TOXICOLOGICAL PROFILE FOR 

ISOPHORONE 

Agency for Toxic Substances and Disease Registry (ATSDR) 

U.S. Public Health Service 

In collaboration with 

U.S. Environmental Protection Agency (EPA) 

December 1989 
ii 

DISCLAMIMER 

Mention of company name or product does not constitute endorsement by 

the Agency for Toxic Substances and Disease Registry. 










1 

1. PUBLIC HEALTH STATEMENT 

1.1 WHAT IS 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 manmade 

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. 
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-term 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 l-l through l-4 show the link between exposure to isophorone and 

known health effects. A Minimal Risk Level (MRL) is also included in Table l3. 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 




7 

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 longterm 

exposure in water was either not available or not suitable to derive 

MRLS. 

The amounts listed in Table l-l 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 

9 

2. HEALTH EFFECTS 

2.1 INTRODUCTION 

This chapter contains descriptions and evaluations of studies and 

interpretation of data on the health effects associated with exposure to 

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. 
10 

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 (10-4 to 10-7), as developed by EPA. 

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

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

noncancer end point for each exposure duration. MRLs include adjustments to 

reflect human variability and, where appropriate, the uncertainty of 

extrapolating from laboratory animal data to humans. Although methods have 

been established to derive these levels (Barnes et al. 1987; EPA 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-l and Figure 2-l). Hazleton Labs (1965a) statistically determined 

the 4-hour LC50 in rats to be 1238 ppm, with 95% confidence limits of 1008- 

1531 ppm. The LC50 is indicated in Table 2-l and Figure 2-l. Exposure to 

885 ppm for 6 hours resulted in the death of l/10 rats (Hazleton Labs 

1965a); the exposure of 885 ppm is considered the acute inhalation LOAEL for 

lethality of isophorone (see Table 2-l and Figure 2-l). The concentration 

of 885 ppm in air (Hazleton Labs 1965a) is also presented in Table l-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. 




15 

2. HEALTH EFFECTS 

In an intermediate duration study, l/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-l and plotted in Figure 2-l as the intermediate duration LOAEL for 

lethality. The concentration of 500 ppm (Dutertre-Catella 1976) is also 

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

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-l and Figure 2-l). 

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-l and Figure 2-l 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-Catella (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 

mm, 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 250 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 

postexposure 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, 5.0% 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-l and Figure 2-l. 

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-week 

study, rats exposed to 37 ppm had statistically significant decreased mean 

absolute liver weights and statistically significant decreased mean livertobody 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 histopathological liver 

lesions were missed. No exposure-related histopathological 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-l and Figure 2-l. The 

concentration of 500 ppm in air (Dutertre-Catella 1976) is also presented in 

Table l-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-l and Figure 2-l. 

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-l and Figure 2-l. The concentration of 25 ppm in air 

(Silverman et al. 1946) is presented in Table l-l. 

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 workers 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 mice, which indicated 

sensory irritation rather than a neurological effect (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-l and 

Figure 2-l. 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 LOAEL for less 

serious effects for intermediate inhalation exposure to isophorone (see 

Table 2-l and Figure 2-l). The concentration of 37 ppm in air is presented 

in Table l-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 l-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 l-4 ppm a NOAEL for 

neurological effects in humans due to intermediate inhalation exposure to 

isophorone (see Table 2-l and Figure 2-l). The concentration of 5 ppm in 

air (Ware 1973) is presented in Table l-l. 

Neurological effects of inhalation exposure to isophorone also have 

been reported in animals. Narcosis and ataxia occurred in rats and guinea 

pigs at high exposure concentrations for 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 doserelated 

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 l-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-l), 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. Althohgh 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 (DutertreCatella 1976). 

2.2.1.5 Developmental Effects 

No studies were located regarding developmental effects in humans 

following inhalation exposure to isophorone. 

As part of an intermediate duration study, in which rats were exposed 

to 500 ppm isophorone in 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. Exposure of females continued throughout gestation, and they were 

allowed to deliver. No differences in pregnancy rate or litter size and no 

abnormalities in pups were found. The pups were not examined for internal 

malformations; therefore, this study was inadequate to determine 

developmental effects 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-l and 

Figure 2-l. 

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 LD5Os 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 l-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 





28 

2. HEALTH EFFECTS 

lethality in rats and mice. For the 13-week study, ,100O 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 l-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 

go-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) go-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-term 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 l-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 NOAEL for liver effects. In the go-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 l-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 treatmentrelated

lesions. In the NTP (1986) go-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. 

In the NTP (1986) study, dosed male mice, but not female mice, had increased 

incidences of chronic focal inflammation of the kidney, but no other 

lesions. The 500 mg/kg/day dose is indicated as a LOAEL for less serious 

renal effects in mice due to chronic oral exposure in Table 2-2 and Figure 

2-2. Dosed male rats had increased incidences of tubular cell hyperplasia 

(possibly pre-neoplastic), epithelial cell hyperplasia of the renal pelvis, 

and tubular mineralization at both doses. The incidence of tubular 

mineralization was higher in low dose males than in high dose males, and was 

coincident with chronic nephropathy, the incidence of which was also higher 

at the low dose. For this reason, NTP (1986) stated that the nephropathy 

was probably not the cause of the increased mortality in the high dose 

males. 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 cell lesions may be 

unique to male rats. Dosed female rats had increased incidences of 

nephropathy, which may have been related to isophorone exposure. The dose 

of 250 mg/kg/day is indicated as a LOAEL for less serious effects on the 

kidney in rats for chronic oral exposure to isophorone in Table 2-2 and 

Figure 2-2. No long-term studies of isophorone administered in food or 

drinking water demonstrating renal 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 5000 ppm in food for 

presentation in Table 1-4. 

Other Systemic Effects. Mean body weight gain was decreased in rats 

treated by gavage with isophorone at 1000 mg/kg/day, but not at 500 

mg/kg/day in a 16-day experiment by NTP (1986). The mice in the 16-day 

study did not have decreased growth. Body weight changes were not 

consistent or dose-related in the rats or mice treated with up to 1000 

mg/kg/day in the 13-week experiment or up to 500 mg/kg/day in the 103-week 

experiment (NTP 1986). Male rats treated with 233.8 mg/kg/day had transient 

decreases in body weight gain during the go-day feeding study by AME Inc 

(1972a), but body weights were not significantly different from controls at 

the end of the study. As 1000 mg/kg/day was a NOAEL for body weight changes 

in rats and mice in 13-week experiments, the decreased mean body weight at 

the same dose in the 16-day 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 go-day studies, no treatmentrelated 

grossly or histologically observable lesions were found in the lungs, hearts, 

hematopoietic tissues, or in the skin or eyes 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). Furthermore, no changes in 

hematological indices and no histopathological lesions in the skeletal 

muscle were found in rats or dogs in the studies by AME Inc (1972a,b). The 
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 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.

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 doserelated 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 after 

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 

2-2 and Figure 2-2); 4/5 died within 2 days after dosing (Hazleton Labs 

1964). At 1450 mg/kg, depression was observed but the rats recovered within 

2 days (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-day NTP (1986) study, mice treated by gavage at 1000 mg/kg/day, but not 

at 500 mg/kg/day, staggered after dosing, indicating an acute response to 

the high dose. Similarly, in the 13-week NTP (1986) study, rats given 1000 

mg/kg/day, but not 500 mg/kg/day, were sluggish and lethargic after dosing, 

also indicating an acute response to the high dose. Therefore, 1000 mg/kg 

is the acute LOAEL for less serious neurological effects (Table 2-2 and 

Figure 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 

(e.g., 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 for 

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 

was administered by gavage in corn oil (NTP 1986), was converted to an 

equivalent concentration of 8000 ppm in food for presentation in Table l-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 

No 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 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 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 q1* of 4.1 x 10-3 (mg/kg/day)-1 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


36 

2. HEALTH EFFECTS 

rats for 8 weeks, 20% of the males but none of the females died (DutertreCatella 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 pigs following dermal application of isophorone (Eastman Kodak 1967; 

Hazleton Labs 1964; Potokar et al. 1985; Truhaut et al. 1972). In these 

studies, undiluted isophorone generally in a volume of 0.5 ml (Table 2-3) 

was applied to the clipped skin of the animals and held under an occlusive 

covering. Hazleton Labs (1964) reported doses in units of mg/kg and found 

that ≥200 mg/kg (LOAEL for less serious effects) resulted in desquamation 

and erythema, while 50 mg/kg (NOAEL) was without effect. Application of 0.1 

or 0.2 mL isophorone to the shaved skin of rats for 8 weeks resulted in 

erythema and scar tissue formation (Dutertre-Catella 1976). These effects 

disappeared rapidly after exposure ceased. These doses are indicated in 

Table 2-3. 

Isophorone is also irritating to the eyes of rabbits. Application of 

0.02-0.1 ml of undiluted isophorone directly to the eye caused severe 

injury, cornea1 opacity, and necrosis (Carpenter and Smyth 1946; Hazleton 

Labs 1964; Truhaut et al. 1972) (see Table 2-3). Hazleton Labs (1964) found 

that the cornea1 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 were not 

performed. In this study, the site of application was occluded for 24 hours 

to prevent evaporation of isophorone from the skin. No significant 

differences between pre-exposure and post-exposure levels of serum 

electrolytes, blood glucose and sulfbydride radicals, SGOT, SGPT, serum 

creatine phosphokinase, or serum lactic dehydrogenase were found in rabbits 

treated dermally with 20 mL isophorone (Dutertre-Catella 1976). No other 

indices of liver 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), l/4 rabbits exposed dermally to 

3160 mg/kg under an occlusive bandage for 24 hours displayed marked 

depression, 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) Ceiling Limit of 5 ppm, which is based on 

worker complaints of fatigue and malaise (ACGIH 1986). 
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 

h u m a n s . 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 1964; 

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 (DutertreCatella 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 alpha 2μ-globulin from the kidney cytosol of rats

treated with isophorone or dihydroisophorone positively identified

isophorone or dihydroisophorone, respectively, in the alpha 2μ--globulin samples,

Following treatment with isophorol, samples, isophorone was found in the alpha 2μglobulin 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 alpha 2μ--globulin and

induce protein droplet nephropathy in male rats.
40

2. HEALTH EFFECTS

alpha 2μ-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 alpha 2μ-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 alpha 2μ-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 alpha 2μglobulin 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 alpha 2μ-globulin, 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.

alpha 2μ-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 alpha 2μ-globulin in humans raises the

question of the relevance to humans of the isophorone-induced kidney lesions

in male rats. alpha 2μ-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 alpha 2μ-globulininduced 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 l-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 

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 CochranArmitage test (NTP 1986). When adjusted for mortality, however, the

increased incidences were significantly different from control in the highdose

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 alpha 2μ-globulin, 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 alpha 2μ-globulin binding component of unleaded

gasoline, and the body of data on alpha 2μ-globulin-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 alpha 2μ-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 alpha 2μ-globulin. The

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 alpha 2μ-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, alpha 2μ-globulin appears to be unique to male rats. If

isophorone induces kidney tumors solely by the suggested mechanism, the

absence of alpha 2μ-globulin in humans raises the question of the relevance to

humans of the isophorone-induced kidney tumors in male rats. Although alpha 2μ

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 cause 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 HFALTH 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. 

(19'85) 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 14C-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 l-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 μg/L was found 

within 10 minutes. The level increased to 141 μg/L in 30 minutes and 

declined to ≤0.05 μg/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 l/4 rabbits suggests that 

isophorone is absorbed dermally (Hazleton Labs 1964), but other systemic 

effects have not been described. 
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 μg/g tissue wet weight. The levels dec1ine.d 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 14C-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 μg/g tissue wet weight 

were as follows: stomach - 6213, pancreas - 2388, adrenals - 1513, spleen - 

1038, liver - 613, brain - 378, lung - 383, heart - 387, 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 - 50. 

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 metabolism of 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-trimethyl-2- 

cyclohexene-l-01 (isophorol), 3,5,5-trimethylcyclohexanone 
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-l-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 μg) and declined further to 30 μg 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. Preliminar results of a pharmacokinetic study 

indicate that following an oral dose of 14C-isophorone, male rats excreted 93% 

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 LD5Os in rats of each chemical alone and in a 1:l (v/v) mixture was 

determined (Smyth et al. 1969). The LD5Os of the mixtures were predicted 

based on the assumption of additivity of the LD5Os 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, 

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 I 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. 

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 

doseresponse data for more subtle systemic toxic effects, Such studies might 

provide information on the mechanisms of lethality and neurotoxicity, as 
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 

wellconducted 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). Wellconducted, 

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 a-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 
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 
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-l-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. 
55 

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 
56

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 (CIIT), and his colleagues at CIIT 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 alpha 2μ-globulin of male F344 rats.

No on-going biomonitoring studies or studies of toxic effects of

isophorone in humans were identified.
57 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY 

Data pertaining to the chemical identity of isophorone are listed in 

Table 3-l. 

3.2 PHYSICAL AND CHEMICAL PROPERTIES 

The physical and chemical properties of isophorone are presented in 

Table 3-2. 



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 

30%), and potassium hydroxide (≅1%) 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 (<l%) 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(viny1) 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, 45-65% 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). 
62 

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. 
63

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-?

slow process (based on the Henry's Law Constant of 4.55~10~~ atm m3 mol ).

Wastewater treatment plants may, however, emit some isophorone from influent
64 

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 10m-6 atm m3

mol-l, a vapor pressure of 0.3 mm Hg at 2O'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, 
65

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 14C-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 NOx in the atmosphere (usually formed at higher 

concentrations in photochemical smogs) producing moderate eye irritation, 

N02, other oxidants (including ozone, various peroxy compounds, and free 

radicals), and 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-l2 cm3 

molecule-i set was calculated. This reaction rate yields a half-life of 

4.7 hours for3an atmospheric 24-hour average HO· concentration of 0.5 x l06

molecules cm (Atkinson 1985). In indoor air, HO· 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 Water 

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 100% 

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 MIT1 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-l summarizes the available data. 


70 

5. POTENTIAL FOR HUMAN EXPOSURE 

In general, isophorone 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. Isophorone 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. Isophorone 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-l 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 (l-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 EXJ?OSURE 

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 197Os), 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 <l ppb. 

Anjou and von Sydow (1967) reported that 0.2% of the essential oil of 

the American cranberry, Vaccinium macrocarnon, consisted of isophorone; they 

did not report the percentage of isophorone or the percentage of essential 


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 <l to 25.7 

ppm, while general area concentrations range from <l 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 ADEQUAGY 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 

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 
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, 

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-l). 

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-l). The average recovery from 

reagent water and effluents was 49-67% for Method 609 and 75 ± 33% 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-l 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-l 

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. 

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).



87 

8. REFERENCES 

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

exposure indices. Fifth ed. American Conference of Governmental Industrial 

Hygienists. Cincinnati, OH, 333. 

*ACGIH. 1988. TLVs Threshold Limit Values and biological exposure indices 

for 1988-1989. American Conference of Governmental Industrial Hygienists. 

Cincinnati, OH, 24. 

*Alden CL. 1986. A review of unique male rat hydrocarbon nephropathy. 

Toxicol Path01 14(1):109-111. 

*Altshuller AP, Bufalini JJ. 1971. Photochemical aspects of air 

pollution: A review. Environ Sci Technol 5:39-64. 

*AME Inc (Affiliated Medical Enterprises, Inc.). 1972a. 90-Day subchronic 

toxicity of isophorone in the rat (final report). Unpublished study 

performed by Affiliated Medical Enterprises, Inc. Princeton, NJ for Rohm 

and Haas Co. Philadelphia, PA. OTS 8d submission Dot ID. 87812178, 

Microfiche No. 205975. 

*AME Inc (Affiliated Medical Enterprises, Inc.). 1972b. go-day subchronic 

toxicity of isophorone in the dog (final report). Unpublished study 

performed by Affiliated Medical Enterprises, Inc. Princeton, NJ, for Rohm 

and Haas Co. Philadelphia, PA. OTS 8d submission Dot ID. 87812179, 

Microfiche No. 205975. 

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

threshold limit values and volatilities for 214 industrial chemicals in air 

and water dilution. J Appl Toxicol 3:272-290. 

*Anjou K, von Sydow E. 1967. The aroma of cranberries. II. Vaccinium 

macrocarpon. Acta Chem Stand 21(8):2076-2082. 

*Atkinson R. 1985. Kinetics and mechanisms of the gas-phase reactions of 

the hydroxyl radical with organic compounds under atmospheric conditions. 

Chem Rev, 8:69-201, 

*Atkinson R. 1987. A structure-activity relationship for the estimation of 

rate constants for the gas-phase reactions of OH radicals with organic 

compounds. Int J Chem Kinet 19:799-828. 

-------------------- 

*Denotes studies cited in text 
88 

8. REFERENCES 

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

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

Integrated risk information system supportive documentation. Washington, 

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

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

*Barrows ME, Petrocelli, SR, Macek KJ, Carroll J. 1978. Bioconcentration 

and elimination of selected water pollutants by bluegill sunfish. Am Chem 

Sot Div Environ Chem 18:345-346. 

*Barrows ME, Petrocelli SR, Macek KJ, Carroll JJ. 1980. Bioconcentration 

and elimination of selected water pollutants by bluegill sunfish (Lepomis 

macrochirus). In: Dyn Exposure Hazard Assess Toxic Chem. Ann Arbor 

Science, Ann Arbor, MI, 379-392. 

*Bierbaum PJ and Parnes WD. 1974. Survey of Electrical, Division of 

Bristol,Brass Corporation, South Winsor, Connecticut. Cincinnati, OH: U. S. 

Department of Health and Human Service, Public Health Service, Centers for 

Disease Control, National Institute of Occupational Safety and Health, l-29. 

*Bio/dynamics. 1984a. Inhalation teratology probe study in rats and mice. 

Project No. 323771. Unpublished study performed by Bio/dynamics Inc. East 

Millstone, NJ. OTS Section 4 submission Dot. ID 40-8455042. Microfiche No. 

OTS0507219, l-33. 

*Bio/dynamics. 1984b. Inhalation teratology study in rats and mice. 

Final Report 3223772. Unpublished study performed by Bio/dynamics Inc. 

East Millstone, NJ for Exxon Biomedical Science, East Millstone NJ. OTS 

Section 4 submission Dot. ID 40-855049. Microfiche No. OTS 0507224, l-107. 

Browning E. 1959. Toxic Solvents: A Review. Br J Ind Med 16:23-39. 

Browning E. 1965. Toxicity and metabolism of industrial solvents. Ketones 

(8). Elsevier Publishing Co., 412-462. 

*Bucher JR. 1988. Written communication (September 14) regarding the 

review of the toxicological profile for isophorone to James Selkirk, Chief 

CTEB, NIH, NIEHS, EHS, DHHS, Research Triangle Park, NC. . 

*Bursey JT, Pellizzari ED. 1982. Analysis of industrial wastewater for 

organic pollutants in consent decree survey. Environmental Research 

Laboratory Office of Research and Development. U.S. EPA, Athens, GA, l-34. 

*Camanzo J, Rice CP, Jude DJ, Rossmann R. 1987, Organic priority 

pollutants in nearshore fish from 14 Lake Michigan tributaries and 

embayments. J. Great Lakes Res. 13:296-309. 

*Carpenter CP, Smyth HF. 1946. Chemical burns of the rabbit cornea. Am 

Inst Opthal 29:1363-1372. 
89 

8. REFERENCES 

*CAS. 1988. CAS Online Registry File. 8-3-88. 

Charbonneau M, Swenberg JA. 1988. Studies on the biochemical mechanism of 

alpha 2μ-globulin nephropathy in rats. CIIT Activies 8(6):1-5. 

*CLSDB. 1987. Contract Laboratory Statistical Data Base. Printout of data 

base provided by Viar Corp. April 13, 1987. 

*CMA . 1981. Report of the Chemical Manufacturers Association Ketones 

Program Panel, Chemical Manufacturers Association, Washington, DC. OTS 

Section 4 submission. Microfiche No. OTS0512076. 

*CMA. 1984. Voluntary Testing Program under Section 4 of the Toxic 

Substances Control Act. Submission of Test Data. Volume III. Isophorone 

Mutagenicity Studies. Unpublished studies performed by Microbiological 

Associates, Bethesda, MD for Chemical Manufacturers Association, Washington, 

DC. OTS Section 4 submission. Dot. ID. 40-8455047. Microfiche No, 

OTS0507222. 

*Cole RH, Frederick RE, Healy RP, Rolan RG. 1984. Preliminary findings of 

the priority pollutant monitoring project of the nationwide urban runoff 

program. J Water Pollut Control Fed 56:898-908. 

*Dean J. (ed) 1985. Lange's Handbook of Chemistry. 13th ed. New York: 

McGraw-Hill Book Company. p 7-468. 

*DeCeaurriz JC, Micillino JC, Bonnet P, Guenier JP. 1981a. Sensory 

irritation caused by various industrial airborne chemicals. Toxicol Lett 

@MST) 9(2):137-143. 

*DeCeaurriz J, Bonnet P, Certin C, Muller J, Guenier JP. 1981b. 

[Chemicals as central nervous system depressants. Benefits of an animal 

model.] Cah Notes Dot 104(3):351-355. (French) 

*DeCeaurriz J, Micillino JC, Marignac B, Bonnet P, Muller J, Guenier JP. 

1984. Quantitative evaluation of,sensory-irritating and neurobehavioral 

properties of aliphatic ketones in mice. Food Chem Toxicol 22(7):545-549. 

*DeVault DS. 1985. Contaminants in fish from Great Lakes Harbors and 

Tributary mouths. Arch Environ Contam Toxicol 14(5):587-594. 

Dow Chemical Company. 1962. Results of range finding toxicological tests 

on isophorone. Unpublished report by the Dow Chemical Company, Biochemical 

Research Laboratory, Midland, MI, OTS 8d submission Dot. ID 878210479, 

Microfiche No. 206147. 
90 

8. REFERENCES 

*Dutertre-Catella H. 1976. These. Contribution a l'etude analytique 

toxicologique et biochimique de l'isophorone. Universite Rene Descartes de 

Paris. Serie E - No 318. 

*Dutertre-Catella CH, Nguyen PL, Dang Quoc Q, Truhaut R. 1978. Metabolic 

transformations of the 3,5,5-2-cyclohexene-l-one trimethyl (isophorone). 

Toxicol Eur Res 1(4):209-216. 

*Eastman Kodak. 1967. Toxicity and Health Hazard Summary. Eastman Kodak 

co., Rochester, NY. OTS 8d submission Dot ID. 878214399, Microfiche No. OTS 

0206524. 

*EPA. 1974. New Orleans area water .supply study draft analytical report by 

the lower Mississippi River facility, Slidell, LA. U.S. EPA, Dallas, TX, l30. 

*EPA. 1975. Preliminary assessment of suspected carcinogens in drinking 

water. Interim report to congress, June, 1975. Washington, DC. 

*EPA. 1980a. Guidelines and methodology used in the preparation of health 

effect assessment chapters of the consent decree water criteria documents. 

US Environmental Protecton Agency. Federal Register 45:79347-79357. 

*EPA. 1980b. Ambient Water Quality Criteria for Isophorone. Prepared by 

the Office of Health and Environmental Assessment, Environmental Criteria 

and Assessment Office, Cincinnati, OH for the Office of Water Regulations 

and Standards, Washington, DC. EPA 440/5-80-056. NTIS PB 81-117673. 

EPA. 198Oc. Water Quality Criteria Documents: Availability. Federal 

Register 45:79318-79379b (11/28/88). 

*EPA. 1982. Methods for Organic Chemical Analysis of Municipal and 

Industrial Wastewater, Cincinnati, OH. 

*EPA. 1985a. Exposure Analysis Modeling System: Reference Manual for 

EXAMS II. Prepared by the Environmental Research Laboratory, Office of 

Research and Development, Athens, GA. EPA/600/3-85-038. 

*EPA. 1985b. 40 CFR Parts 117 and 302. Notification Requirements; 

Reportable Quantity Adjustments; Final Rule and Proposed Rule. Federal 

Register 50(65):13456-13522 (4/4/85). 

*EPA. 1986. Health and Environmental Effects Profile for Isophorone. 

Prepared by the Office of Health and Environmental Assessment, 

Environmental Criteria and Assessment Office, Cincinnati, OH for the Office 

of Solid Waste and Emergency Response, Washington, DC, l-67. 

*EPA. 1987a. U.S. EPA contract laboratory program. Statement of work for 

organic analysis. U.S. EPA, Washington, DC. 
91 

8. REFERENCES 

*EPA. 1987b. Health Effects Assessment for Isophorone. Prepared by the 

Office of Health and Environmental Assessment, Environmental Criteria and 

Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial 

Response, Washington, DC, l-21. 

*EPA. 1988a. Analysis of Clean Water Act Effluent Guidelines Pollutants. 

Summary of the chemicals regulated by industrial point source category. 40 

CFR Parts 400-475. Draft. Prepared by the Industrial Technology Division 

(WH 552), Office of Water Regulations and Standards, Office of Water, U.S. 

EPA, Washington, DC. 

*EPA. 1988b. Integrated Risk Information System (IRIS). Reference dose 

(RfD) for oral exposure for isophorone. Online. (Revised; verification 

date 5/15/86). Office of Health and Environmental Assessment. 

Environmental Criteria and Assessment Office, Cincinnati, OH. 

*Farley FF. 1977. Photochemical reactivity classification of hydrocarbons 

and other organic compounds. In: EPA-600/3-77-OOlB. Inter Conf 

Photochemical Oxidant Pollut Control. Dimitriades B,'ed. Research 

Triangle Park, NC, 713-726. 

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

guidelines. Prepared by chemical communication subcommittee Federal-State 

Toxicology and Regulatory Alliance Committee (FSTRAC). 

*Ghassemi M, Quinlivan S, Bachmaier J. 1984. Characteristics of leachates 

from hazardous waste landfills. J Environ Sci Health, Part A A19(5):579- 

620. 

*Hall LW Jr, Hall WS, Bushong SJ, Herman RL. 1987. In situ striped bass 

(Morone saxatilis) contaminant and water quality studies in the Potomac 

River. Aquat Toxicol 10(2-3):73-99. 

*Hannah SA, Austern BM, Eralp AE, Wise RH. 1986. Comparative removal of 

toxic pollutants by six wastewaters treatment processes. J Water Pollut 

Control Fed 58:27-34. 

*Harrison FL, Bishop DJ, Mallon BJ. 1985. Comparison of organic 

combustion products in fly ash collected by a Venturi wet scrubber and an 

electrostatic precipitator at a coal-fired power station. Environ Sci 

Technol 19(2):186-193. 

*Haruta H, Yagi H, Iwata T, Tamura S. 1974. Syntheses and plant growth 

retardant activities of quaternary ammonium compounds derived from a-ionone 

and isophorone. Agric Biol Chem 38:417-422. 

*Hauser TR, Bromberg SM. 1982. EPAs monitoring program at Love Canal 1980. 

Env Monit Assess 2:249-271. 
92 

8. REFERENCES 

*Hawley GG. 1981. The Condensed Chemical Dictionary. 10th ed. p. 581. 

*Hawthorne SB, Sievers RE. 1984. Emission of organic air pollutants from 

shale oil wastewaters. Environ Sci Technol 18(6):483-490. 

*Hawthorne SB, Sievers RE, Barkley RM. 1985. Organic emissions from shale 

oil wastewaters and their implications for air quality. Environ Sci Technol 

19(10):992-997. 

*Hazleton Labs. 1964. Acute toxicity studies, mice, rats, rabbits, guinea 

pigs. Unpublished study performed by Hazleton Laboratories, Inc. Falls 

Church, VA for Exxon Chem Amers. Houston, TX. OTS 8d submission Dot ID. 

878210933, Microfiche No. 206267. 

*Hazleton Labs. 1965a. LC50 determination, acute inhalation exposure - 

rats. Final Report. Prepared by Hazleton Laboratories Inc. Falls Church, 

VA for Exxon Chem Amers. Houston, TX. OTS 8d submission Dot ID. 878210933, 

Microfiche No. 206267. 

*Hazleton Labs. 1965b. Human sensory irritation thresholds. Five ketones 

- final report. Prepared by Hazleton Laboratories, Inc. Falls Church, VA 

for Exxon Chem Amers. Houston, TX. OTS 8d submission Dot ID. 878210936, 

Microfiche No. 206267. 

*Hazleton Labs. 1968. Assessment and comparison of subacute inhalation 

toxicities of three ketones. Final Report. Prepared by Hazleton 

Laboratories, Inc. Falls Church, VA for Exxon Chem Amers. Houston, TX. 

OTS 8d submission Dot ID. 878210935, Microfiche No. 206267. 

*Hites RA. 1979. Sources and fates of industrial organic chemicals. 

Proc Nat1 Conf Munic. Sludge Manage 8:107-119. 

*HSDB. 1988. Online: 7/27/88, l-6. 

*Imbriani M, Ghittori S, Pezzagno G, Capodaglio E. 1985. Urine/air 

partition coefficients for some industrially important substances. G Ital 

Med Lav 7(4):133-140. 

*Johansson E, Ryhage R. 1976. Gas chromatographic mass spectrometric 

identification and determination residual by products in clofibrate 

preparations. J Pharm Pharmacol 28(12):927-929. 

*Jungclaus GA, Games LM, Hites RA. 1976. Identification of trace organic 

compounds in tire manufacturing plant wastewaters. Anal Chem 48:1894-1896. 

*Kawasaki M. 1980. Experiences with the test scheme under the chemical 

control law of Japan: An approach to structure-activity correlations. 

Ecotoxic Environ Safety 4:444-454. 
93 

8. REFERENCES 

*Keith IH, Garrison AW, Allen FR, et al. 1976. Identification of organic 

compounds in drinking water from thirteen United States cities. In: Ident 

Anal Organic Pollut Water. Keith LH, ed. Ann Arbor, MI: Ann Arbor Press,' 

329-373. 

*Kinzer G, Riggin R, Bishop T, Birts MA, Howard CC. 1984. EPA Method 

Study 19, Method 609 (Nitroaromatics and Isophorone). Govt Reports 

Announcements & Index, Issue 16, 77 pages. 

*Kominsky JR. 1981. Health hazard evaluation determination report no. HE 

78-107-563, Swinston Company, Pittsburgh, PA. 

*Lee SA, Frederick L. 1981. Health hazard evaluation report no. HHE80-103- 

827. Joel and Aronoff, Ridgefield, NJ, 18 pages. 

*Levy A. 1973. The photochemical smog reactivity of organic solvents. 

Solvent theory and practices. American Chemical Society, Washington, 

DC: Adv Chem Ser 124:70-94. 

*McFall JA, Antoine SR, DeLeon IR. 1985. Base-neutral extractable organic 

pollutants in biota and sediments from Lake Pontchartrain. Chemosphere 

14(10):1561-1569. 

*McKee RH, Phillips RD, Lerman SA, et al. 1987. The genotoxic potential of 

isophorone [Abstract]. Environ Mutagen 9(8):71. 

*McShane SF, Pollock TE, Lebel A, Stirrat BA. 1987. Biophysical treatment 

of landfill leachate containing organic compounds. Proc Ind Waste Conf 

41:167-177. 

*NATICH. 1987. NATICH data base report on state, local and EPA air toxics 

activities. National air toxics information clearinghouse. Prepared by the 

Office of Air Quality Planning and Standards, Research Triangle Park, NC, 

State and Territorial Air Pollution Program Administrators, and Association 

of Local Air Pollution Control Officials. 

*NIOSH. 1978a. Health hazard evaluation determination report no. 77-78- 

466. Prefinish Metals, Inc., Elk Grove Village, Illinois, l-14. 

*NIOSH. 1978b. Criteria for a recommended standard: occupational 

exposure to ketones. Cincinnati, OH: U.S. Department of Health and Human 

Services, Public Health Service, Centers for Disease Control, National 

Institute for Occupational Safety and Health. DHHS (NIOSH) publication no. 

78-173. 244 p. 
94 

8. REFERENCES 

*NIOSH. 1984. NIOSH manual of analytical methods. .3rd ed. Cincinnati, 

OH: U. S. Department of Health and Human Service, Public Health Service, 

Centers for Disease Control, National Institute for Occupational Safety and 

Health. p 2508-l to 2508-3. 

*NTP (National Toxicology Program). 1986. Technical report series no. 

291. Toxicology and carcinogenesis studies of isophorone (CAS No. 78-59-l) 

in F344/N rats and B6C3Fl mice (gavage studies). Research Triangle Park, 

NC: U.S. Department of Health and Human Services. Public Health Service, 

National Institutes of Health, NIH publication no. 86-2547. 

*OHM-TADS. 1988. Online: 8/4/88, 4-5. 

*OSHA. 1989. Air Contaminants. Final Rule. U.S. Department of Labor. 

Occupational Safety and Health Administration. Code of Federal Regulations. 

29 CFR 1910. Fed. Reg. 54(12):2941. 

*Ozretich 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 

Technology, 3rd ed 13:898, 899, 918-922. 

*Perry DL, Chuang CC, Jungclaus GA, Warner JS. 1979. Identification of 

organic compounds in industrial effluent discharges. Performed by Battelle 

Columbus Laboratories, Columbus, OH for EPA, Environmental Research 

Laboratory, ORD, Athens, GA. EPA-600/4-79-016. NTIS PB294794. p. 51. 

*Potokar M, Grundler OJ, Heusener A, et al. 1985. Studies on the design of 

animal tests for the corrosiveness of industrial chemicals. Food Chem 

Toxicol 23(6):615-617. 

*Price KS, Waggy GT, Conway RA. 1974. Brine shrimp bioassay and seawater 

BOD of petrochemicals. J Water Pollut Contr Fed 46:63-77. 

Proctor NH, Hughes JP. 1978. Chemical Hazards of the Workplace. 

Philadelphia, PA: JB Lippincott Co, 300-301, 

*Rowe VK, Wolf MA. 1963. Ketones. In: Patty FA (ed). Industrial 

Hygiene and Toxicology, 2nd ed. Vol II. Interscience, New York, NY, 1722- 

1724; 1763-1765. 

*RTECS. 1988. Online 8/4/88, l-3. 

*Sadtler Index. 1966. Ultraviolet spectrum j/44. 

*Salisbury S. 1983. Health hazard evaluation report no. HETA 82-207- 

1278, Garden City Engraving, Augusta, GA. 
95 

8. REFERENCES 

*Samimi B. 1982. Exposure to isophorone and other organic solvents in a 

screen printing plant. Am Ind Hyg ASSOC J 43(1):43-48. 

*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, l-71. 

*Sheldon LS, Hites RA. 1978. Organic Compounds in the Delaware River. 

Environ Sci Technol 12:1188-1194. 

Short BG, Swenberg JA. 1988. Pathologic investigations of the mechanism of 

unleaded gasoline-induced renal tumors in rats. CIIT Activities 8(7):1-6. 

*Silverman L, Schulte HF, First MW. 1946. Further studies on sensory 

response to certain industrial solvent vapors. J Ind Hyg Tox 28(6):262-266. 

*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 

Ind Hyg Tox 24:46-50. 

*Smyth HF Jr., Weil CS, West JS, Carpenter CP. 1969. An exploration of 

joint toxic action: Twenty-seven industrial chemicals intubated in rats in 

all possible pairs. Tox Appl Pharm 14:340-347. 

*Smyth HF Jr., Weil CS, West JS, Carpenter CP. 1970. An exploration of 

joint toxic action. II. Equitoxic versus equivolume mixtures. Tox Appl 

Pharm 17:498-503. 

*State of Kentucky. 1986. New or modified sources emitting toxic air 

pollution. 401 KAR 63:022. 

*Stonebraker RD, Smith AJ Jr. 1980. Containment and treatment of a mixed 

chemical discharge from "The Valley of the Drums" near Louisville, Kentucky. 

In: Control Hazard Water. Spills, Proc. Natl. Conf. Nashville, TN, l-10. 

*Strasser J Jr. 1988. Written communication to Sharon Wilbur, Syracuse 

Research Corporation, Syracuse, NY and Poster Presentation from J. Strasser, 

CIIT, RTP, NC. August 23. 

*Strasser J Jr., Charbonneau M, Borghoff SJ, Turner MJ, Swenberg JA. 1988. 

Renal protein droplet formation in male Fischer 344 rats after isophorone 

(IPH) treatment. Toxicologist 8:136. 
96 

8. REFERENCES 

*Suffet IH, Brenner L, Cairo PR. 1980. Gas chromatography-mass 

spectrometry identification of trace organics in Philadelphia, 

Pennsylvania, USA drinking waters during a two-year period. Water Res 

14:853-867. 

*Swenberg JA, Short B, Borghoff S, Strasser J, Carbonneau M. 1989. The 

comparative pathobiology of alpha 2μ-globulin nephropathy. Toxicol Appl 

Pharmacol 97:35-46. 

*Tabak HH, Quave SA, CI Mashni, Barth EF. 1981a. Biodegradability studies 

for predicting the environmental fate of organic priority pollutants. In: 

Test protocols for environmental fate and movement of toxicants. Proc of a 

Sym Assoc of Official Anal Chem 94th Ann Mtg Washington, DC, 267-327. 

*Tabak HH, Quave SA, Mashni CI Barth EF. 1981b. Biodegradability studies 

with organic priority pollutant compounds. J Water Pollut Contr Fed 

53:1503-1518. 

*Truhaut R, Dutertre-Catella H, Phu-Lich MN. 1970. [First results of 

studying the metabolism of an industrial solvent on the rabbit: 

isophorone.] CR Acad SC Paris Seril D 271:1333-1336. (French) 

*Truhaut R, Dutertre-Catella H, Phu-Lich N, Daunet J. 1972. [Toxicity of 

an industrial solvent, isophorone: irritating effect on the skin and mucous 

membranes.] Eur J Toxicol 5(1):31-37. (French) 

*Union Carbide. 1968. Ketones booklet F-419771. Union Carbide 

Corporation. New York, NY, 21 pages. 

Union Carbide and Carbon Corp. 1956. Isophorone data indicating relative 

degree of hazard to animals. Unpublished report by Union Carbide and Carbon 

Corp. New York, NY. OTS 8d submission by E.I. du Pont de Nemours and Co. 

Wilmington, DE. Dot ID 878211783, Microfiche No. 205868. 

*USITC. 1986. Synthetic Organic Chemicals. U.S. Production and Sales, 

1985. U.S. Government Printing Office, Washington, DC. 5 pages. 

*USITC. 1987. Synthetic Organic Chemicals. U.S. Production and Sales, 

1986. U.S. Government Printing Office, Washington, DC. 4 pages. 

*Veith GD;, Macek KJ, Petrocelli SR, Carroll J. 1980. An evaluation of 

using partition coefficients and water solubility to estimate 

bioconcentration factors for organic chemicals in fish. ASTM STP 707. 

Aquatic Toxicology. In: Easton JG, et al., eds. Amer Sot Test.Mater, 116- 

129. 

*VIEW database. 1988. Agency for Toxic Substances and Disease Registry 

(ATSDR), Office of External Affairs, Exposure and disease Registry Branch. 

October 1988. 
97 

8. REFERENCES 

*VIEW database. 1989. Agency for Toxic Substances and Disease Registry 

(ATSDR), Office of External Affairs, Exposure and Disease Registry Branch. 

June 1989. 

*Ware GD. 1973. Written communication (June 26) to Herbert Stokinger. 

Chairman, Committee on Threshold Limits, American Conference of 

Governmental Industrial Hygienists to Western Electric Co., Kearny, PA, 2 p. 

*Weast RC. 1985. CRC Handbook of Chemistry and Physics. CRC Press, Inc., 

Boca Raton, FL, p. C328. 

*Yoshioka Y, Nagase H, Ose Y, Sato T. 1986. Evaluation of the test method 

"activated sludge, respiration inhibition test" proposed by the OECD. 

Ecotoxicol Environ Saf 12(3):206-212. 

99 

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. 
100 

9. GLOSSARY 

Immediately Dangerous to Life or Health (IDIX) -- 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(L0) (LCLO) -- The lowest concentration of a chemical in 

air which has been reported to have caused death in humans or animals. 

Lethal Concentration(50) (LC50) -- A calculated concentration of a chemical 

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

death in 50% of a defined experimental animal population. 

Lethal Dose(50) (LDLO) -- The lowest dose of a chemical introduced by a 

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

or animals. 

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

to cause death in 50% of a defined experimental animal population. 

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

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

significant increases in frequency or severity of adverse effects between 

the exposed population and its appropriate control. 

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

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

experimental animal population. 

Malformations -- Permanent structural changes that may adversely affect 

survival, development, or function. 

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

is likely to be without an appreciable risk of deleterious effects 

(noncancerous) over a specified duration of exposure. 
101 

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 (NOAEL) -- That dose of chemical at which 

there are no statistically or biologically significant increases in 

frequency or severity of adverse effects seen between the exposed 

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

dose, but they are not considered to be adverse. 

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the 

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

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

air averaged over an 8-h shift. 

q*1 -- The upper-bound estimate of the low-dose slope of the dose-response 

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

calculate an estimate of carcinogenic potency, the incremental excess cancer 

risk per unit of exposure (usually g/L for water, mg/kg/day for food, and 

g/m3

 for air). 

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

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

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

during a lifetime. The RFD is operationally derived from the NOAEL (from 

animal and human studies) by a consistent application of uncertainty factors 

that reflect various types of data used to estimate RfDs and an additional 

modifying factor, which is based on a professional judgment of the entire 

database on the chemical. The RfDs are not applicable to nonthreshold 

effects such as cancer. 

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

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

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

either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities 

are measured over a 24-h period. 

Reproductive Toxicity -- The occurrence of adverse effects on the 

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

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

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

alterations in sexual behavior, fertility, pregnancy outcomes, or 

modifications in other functions that are dependent on the integrity of this 

system. 
102 

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. 
103 

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 PRINTING OFFICE 1991 535-152