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Isophorone
CASRN 78-59-1
Contents
0063
Isophorone; CASRN 78-59-1
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Isophorone
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 01/01/1991
Inhalation RfC Assessment (I.B.) message 03/01/1991
Carcinogenicity Assessment (II.) on-line 11/01/1992
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Isophorone
CASRN -- 78-59-1
Last Revised -- 01/01/1991
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
No observed effects NOEL: 150 mg/kg/day 1000 1 2E-1
mg/kg/day
90-Day Dog Feeding LEL: None
Study
Nor-Am Agricultural
Products, Inc., 1972a
Kidney pathology NOEL: None
2-Year Rat Gavage LEL: 250 mg/kg/day
Study (179 mg/kg/day)
NTP, 1984
*Conversion Factors: The LEL of 179 mg/kg/day is based on a 5 day/week
treatment schedule
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Nor-Am Agricultural Products, Inc. 1972a. MRID No. 00123976. Available from
EPA. Write to FOI, EPA, Washington, DC 20460.
NTP (National Toxicology Program). 1984. NTP Technical Report on the
Toxicology and Carcinogenisis Studies of Isophorone in F344/N Rats and B63F1
Mice (Gavage). NIH Publication No. 84-2547, NTP-83-168.
Beagle dogs (4/sex/dose) were administered gelatin capsules containing 0, 35,
75, or 150 mg isophorone/kg/day 7 days/week for 90 days (Nor-Am Agricultural
Products, 1972a). All dogs survived the study in good condition. Food
consumption was within normal LIMITS and body weight was not affected by
treatment. All organs appeared normal at gross examination and no significant
changes in organ weight were produced with the ingestion of isophorone. There
were no definitive signs of cellular change in any of the tissues examined. A
NOEL for systemic toxicity was established at 150 mg/kg/day (HDT) due to the
lack of effects produced at any dose tested.
NTP (1984) administered 0, 250, or 500 mg isophorone/kg/day, 5 days/week for
103 weeks by corn oil gavage to groups of 50 F344/N rats/sex and 50 B63F1
mice/sex (averaged daily doses: 0, 179, and 357 mg/kg/day). Doses selected
for the 2-year studies were based on 16-day repeated-administration studies in
which rats and mice of each sex received 0-2000 mg/kg/day and on 13-week
studies in which rats and mice of each sex received doses ranging from 0-1000
mg/kg/day by corn oil gavage.
Dosed male rats showed a variety of proliferative lesions of the kidney
(tubular cell hyperplasia, 0/50, 1/50, 4/50; tubular cell carcinoma, 0/50,
0/50, 2/50; tubular cell adenocarcinoma, 0/50, 3/50, 0/50; and epithelial
hyperplasia of the renal pelvis, 0/50, 5/50, 5/50 in the 0, 250, and 1000
mg/kg/day, respectively). Dosed male rats also exhibited increased
mineralization of the medullary collecting ducts (1/50, 31/50, 20/50 in the 0,
250, and 1000 mg/kg/day, respectively), and male rats receiving 250 mg/kg/day
showed a more severe nephropathy than is commonly seen in aging F344/N rats.
With the exception of a moderate increase in nephropathy, female rats did not
show chemically related increased incidences of neoplastic or nonneoplastic
lesions.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- An uncertainty factor of 100 was used to account for the inter- and
intraspecies differences. An additional UF of 10 was used to account for the
use of a subchronic study. (The use of the chronic study to estimate the RfD
would not evoke this latter 10-fold factor, but would necessitate a 10-fold
factor for the use of a LOAEL. In either case the RfD is the same.)
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Data Considered for Establishing the RfD
1) 90-Day Feeding - dog: Principal study - see previous description; core
grade minimum
2) NTP 2-Year Bioassay - rats and mice: Co-principal study - see previous
description; no core grade (NTP, 1984)
3) 90-Day Feeding - rat: Isophorone was fed in the diet to CFE weanling rats
(20/sex/dose) at levels of 0, 750, 1500, and 3000 ppm (Male: 0, 57, 102.5, and
233.8 mg/kg/day; Female: 0, 78.9, 163.8, and 311.8 mg/kg/day) for 90 days.
The only effect noted was decreased body weights for males in the high-dose
group for several weeks. Body weights were not different from controls by the
end of the study. (Note: Dosing in the 90-day rat study was in the diet
[prepared weekly], but in the two principal studies animals were dosed by
gavage. Since the stability of isophorone in feed has not been determined,
the actual dosage levels in the 90-day rat study are unknown); (Nor-Am
Agricultural Prod., Inc., 1972b)
Data Gap(s): Chronic Rat Feeding Study, Chronic Dog Feeding Study, Rat
Reproduction Study, Rat Teratology Study, Rabbit Teratology Study, Mouse
Oncogenicity Study
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Low
RfD -- Low
The critical study is of adequate quality and is given a medium confidence
rating. Since numerous data gaps exist for isophorone, the data base is given
a low confidence rating. Low confidence in the RfD follows.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- U.S. EPA, 1980
The ADI in the Ambient Water Quality Criteria Document was extensively
reviewed by the Agency and was reviewed by the public.
Other EPA Documentation -- Pesticide Registration Files
Agency Work Group Review -- 12/02/1985, 02/05/1986, 05/15/1986, 03/22/1989, 05/18/1989
Verification Date -- 05/18/1989
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Isophorone
CASRN -- 78-59-1
The health effects data for isophorone were reviewed by the U.S. EPA
RfD/RfC Work Group and determined to be inadequate for derivation of an
inhalation RfC. The verification status of this chemical is currently not
verifiable. For additional information on health effects of this chemical,
interested parties are referred to the EPA documentation listed below.
U.S. EPA. 1980. Ambient Water Quality Criteria Document 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. NTIS PB 81-117673.
U.S. EPA. 1986. Health and Environmental Effects Profile for Isophorone.
Prepared by the Office of Health and Environmental Assessment, Environmental
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC. NTIS PB 88-242359/AS.
Agency Work Group Review -- 11/15/1990
EPA Contacts:
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Isophorone
CASRN -- 78-59-1
Last Revised -- 11/01/1992
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- C; possible human carcinogen
Basis -- Based on no data in humans; limited evidence of carcinogenicity of
one tumor type in one sex of one animal species as shown by an increase of
preputial gland carcinomas in male rats. The apparent renal tubular cell
tumor in the male rat is associated with alpha-2u-globulin, considered to be
of questionable relevance to humans.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Limited. Evidence of carcinogenicity is limited to one sex of one animal
species as shown by an increased incidence of preputial gland tumors in male
rats; an apparent increase in hepatocellular and integumentary tumors in male
mice was complicated by high mortality. No increases were seen in females of
either species.
NTP (1986) administered isophorone via corn oil gavage to F344/N rats
(50/sex/group) at 0, 250 and 500 mg/kg/day, 5 days/week for 103 weeks.
Preputial gland carcinomas were reported in 5 males in the high-dose group; no
tumors were reported in the control or low-dose groups.
Survival of high-dose male rats (28%) was significantly reduced after 96
weeks compared with controls (66%) and low-dose males (66%). The first
preputial gland tumor appeared at week 56. The tumor incidences, after
adjustment for survival, were 0/49, 0/46 and 5/44 for control, low- and high-
dose groups, respectively. The positive trend in tumor incidence was
statistically significant by the Life Table Test. The tumor incidence in the
high-dose group was statistically significantly elevated when compared with
the NTP historical controls (i.e., 12/1094 as of 1986) by the Fisher Exact
Test. After survival adjustment, this group differed from the concurrent
control as well. The treated male rats showed renal cell hyperplasia and a
small number of renal tubular cell adenomas and adenocarcinomas after week 99
when the survival rate was down to 32%. Female rats showed a moderate
increase in nephropathy, with no neoplastic lesions.
Detailed review and analysis show that the isophorone induced male rat
kidney tumor has met the criteria established by the U.S. EPA for associating
renal tumors with alpha-2u-globulin (U.S. EPA, 1991a). The criteria were met
as follows: (1) there was an increased number and size of hyaline droplets in
renal proximal tubule cells of treated male rats; (2) the accumulating protein
in the hyaline droplets was alpha-2u-globulin (Strasser et al., 1988); (3)
additional aspects of the pathological sequence of lesions associated with
alpha-2u-globulin nephropathy were present; (4) sex and species-specificity
were demonstrated: the formation of renal tumors was specific to male rats;
(5) there was noncovalent binding between isophorone and alpha-2u-globulin
(Thier et al., 1990); and (6) the presence of isophorone decreased alpha-2u-
globulin degradation (Lehman-McKeeman et al., 1990). The renal tubular cell
tumor induced by isophorone in the male rat is associated with alpha-2u-
globulin, a protein specific to male rats, and is, therefore, considered to
have questionable relevance to humans (U.S. EPA, 1991a).
In the same study by NTP (1986), B6C3Fl mice (50/sex/group) were
administered isophorone by gavage at 0, 250 and 500 mg/kg/day, 5 days/week for
2 years. Survival of male mice was very low for control and treated animals
(32, 32 and 38% for control, low- and high-dose mice, respectively). Dosed
male mice showed an increased frequency of coagulative necrosis and
hepatocytomegaly as compared to controls. In the high-dose male mice,
isophorone exposure appeared to be associated with increased incidence of
hepatocellular adenomas or carcinomas (combined incidence: control, 18/48;
low-dose, 18/50; and high-dose, 29/50) and of mesenchymal tumors of the
integumentary system such as fibromas, fibrosarcomas, neurofibrosarcomas or
sarcomas (incidence of combined tumors: control, 6/48; low-dose, 8/50; and
high-dose, 14/50). An increased incidence of lymphomas or leukemias was
reported in the low-dose male mice (18/50) when compared to vehicle controls
or high-dose males (8/48 and 5/50, respectively). The survival of male mice,
however, was low (final rates: control, 16/50; low-dose, 16/50; and high-dose,
19/50). No significant elevation or trends for these sites was found when the
data were analyzed with the Life Table Test. The survival was so low in both
the treatment and control groups that the NTP and U.S. EPA consider the
results in male mice to be "equivocal." No treatment-related neoplasms were
observed in female mice.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Isophorone was not mutagenic in Salmonella/microsome assays, but a
positive response was reported at moderately high concentrations (greater than
or equal to 400 ug/mL) without S9 activation in the L5178Y tk+/tk- mouse
lymphoma cell forward mutation assay (McGregor et al., 1988). In the absence
of S9 mix, isophorone induced sister chromatid exchanges in the Chinese
hamster ovary cell but chromosomal aberrations in these cells were not induced
either with or without S9 mix (NTP, 1986).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1.SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 9.5E-4 per (mg/kg)/day
Drinking Water Unit Risk -- 2.7E-8 per ug/L
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
------------------------------------
E-4 (1 in 10,000) 4E+3 ug/L
E-5 (1 in 100,000) 4E+2 ug/L
E-6 (1 in 1,000,000) 4E+1 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- preputial gland carcinoma
Test Animals -- rat/F344/N, male
Route -- oral, gavage
Reference -- NTP, 1986
---- Dose ----- Tumor
Admin- Human Incidence
istered Equivalent
(mg/kg)/day (mg/kg)/day
----------- ----------- ---------
0 0 0/49
179 32 0/46
357 64 5/44
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The tumor incidences were adjusted for survival by subtracting the animals
that died before the first tumor appearance at week 56 from the initial number
of 50 animals in each denominator.
The human equivalent dose was determined using a surface area correction
factor. The daily adjusted animal dose (i.e., the administered animal dose
multiplied by 5/7 to adjust from 5 to 7 days), is divided by a ratio of the
human weight (70 kg) to rat weight (0.4 kg) raised to the 1/3 power.
The unit risk should not be used if the water concentration exceeds 4E+5
ug/L, since above this concentration the slope factor may differ from that
stated.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
An adequate number of rats were observed and treated for an adequate
duration of exposure at two dose levels and controls. The compound was given
to the animals by gavage rather than in feed or drinking water. Exposure to a
chemical by gavage can give different results than through drinking water. The
crude adjustment for survival may not result in the same unit risk that would
be obtained using a model also incorporating time-to-tumor, because the dose
groups differed significantly in their survival experiences.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1991b
The 1991 Drinking Water Health Advisory for Isophorone has received Agency
review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 05/03/1989, 10/05/1989, 06/02/1992, 06/03/1992, 08/05/1992
Verification Date -- 08/05/1992
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Isophorone
CASRN -- 78-59-1
Last Revised -- 11/01/1992
__VI.A. ORAL RfD REFERENCES
Nor-Am Agricultural Products, Inc. 1972a. MRID No. 00123976. Available from
EPA. Write to FOI, EPA, Washington DC. 20460.
Nor-Am Agricultural Products, Inc. 1972b. MRID No. 00123977. Available from
EPA. Write to FOI, EPA, Washington DC. 20460.
NTP (National Toxicology Program). 1984. NTP Technical Report on the
Toxicology and Carcinogenisis Studies of Isophorone in F344/N Rats and B63F1
Mice (Gavage). NIH Publication No. 84-2547, NTP-83-168.
U.S. EPA. 1980. Ambient Water Quality Criteria Document for Isophorone.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste,
Washington, DC. EPA 440/5-80-056. NTIS PB 81-117673.
__VI.B. INHALATION RfC REFERENCES
U.S. EPA. 1980. Ambient Water Quality Criteria Document 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. NTIS PB 81-117673.
U.S. EPA. 1986. Health and Environmental Effects Profile for Isophorone.
Prepared by the Office of Health and Environmental Assessment, Environmental
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC. NTIS PB 88-242359/AS.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Lehman-McKeeman, L.D., M.I. Rivera-Torres and D. Caudill. 1990. Lysosomal
degradation of a2u-globulin and a-2u-globulin-xenobiotic conjugates. Toxicol.
Appl. Pharmacol. 103(3): 539-548.
McGregor, D.B., A. Brown, P. Cattanach et al. 1988. Response of the L5178Y
tk+/tk- mouse lymphoma cell forward mutation assay. III. 72 coded chemicals.
Environ. Molec. Mut. 12: 85-154.
NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis
studies of isophorone (CAS No. 78-59-1) in F344/N rats and B6C3F1 mice (gavage
studies). NTP TR-29l. NIH Pub. No. 86-2547.
Strasser, J., Jr., M. Charbonneau, S.J. Borghoff, M.J. Turner and J.A.
Swenberg. 1988. Renal protein droplet formation in male Fischer 344 rats
after isophorone (IPH) treatment. Toxicologist. 8(1): 136.
Thier, R., H. Peter, H.J. Wiegand and H.M. Bolt. 1990. DNA binding study of
isophorone in rats and mice. Arch. Toxicol. 64: 684-685.
U.S. EPA. 1991a. Alpha(2u)Globulin: Association with Chemically Induced
Renal Toxicity and Neoplasia in the Male Rat. EPA/625/3-91/019F.
U.S. EPA. l991b. Drinking Water Health Advisory on Isophorone. Office of
Water, Washington, DC.
_VII. REVISION HISTORY
Substance Name -- Isophorone
CASRN -- 78-59-1
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1988 I.A.2. Principal study corrected
06/30/1988 I.A.2. Principal study year corrected
04/01/1989 I.A. Oral RfD summary noted as pending change
06/01/1989 I.A. Withdrawn; new Oral RfD verified (in preparation)
06/01/1989 II. Carcinogen assessment now under review
09/01/1989 I.A. Oral RfD summary replaced; RfD changed
09/01/1989 VI. Bibliography on-line
07/01/1990 II. Carcinogen summary on-line
07/01/1990 IV.F.1. EPA contact changed
07/01/1990 VI.C. Carcinogen references added
08/01/1990 II.D.2. Verification date corrected and review date added
12/01/1990 I.B. Inhalation RfC now under review
01/01/1991 I.A. Text edited
01/01/1991 II. Text edited
03/01/1991 II.D.3. Secondary contact changed
03/01/1991 I.B. Inhalation RfC message on-line
03/01/1991 VI.B. Inhalation RfC references added
04/01/1991 VI.C. Carcinogen references added
01/01/1992 IV. Regulatory actions updated
05/01/1992 II. Carcinogenicity assessment noted as pending change
09/01/1992 II.D.2. Work group review dates added
10/01/1992 II. Carcinogenicity assessment replaced; new oral quant.
10/01/1992 VI.C. Carcinogenicity references replaced
11/01/1992 II.D.2. Dates corrected
VIII. SYNONYMS
Substance Name -- Isophorone
CASRN -- 78-59-1
Last Revised -- 01/31/1987
78-59-1
Isoacetophorone
Isoforon
Isophoron
alpha-Isophoron
Isophorone
alpha-Isophorone
3,5,5-Trimethyl-2-cyclohexenone
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0063.HTM
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