v>EPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440 5-80-056
Octooer 1980
Ambient
Water Quality
Criteria for
Isophorone
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AMBIENT WATER QUALITY CRITERIA FOR
ISOPHORONE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
-------
DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
11
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Hater Act were developed and a notice of their
availability was published for public comment on March 15, 1979 {44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.O.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
David J. Hansen, ERL-Gulf Breeze
U.S. Environment3"1 Protection Agency
Mammalian Toxicology and Human Health Effects:
Joseph Santodonato (author)
Syracuse Research Corporation
William Buck
University of Illinois
Terence M. Grady (doc. mgr.), ECAO-Cin Edward Calabrese
U.S. Environmental Protection Agency University of Massachusetts
Donna Sivulka (doc. mgr.), ECAO-Cin
U.S. Environmental Protection Agency
Jacqueline V. Carr
U.S. Environmental Protection Agency
Burt Cooper
National Institute for Occupational
Safety and Health
Pamela Ford
Rocky Mountain Poison Center
Dinko Kello
Institute for Medical Research
Zagreb, Yugoslavia
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara, ECAO-Cin
U.S. Environmental Protection Agency
William W. Carlton
Purdue University
W. Emile Coleman, HERL
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Wallace Hayes
University of Mississippi
Curtis Klaassen
University of Kansas Medical Center
Fred Oehme
Kansas State University
Sharon Bramson
City University of New York
Technical Support Services Staff: D.J. Reisman, M.A: Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, C. Russom, R. Rubinstein.
IV
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Aquatic Toxicity B-l
Chronic Toxicity B-l
Plant Effects B-2
Residues B-2
Summary B-2
Criteria B-3
References B-9
Mammalian Toxicology and Human Health Effects C-l
Exposure C-l
Ingestion from Water C-l
Ingestion from Food C-3
Inhalation C-4
Dermal C-4
Pharmacokinetics C-5
Absorption C-5
Distribution C-5
Metabolism and Excretion C-5
Effects C-6
Acute, Subacute and Chronic Toxicity C-6
Synergism and/or Antagonism C-l6
Teratogenicity and Mutagenicity C-17
Carcinogenicity C-17
Criterion Formulation C-18
Existing Guidelines and Standards C-18
Current Levels of Exposure C-19
Special Groups at Risk C-19
Basis and Derivation of Criterion C-19
References C-23
Appendix C-28
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CRITERIA DOCUMENT
ISOPHORONE
CRITERIA
Aquatic Life
The available data for isophorone indicate that acute toxicity to
freshwater aauatic life occurs at concentrations as low as 117,000 ug/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
isophorone to sensitive freshwater aquatic life.
The available data for isophorone indicate that acute toxicity to
saltwater aquatic life occurs at concentrations as low as 12,900 ug/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
isophorone to sensitive saltwater aauatic life.
Human Health
For the protection of human health from the toxic properties of isopho-
rone ingested through water and contaminated aauatic organisms, the ambient
water criterion is determined to be 5.2 mg/1.
For the protection of human health from the toxic properties of isopho-
rone ingested through contaminated aauatic organisms alone, the ambient
water criterion is determined to be 520 mg/1.
VI
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INTRODUCTION
Isophorone is a high-boiling colorless liauid of low volatility with an
odor resembling peppermint. Its salient physical properties are summarized
in Table 1. Isophorone is an excellent solvent for many oils, fats, gums,
natural, and synthetic resins (Rowe and Wolf, 1963), but it is used mainly
as a solvent for vinylic resins applied by roller coating (Blackford,
1975). Isophorone is also used as a solvent for cellulose derivatives, lac-
ouers, and pesticide formulations, particularly anilide and carbamate herbi-
cides. Because of its structure, isophorone is useful as a chemical inter-
mediate and is utilized in the synthesis of 3,5-xylenol, 3,3,5-trimetdylcy-
clohexanol, and plant growth retardants (Haruta, et al. 1974).
Isophorone is prepared commercially by two methods, both of which re-
auire acetone as a starting material (Rowe and Wolf, 1963). Acetone is pas-
sed over calcium oxide, hydroxide, carbide, or mixtures of these at 350*C,
or is heated at 200-250"C under pressure. The isophorone is separated from
the resultant products by distillation. Because fewer than three companies
manufacture isophorone, production figures are not published by the U.S.
Tariff Commission. The production of isophorone can, however, be estimated
from acetone consumption data. In 1973, 35 million pounds of acetone were
consumed for isophorone production (Blackford, 1975). Blackford estimated
that, for every pound of methyl isobutyl ketone produced, 1.25 pounds of
acetone are reauired. This corresponds to a yield of slightly above 90 per-
cent. Assuming a 90 percent yield, and an acetone consumption figure of 35
million pounds, the estimated 1973 production of isophorone was 31.5 million
pounds.
A-l
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TABLE 1
Physical Properties of Isophorone*
Empirical Formula
Molecular Weight
Freezing Point
Boiling Point (760 mm)
Specific Gravity (20/20°C)
Refractive Index nD (20°C)
Vapor Pressure (25*C)
Air Saturation
Evaporation Rate (ether = 1)
Water Solubility (weight % at 20*C)
Commercial Purity** (weight %)
Impurities:
e-isophorone
mesitylene (1,3,5-trimethylbenzene)
mesityl oxide (2-methyl-2 pertene-4-one)
phorone (2,6-dimethyl-2,5-heptadiene-4-one)
isoxylitones
water
138.21
-8.TC
215.2*C
0.9229 g/cc
1.4781
0.44 mm Hg
0.06SS
200
1.2
96-98*
2-4%
trace
trace
trace
trace
trace
Structure:
3,5,5-trimethyl-2-cyclohexene-l-one
* Source: U.S. EPA, 1979; Union Carbide, 1975;
Occupational Safety and Health (NIOSH), 1978.
**Isophorone plus trimethylcyclohexenone.
National Institute for
A-2
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The National Institute for Occupational Safety and Health (NIOSH, 1978)
estimates that more than 1.5 million workers are exposed annually to isopho-
rone. In the industrial handling of isophorone, inhalation of the vapor is
the most likely mode of contact, although skin and eye contact with the
liquid may also occur. Because of the odor and the taste of isophorone, in-
gestion is not expected unless by accident. In the environment, isophorone
has been detected in a few samples of drinking water, but not in ambient
air, soil, or food.
A-3
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REFERENCES
Blackford, J.S. 1975. Acetone. Chemical Economics Handbook. Stanford Re-
search Institute, Menlo Park, California.
Haruta, H., et al. 1974. New plant growth retardants. II. Syntheses and
plant growth retardant activities of quaternary ammonium compounds derived
from -isnone and isophorone. Agric. Biol. Chem. 38: 417.
National Institute for Occupational Safety and Health. 1978. Criteria for
a recommended standard occupational exposure to ketones. NIOSH Publ. No.
78-173. U.S. Oept. Health Education and Welfare.
Rowe, V.K. and M.A. Wolf. 1963. Ketones. In,: F.A. Patty (ed.), Industrial
Hygiene and Toxicology. 2nd ed. Interscience Publishers, New York.
Union Carbide Corp. 1975. Ketones technical booklet (F-41971A). Chemical
and Plastics Oiv., New York.
U.S. EPA. 1979. Pesticides Tolerance Division, internal memo from W.E.
Parkin (Toxicology Branch) to D.M. Baker (Pesticides Control Branch) regard-
ing pesticide petition no. 2F1224. May 11, 1972. Provided by David Ritter,
Off. Tox. Subst., Off. Pest. Prog.
A-4
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Aquatic Life Toxicology*
INTRODUCTION
Static acute toxicity tests have been reported for isophorone and the
bluegill and Daphnia magna. The 50 percent effect concentrations were
between 117,000 and 224,000 ug/1- A bioconcentration test with bluegill
indicated negligible uptake of isophorone.
As with freshwater organisms, most of the available data for the
effects of isophorone on saltwater organisms result from static tests with
unmeasured concentrations. An embryo-larval test has been conducted with
the sheepshead minnow.
EFFECTS
Acute Toxicity
Daphnia magna has been tested and the 48-hour EC50 is 117,000 ug/l
(Table 1) which indicates little, if any, difference in sensitivity compared
with the bluegill. The 96-hour LC5Q for the bluegill is 224,000 wg/l.
The 96-hour LC5Q for the mysid shrimp is 12,900 yg/1 and this species
is much more sensitive than the sheepshead minnow. The 96-hour IC™ for
the sheepshead minnow (U.S. EPA, 1978) was between 166,000 and 295,000 ug/1
(Table 5).
Chronic Toxicity
The chronic value for the sheepshead minnow obtained from an embryo-
larval test (U.S. EPA, 1978) is 110,000 ug/1 (Table 2). The limits on this
test were 80,000 to 156,000 ug/1 which is just below the acute LC,-n range
DU
(Table 5) and results in an acute-chronic ratio between 1.5 and 2.7.
*The reader is referred to the Guidelines for Deriving Water Quality
Criteria for the Protection of Aquatic Life and Its Uses in order to better
understand the following discussion and recommendation. The following
tables contain the appropriate data that were found in the literature, and
at the bottom of each table are calculations for deriving various measures
of toxicity as described in the Guidelines.
3-1
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Plant Effects
The 96-hour EC™ values for cell number production and Inhibition of
chlorophyll a_ by the freshwater alga, Selenastrum capricornutum, are 122,000
and 126,000, respectively (Table 3). These effect concentrations are essen-
tially the same as those for the bluegill and Daphnia magna.
Chlorophyll a_ was inhibited and cell numbers were reduced by 50 percent
after 96-hour exposures of the saltwater alga, Skeletonema costatum, to
isophorone concentrations of 110,000 and 105,000 ug/1, respectively (Table
3).
Residues
A 28-day exposure (U.S. EPA, 1978) to C-isophorone resulted in bio-
concentration by the bluegill to 7 times that in the water (Table 4). The
half-life of isophorone in the whole body was one day. Thin-layer chromato-
graphy was used to verify the analytical results.
Summary
The cladoceran, Daphnia magna, and bluegill have been acutely tested
with isophorone and the 50 percent effect concentrations were 117,000 and
224,000 ug/1, respectively. The EC5Q values for a freshwater alga were
within that range. The bioconcentration factor for the bluegill was 7 with
a half-life of one day.
The mysid shrimp was much more sensitive than the sheepshead minnow
with a 96-hour LC5Q value of 12,900 ug/1 for the former ana between
166,000 and 295,000 ug/l for the latter. The acute IC™ value for the
sheepshead minnow was only slightly higher than the chronic value of 110,000
ug/1 for the same species. The ECcQ values for an alga were 105,000 and
110,000 ug/1.
3-2
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CRITERIA
The available data for isophorone indicate that acute toxicity to
freshwater aauatic life occurs at concentrations as low as 117,000 yg/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
isophorone to sensitive freshwater aauatic life.
The available data for isophorone indicate that acute toxicity to
saltwater aauatic life occurs at concentrations as low as 12,900 ug/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. Mo data are available concerning the chronic toxicity of
isophorone to sensitive saltwater aauatic life.
B-3
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Tabl* t. Actit* value* for Isophoron* (U.S. EPA, 1978}
Specie*
Cladoceran,
Daphnla magna
Blueglll,
Leponls macrochlrus
Hysld shrlMp,
Hysldopsls bah lo
LC50/EC50
ftothod* (ua/D
FRESHWATER SPECIES
S, U 117,000
S, U 224,000
SALTWATER SPECIES
S, U 12.900
Sp«cl*s Adit*
Value (va/II
117,000
224,000
12,900
* S » static, U * unmeasured
No Final Acute Values are calculable sfnce the Mini nun data base
requirements are not net.
B-4
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Table 2. Chronic values tor Icophorone (U.S. EPA, 1978)
Species Test*
Chronic
Llalts Val«e
(ng/1) (H9/D
SALTWATER SPECIES
Sheepshead minnow,
Cyprlnodon varlegatus
ELS 80,000- 110,000
156,000
* ELS = early life stage
Acute-Chronic Ratio
Chronic
Value
Acute
Value
Sheepshead minnow,
Cyprlnodon varlegatus
110,000 166,000- 1.5-2.7
295,000
B-5
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TabU 3. Plant values for Isoplnron* (U.S. EPA. 1976}
Result
Effect (yq/l)
FRESHWATER SPECIES
Alga, Cell number 122,000
Selenostrum capr Icornutom 96-hr EC50
Alga, Chlorophyll a_ 126,000
Selenastrum caprIcornutum 96-hr EC50
SALTWATER SPECIES
Alga, Call number 105.000
Skeletonema costatuin 96-hr EC50
Alga, Chlorophyll^ 110,000
Skeletonema costatum 96-hr EC50
B-6
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Table 4. Residues for Isophorone (U.S. EPA, 1970)
BIocon centratIon OuratIon
Species Tissue Factor (days)
FRESHWATER SPECIES
BlueglI I, whole body 7 26
Lepomls macrochIrus
B-7
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Table 5. Other data for Isopftoroo* (U.S. EPA. 1976)
Result
Spec las Duration Effect (pa/O
SALTWATER SPECIES
Sheepshead minnow. 96 hrs LC50 166,000-
Cyprlnodon varlegatus 295,000*
* Author did not calculate the LC50.
B-8
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REFERENCES
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency. Contract No.
68-01-4646.
B-9
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Mammalian Toxicology and Human Health Effects
EXPOSURE
Ingestion from Water
Isophorone has been detected in several samples of drinking
water (Table 1), but these identifications cannot be used to imply
a continuous occurrence. The sources of the isophorone contamina-
tion were not identified, but they would appear to be of indus-
trial origin.
The U.S. EPA has quantified levels of isophorone in finished
drinking water in the New Orleans area (U.S. EPA, 1974). At the
Carrollton Water Plant (City of New Orleans), and at two water
treatment sites in Jefferson Parish, the highest measured isopho-
rone concentrations were 1.5, 2.2, and 2.9 ug/1, respectively.
The National Organics Reconnaissance Survey (NORS), initiated
in 1974, was designed to provide an estimate of the nationwide
distribution of organic compounds in drinking water (U.S. EPA,
1975). In a comprehensive organic analysis of the finished drink-
ing waters of 10 cities, isophorone was identified only in Cincin-
nati (Ohio), at a level of 0.02 ug/1. The Cincinnati water source
was categorized as being contaminated with industrial discharges.
Isophorone was not found in the waters of Miami (Fla.), Seattle
(Wash.), Ottumwa (Iowa), Philadelphia (Pa.), Tucson (Ariz.), New
York (N.Y.), Lawrence (Mass.), Grand Forks (N.Dak.), or Terrebonne
Parish (La.) .
EPA also maintains an inventory of organic compounds that
have been isolated and identified in drinking water in the United
States (U.S. EPA, 1975). Two hundred and fifty-three compounds
C-l
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TABLE 1
Water Types Contaminated with Isophorone
Finished
Drinking
Water
Effluent from
River
Latex
Plant
Chemical
Plant
Tire
Plant
Concentration
Reference
X
9.5 ug/1 highest concen-
tration reported in a
nationwide survey
1.5-2.9 ug/1, treated
river water, New Orleans
area
trace (<0 .01 ppb),
Delaware River
levels not reported
0.04 rog/1
U.S. EPA (1975)
U.S. EPA (1974)
Sheldon and Hites
(1978)
Shackelford and
Keith (1976)
Jungclaus, et al.
(1976)
C-2
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were compiled from an extensive search of the chemical literature
and from EPA reports generated from the Agency's analytical activ-
ities. Although the compounds included in the inventory were
based upon an analysis of only a few (unspecified) public water
supplies, isophorone was nevertheless detected at concentrations
as high as 9.5 ug/1.
In a primarily qualitative study, Sheldon and Hites (1978)
recently found trace quantitites (<0.01 ppb) bf isophorone in
water samples from the Delaware River near a highly industrialized
region. Isophorone was also identified as a contaminant (approxi-
mate concentration, 0.04 mg/1) in the wastewater from a tire manu-
facturing plant (Jungclaus, et al. 1976). Shackelford and Keith
(1976) have reported that isophorone has been detected in the ef-
fluents from latex and chemical plants in Alabama, but no levels
were reported.
Ingestion from Food
Pertinent data could not be located in the available litera-
ture concerning the presence of isophorone in food.
A bioconcentration factor (BCF) relates the concentration of
a chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seems to be pro-
portional to the percent lipid in the tissue. Thus, the per
capita ingestion of a lipid-soluble chemical can be estimated from
the per capita consumption of fish and shellfish, the weighted
average percent lipids of consumed fish and shellfish, and a
steady-state BCF for the chemical.
C-3
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Data from a recent survey on fish and shellfish consumption
in the United States was analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion
of the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
A measured steady-state bioconcentration factor of 7 was ob-
tained for isophorone using bluegills (U.S. EPA, 1978). Similar
bluegills contained an average of 4.8 percent lipids (Johnson,
1980). An adjustment factor of 3.0/4.8 = 0.625 can be used to
adjust the measured BCF from the 4.8 percent lipids of the blue-
gill to the 3.0 percent lipids that is the weighted average for
consumed fish and shellfish. Thus, the weighted average biocon-
centration factor for isophorone and the edible portion of all
aquatic organisms consumed by Americans is calculated to be 7 x
0.625 = 4.38.
Inhalation
No monitoring information is available on the levels of iso-
phorone in ambient air.
Dermal
No information is available on the importance of dermal ab-
sorption in total human exposure to isophorone. It has been
demonstrated that isophorone can be absorbed through the skin of
C-4
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rabbits (see Acute, Subacute, and Chronic Toxicity section). For
those humans exposed only to background levels of isophorone, how-
ever, dermal absorption is not likely to be a significant route of
exposure.
PHARMACOKINETICS
Absorption
No quantitative information is available on the absorption of
isophorone in animals or man. The demonstrated toxicity of iso-
phorone by oral, inhalation and dermal exposures (see Acute, Sub-
acute, and Chronic Toxicity section) indicates that it is capable
of passage across epithelial membranes.
Distribution
The tissue distribution and accumulation of isophorone has
not been studied.
Metabolism and Excretion
Isophorone appears to undergo oxidation at the 3-methyl group
following oral administration of 1 g/kg to rabbits (Truhaut, et
al. 1970). This reaction, shown below, precedes glucuronide con-
jugation and urinary elimination.
C-5
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The complete reaction sequence for isophorone biotransformation
h~as not been determined and no quantitative data on the extent of
glucuronic acid conjugation are available.
Isophorone has been detected as a urinary metabolite of
3,5,5-trimethylcyclohexanone in rats and rabbits (Truhaut, et al.
1973). A large percentage of the metabolite was present as a glu-
curonide conjugate.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Effects on Experimental Mammals: The acute toxicity of iso-
phorone is summarized in Table 2. Oral l>b$Q values of about 2
gm/kg body weight have been reported for rats and mice by several
a u th or s.
The Union Carbide Corporation reported a single skin penetra-
tion LD5Q value of 1.39 g/kg in rabbits in a 1975 technical
data booklet. Single skin penetration refers to a 24-hour covered
skin contact with the isophorone, but details regarding the number
of animals exposed and any other aspects of the experimental pro-
tocol were not presented.
Smyth and Seaton (1940) reported that 750 ppm was the highest
concentration of isophorone to which rats and guinea pigs could be
exposed for several hours with no symptoms other than slight eye
and nose irritation. The symptoms exhibited by the animals fol-
lowing exposures to higher concentrations included eye and nose
irritation, lacrimation, swelling of the nose, instability, respi-
ratory difficulty or irregularity, marked increase in intestinal
peristalsis, and light narcosis (Table 3). Exposures lasting 12
C-6
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TABLE 2
Acute Toxicity of Isophorone
Number Treated
Route Animal per dose level*
Oral Rats n.s.
Rats 5
Rats 5
Rats n.s.
M i ce n.s.
Dermal Rabbits n.s.
Inhalation** Kats and n.s.
Guinea Pigs
Rats n.s.
Guinea Pigs n.s.
Rats 6
Dose
1.87 y/kg
2.10 g/kg
2.12 g/kg
2.37 g/kg
2.00 g/kg
1.39 q/kg
750 ppm
1840 ppn
4600
Air saturated
with 1 soph or one
Duration Mortality
Lt>50
14 -day LDjo
14-day LD50
LD50
U>50
LD50
"several" No death or
hours serious symptoms
4 hrs. Caused death in
some animals
B his. No deaths
8 hrs. One death
Reference
Union Carbide
(1975)
Smyth, et al.
(1969)
Say tli, et al .
(1970)
Bukhalovski i ,
& Shugeav (1976)
Bukhalovskii ,
I Shugeav (1976)
Union Carbide
(1975)
Smyth and yea ton
(1940)
Smyth and Seaton
(194U)
Smyth and Seaton
(1940)
Union Carbide
(1975)
an.s. = not specified.
kfeOO ppm is the maximum attainable concentration oC Isophorone in air (see discussion on page C-13 and appendix).
C-7
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TABLE 3
Symptoms Resulting From Acute Exposure of Guinea Pigs to Isophorone Vapors3'^,*
Concentrati
Symptoms
Maximum exposure period (minutes)
Nasal irritatipn (rub nose)
Eye irritation (blink)
Lacr imation
Nose swollen
Instability
Respiratory difficulty
Diarrhea
Light narcosis
First death
4,600
480
(1)
(1)
5
B
40
60
120
180
(2)
1,840
360
(1)
(1)
15
20
50
120
180
200
(2)
1,370
480
(1)
(1)
20
30
80
ISO
240
255
(2)
on in PPM
880
720
(1)
(1)
75
75
135
360
480
600
(2)
750
1,440
15
15
(2)
(2)
(2)
(2)
(2)
(2)
(2)
300
1,440
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
*Source: Smyth and Seaton, 1940
aNumbers are time in minutes for first animal to display symptom indicated. Time required
for similar effects to be displayed by rats was about 2/3 of that for guinea pigs
"600 ppm is the maximum attainable concentration of Isophorone in air (see discussion on
pag'e C-13 and appendix)
(1) At very start of exposure
(2) Not observed within maximum exposure period
C-8
-------
hours or more resulted in increased heart rates. Corneal opacity
or necrosis, as revealed by fluorescein staining, was found in the
guinea pigs following exposures of four hours or longer to isopho-
rone at 840 ppm. Corneal effects were never observed in the
rats.
Eight-hour inhalation exposures to isophorone at 4,600 ppm
did not result in any deaths to guinea pigs, but in rats four
hours at 1,840 ppm was the minimum lethal exposure (Smyth and
Seaton, 1940). When death occurred it was usually during the ex-
posure period due to paralysis of the respiratory center (narco-
sis). A few deaths were attributed to lung irritation.
It must be noted that Rowe and Wolf (1963) have indicated
that the isophorone vapor concentrations reported by Smyth and
Seaton in this study (1940), and those in a related subacute study
described subsequently (Smyth, 1941; Smyth, et al. 1942), could
not have been attained under the conditions employed. Later in-
vestigation led to the conclusion that the material used in the
Smyth studies was an impure commercial product containing appreci-
able amounts of material(s) more volatile than isophorone (Rowe
and Wolf, 1963). Smyth maintained vapor concentrations in a flow-
through chamber by bubbling air through the solvent in a constant
temperature bath and diluting the vapor stream with pure air, and
monitored the concentrations with an interferometer. Since the
concentration of vapors within the exposure chamber was measured
by means of an interferometer calibrated against pure isophorone,
it was apparently assumed that the vapors present in the chamber
were isophorone only.
C-9
-------
A calculation of the maximum attainable concentration of iso-
phorone in air at standard temperature and pressure, presented in
the appendix, yields a value of approximately 600 ppm. This cal-
culation indicates that the allegation of Rowe and Wolf is prob-
ably correct and implies that the value of the Smyth data is
seriously compromised.
The microscopic pathology of those animals surviving acute
exposure by 14 days was almost never severe and was essentially
reversible (Smyth and Seaton, 1940). Pathological findings were
reported for 95 percent of the lungs (general congestion; alveolar
and bronchiolar secretion, red cell leakage and epithelial cell
desquamation; and secondary pneumonia), 56 percent of the kidneys
(cloudy swelling, dilation, granular detritis and hyaline casts in
convoluted tubules; dilation of Bowman's capsule; general conges-
tion), 30 percent of the hearts (dilation of coronary vessels), 17
percent of the livers (congestion; hemorrhages into parenchyma;
cloudy swelling) and 10 percent of the spleens (congestion). The
typical hematologic response to acute isophorone intoxication was
a temporary drop in red cells and hemoglobin, with white cells
appearing to be unchanged.
Union Carbide (1975) reported that a single 8-hour inhalation
exposure to air saturated with isophorone (calculated concentra-
tion approximately 600 ppm) killed 1 of 6 rats.
In 1942, Smyth, et al. compared the subacute inhalation tox-
icity of isophorone in rats and guinea pigs. The mortality and
pathological details of this study were originally reported by
Smyth (1941). Groups of 10 rats and 10 guinea pigs were re-
C-10
-------
portedly exposed to isophorone vapor at 25 to 500 ppm for 8 hrs/
day, five days a week for six weeks, but the experimental methods
utilized were similar to those described for the Smyth and Seaton
(1940) study. Since it appears that this experiment was also con-
ducted with impure material and that the concentration of the iso-
phorone tested is not accurately known (Rowe and Wolf, 1963),
these results are also of limited value. The dose-related effects
produced by the 25 to 500 ppm exposures are summarized in Table 4.
Although about half the guinea pigs exposed to isophorone at 500
ppm died before the 30th exposure, no guinea pigs died from expo-
sures at 100 ppra or less, and no rats died from inhalation of
vapor at 50 ppm or less.
When death resulted from subacute inhalation exposure it ap-
peared to be due to a combination of kidney and lung damage, al-
though none of the surviving animals showed any severe grade of
injury to these organs (Smyth, 1941; Smyth, et al. 1942). The
microscopic findings of various tissues from the survivors was
rather uniform, varying in degree with the concentration breathed.
The lungs were frequently injured, showing primarily congestion
and leakage of red blood cells into alveoli. Cloudy swelling with
increased secretion and dilation of Bowman's capsule was a common
finding in the kidney, but the action of isophorone on the liver,
heart and spleen was negligible. Guinea pigs exposed to 500 ppm
showed an increase in polymorphonuclear white cells and a corres-
ponding fall in lymphocytes, but no other consistent changes in
hematologic parameters were found.
C-ll
-------
TABLE 4
Subacute Inhalation Toxicity of Isophorone*
Animal
Rats
male, Wistar,
90-120 g
Guinea Pigs
both sexes,
250-300 g
Concentration*
(ppm)
25
50
100
200
25
Duration
Hr/Oay (Days)
8 42 (30 exposures,
5 days/wk x 6 wks)
6 42 (30 exposures,
5 days/wk x 6 wks)
8 42 (30 exposures,
5 days/wk x 6 wks)
B 42 (30 exposures,
5 days/wk x 6 wks)
8 42 (30 exposures,
5 days/wk x 6 wks)
Hortalltyb
Ot
0«
20%
10%
0%
Details
No apparent signs of toxicity
Evidence of lung and kidney
pathology
Evidence of lung, spleen and
kidney pathology
Evidence of lung, spleen and
kidney pathology; conjunctivitis
and nasal irritation; urine
albumin
No apparent signs of toxicity
100
200
500
42 (30 exposures,
5 days/wk x 6 wks)
42 (30 exposures,
5 days/wk x 6 wks)
42 (30 exposures,
5 days/wk x 6 wks)
0%
25%
40%
Evidence of lung and kidney
pathology; weight loss
Evidence of lung and kidney
pathology; weight loss
evidence of lung, kidney and
liver pathology; conjunctivitis
and nasal irritation; weight
loss; increase in polymorpho-
nuclear white cells with a cor-
responding fall in lymphocytes
*Source: Smyth, 1941
aRowe and Wolf (1963) have indicated that the isophorone used in this study was impure and that the reported concen-
trations are higher than actually present (see discussion on page C-13 and appendix).
^percentage of animals dying; usually 10 animals were tested at each dosage.
C-12
-------
Smyth (1941) indicated that during the course of the study,
both control and exposed animals, especially the guinea pigs, were
troubled with infections (parasites, intestinal protozoa and bac-
teria). Although the affected animals were reportedly eliminated
from consideration, the significance of the infection on the other
animals is difficult to ascertain.
Subacute (90 day) feeding studies on isophorone in rats and
dogs have also been conducted (Parkin, 1972).
In the rat study, CFE albino weanlings were divided into 4
groups of 20 males and females each and fed isophorone at 0, 750,
1,500 or 3,000 ppm in the daily diet (Parkin, 1972). Individual
body weights, food and compound consumption were tabulated weekly.
After four weeks and at 90 days, five rats/sex/group were killed
and blood was collected for hematological and clinical chemistry
determinations. Urine was collected from an additional five males
and five females per group at the same time and was also compre-
hensively analyzed. The rats sacrificed after four weeks were
examined for gross pathology only; but after 90 days, tissues from
10 rats of each sex from the control and 3,000 ppm groups were
examined histologically. The livers and kidneys from five rats/
sex from the 750 and 1,500 ppm groups were also examined. Two
rats died during the study, one in the control group and one in
the 3,000 ppm group, of an unspecified infection unrelated to the
administration of isophorone. The body weights and food consump-
tion were not significantly affected at the end of the study by
feeding isophorone although the body weights of the males in the
C-13
-------
3,000 ppm group were significantly depressed for several weeks
during the study. There was no significant difference between the
treated and control groups regarding hematology, blood chemistry,
or urinalysis, and no pathological lesions were observed by either
gross or microscopic examination.
In the dog study, four male and four female beagles were fed
isophorone for 90 days at doses of 0, 35, 75, and 150 mg/kg/day,
in gelatin capsules (food containing isophorone was refused). The
dogs were weighed weekly and bled monthly for hematological blood
chemistry evaluation, and urine was collected and analyzed on the
same schedule as the blood. All the animals survived the study
and were killed after 90 days and examined grossly. Twenty-eight
selected tissues from the control and high level (150 mg/kg)
groups were examined histologically, as were liver and kidney
specimens from the intermediate exposure groups.
All dogs survived the study in excellent condition (Parkin,
1972). Food consumption was within normal limits and body weight
was not affected by treatment.
The hematology, biochemical, and urinalysis tests indicated a
lack of adverse effect of 90 doses of isophorone. All organs ap-
peared normal at gross examination and no significant changes in
organ weight were produced with the ingestion of isophorone.
There was no evidence of any definitive signs of cellular change
in any of the tissues examined.
Isophorone has been shown to be weakly irritating to the skin
of rabbits, but its effect was stronger on the ocular mucosa where
it induced reversible irritation of the conjunctiva and corneal
C-14
-------
opacity (Truhaut, et al. 1972). These latter results are consis-
tent with the moderate rabbit eye irritation ratings for isopho-
rone reported by Carpenter and Smyth (1946) and Union Carbide
(1963).
Effects on Humans: The most significant consequence of human
exposure to low levels of isophorone vapor is irritation of muco-
sal membranes. In this respect isophorone is probably the most
irritating of all ketonic solvents. Smyth and Seaton (1940) re-
ported that groups of 11 or 12 human subjects exposed in a small
room for a few minutes to measured isophorone concentrations of
40, 85, 200, and 400 ppm experienced eye, nose, and throat irrita-
tion, but it appears that these measured concentrations were
higher than the isophorone that was actually present (see previous
discussion regarding mammals). A few complaints of nausea, head-
ache, dizziness, faintness, inebriation, and a feeling of suffoca-
tion resulted from inhalation of isophorone at 200 and 400 ppm in
air. However, the symptoms of irritation and narcotic action were
less severe at concentrations of 40 and 85 ppm.
In a sensory threshold study, Silverman, et al. (1946) ex-
posed humans to the vapors of several industrial solvents includ-
ing isophorone. Twelve unconditioned subjects of both sexes were
exposed to the vapors for 15-minute periods in a 1,200 ft^ cham-
ber. They found that exposure to isophorone at 25 ppm produced
irritation of the eyes, nose, and throat, and that isophorone
vapor was considered by the subjects to be the most irritating of
all the ketonic solvents tested. The highest tolerable level for
an 8-hour isophorone exposure was judged to be 10 ppm by a
C-15
-------
majority of the subjects. It should be noted that the concentra-
tion of isophorone in the exposure chamber was calculated (nomi-
nal) rather than measured analytically, so the true concentration
may have been different than reported [National Institute Occupa-
tional Safety and Health (NIOSH), 1978].
Union Carbide (1963) indicated than one minute exposures to
200 ppm isophorone are intolerable for humans. A concentration of
40 ppm was intolerable to half of an unspecified number of human
volunteers after four minutes. Union Carbide also noted that iso-
phorone did not cause allergic contact sensitization in any of the
ten human volunteers.
Synergism and/or Antagonism
Smyth and coworkers (1969, 1970) have examined the joint
toxic action of isophorone with 26 industrial liquid chemicals
based on acute L.D5Q data from oral intubations of female
albino rats. In the initial study (Smyth, et al. 1969), LD5QS
were determined for each of the compounds alone and for 1:1 (v/v)
mixtures of the compounds. Based on the assumption of simple sim-
ilar action, isophorone exhibited greater than additive toxicity
in combination with nine compounds and less than additive toxicity
in combination with 17 compounds. The significance of the inter-
actions was determined by modifying the interactive ratios (pre-
dicted/observed LC5g) so that the distribution approximated
normality. Significant interaction was then defined as those
ratios which were beyond 1.96 standard deviations from the mean
ratio. By this criterion, none of the mixtures containing iso-
phorone deviated significantly from the assumption of simple
C-16
-------
similar action. In a subsequent study (Smyth, et al. 1970), equal
volume mixtures of isophorone and propylene oxide showed markedly
less than additive toxicity, but equitoxic mixtures showed slight-
ly greater than additive toxicity. An equitoxic mixture was de-
fined as a mixture of chemicals in volumes directly proportional
to their respective rat oral LD5Q values, so that each compo-
nent contributed the same degree of toxicity to the mixture.
Teratogenicity and Mutagenicity
Pertinent data could not be located in the available litera-
ture.
Carcinogenicity
Isophorone is being tested for carcinogenicity in rats and
mice by gavage by the National Cancer Institute (NCI, 1979a).
Apparently, isophorone was selected on the basis of its reported
presence in municipal water supplies, the large number of workers
exposed industrially (>1,500,000), a projected increase in produc-
tion levels (>25 million pounds are currently being produced), and
the existing paucity of epidemiological, animal, and metabolic in-
formation (NCI, 1979b).
C-17
-------
CRITERION FORMULATION
Existing Guidelines and Standards
The current 8-hour time-weighted average (TWA) threshold
limit value (TLV) for isophorone established by the American Con-
ference of Governmental Industrial Hygienists (ACGIH, 1977) is 5
ppm (>~25 mg/m3). The TLV was lowered from 25 ppm (-^140
mg/m3) to 5 ppm in response to a June 1973 communication from
the Western Electric Company to the TLV committee regarding
fatigue and malaise among workers exposed to levels of 5 to 8 ppm
for one month (ACGIH, 1974). When isophorone levels in air were
lowered to 1 to 4 ppm (--»-6-23 mg/m3) by increasing exhaust
ventilation, no further complaints were received.
The current Federal standard for occupational exposure to
isophorone is 25 ppm (140 mg/m3) as an 8-hour time-weighted
average concentration limit in the air of the working environment
(39 FR 23540). This standard is based on the TLV adopted by the
ACGIH in 1968, and is intended to prevent irritative and narcotic
effects. NIOSH currently recommends a permissible exposure limit
of 4 ppm (23 mg/m3) as a TWA concentration for up to a 10-hour
workshift, 40-hour work week (NIOSH, 1978) . The NIOSH recommended
standard is essentially based on the 1974 ACGIH TLV documenta-
tion.
Isophorone was exempted from the requirement of a tolerance
under the Federal Food, Drug and Cosmetic Act when used as an
inert solvent or cosolvent in pre-emergence pesticide formulations
and for post-emergence use both on rice before the crop begins to
head and on sugar and table beets (39 FR 37195).
C-18
-------
Current Levels of Exposure
As detailed in the Exposure section of this report, only
limited monitoring data are available regarding levels of isopho-
rone in water, and virtually no information is available on am-
bient levels in air or food. Since there is a lack of extensive
monitoring data on isophorone levels in drinking water, it is dif-
ficult to predict the magnitude or extent of human population
exposure.
Although isophorone has been detected at levels of less than
3 ppt in several water samples/ a maximum daily intake can be cal-
culated from the highest reported level of 9.5 ug/1; (U.S. EPA,
1975) by assuming: (a) that 100 percent exposure comes from an
average daily consumption of 2 liters of water plus 6.5 grams
fish/shellfish; (b) a bioconcentration factor of 4.38 {U.S. EPA,
1979); and (c) 100 percent gastrointestinal absorption of the
ingested isophorone. Thus, the daily intake of isophorone from
water would be 19.3 ug/day (9.5 ug/1 x [2 liters + (4.38 x
0.0065)] x 1.0) .
Special Groups at Risk
Certain occupations (particularly individuals who are exposed
to isophorone as a solvent) have elevated levels of exposure rela-
tive to the general population.
Basis and Derivation of Criterion
The data base for deriving an ambient water quality criterion
for isophorone is relatively poor. The compound has not been
C-19
-------
tested for carcinogenicity, mutagenicity, teratogenicity or chron-
ic toxicity. With the exception of its irritant properties, no
information is available on the effects of isophorone on humans.
The only suitable data for deriving a criterion comes from
the 90 day feeding study in rats and dogs (Parkin, 1972). In this
study, dogs evidenced no-observable-effects (based on hematology,
blood chemistry, urinalyses and gross or microscopic pathology) at
dose levels of 35, 75, and 150 mg/kg/day. In the rats, the only
effect was transient weight loss in the 3,000 ppm group, with no
effects noted in the 750 and 1,500 ppm exposure groups. Assuming
a food consumption of approximately 10 percent of the body weight
per day, the data on rats supports the NOEL of 150 mg/kg/day in
dogs. This NOEL can be used to estimate an acceptable daily in-
take (ADI) for man by applying a safety factor of 1,000, This
safety factor is justified because of the existence of only scanty
human data and the lack of chronic toxicity data in animals.
Thus, the estimated ADI for man is 150 ug/kg or 10.5 mg/man assum-
ing a 70 kg body weight.
An ambient water quality criterion can be calculated using
the following assumptions:
1. Two liters of water consumed per day.
2. 0.0065 kg of fish consumed per day.
3. Bioconcentration factor of 4.38.
4. 100 percent gastrointestinal absorption.
C-20
-------
Therefore :
1'
(2 1 + (4t38xo.o65]) x 1.0
' 5'18 mg/1
-------
the assumed exposure while eating contaminated fish products
accounts for 1 percent. The criterion level can similarly be ex-
pressed as 520 mg/1 if exposure is assumed to be from the consump-
tion of fish and shellfish products alone.
C-22
-------
REFERENCES
Altman, P.L. and D.S. Dittmer. 1974. Biology Data Book. 2nd ed.
Fed. Am. Soc. Exp. Biol. Bethesda, Md.
American Conference of Governmental Industrial Hygienists. 1974.
Documentation of the Threshold Limit Values for Substances in
Workroom Air. 3rd ed. Cincinnati, Ohio
American Conference of Governmental Industrial Hygienists. 1977.
Threshold Limit Values for Chemical Substances and Physical Agents
in the Workroom Environment with Intended Changes for 1977. Cin-
cinnati, Ohio.
BuklalovsJcii, A.A. and B.B. Shugeav. 1976. Toxicity and hygienic
standardization of isophorone, dihydroisophorone, and dimethyl-
phenylcarbinol. Prom-st. Sint. Kauch.
Carpenter, C.P. and H.F. Smyth. 1946. Chemical burns of the rab-
bit cornea. Am. Inst. Opthal. 29: 1363.
Johnson, K. 1980. Memorandum to D. Kuehl. U.S. EPA. March 10.
Jungclaus, G.A., et al. 1976. Identification of trace organic
compounds in tire manufacturing plant waste waters. Anal. Chem.
48: 1894.
C-23
-------
National Cancer Institute. 1979a. Chemicals on standard proto-
col. Carcinogenesis Testing Program.
National Cancer Institute. 1979b. Personal Communications. En-
closures provided by Sharon Leeney, Secretary to the Assistant Co-
ordinator for Environ. Cancer, NCI (Dr. Thomas Cameron): (1) Sum-
mary of data for chemical selection - isophorone? (2) Minutes -
chemical selection working group, August 25, 1977; (3) Minutes -
sixth meeting of the chemical selection subgroup of the clearing-
house on environmental carcinogens. November 1, 1977.
National Institute for Occupational Safety and Health. 1978.
Criteria for a recommended standard...occupational exposure to
ketones. NIOSH Publ. No. 78-173. U.S. Dept. Health Edu. Wel-
fare .
Parkin, W.E. 1972. Memorandum to D.M. Baker. Pesticide Toler-
ance Div., Off. Toxic Subst. U.S. EPA. May 11.
Rowe, V.K. and M.A. Wolf. 1963. Ketones. In; F.A. Patty (ed.),
Industrial Hygiene and Toxicology. 2nd ed. Interscience Pub-
lishers, New York.
Shackelford, W.M. and L.H. Keith. 1976. Frequency of organic
compounds identified in water. U.S. EPA. 600/4-76-062. Athens,
Georgia. p. 626.
C-24
-------
Sheldon, L.S. and R.A. Hites. 1978. Organic compounds in Dela-
ware River. Environ. Sci. Technol. 12: 1188.
Silverman, L., et al. 1946. Further studies on sensory response
to certain industrial solvent vapors. Jour. Ind. Hyg. Toxicol.
28: 262.
Smyth, Jr., H.F. 1941. Response of guinea pigs and rats to re-
peated inhalation of the vapors of isophorone. Rep. 4. Mellon
Inst. Ind. Res.
Smyth, Jr., H.F. and J. Seaton. 1940. Acute response of guinea
pigs and rats to inhalation of the vapors of isophorone. Jour,
Ind. Hyg. Toxicol. 22: 477.
Smyth, Jr., H.F., et al. 1942. Response to guinea pigs and rats
to repeated inhalation vapors of mesityl oxide and isophorone.
Jour. Ind. Hyg. Toxicol. 24: 46.
Smyth, Jr., H.F., et al. 1969. Exploration of joint toxic
action: Twenty-seven industrial chemicals intubated in rats in all
possible pairs. Toxicol. Appl. Pharmacol. 14: 340.
Smyth, Jr., H.F., et al. 1970. An exploration of joint toxic
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C-25
-------
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
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Truhaut, R., et al. 1970. Metabolic study on an industrial sol-
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Truhaut, R., et al. 1972. Toxicity of an industrial solvent, iso-
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Truhaut, R., et al. 1973. Metabolic transformations of 3,5,5-tri-
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C-26
-------
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens
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C-27
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APPENDIX
Calculation of appropriate isophorone concentration in satu-
rated air.
For a sample of ideal gas,
PV « nRT
where
P - pressure
V = volume
n = number of moles
R * universal gas constant
T * absolute temperature
Since n * —-*—, the ideal gas equation can be rearranged as
mw
follows to calculate the approximate number of grams of compound
contained in a particular volume of gas at a specified temperature
and pressure:
PV » -2— RT
mw
PV(mw)
RT
At 25°C, the vapor pressure of isophorone is 0.44mm. Assum-
ing a 1 liter volume of air,
x 1 liter x 138.21
0.082 * x 298°K
0.00327 g = 3.27 mg
C-28
-------
The approximate ppm equivalent concentration of isophorone in
saturated air can then be calculated from the relationship:
(mg/1) (24,450 ml/mole) = ffl
mw
(3.27 mg/1) (24,450 ml/mole)
138.21 g/mole 578 ppm'
C-29
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