988).
Isophorone was widely distributed to the tissues of rats and a rabbit
following treatment with isophorone at a gavage dose of 4000 mg/kg
(Dutertre-Catella 1976). The rats died within 1-5 hours and the rabbit
died within an hour after dosing at which times the tissues were sampled for
analysis. In rats, tissue levels of isophorone in ^g/g tlssue wet weight
were as follows: stomach - 6213, pancreas - 2388, adrenals - 1513 spleen
1038, liver - 613, brain - 378, lung - 383, heart - 337> kidney -465
testes - 275, and ovaries - 471. In the rabbit, tissue levels were as'
follows: stomach - 5395, adrenals - 1145, ovaries - 3000, spleen - 545
liver - 515, kidney - 295, heart - 260, and lungs -5q ' '
2.6.2.3 Dermal Exposure
No studies were located regarding the distribution of isophorone
following dermal exposure of humans or animals.
2.6.3 Metabolism
No studies were located regarding the metaboliSra 0f isophorone in
humans following exposure to isophorone by any route.
Rabbits and rats treated orally with isophorone excreted unchanged
isophorone in the expired air and in the urine (Dutertre-Catella et al
1978; Truhaut et al. 1970). The urine also contained 3-carboxy-5,5-
dimethyl-2-cyclohexene-l-one and glucuronic conjugates of 3 3 5-trimethvl-2-
cyclohexene-l-ol (isophorol), 3, 5,5-trimethylcydohexanone
-------
47
2. HEALTH EFFECTS
(dihydroisophorone), and cis- and trans-3,5,5 trimethylcyclohexanols. Rat
urine contained more dihydroisophorone and less isophorol than did rabbit
urine. Dutertre-Catella et al. (1978) proposed that metabolism of
isophorone involves methyloxidation to 3-carboxy-5,5-dimethyl-2-
cyclohexene-1-one, reduction of the ketone group to isophorol, reduction of
the ring double bond to dihydroisophorone, and dismutation of
dihydroisophorone to cis- and trans-3,5,5-trimethylcyclohexanols. The
metabolic pathways are presented in Figure 2-3.
2.6.4 Excretion
2.6.4.1 Inhalation Exposure
No studies were located regarding the excretion of isophorone or its
metabolites following inhalation exposure of humans to isophorone.
Dutertre-Catella (1976) found that the excretion of isophorone in air was
low (110 pg) and declined further to 30 jig at 2.5-3 hours after exposure of
rats to 400 ppm for 4 hours.
2.6.4.2 Oral Exposure
No studies were located regarding the excretion of isophorone or its
metabolites following oral exposure of human to isophorone.
Rats and rabbits excreted unchanged isophorone and metabolites in the
urine and unchanged isophorone in the expired air following oral dosing with
isophorone (Dutertre-Catella et al. 1978), but the rate and extent of
excretion were not reported, Preliminary results of a pharmacokinetic study
indicate that following an oral dose of "^C-isophorone, male rats excreted
932 of the radiolabel in the urine, feces, and expired air in 24 hours, with
the majority in the urine (Strasser 1988).
2.6.4.3 Dermal Exposure
No studies were located regarding the excretion of isophorone or its
metabolites following dermal exposure of humans or animals.
2.7 INTERACTIONS WITH OTHER CHEMICALS
The possible synergistic interactions of isophorone with other
solvents are important because mixed exposures occur in occupational
settings and may occur in the environment. The joint toxicity of isophorone
with 26 other industrial liquid chemicals based on determinations of the
oral LD50S in rats of each chemical alone and in a 1:1 (v/v) mixture was
determined (Smyth et al. 1969). The LD5QS of the mixtures were predicted
based on the assumption of additivity of the LD5QS of each component, and
the ratios of the predicted values to experimentally determined values were
calculated. Greater than additive toxicity was observed for the mixtures of
isophorone with nine chemicals: tetrachloroethylene, propylene glycol,
-------
Hfi
Hf
(TrtHwWiyl-2-cytlohwgne-l-Oiy
(ewemfed as glucuronic conjugate)
Xjr"3
OH
CH3
II
o
Isophorone
«P
H,C
_ COOH
3 - Cait»*y5.5-<*n*rthyl
OHiydicisiphoioiiB
P.5,5Tfjmpfh)r»cycioh©*anprie)
"P
•V
I
v
OH
3.5.S-Trtnwtttytcyclohe»anets
(eis - and trans)
FIGURE 2-3. Metabolic Scheme for Isophorone
Soon*: DMerfrt-CaiHIaetaf. 1978.
-------
49
2. HEALTH EFFECTS
morpholine, ethyl alcohol, ethyl acetate, carbon tetrachloride,
acrylonitrile, acetonitrile, and acetone. Less than additive toxicity was
observed for the mixtures of isophorone with 17 chemicals: Ucon LB-250,
Ucon 50-HB-260, toluene, Tergitol XD, propylene oxide, polyethylene glycol
200, Phenyl Cellosolve, nitrobenzene, acetophenone, aniline, Butyl
Cellosolve, butyl ether, diethanolamine, dioxane, ethyl acrylate, ethylene
glycol, and formalin. When the frequency distribution of the ratios for all
combinations of all chemicals were adjusted to give a normal distribution,
however, none of the ratios for mixtures with isophorone deviated
significantly from the mean ratios, indicating essentially additive
toxicity. In a subsequent study, the additivity of equitoxic mixtures,
defined as a mixture of chemicals in volumes directly proportional to their
oral LD50 in rats, was determined (Smyth et al. 1970). Isophorone showed
less than additive toxicity with Phenyl Cellosolve and Ucon Fluid 50-HB-260,
and greater than additive toxicity with propylene oxide. The mechanism for
such interactions is not known.
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Isophorone produced kidney effects in male rats in the NTP (1986)
study. Strasser (1988) found that isophorone caused protein droplet
formation in the kidneys of male rats, suggesting that isophorone can
induce protein nephropathy. Alden (1986) discussed the possibility that
proteinuric humans and humans with low molecular weight protein nephropathy,
such as people with multiple myeloma (Bence-Jones protein) or mononuclear
cell leukemia (lysozyme), may be more susceptible to chemically-induced
protein nephropathy. He concluded, however, that this syndrome is probably
specific to the male rat.
2.9 ADEQUACY OF THE DATABASE
Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of isophorone is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program (NTP),
is required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure and toxicity information applicable to
human health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
2.9.1 Existing Information on Health Effects of Isophorone
As seen from Figure 2-4, very little information is available
regarding the health effects of exposure of humans to isophorone.
-------
50
2. HEALTH EFFECTS
SYSTEMIC
/
Inhalation
Oral
Dermal
HUMAN
/
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
FIGURE 2-4 Existing Informat*-on on Health Effects of Isophorcmc
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51
2. HEALTH EFFECTS
Experimental studies in humans have attempted to determine the inhalation
thresholds for odor detection and eye, nose, and throat irritation. Reports
on humans occupationally exposed to isophorone also indicate that isophorone
is irritating to the skin, eye, nose, and throat, and may cause symptoms of
dizziness, fatigue, and malaise.
Data are available for acute and intermediate inhalation exposures
that have resulted in death of animals. These exposures also produced
signs of central nervous system toxicity, lung irritation, possible kidney
damage, and possible hematological changes and growth depression. Chronic
inhalation exposure of rats and rabbits resulted in mild liver effects.
Inhalation exposure of pregnant rats and mice during gestation did not
result in fetotoxic or teratogenic effects at concentrations up to 115 ppm,
but results at 150 ppm are difficult to interpret. No information was
available on the effects of chronic inhalation exposure.
Data are available for oral doses associated with death and increased
mortality in acute, intermediate, and chronic exposure. Acute and
intermediate oral studies have also produced signs of central nervous system
toxicity at high doses during exposure. In intermediate duration studies of
oral exposure of animals to isophorone, comprehensive histological
examination of tissues and organs found no effects. Chronic oral exposure
of mice resulted in hyperkeratosis of the forestomach, non-neoplastic liver
lesions, and equivocal evidence of liver tumors, integumentary system
tumors, and malignant lymphomas. Chronic oral exposure of rats resulted in
hyperplastic and neoplastic kidney lesions and preputial gland carcinomas.
Application of isophorone to the skin of animals results in skin
irritation, and application to the eye results in severe eye damage. There
is some information that dermal exposure of rabbits causes signs of
neurotoxicity at high doses. This could indicate that isophorone is
absorbed dermally, but other systemic effects have not been described.
No studies of the genotoxic effects of oral, inhalation, or dermal
exposure to isophorone were found, but studies in bacteria and mammalian
cells indicate that isophorone is at best weakly genotoxic.
2.9.2 Data Needs
Single Dose Exposure. Studies of single inhalation, oral, or dermal
exposure of rats, guinea pigs, and mice have provided data on lethal and
non-lethal levels of isophorone and levels producing signs of neurotoxicity.
Single-dose dermal and ocular studies in animals have demonstrated that
isophorone is irritating to the skin and eyes. Gross clinical and necropsy
observations have been made, but no reliable single-dose study examined the
internal tissues of animals histologically or attempted to identify dose-
response data for more subtle systemic toxic effects. Such studies might
provide information on the mechanisms of lethality and neurotoxicity, as
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52
2. HEALTH EFFECTS
well as Information on the thresholds for systemic toxicity due to single
dose exposure.
Repeated Dose Exposure. Repeated inhalation exposure studies of
isophorone conducted in rats and guinea pigs by Smyth et al. (1942)
reported severe respiratory and kidney lesions, but this study was
criticized by Rowe and Wolf (1963) for using impure isophorone and
overestimating the concentrations. Furthermore, dose - response data were
poorly reported and results in rats and guinea pigs were reported together
A study by Hazleton Labs (1968) suggested hematological and liver weight
effects in rats, but only one exposure concentration was used. A 4-6 month
inhalation study in rats reported ocular and nasal irritation but no
exposure-related effects on lungs or livers (Dutertre-Catella 1976).
Results were poorly reported and only one concentration was used. A well-
conducted subchronic inhalation study that uses several concentrations of
pure isophorone and monitors for clinical signs, hematological and
biochemical changes, and gross and histopathological changes in animals
would provide dose-response data for toxicological endpoints and remove
uncertainties associated with the study by Smyth et al. (1942). Well-
conducted, repeated-dose oral studies in rats, mice, and dogs at several
dosage levels including maximum tolerated doses produced no systemic
effects. A 2-week dermal study in rabbits revealed no biochemical evidence
of liver damage (Dutertre-Catella 1976), but other indices of toxicity were
not examined. An 8-week dermal study in rats revealed erythema and scar
tissue formation, which disappeared after exposure ceased (Dutertre-Catella
1976). As screen printers are repeatedly exposed dermally to isophorone and
the extent of dermal absorption is not known, better repeated dermal dose
studies examining systemic toxicity in animals might provide information on
whether repeated dermal exposure of humans poses a threat of toxic
potential.
Chronic Exposure and Carcinogenicity. Well-conducted chronic oral
studies provide information on the systemic and carcinogenic effects of
isophorone in rodents. In a chronic oral study, male rats exposed to
isophorone developed kidney and preputial gland tumors. The relevance of
these tumors in male rats to humans has been questioned; therefore,
additional research to clarify the relevance is desirable. Indeed, on-going
studies are being conducted (see Section 2.9.3). In a chronic inhalation
study, rats and rabbits had ocular and nasal irritation and slight liver
effects (Dutertre-Catella 1976), but few animals and only one concentration
were used. No chronic dermal studies were located. It is not possible to
predict that effects following chronic inhalation or dermal exposure to
isophorone would be similar to those following chronic oral exposure,
partially because the pharmacokinetic disposition of isophorone has not been
compared for the three routes of exposure. Available toxicokinetic data
(see Section 2.6) indicate that isophorone is metabolized to
dihydroisophorone, isophorol, and other products after oral dosing of rats
and rabbits, but different metabolic pathways may operate following
inhalation and dermal exposure. Differences in absorption and tissue
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53
2. HEALTH EFFECTS
distribution among the three routes of exposure could also account for
differences in toxic response. Chronic inhalation and dermal studies in
animals might provide dose-response data on the systemic effects that could
be related to possible systemic effects of inhalation and dermal exposure of
humans. Long-term exposure of humans to isophorone by inhalation and by
skin contact occurs in occupational settings.
Genotoxicity. The available genotoxicity studies (Salmonella/microsome
assays, mutations in mouse lymphoma cells, tests of unscheduled DNA
synthesis, sister chromatid exchange, and chromosome aberrations in cultured
mammalian cells, and an in vivo micronucleus tests) indicate that isophorone
may be weakly genotoxic. Additional genotoxicity tests would add to the
rather limited data base on genotoxicity, but probably would not change the
conclusion that isophorone in weakly genotoxic.
Reproductive Toxicity. An intermediate duration study examined only
the pregnancy rate and litter size in rats exposed to isophorone by
inhalation for 3 months before mating. Histological examination of
reproductive organs of rats, mice, and dogs exposed orally to isophorone in
subchronic and chronic studies indicate no treatment-related lesions, but
multigeneration or continuous breeding studies have not been conducted.
Such studies would provide further information regarding the reproductive
effects of isophorone in animals, which may then be related to possible
reproductive effects in humans.
Developmental Toxicity. Developmental studies by the inhalation route
in rats indicated growth retardation in the rat fetuses at a concentration
of 115 ppm, and maternal toxicity at all concentrations tested (>25 ppm).
Exencephaly was seen in several rat and mouse fetuses after exposure of the
dams to 150 ppm during the organogenesis period. The developmental effects
following oral or dermal exposure have not been studied. It is not known
whether isophorone crosses the placenta, but there is no reason to assume
that it would not do so. Further developmental studies in animals by
relevant environmental routes, such as drinking water and diet, would
provide information on possible fetotoxic and teratogenic effects in animals
that might be relevant to humans. Studies in drinking water and diet are
particularly relevant because isophorone has been detected in groundwater,
ambient water, drinking water, oysters, and cranberries (see Section 5.4 on
environmental monitoring).
Immunotoxicity, No histopathological effects on immunological organs
and tissues of animals were found in subchronic and chronic oral studies,
but a battery of immunotoxicity tests has not been performed. Such tests
provide a more sensitive assessment of possible immunotoxic effects than do
histological examinations of tissues and organs of the immunological system.
Isophorone is a skin irritant in rabbits, guinea pigs, and humans, but it
has not been tested for sensitization. Such tests might provide information
on whether an allergic response to isophorone is likely. The potential for
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54
2. HEALTH EFFECTS
dermal contact by humans occurs in occupational settings and in soil at
waste sites.
Neurotoxicity. No histopathological effects on organs and tissues of
the neurological systems of animals were found in subchronic and chronic
oral studies, but signs of central nervous system toxicity were reported in
inhalation, oral, and dermal studies. A battery of tests for neurotoxicity
would provide further information of the neurotoxicity in animals, which
then might be related to possible neurotoxic effects in humans.
Epidemiological and Human Dosimetry Studies. The only known health
effects of isophorone in humans are eye, nose, and throat irritation, and
fatigue and malaise. This information comes from two limited industrial
hygiene surveys, two experimental studies in human volunteers, and a
communication to the ACGIH. Effects in animals, however, include CNS
depression, liver and kidney damage, hyperkeratosis of the forestomach, some
evidence of cancer, and suggestive evidence of developmental toxicity. As
discussed in Chapter 5, isophorone has been detected in surface water,
drinking water, industrial effluents, urban runoff, and water and soil at
waste sites. Isophorone has a relatively low vapor pressure (Union Carbide
1968) and high reactivity with hydroxyl radicals (Atkinson 1985, 1987);
therefore, exposure to isophorone in the ambient atmosphere distant from the
source is unlikely. Indeed, monitoring data for isophorone in air are
lacking. Inhalation as well as dermal exposure, however, occurs in
occupational settings where isophorone is used as a solvent. Epidemiology
studies of people who live in areas where isophorone has been detected in
ambient and drinking water, near industries releasing isophorone, or near
hazardous waste sites, and of people occupationally exposed, could provide
information on whether isophorone produces effects in humans similar to
those seen in animals, or other toxic effects.
No studies were located that monitored human tissues for isophorone or
its metabolites. Furthermore, analytical methods for the detection of
isophorone or its metabolites in humans tissues and fluids were not located.
Metabolism studies in rats and rabbits, however, indicated that isophorone,
isophorol, dihydroisophorone, 3-carboxy-5,5-dimethyl-2-cyclohexene-1-one,
and cis- and trans-3,5,5-trimethylcyclohexanols were excreted in the urine
following oral exposure to isophorone (Dutertre-Catella et al. 1978). if
isophorone and these or other metabolites can be detected in the urine of
humans and be correlated with exposure, it may be possible to monitor humans
for exposure. If toxic effects of isophorone are identified in humans, it
may then be possible to correlate urinary levels of isophorone or its
metabolites with systemic effects.
Biomarkers of Disease. No disease states in humans produced by
exposure to isophorone are known. If epidemiological studies are conducted
that correlate exposure with diseases, It may be possible to identify subtle
changes associated with a particular disease state.
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2. HEALTH EFFECTS
Disease Registries. At present, the only known health effects of
isophorone in humans are eye, nose, and throat irritation, and fatigue and
malaise. If epidemiological studies identify particular diseases produced
by isophorone, it may be possible to determine the number of people affected
and the factors associated with identifying the disease in certain
populations, such as exposure to high levels near hazardous waste sites.
Bioavailability from Environmental Media. No studies were located
regarding the bioavailability of isophorone from environmental media.
Furthermore, no reports were located indicating that isophorone or its
metabolites have been detected in human tissues or fluids. Since the
monitoring literature reports that isophorone is present in the environment
as well as in environmental organisms, the lack of data does not
necessarily indicate a lack of bioavailability. Fish may be the only source
of isophorone in the environment that is not subject to large spatial and
temporal variations in concentration, as appears to be the case with
drinking water. In particular, fish in the Lake Michigan area are known to
contain isophorone (Camanzo et al. 1987), and analysis of the body fluids of
people who consume the fish may allow a determination of the existence of
exposure and an estimation of the degree of exposure.
Food Chain Bioaccumulation. No studies were located regarding the
food chain bioaccumulation of isophorone from environmental media. The
monitoring literature reports that isophorone is present in the environment
as well as in environmental organisms. The monitoring data further suggest
that isophorone levels in fish do not correlate well with the lipid content
of the fish (see Section 5.4). Thus, structure-activity relationships
developed to estimate levels in biological media based on the partitioning
properties of a chemical may not provide accurate information for
isophorone. Furthermore, only one bioaccumulation study was available. In
this study, which indicated a low potential for bioaccumulation, fish were
exposed to isophorone in water rather than in food. From these data, it
appears that food chain bioaccumulation may be occurring, and a clearer
understanding of the potential for this would aid in determining how levels
in the environment affect the food chain and potentially impact on human
exposure levels.
Absorption, Distribution, Metabolism, Excretion. The only
toxicokinetic data of isophorone are the in vivo metabolism studies in rats
and rabbits following oral exposure (Dutertre-Catella et al. 1978) and the
preliminary disposition data of Strasser (1988). These studies indicate
that isophorone is metabolized to dihydroisophorone and isophorol in animals
following oral exposure. Different metabolic pathways and patterns of
distribution and excretion, however, may operate after inhalation or dermal
exposure. Differences in the rate and extent of absorption, metabolic
pathways, and disposition may account for differences in the toxicity of a
chemical following exposure by different routes. Thus, further studies in
animals of the rate and extent of absorption and excretion following
exposure by all three routes and of distribution and metabolism following
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2. HEALTH EFFECTS
inhalation and dermal exposure, and in vitro studies to elucidate metabolic
pathways would provide the information to fully characterize the
pharmacokinetics of isophorone in animals. Ethical considerations limit the
testing of humans, but the determination of the urinary excretion of
isophorone and its metabolites by humans with known exposure to isophorone
(e.g., workers in the printing trades), may provide a means of monitoring
humans for exposure.
Comparative Toxicokinetics. The metabolism studies by Truhaut et al
(1970) and Dutertre-Catella et al. (1978) indicated that metabolism of
isophorone in rats and rabbits was qualitatively similar, but the proportion
of the metabolites excreted was different. Differences in the
toxicokinetics of a chemical among species may account for differences in
toxic responses. The potential for isophorone to produce toxic effects has
been investigated in rats, mice, dogs, guinea pigs, and rabbits, but the
animal species that serves as the best model for extrapolating results to
humans is not known. Ethical considerations limit the amount of information
that can be obtained by testing isophorone in humans, but analysis of the
urine of people with known exposure to isophorone for parent compound or
metabolites could provide knowledge of the metabolic pathways in humans.
Qualitative and quantitative comparison of human metabolites with those of
animals could help identify the most appropriate species to serve as a model
for predicting toxic effects in humans and studying the mechanisms of
action.
2.9.3 On-going Studies
A manuscript of the study demonstrating protein droplet formation in
the kidneys of male rats following acute oral exposure to isophorone and of
the distribution study by Strasser will be submitted for publication to
Toxicology and Applied Pharmacology (Strasser 1988). These studies were
presented as a Poster Presentation at the Society of Toxicology meetings in
February, 1988, and an abstract (Strasser et al. 1988) has been published.
In addition, the manuscript to be submitted to Toxicology and Applied
Pharmacology will contain added information on the distribution of
radiolabel in female rats and in the preputial gland of male rats (Strasser
1988) .
James Swenberg, formerly at the Chemical Industry Institute of
Toxicology (CUT), and his colleagues at CUT are continuing the
investigation of the mechanism of hydrocarbon-induced nephropathy and the
induction of renal tumors in male rats (Swenberg et al. 1989). These
investigations include isophorone. Swenberg and colleagues are also
investigating whether low molecular weight proteins found in humans behave
similarly to Q2^-globulin of male F344 rats.
No on-going biomonitoring studies or studies of toxic effects of
isophorone in humans were identified.
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3. CHEMICAL AND PHYSICAL INFORMATION
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Data pertaining to the chemical identity of isophorone are listed in
Table 3-1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The physical and chemical properties of isophorone are presented in
Table 3-2.
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58
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Isophorone
Chemical Name
Synonyms
Trade Name(s)
Chemical Formula
Chemical Structure
Identification Numbers:
CAS Registry
NIOSH RTECS
EFA Hazardous Waste
OHM-TADS
DOT/UN/NA/IMCO
HSDB
NCI
Value
2-Cyclohexen-l-one,
3,5,5-trimethyl-
Isoacetophorone
Isoforon
l,5,5-Trimethyl-3-
oxocyclohexene
No data
C9 H14 0
7B-59-1
GW7700000
No data
7216766
No data
619
C55618
Reference
CAS 1988
CAS 1988; SANSS 1988
CAS 1988
SANSS 1988
CAS 1988
RTECS 1988
OHM-TADS 1988
HSDB 1988
HSDB 1988
CAS - Chemical Abstracts Service
NIOSH - National Institute for Occupational Safety and Health
RTECS - Registry of Toxic Effects of Chemical Substances
OHM-TADS - Oil and Hazardous Materials/Technical Assistance
Data System
DOT/UN/NA/IMCO - Department of Transportation/United Nations/North
America/International Maritime Dangerous Goods Code
HSDB - Hazardous Substances Data Bank
NCI - National Cancer Institute
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3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Isophorone
Property
Value
Reference
Molecular weight
Color
Physical state
Freezing point
Boiling point
Specific gravity, 20/2CTC
Odor
Odor threshold
Water
Air
Solubility
Water
Organic Solvents
Partition coefficients
Log octanol/water
Log Koc
Vapor pressure
Henry's Law constant
Autoignition temperature
Flashpoint, open cup
Flammability limits
Conversion factors
ppm (v/v) to mg/m3
in air (20°C)
mg/m3 to ppm (v/v)
in air (20°C)
138.21
Water-white
Liquid
- 8.1°C
215.3°C
0.9229
Mild
5.4 ppm (w/v)
0.20 ppm (v/v)
12,000 mg/L (20°C)
14,500 mg/L (25°C)
Soluble in ether,
acetone, alcohol
1.67 (20°C)
(Experimental)
No data
0.3 mm Hg (20°C)
4.55xl0"6
atm-m^/mol (20°C)
864°F (462°C)
184°F (84°C)
0.8-3.5 vol %
ppm (v/v) x 5.75 - mg/m3
mg/m3 x 0.174 - ppm (v/v)
1968
Union Carbide
Hawley 1981
Hawley 1981
Union Carbide
Union Carbide
Union Carbide 1968
Union Carbide 1968
1968
1968
Amoore and Hautala
1983
Amoore and Hautala
1983
Union Carbide 1968
Veith et al. 1980
Weast 1985
Veith et al. 1980
Extrapolated using
data from Union
Carbide 1968
Calculated from
vapor pressure and
water solubility
data
Hawley 1981
Dean 1985
HSDB 1988
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61
4. PRODUCTION, IMPORT, USE, AND DISPOSAL
4.1 PRODUCTION
According to the most recent edition of the United States
International Trade Commission publication on U.S. production and sales of
synthetic organic chemicals (USITC 1987), Union Carbide (Institute, WV), is
the only domestic manufacturer of isophorone. A comparison of the list of
isophorone manufacturers in USITC (1987) and USITC (1986) shows that Exxon
Corporation (Bayway, NJ) also manufactured this chemical, but discontinued
production in 1985. Because of the limited number of domestic manufacturers
of isophorone and their desire to maintain confidentiality, up-to-date
information regarding the production volume of isophorone in the U.S. is not
available. In 1973, 35 million pounds of isophorone were produced in the
United States (Papa and Sherman 1981) and in 1980, approximately 20-30
million pounds were produced (CMA 1981). The decrease may be because of
replacement of isophorone with less costly solvents (CMA 1981).
Isophorone can be prepared by (1) passing acetone vapor over a
catalyst bed of magnesium aluminate, zinc oxide-bismuth oxide, or calcium
oxide under pressure at 300-400°C or (2) reacting acetone, water (up to
30X), and potassium hydroxide ("lX) in a column under a pressure of about 35
atm and at a temperature of about 200°C (Papa and Sherman 1981). Commercial
isophorone usually contains some unconjugated isomer (up to 5%) and small
amounts (<1X) of xylitone (Papa and Sherman 1981). Isophorone tends to
discolor on prolonged storage; stabilization against color formation can be
provided by treatment with p-toluenesulfonic acid, acidified Fuller's earth,
diazines, or diisopropylamine (Papa and Sherman 1981).
4.2 IMPORT
During 1984, 2,158 million pounds of isophorone were imported into the
United States (HSDB 1988).
4.3 USE
Isophorone Is a solvent for a large number of natural and synthetic
polymers, resins, waxes, fats, and oils. Specifically, it is used as a
solvent for concentrated vinyl chloride/acetate-based coating systems for
metal cans, other metal paints, nitrocellulose finishes, printing inks for
plastics, some herbicide and pesticide formulations, and adhesives for
plastics, poly(vinyl) chloride and polystyrene materials (Papa and Sherman
1981). Isophorone also Is an intermediate in the synthesis of 3,5-xylenol,
3,3,5-trimethylcyclohexanol (Papa and Sherman 1981), and plant growth
retardants (Haruta et al. 1974). Of the total production, 45-65X is used in
vinyl coatings and inks, 15-25% in agricultural formulations, 15-30!! in
miscellaneous uses and exports, and 10% as a chemical intermediate (CMA
1981).
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4, PRODUCTION, IMPORT, USE, AND DISPOSAL
4.4 DISPOSAL
Isophorone may be disposed of by incineration, wastewater treatment, or
sanitary landfill (OHM-TADS 1988),
4.5 ADEQUACY OF THE DATABASE
Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (In
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of isophorone is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program (NTP),
is required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure and toxicity Information applicable to
human health'assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
4.5.1 Data Needs
Production, Use, Release, and Disposal. Industrial production methods
for isophorone 'are well described in the literature (including the patent
literature) and there does not appear to be a need for further information
in this area. Uses of isophorone are documented, but a recent detailed
breakdown of the percentage of production consumed by each use category is
lacking. There is also a lack of data regarding the presence of isophorone
in retail products, such as paints and paint thinners. This information,
which is useful for estimating the potential for environmental releases from
various industries as well as the potential environmental burden, is
difficult to obtain in detail since it is considered confidential business
information for those industries that manufacture isophorone. Release
information is similar to use information in that it is not easily obtained
and can be used to estimate environmental burdens and potentially exposed
populations. According to the Emergency Planning and Community Right to
Know Act of 1986 (EPCRTKA), (<313), (Pub. L. 99-499, title III, (313),
industries are required to submit release information to the EPA. The Toxic
Release Inventory (TRI), which contains release information for 1987, became
available in May of 1989. This database will be updated yearly and should
provide a more reliable estimate of industrial production and emission.
Disposal information is useful for determining environmental burden and
potential sources of high environmental exposures. There is a lack of data
on current disposal practices for this chemical.
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5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
Isophorone is released to the air mainly in urban centers, as a result
of evaporation of solvents containing this chemical. Isophorone can enter
surface waters from industrial effluent discharges or from runoff from soils
at hazardous waste or other contaminated sites. Isophorone disappears
rapidly in air by hydroxyl radical reaction (half-life <5 hours), but may
persist in natural waters from several days to about a month.
Volatilization and sorption are not expected to be significant removal
mechanisms from water. In soils, isophorone is expected to degrade
microbially, but no rate data are available. Isophorone has been monitored
in effluents (range <5-1380 ppb), ambient water (range <0.6-100 ppb),
drinking water (from contaminated surface water) (range 0.02-9.5 ppb), and
soils at hazardous waste sites (range 0.16-6500 ppm). At this time,
isophorone has been found in at least 9 out of 1177 National Priority List
(NPL) hazardous waste sites in the United States (VIEW database 1989).
Occupational exposures occur mainly by inhalation and dermal contact and are
documented most frequently in the printing trades. Air concentrations in
screen printing facilities range from <0.47-25.7 ppm. A 1988 estimate by
the National Institute for Occupational Safety and Health reported that
37,469 workers (9211 of whom were female) were exposed to isophorone in both
trade name products and chemical named products.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
Since isophorone is used mainly as a solvent (see Subsection 4.3) that
is evaporated during or after use, the vast majority of environmental
releases are to the air. Use patterns indicate that most air releases are
in urban centers, with a smaller percentage of release in rural areas.
Nonetheless, very little ambient air monitoring data exist to confirm this,
probably because of its short atmospheric lifetime (half-life <5 hours).
Apparently, a major source of isophorone in the environment is the printing
industry, since these operations usually do not use emission control
technologies to reduce emitted isophorone concentrations (Bierbaum and
Parnes 1974; Kominsky 1981; Lee and Frederick 1981; Samimi 1982). Other
industries e.g. metal coating that use similar ventilation methods (NIOSH
1978a) are major sources of atmospheric isophorone. Coal-fired power plants
may also emit isophorone to the air, since isophorone has been detected in
the fly ash of one such plant (Harrison et al. 1985).
Volatilization from surface waters is not expected to be a significant
source of isophorone in the atmosphere, since this is anticipated to be a
slow process (based on the Henry's Law Constant of 4.55x10*^ atm m mol" ).
Wastewater treatment plants may, however, emit some isophorone from influent
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5. POTENTIAL FOR HUMAN EXPOSURE
water to the air, particularly if gas stripping methods are used (Hawthorne
and Sievers 1984, Hawthorne et al. 1985). Drinking water plants that
practice aeration of influent water may also emit small amounts of
isophorone to air.
5.2.2 Water
Little data are available to estimate releases of isophorone to water.
During isophorone manufacture, process water may contact the isophorone and
carry some of it to wastewater streams. During use of isophorone, paint
spray booths that use water curtains, wash water, and process water all may
contain isophorone, Isophorone has been detected in the United States in
industrial effluent discharges (Bursey and Pellizzari 1982; Hawthorne and
Sievers 1984; Hawthorne et al. 1985; Jungclaus et al. 1976), hazardous waste
landfill leachate and runoff (Ghassemi et al. 1984; Hauser and Bromberg
1982; Stonebraker and Smith 1980), and urban runoff (Cole et al. 1984).
Specific industrial categories that produce wastewaters containing
isophorone include timber products, petroleum refining, paint and ink, pulp
and paper, automobile and other laundries, pharmaceuticals, foundries,
transportation equipment, and publicly-owned treatment works (Bursey and
Pellizzari 1982). It is likely that treated waters from these industries
that are often discharged to surface waters will contain isophorone (Bursey
and Pellizzari, 1982).
5.2.3 Soil
The only direct measurements of isophorone in soil were found for
samples taken from hazardous waste sites. Ghassemi et al. (1984) found
isophorone in leachates from hazardous waste landfills, and Hauser and
Bromberg (1982) detected the presence of isophorone in the
"sediment/soil/water" of Love Canal. These studies suggest that isophorone
also was present in the soil. The Contract Laboratory Program Statistical
Data Base (queried April 13, 1987) reported that isophorone has been
detected at 4 of 357 hazardous waste sites at a concentration range of 1.68-
6500 ppm.
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning
Isophorone has a water solubility of 12,000 ppm, a log octanol/water
partition coefficient of 1.67, a Henry's Law constant of 4.55 X 10"^ atm ra^
mol'l, a vapor pressure of 0.3 mm Hg at 20'C, a log sediment sorption
coefficient of approximately 1.46, and a log bioconcentration factor (BCF)
of 0.85. Isophorone is released to air and water from its manufacturing and
use. Based on its water solubility, some isophorone may wash out of the
atmosphere; however, only limited amounts will be washed out because of the
short atmospheric half-life of isophorone. Particularly during the day,
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5. POTENTIAL FOR HUMAN EXPOSURE
when hydroxyl radical (HO-) concentrations are highest, very little
atmospheric transport will occur due to its fast reaction with HO-.
In water, neither volatilization nor sorption to sediments is expected
to be an important transport mechanism. The results of two EXAMS model runs
and the value of the Henry's Law constant (calculated from the solubility
and the vapor pressure) suggest that volatilization will not be important in
shallow ponds or in lakes. EXAMS is an environmental model that predicts
the behavior of a chemical in surface waters (EPA 1985a). Using the code
test data for a pond developed by the Athens Environmental Research
Laboratory of EPA, the half-life for volatilization was calculated to be 104
days, while for a lake, the half-life was calculated to be 288 days. Input
data included molecular weight, vapor pressure, Henry's Law constant,
octanol/water partition coefficient, sediment sorption coefficient, and
water solubility. Equations correlating solubility or octanol/water
partition coefficients with sorption partition coefficients (Koc) were not
developed using structures similar to isophorone, however, and the Koc value
entered into the EXAMS model thus should be viewed as tentative. The
volatilization rates predicted by the EXAMS model appear to be consistent
with the observation of Hawthorne and Sievers (1984), who reported that
isophorone could be analyzed in wastewater by purge and trap methods but was
not found in the air above the wastewater in a closed system without a
purge.
McFall et al. (1985) reported isophorone concentrations in sediments of
Lake Pontchartrain, LA, an estuary located in the Mississippi River delta.
Sediments containing isophorone were detected in the Inner Harbor Navigation
Canal (IHNC), the Rigolets, and the Chef Menteur Pass. Concentrations In
the overlying waters were not reported. Therefore, the sorption partition
coefficient in these sediments could not be derived from these experimental
data.
The bioconcentration of isophorone in bluegill sunfish has been
reported by Barrows et al. (1978, 1980) and Veith et al. (1980) (all
reports used the same BCF value). These researchers reported a
bioconcentration factor of 7 (log BCF - 0.85) as determined in a continuous-
dilution flow-through system using l^C-labeled isophorone. This value
suggests that concentrations of isophorone in fish living in isophorone-
contaminated waters will not be more than an order of magnitude higher than
concentrations in the water. Nonetheless, concentrations of Isophorone have
been found in fish in Lake Michigan tributaries and embayments (Camanzo
et al. 1987) (see section 5.4) at concentrations ranging from below the
detection limit (<*0.02 mg/kg) to 3.61 mg/kg wet weight. McFall et al.
(1985) also analyzed oysters from the IHNC and clams from the Rigolets and
the Chef Menteur Pass in Lake Pontchartrain for isophorone. Oysters from
the IHNC had detectable levels of isophorone (38 ppb dry weight), but clams
did not; the detection limits were not specified and no BCF can be
calculated with the data supplied. These data indicate, however, that
isophorone can be found in aquatic organisms at mg/kg levels, although no
-------
66
5. POTENTIAL FOR HUMAN EXPOSURE
correlation was found between the concentration of isophorone and lipid
content in the organism (Camanzo et al. 1987).
5.3.2 Transformation and Degradation
5.3.2.1 Air
No studies were located regarding the rates or products of reaction of
isophorone in the atmosphere. Isophorone does not significantly absorb light
above wavelengths of 290 nm (Sadtler Index 1966 [UV #44]); hence, it is not
expected to undergo direct photolysis. However isophorone can react with
photochemically produced N0X in the atmosphere (usually formed at higher
concentrations in photochemical smogs) producing moderate eye irritation,
NO2, other oxidants (including ozone, various peroxy compounds, and free
radicals), arid formaldehyde as indicated in smog chamber studies (Altshuller
and Bufalini 1971; Farley 1977; Levy 1973). Probably, the most significant
reaction of isophorone in the atmosphere is its reaction with HO-
Addition of HO will occur at the double bond of the compound and may be
followed by multiple reaction pathways (Atkinson 1985). Recently, Atkinson
(1987) developed a method to estimate the HO- reaction rate based on
structure. Using this method, an overall reaction rate of 81.5 x 10"^^ cm^
molecule"! sec"-'- was calculated. This reaction rate yields a half-life of
4.7 hours for an atmospheric 24-hour average HO- concentration of 0.5 x 10*>
molecules cttT^ (Atkinson 1985). In indoor air, HO1 concentrations probably
are significantly lower (Atkinson 1985); therefore, reaction half-lives of
HO* with isophorone in indoor air probably will be much longer than in
outdoor air. Thus, isophorone is expected to persist much longer in indoor
air than in outdoor air unless the indoor/outdoor air exchange rate is high.
5.3.2.2 Vater
The aerobic biodegradation of isophorone has been studied using sludge
and wastewater inocula as well as combined biological and physical treatment
methods. Isophorone appears to biodegrade under most conditions simulating
those in sewage treatment plants. No studies regarding biodegradation or
abiotic reactions involving photolysis or oxidation of isophorone In surface
and groundwater were located in the literature.
Aerobic biodegradation of isophorone appears to be possible in sewage
sludge or settled domestic wastewater. The exact conditions, however,
appear to be important. For example, Tabak et al. (1981a,b) reported 100X
degradation of isophorone in 7 days using settled domestic wastewater
amended with 5 ppm of yeast extract. Price et al. (1974) reported that the
equivalent of 42% theoretical oxygen demand for the compound was consumed in
20 days with a domestic wastewater seed without the yeast extract, and
Kawasaki (1980) reported that isophorone was resistant to biodegradation in
a test developed by the Japanese Ministry of International Trade and
Industry (MITI). The MITI test Is essentially a BOD test conducted over 14
days with a seed obtained from soil and sludge samples taken throughout
-------
67
5. POTENTIAL FOR HUMAN EXPOSURE
Japan. The results are reported as a pass if 30% or more of the theoretical
BOD is consumed and as a fail if less than 30% is consumed. During the
operation of two model sewage treatment plants, Hannah et al. (1986) and
McShane et al. <1987) reported that virtually all of the isophorone added to
the influent water was removed during the activated sludge portion of the
treatment process. The hydraulic detention times for both systems were on
the order of several hours. None of the test concentrations were near the
activated sludge EC50 of 100 ppm (Yoshioka et al. 1986). Some of the
removal may have been due to adsorption to the sludge as Hannah et al.
(1986) reported that the sludge from their process contained isophorone at
concentrations that exceeded the influent water concentrations.
While the evidence presented in the literature cited above suggests
that isophorone can be virtually completely removed under sewage treatment
plant conditions, monitoring data presented in Section 5.4 indicate that
isophorone is still present in treated wastewater and in ambient water.
This, in turn, suggests that the exact conditions under which isophorone is
rapidly biodegraded or removed are not well understood. The presence of
this compound in treated wastewater is indicative that the proper removal
conditions were not employed for these systems, or that the input
concentrations into sewage treatment plants were high enough that the
capacity of the treatment plants were exceeded.
5.3.2.3 Soil
No studies were located regarding the transformation of isophorone in
soils. Based on the information presented above and the lack of any
monitoring data that report isophorone in groundwater or soils (except for
hazardous waste sites), it appears that isophorone may not be discharged to
soils in large amounts, and the small amounts that are deposited may degrade
rapidly in soil. Another explanation, however, is that there is a lack of
studies determining isophorone content in soil.
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
No ambient air monitoring for isophorone was located in the literature.
The estimated atmospheric half-life of isophorone is <5 hours may account
for the lack of monitoring data, since concentrations will decrease rapidly
with distance from the source. Another explanation, however, is that no
studies have been conducted that analyzed for isophorone in air.
5.4.2 Water
Isophorone has been detected in surface waters, sediments, drinking
water, industrial effluents, urban runoff, and in runoff waters from
hazardous waste sites. Table 5-1 summarizes the available data.
-------
TABLE 5-1. Detection of Isophorone in Water
IMIa Type location Stapling f of Saplt Analytical Concentration X Reference
Dates Saiples Type Method Range (ppb) Mean Occurrence
Surface Mater
Delaware River
8/77-3/78
NS
grab/
GC/K
<0.6-3
NS
MS
Hites 1979
coapotite
Maai* ttver
winter '76-'77
16
grab
ec/w
trace
RS
RS
Sheldon and Kites 1978
Maart fiver
tuaeer '76
IS
grab
GC/K
NO
NO
HA
Sheldon and Hites 1978
Oientangy River, OH
re
NS
grab
GC/FIO
<5
NO
0
Shafer 1982
PnttT River toy Quanttco 1986
as
grab
GC/K
<2
NO
0
Hall et al. 1987
Sediaents
Lake Pontchartrafn
5/80-6/80
10
grab
GC/KS
0.9"-12
2.9
RS
Ncfall et at. 1985
Orirtira Utter
Cincinnati, OH
MS
RS
RS
MS
O.QZ
NS
RS
EPA 1975
Mew Orleans, LA
8/74-9/7*
NS
centiiueus
GC/K
1.5-9.5
NS
NS
EPA 1974
adsorption
Keith et al. 1976
Philadelphia, M
2/75-1/77
12
grab
GC/HS
RS
NS
1T
Suffet et al. I960
Effluents
Me oil sites
7/81-12/82
RS
grab
SC/BS
1I.3*-5.8b
OS
100
Namlwine Sievers 19&4
lire arofacturing
RS
RS
grab
GC/HS
40
RS
WO
Jwgclaui et al. 1976
plant
Perry et al. 1979
Utepecifled effluent
RS
NS
MS
GC/K
MS
RS
NS
Mil ladelphia sewage
8/77-V78
«S
graft/
GC/K
100
NS
RS
Nites 1979
treataent pint influent
coposite
Htiladel^iU sewage
8/77-3/78
RS
•tab/
GC/K
10
NS
RS
Rites 1979
tiedaent pint effluent
ccapoaite
Plastics effluents
RS
NS
grab
GC/FIO
40.5
RS
100
Shafer 19B2
Ship holding tat
RS
RS
grab
GC/FID
<50
NS
0
Shafer 1982
Secondary sewage effluent MS
as
greto
GC/F1D
120
NS
100
Shafer 1982
Owiral industry
final effluent
RS
RS
grab
GC/FIO
<5
NS
0
Shafer 1982
CVairal Manufacturing
plant final effluent
RS
RS
»rab
GC/FIO
< 20
NS
0
Shefer 1982
Tiaber product*
MS
2*
MS
GC/MS
55-111
83
MS
Bursey and Pellfirari 1982
Petrol eua refining
MS
1c
MS
GDIS
1380
NS
RS
Bursey and Pel liner 1 1982
Paint ad li*
MS
5e
MS
KC/HS
24-946
185
NS
Bursey and Pellliiari 1982
Pulp and paper
MS
1c
RS
tow
755
NS
MS
Bursey and Pellinari 1982
Auto t other tawdries
RS
2*
MS
gc/w
43-44
43
NS
Bursey and Pel li liar 1 1982
"O
o
H
PI
Z
H
i—<
>
f
3
50
s
*0
o
w
c
tn
On
QO
-------
VI (continued)
Media Type location Saaptfng f erf Sa^>|e Analytical Concentration X fteferewe
Dates Saaples Type Method It arise Hean ocamnn
lim nuttetw
It
1e
NS
GC/MS
237
NS
NS
tarsey and fellixzarJ 1M2
FWd'ICt
*s
lc
RS
UC/*S
116
NS
NS
Nureey and Pellizzarl 1982
Transportation Equip.
Its
2°
NS
GC/NS
28-318
17J
NS
•ursey and tetlitzarl 1982
PTOUs0
*5
15c
NS
GC/H5
*.2-114
11.5
NS
¦ursey anj FeUizzari 1982
UrtMn Riraff
UaaMnQton, K
W-7782
s&
ir*
IK
n
4
Cole et el. 1904
Hazards* Waste Site*
Love Canet
8/90-10/80
MS
Nrsb
GC/W
NSf
NS
NS
Mauser nj lrtAart 1982
Valley of the Unas
1979
2s
¦rab
NS
15-37'
26
NS
Stanebrakef -and Mth 1980
11 Diqmat Sites
NS
8
Oral*
NS
29"
NS
12.5
Ghasnari et al. 1984
commit*
I
Cooper Read site. M
K
NS
NS
NS
NS*
NS
NS
vrtv database 1988
tiomri
f*i i«t TV
W5
NS
NS
NS
2500*
NS
NS
VIEW database 1988
1 ^
Suait Nationet site,
rtfl
IS
NS
NS
NS
NS"
NS
NS
VIEW database 1988
IMpecified site
K
t
NS
NS
NS®
NS*
78
NS
a SOS 1987
Unspecified site
NS
1
NS
NS
91
NS
aSDS 1987
Unspecified site
NS
2
NS
N5
NS*
315
NS
asp* 1987
Unspecified site
HS
1
NS
NS
nS*
1
NS
CLSM 1987
IMpecified site
MS
1
NS
NS
NS*
360
NS
CLSN 1987
IMpecified site
NS
1
NS
RS
NS*
538
NS
USDS 1987
UMpecif led site
NS
1
NS
HS
NS*
48
NS
CLSM 1987
Unspecified site
NS
1
NS
HS
NS*
12
NS
CtSDt 1987
IMpecified site
NS
1
NS
¦S
NS*
20
NS
asoe 1987
IIMpacified site
NS
1
NS
NS
»s»
48
NS
aSD8 1987
IMpecified site
NS
1
NS
¦S
NS*
157
NS
CLSM 1987
IMpecified site
NS
1
NS
NS
NS*
11
NS
O.SD8 1987
IMpecified site
NS
2
NS
IB
NS*
57.6
NS
aSM 1987
' ««r»gi of 8 taptcs
• M In air per «. Msteaater 1rm purge and trap nlyiit
' nafaer of positive h^Ib
0 Pubi icly oaned treataent uortt
* detected in grtxKfcwtw
III not detected
M not afpilcaMe
us not specified
OC/W5 gw chnmXogr**ry/aa«* spectroscopy
OC/f ID 9» chraaatogravhy/flaae ioniiatiwi detector
detected in sediannt, soil, or Meter
' detected in Meter
detected fn te«rhat*
detected fn grtfuvfaeter
TJ
s
m
z
H
1-4
>
f
•*1
o
JO
s
M3
O
M
d
po
w
o\
vo
-------
70
5. POTENTIAL FOR HUMAN EXPOSURE
In general, Lsophorone is found In urban centers and appears to result
from industrial activities. For example, its presence in the Delaware River
near Philadelphia is the result of industrial effluents that are discharged
into the sewer system (Hites 1979). The sewage is treated in Philadelphia's
Northeast Sewage Treatment plant, which discharges its effluent into the
Delaware River. lsophorone was detected in the Delaware River in the
winter only; in the summer, biodegradation or other processes (e.g.,
sorption) may have removed it from the water column. lsophorone has been
detected in the sediments of Lake Pontchartrain, which is located in the
delta plain of the Mississippi River. Its presence probably is due to the
many industries that are situated along the Mississippi River and use the
river water as process water. Levels of isophorone in surface waters range
from a trace to 100 ppb; however, this range represents only a few
determinations.
The presence of isophorone in drinking water is probably the result of
using contaminated surface water as a source of drinking water. Of the
three cities for which drinking water data are listed, Philadelphia receives
its drinking water from the Delaware River, Cincinnati from the Ohio River,
and New Orleans from the Mississippi River. These rivers receive numerous
industrial effluents.
As listed in Table 5-1, isophorone has been detected in the effluents
of a variety of industries. Levels in industrial effluents range from 4.2-
1380 ppb. Five reports of positive identifications were found in the open
literature: a shale oil site; a tire manufacturing plant; sewer pump sample
receiving wastes from phenolic resins manufacturing or processing, vinyl
acetate, and polyvinylchloride process areas; final effluent from a sewage
treatment system receiving wastes from plants producing plasticizers, butyl
rubber, and olefin; and an unspecified effluent. The remaining samples
listed in Table 5-1 are from an EPA data base of over 4000 analyses of
organic pollutants in industrial wastewater made during the survey conducted
in response to the consent decree between the Natural Resources Defense
Council and EPA, June 7, 1976 (Bursey and Pellizzari 1982).
Isophorone also has been detected in urban runoff from Washington, DC
(Cole et al. 1984). It has been detected in water (unspecified type) at 13
of 357 hazardous waste sites as shown in the contract laboratory statistical
data base (1-538 ppb).
5.4.3 Soil
Isophorone has been identified in soil only at hazardous waste sites.
The contract laboratory program statistical data base reports that
isophorone has been detected at 1.68-6500 ppm in 4 of 357 hazardous waste
sites.
-------
71
5. POTENTIAL FOR HUMAN EXPOSURE
5.4.4 Other Media
Isophorone has been detected in oysters (but not in clams) in Lake
Pontchartrain, LA; the mean of eight samples of oysters from the Inner
Harbor Navigation Canal section of the lake contained 38 ppb dry weight of
isophorone. Hall et al. (1987) and De Vault (1985) did not detect
isophorone in the fish in the Potomac River and Great Lakes Harbors and
tributaries, respectively; in these cases, isophorone was not detected in
the water either. Camanzo et al. (1987) reported finding isophorone in
nearshore fish from 14 Lake Michigan tributaries and embayments; their
results are presented in Table 5-2. Sampling was performed in 1983.
Isophorone was detected in fish samples from all but 2 of the sites; the
mean of the samples that had detectable levels of the compound was 1.17
mg/kg wet weight. In addition to isophorone, the authors also reported the
lipid content of the composite fish samples. No correlation could be found
between isophorone concentration and lipid content.
Johansson and Ryhage (1976) reported that isophorone was present in one
of three samples of the pharmaceutical clofibrate [ethyl 2-(4-
chlorophenoxy)-2-methylpropionate], which lowers elevated serum lipids. The
analysis was performed on samples available from Sweden, but clofibrate is
also available in the United States. The concentration of isophorone
present in samples of the drug available in the United States was not
reported.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
No ambient air monitoring data are available for isophorone;
consequently, no potential inhalation exposures from ambient air can be
estimated. Inhalation of isophorone from showering with contaminated water
cannot be estimated from the available data (no measurements have been
made).
Isophorone concentrations in surface waters and drinking waters are
expected to vary considerably with season and with fluctuations in
industrial discharges. Considering the dates of most of the positive
identifications in surface and drinking water (middle to late 1970s), the
effect of more stringent discharge limits in some industries since that
time, and the probable seasonal, spatial, and temporal variations in
concentrations, it is not possible to make an accurate estimate of
ingestion intake of Isophorone from drinking water without significant
uncertainty. From the available data, it appears that long-term ingestion
of Isophorone from drinking water will be limited to those systems that
receive their water from contaminated surface water sources and the
seasonally averaged concentration in these waters probably will be <1 ppb.
Anjou and von Sydow (1967) reported that 0.2X of the essential oil of
the American cranberry, Vacclnium macrocarpon. consisted of isophorone; they
did not report the percentage of isophorone or the percentage of essential
-------
TABLE 5-2. Detection of Isophorone in F
Sampling # of
Location Fish Dates Samples9
St. Joseph River
Kalamazoo River
Grand River
Muskegon River
White Lake
Cannon Carp
Smallmouth Bass
Common Carp
Largemouth Bass
Common Carp
Channel Catfish
Conmon Carp
Pumpkinseed
Conrnon Carp
Bowfin
Pere Marquette River
Common Carp
Manistee River
Platte River
Boardwan River
Grand Traverse Bay
Bowfin
Coomon Carp
Bowfin
Common Carp
Northern Pike
Smallmouth Bass
Rock Bass
Common Carp
Lake Trout
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
1983
5
7
4
4
3
6
4
3
4
5
6
8
4
4
3
6
6
3
3
4
near Lake Michigan
Mean
Concentration X Lipid
ND
0.74
23.1
3.7
0.12
0.72
ND
ND
0.94
0.40
0.66
ND
3.13
ND
ND
0.76
2.32
ND
5.9
3.1
4.0
13.5
17.9
2.4
15.4
12.1
11.0
13.5
10.5
11.5
14.7
3.5
TJ
O
H
m
z
H
M
>
r
"i
o
pa
sc
cj
m
x
TJ
O
to
C
m
3.61
1.44
5.4
3.5
0.47
2.33
16.2
18.8
-------
TABLE 5-2 (continued)
Sanpling
# of
MeanX
Location
Fish
Dates
Samples8
Concentration
X Lipid
Manistiaue River
Snlliaouth Bass
1983
5
1.03
4.5
Northern Pike
1983
3
NO
2.1
Whitefish River
Common Carp
1983
11
0.88
16.4
Rock Bass
1983
7
0.69
3.0
Escaraba River
Conmon Carp
1983
5
0.41
12.9
Northern Pike
1983
6
0.48
2.9
Ford River
Northern Pike
1983
6
NO
3.0
Rock Bass
1983
5
ND
3.1
8 All saaples are coaposites of the stated nunber of fish and were analyzed by gas
diromatography/mass spectroscopy.
D mg/kg net weight
c Not Detected
Source: Caoanzo et al. 1967
hd
O
H
m
ss
H
>
f
*}
o
50
EC
G
s
Ti
O
c
w
U3
-------
74
5. POTENTIAL FOR HUMAN EXPOSURE
oil in whole cranberries. Without this information it is not possible to
estimate the concentration of isophorone in whole cranberries and compare
the concentration to other sources. However, frequent consumption of
cranberry containing products is unlikely to represent significant intake of
isophorone. Ingestion of Isophorone from consumption of fish and shellfish
cannot validly be estimated from the available data (see Table 5-2).
Potential dermal exposure levels also are difficult to estimate from
the available data. Dermal exposure from bathing in contaminated waters
cannot be estimated without significant uncertainty. Other potential dermal
exposures cannot be estimated with the available data.
Occupational exposures have been documented most frequently in the
screen printing trade and are summarized In Table 5-3. During screen
printing operations, both dermal and inhalation exposures can occur.
Breathing zone concentrations during screen printing range from <1 to 25.7
ppm, while general area concentrations range from <1 to 16 ppm. The
exposure level varies significantly with the ventilation present in the work
area. While exposure estimate for a specific screen printing operation is
possible, no reasonable estimates can be made for other operations that may
use isophorone because of lack of data.
The relative contributions of the exposure routes and sources are as
follows. For persons exposed to isophorone in the workplace, total doses
will probably be substantially higher than those exposed only to ambient air
and drinking water, and their inhalation and dermal exposures for the
occupationally exposed can be assumed to result exclusively from the
workplace exposures. Inhalation and dermal exposure for persons not exposed
to isophorone in the workplace will most likely result from showering or
bathing, but only in locations that receive their drinking water from
contaminated surface water sources. These exposures are expected to be very
small. In locations that do not have the potential for isophorone in the
drinking water, any ingestion, inhalation, or dermal exposure is unlikely.
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE
Populations with potentially high exposure include those occupationally
exposed to isophorone (e.g., screen print workers, some adhesives
formulators and users, some coatings manufacturing and use workers).
Individuals living near hazardous waste sites may be exposed to isophorone
dermally, but probably not by inhalation. These individuals also may be
exposed to Isophorone by ingestion if they drink water from contaminated
wells located down gradient from the site.
5.7 ADEQUACY OF THE DATABASE
Section 104 (I) (5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
-------
TABLE 5-3. Occipational Monitoring of Isophorone
Concentration (pom) Number of X
Company Process Saaple Type Range Mean Samples Positive Reference
Pre-Finish Metals
Uire Coating
Area
<1 - 3.37
1.13
24
33
NI0SH 1978a
Pre-Finish Metals
Wire Coating
Personal
<1 - 3.37
1.13
19
42
NI0SH 1978a
Joel and Aronoff
Screen Printing
Personal
<0.5 - 14
7.35
14
14
Lee and Fredrick 1981
Unspecified
Screen Printing
Area
3.5 - 16
10.2
46
100
Samimi 1982
Unspecified
Screen Printing
Personal
8.3 - 23
14.7
78
100
Sanini 1982
Electrocal
Screen Printing
Area
0.70 - 1.22
0.957
6
100
Bierfoaua and Parties 1974
Electrocal
Screen Printing
Personal
0.84 - 1.39
1.10
3
100
Bierbaua and Parries 1974
Swinston Co.
Screen Printing
Personal
<0.47 - 25.7
12.9
7
29
KoninsJcy 1981
Garden City Engraving
Screen Printing
Area
<0.67 - 2.5
1.18
7
57
Salisbury 1983
Garden City Engraving
Screen Printing
Personal
<0.58 - 3.4
1.42
8
75
Salisbury 1983
o
H
m
z
H
i—i
>
f
>*)
O
pa
Mean of the positivs sables
o
W
M
-------
76
5. POTENTIAL FOR HUMAN EXPOSURE
effects of isophorone is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program (NTP),
is required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure and toxicity information applicable to
human health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
5.7.1 Data Needs
Physical and Chemical Properties. Physical and chemical properties are
essential for estimating the partitioning of a chemical in the environment,
Many physical and chemical properties are available for isophorone, but most
do not have extensive experimental descriptions accompanying the data;
therefore, an evaluation of the accuracy of the data is difficult.
Specifically, measured vapor pressure, Koc, and Henry's Law constant at
environmentally significant temperatures would help to remove doubt
regarding the accuracy of the estimated data. The data on physical
properties form the basis of much of the input requirements for
environmental models that predict the behavior of a chemical under specific
conditions, including hazardous waste landfills. The data on the chemical
properties, on the other hand, can be useful in predicting certain
environmental fates of this chemical.
Environmental Fate. Sensitized photolysis studies in water and
oxidation/reduction studies in both air and water are lacking, as are
biodegradation studies in surface and groundwaters. These kinds of studies
are important, since they represent the fundamental removal mechanisms
available to isophorone in the environment. In addition, the kinetic
studies for the atmospheric reactions are important for understanding the
significance of a removal mechanism and predicting the reactions that may
control the fate of a chemical in the environment.
Exposure Levels in Environmental Media. Environmental monitoring data
are not available for soil and air, and the data available for water,
sediments, and biota are not sufficient to determine ambient
concentrations. These data would be helpful in determining the ambient
concentrations of isophorone so that exposure estimates of the general
population and the bioconcentration factor of this chemical in aquatic
organisms can be made.
Exposure Levels in Humans. No information is available concerning
exposure levels of isophorone in humans. A data base would be helpful in
determining the current exposure levels, and thereby allowing an estimation
of the average daily dose associated with various sources (e.g., living near
a hazardous waste site; drinking water containing isophorone). A monitoring
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77
5. POTENTIAL FOR HUMAN EXPOSURE
program involving analyses of human tissues would be useful in assessing the
magnitude of environmental exposures. Monitoring of human tissues from
different locations and seasons and using different category of the
population would be helpful so that the effects of such variables as
occupational, geographical, and seasonal can be assessed.
Exposure Registries. An exposure registry (e.g., for occupationally
exposed groups) currently is not available. The development of a registry
of exposures would provide a useful reference tool in assessing exposure
levels and frequencies. In addition, a registry developed on the basis of
exposure sources would allow an assessment of the variations in exposure
levels from one source to another and the effect of geographical, seasonal,
regulatory actions on the level of exposure within a certain source. These
assessments, in turn, would provide a better understanding of the needs for
research or data acquisition based on the current exposure levels.
5.7.2 On-going Studies
No on-going studies were located in the available literature.
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79
6. ANALYTICAL METHODS
6.1 BIOLOGICAL MATERIALS
No study was located regarding the analysis of isophorone in human
biological materials, but animal studies (see Section 2.6) suggest that
methods are available. In general, isophorone was extracted from the urine
using ether (continuous extraction for 48 hours) followed by evaporation of
the ether (Dutertre-Catella et al. 1978; Truhaut et al. 1970). The
resulting residue was subjected to gas chromatography with flame ionization
detector using the retention time as the indicator for the presence of
isophorone or metabolites. In distribution studies, isophorone was
extracted from minced tissues with dichloromethane, and the extract was
analyzed by gas chromatography using the flame ionization detector
(Dutertre-Catella 1976). In addition to these methods for analyzing
isophorone in mammalian urine and tissues, Ozretich and Schroeder (1986)
described a method for analyzing isophorone in fish tissue (Table 6-1).
6.2 ENVIRONMENTAL SAMPLES
Isophorone can be analyzed in municipal and industrial wastewater by
EPA Test Method 609 - Nitroaromatics and Isophorone, or by EPA Test Method
625 Base/Neutrals and Acids (EPA 1982; Shafer 1982). These methods are
adequate for measuring isophorone in most wastewaters, although interfering
compounds may be present in some wastewaters. Method 609 involves the
extraction of isophorone with methylene chloride followed by solvent
exchange to hexane and analysis by gas chromatography (GC) using a flame
ionization detector (FID). Method 625 is similar to Method 609, but the
extraction is performed at pH 11 and is followed by concentration (without
solvent exchange) and GC/MS analysis. The Contract Laboratory Procedure
(EPA 1987a) is essentially identical (Table 6-1). The average recovery from
reagent water and effluents was 49-672 for Method 609 and 75 ± 33X from
reagent water for method 625. Method 609 shows a pronounced negative bias
(the concentration detected by the method is lower than the true
concentration present) (Kinzer et al. 1984). Table 6-1 presents accuracy
and detection limit data for the methods. In air, isophorone can be analyzed
by NIOSH Method 2508 (NIOSH 1984). The method involves drawing a 2 to 25
liter air sample through a petroleum based charcoal tube followed by carbon
disulfide desorption and analysis by GC-FID. The method has a range of 0.2-
10 mg per tube and a detection limit of 0.02 mg per tube. Table 6-1
presents accuracy information for this method.
The method for analyzing soil in the EPA Contract Laboratory Program
involves the extraction of isophorone using methylene chloride followed by
analysis by GC/MS. The usual detection limit is 330 ppb, although the exact
detection limit is matrix dependent.
-------
TABLE 6-1. Analytical Methods for Isophorone
Sample
Matrix
Sample
Preparation
Analytical
Method
Sample
Detection
Limit
Accuracy
Reference
Air
Water
Soi I
Fish
Tissue
Charcoal tube GC-FID
collection and
CSj desorption
Methylene chloride GC-FID
extraction, hexane
solvent exchange,
concentration
Methylene chloride GC/MS**
extraction and
concentration
Methylene chloride GC/MS
extraction and
concentration
Macerate tissue GC/MS
mixed uith anhydrous
Na^SO^, extract with
acetonitrile by sono-
cation. Concentrate
extract, clean-up
by column chromato-
graphy
2 mg/iir
5.7 /ig/L
2.2 itg/L
330 iig/kg
NS
104.9
49-67c
75 t 33
NS
61
NIOSH 1984
EPA 1982
Kinzer et al.
1984
EPA 1982
EPA 1987a
(CLP)
EPA 1987a
CCLP)
Ozretich and
Schroeder 1986
>
H
O
>
t-
S
w
H
EC
O
o
Ln
CO
©
" Average percent recovery
Gas chromatography flame ionization detector
' Laboratory water and effluents
Gas chromatography mass spectrometry
e Laboratory water
NS, not specified
-------
81
6. ANALYTICAL METHODS
6.3 ADEQUACY OF THE DATABASE
Section 104 (i) (5) of CERCLA, directs the Administrator of ATSDR (in
consultation with the Administrator of EPA and agencies and programs of the
Public Health Service) to assess whether adequate information on the health
effects of isophorone is available. Where adequate information is not
available, ATSDR, in cooperation with the National Toxicology Program (NTP),
is required to assure the initiation of a program of research designed to
determine these health effects (and techniques for developing methods to
determine such health effects). The following discussion highlights the
availability, or absence, of exposure and toxicity information applicable to
human health assessment. A statement of the relevance of identified data
needs is also included. In a separate effort, ATSDR, in collaboration with
NTP and EPA, will prioritize data needs across chemicals that have been
profiled.
6.3.1 Data Needs
Methods for Parent Compound and Metabolites in Biological Materials.
No information is available concerning the analysis of isophorone in
biological materials. If information were available, it would allow both
investigators and reviewers to assess the accuracy and uncertainty of the
methods used. Furthermore, the ready availability of tested analytical
methods would permit a standardized approach to the analysis of biological
materials and allow a comparison of the levels of exposure with the possible
health effects in humans.
Methods for Biomarkers of Exposure. No methods are available for the
analysis of isophorone biomarkers of exposure in biological materials. If a
method for the determination of the level of a specific biomarker were
available in a biological medium, it could be used to indicate the level of
exposure and the possible resultant health effect.
Methods for Parent Compound and Degradation Products in Environmental
Media. Adequate methods appear to be available for the analysis of
isophorone in groundwater, surface water, soil, and workplace air. No
methods were found for the analysis of isophorone in ambient air, where
concentrations are expected to be much lower than in workplace air. If the
parent compound is stable as in the present case, it is essential that its
concentrations in different environmental media be known so that the level
of its exposure can be estimated.
No adequate methods appear to be available for the analysis of
isophorone degradation products in environmental media. In cases where a
degradation product of a chemical is toxic, it is important that Its
concentration in the environment be known. In certain instances, monitoring
the level of a degradation product may be used as an indirect measurement of
the parent compound in the environment.
-------
82
6. ANALYTICAL METHODS
6.3.2 On-going Studies
No studies were located regarding on-going analytical methods
development for isophorone.
-------
83
7. REGULATIONS AND ADVISORIES
International guidelines for isophorone were not located. National and
state regulations and guidelines pertinent to human exposure to isophorone
are summarized in Table 7-1.
Isophorone is regulated by the Clean Water Effluent Guidelines for the
following industrial point sources: electroplating, steam electric,
asbestos manufacturing, timber products processing, metal finishing, paving
and roofing, paint formulating, ink formulating, gum and wood, carbon black,
aluminum forming, and electrical and electronic components (EPA 1988a).
-------
84
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable to Isophorone
Agency Description Value Reference
National
Regulations
a. Air
OSHA Permissible Exposure Limit 4 ppm
b. Water
OSHA 1989
29 CFR 1910.1000
EPA OWRS Ambient Water Quality
Criterion
c. Non-specific Media
EPA OERR Reportable Quantity
5.2 mg/L
5000 lb
EPA 1980b
45 FR 79318
(11/28/80)
EPA 1985b
50 FR 13456
(4/4/85)
40 CFR 117
and 302
Guidelines
a. Air
ACGIH
NIOSH
Ceiling Limit for 5 ppm
Occupational Exposure
Recommended Exposure Limit 4 ppm
for Occupational Exposure
as a TWA for up to 10-hour
workshift
ACGIH 1988
NIOSH 1978b
b. Other
EPA Reference Dose for Chronic 0.15 EPA 1988b
Oral Exposure mg/kg/day
EPA ql* for Oral exposure 4x10"-* EPA 1986,1987b
(proposed) (mg/kg/day)"*
EPA
Cancer Classification Group Ca EPA 1987b
(proposed)
-------
85
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (continued)
Agency
Description
Value
References
State
State Drinking water quality
agencies guidelines
Kansas
State Acceptable ambient air
concentrations
Connecticut
Nevada
FSTRAC 1988
New York
Virginia
Acceptable Ambient Limit
Kentucky
5200 fig/L
460 tig/rsi^
(8 hr avg)
0.595 rag/m^
(8 hr avg)
83.3 jig/m3
(annual avg)
200 fig/rc?
(24 hr avg)
2.5 rag/m-*
NATICH 1987
State of Kentucky
1986
a Possible Human Carcinogen
-------
87
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*NTP (National Toxicology Program). 1986. Technical report series no.
291. Toxicology and carcinogenesis studies of isophorone (CAS No. 78-59-1)
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*0zretich RJ, Schroeder WP. 1986. Determination of selected neutral
priority pollutants in marine sediment, tissue, and reference materials
utilizing bonded-phase sorbents. Anal. Chem. 58:2041-2048.
*Papa AJ, Sherman PD. 1981. Ketones. Encyclopedia of Chemical
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organic compounds in industrial effluent discharges. Performed by Battelle
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*Potokar M, Grundler OJ, Heusener A, et al. 1985. Studies on the design of
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*Price KS, Waggy GT, Conway RA. 1974. Brine shrimp bioassay and seawater
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*Samimi B. 1982. Exposure to isophorone and other organic solvents in a
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*SANSS. 1988. Online: 7/31/88, 1-2.
*Shafer KH. 1982. Determination of nitroaromatic compounds and isophorone
in industrial and municipal waste waters. U.S. EPA, Off Res Dev, 1-71.
*Sheldon LS, Hites RA. 1978. Organic Compounds in the Delaware River.
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*Smyth HF Jr., Seaton J. 1940. Acute response of guinea pigs and rats to
inhalation of the vapors of isophorone. J Ind Hyg Tox 22(10):477-483.
*Smyth HF Jr., Seaton J, Fischer L. 1942. Response of guinea pigs and
rats to repeated inhalation of vapors of mesityl oxide and isophorone. J
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*Smyth HF Jr., Weil CS, West JS, Carpenter CP. 1969. An exploration of
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*Strasser J Jr. 1988. Written communication to Sharon Wilbur, Syracuse
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9. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or less,
as specified in the Toxicological Profiles.
Adsorption Coefficient (KoC) -- The ratio of the amount of a chemical
adsorbed per unit weight of organic carbon in the soil or sediment to the
concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or
soil (i.e. , the solid phase) divided by the amount of chemical in the
solution phase, which is in equilibrium with the solid phase, at a fixed
solid/solution ratio. It is generally expressed in micrograms of chemical
sorbed per gram of soil or sediment.
Bioconcentration Factor (BCF) -- The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete time
period of exposure divided by the concentration in the surrounding water at
the same time or during the same time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or group
of studies which produces significant Increases in incidence of cancer (or
tumors) between the exposed populaton and its appropriate control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling Value (CL) -- A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure -- Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity -- The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally to
the time of sexual maturation. Adverse developmental effects may be detected
at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the insult
occurred. The terms, as used here, include malformations and variations,
altered growth, and in utero death.
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.
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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) (LCuq) -- 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) (LDjx)) 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 50X of a defined experimental animal population.
I
Lowest-Observed-Adverse-Effect Level (L0AEL) -- The lowest dose of chemical
in a study or group of studies which produces statistically or biologically
significant increases in frequency or severity of adverse effects between
the exposed population and its appropriate control.
LTjq (lethal time) -- A calculated period of time within which a specific
concentration of a chemical is expected to cause death in 50% of a defined
experimental animal population.
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level -- An estimate of daily human exposure to a chemical that
is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
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9. GLOSSARY
Mutagen - - A substance that causes mutations. A mutation is a change in the
genetic material in a body cell. Mutations can lead to birth defects,
miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NGAEL) -- That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (KoW) -- The equilibrium ratio of the
concentrations of a chemical in n-octanol and water, in dilute solution.
Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace
air averaged over an 8-h shift.
q* - - The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q^* can be used to
calculate an estimate of carcinogenic potency, the incremental excess cancer
risk per unit of exposure (usually g/L for water, mg/kg/day for food, and
%/m? for air) .
Reference Dose (RfD) --An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious effects
during a lifetime. The RfD is operationally derived from the NOAEL (fron
animal and human studies) by a consistent application of uncertainty factors
that reflect various types of data used to estimate RfDs and an additional
modifying factor, which is based on a professional judgment of the entire
database on the chemical. The RfDs are not applicable to nonthreshold
effects such as cancer.
Reportable Quantity (RQ) -- The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 lb or
greater or (2) for selected substances, an amount established by regulation
either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities
are measured over a 24-h period.
Reproductive Toxicity -- The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of this
system.
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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.
TD50 (toxic dose) -- A calculated dose of a chemical, introduced by a route
other than inhalation, which is expected to cause a specific toxic effect in
50% of a defined experimental animal population.
Teratogen - - A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV) -- A concentration of a substance to which most
workers can be exposed without adverse effect. The TLV may be expressed as a
TWA, as a STEL, or as a CL.
Time-weighted Average (TWA) --An allowable exposure concentration averaged
over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the variation in
sensitivity among the members of the human population, (2) the uncertainty
in extrapolating animal data to the case of humans, (3) the uncertainty in
extrapolating from data obtained in a study that is of less than lifetime
exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL
data. Usually each of these factors is set equal to 10.
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APPENDIX: PEER REVIEW
A peer review panel was assembled for isophorone. The panel consisted
of the following members: Dr. Rip G. Rice, Private Consultant, Rice
Incorporated, Ashton, MD; Dr. Anthony P. DeCaprio, Private Consultant,
Albany, NY; Dr. Bhola N, Banerjee, Private Consultant, Potomac, MD; and Dr.
Judith S. Bellin, Private Consultant, Washington, DC These experts
collectively have knowledge of isophorone's physical and chemical
properties, toxicokinetics, key health end points, mechanisms of action,
human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer review
specified in the Superfund Amendments and Reauthorization Act of 1986,
Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the peer
reviewers' comments and determined which comments will be included in the
profile. A listing of the peer reviewers' comments not incorporated in the
profile, with a brief explanation of the rationale for their exclusion,
exists as part of the administrative record for this compound. A list of
databases reviewed and a list of unpublished documents cited are also
included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility for
the content of this profile lies with the Agency for Toxic Substances and
Disease Registry.
»US GOVERNMENT PR1NTINC OFFICE:1 > * 3 .TSj.nz/
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