Cyclohexanone (CASRN 108-94-1)
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0219
Cyclohexanone;
CASRN 108-94-1
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 Cyclohexanone
File First On-Line 09/30/1987
Category (section) |
Status |
Last Revised |
---|---|---|
Oral RfD Assessment (I.A.) | on-line | 09/30/1987 |
Inhalation RfC Assessment (I.B.) | no data | |
Carcinogenicity Assessment (II.) | no data |
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Cyclohexanone
CASRN — 108-94-1
Last Revised — 09/30/1987
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 |
---|---|---|---|---|
Body weight Chronic Rat Oral Lijinsky and Kovatch, |
NOAEL: 3300 ppm in LOAEL: 6500 ppm in |
100
|
1
|
5E+0
mg/kg/day |
*Conversion Factors: Water intake = 49 mL/day; rat body weight = 0.35 kg
__I.A.2. Principal and Supporting Studies (Oral RfD)
Lijinsky, W. and M. Kovatch. 1986. A chronic toxicity study of cyclohexanone
in rats and mice (NCI study). J. Natl. Cancer Inst. 77(4): 941-949.
A chronic bioassay study with cyclohexanone was conducted with F344 rats and
B6C3F1 mice (Lijinsky and Kovatch, 1986). Cyclohexanone was administered as a
solution in the drinking water; rats were dosed at 3300 or 6500 ppm levels,
male mice at 6500 or 13,000 ppm, and female mice at 6500, 13,000 or 25,000 ppm
levels. Each treatment group consisted of 52 animals/sex for both mice and
rats. Survival and weight gain were similar to the controls in both sexes of
either species treated with the lowest dosage of cyclohexanone, but weight
gain was depressed at all of the higher doses. Female mice treated with both
the higher doses (13,000 or 25,000 ppm) and male mice treated with the high
dose (13,000 ppm) exhibited increased mortality as compared with controls;
50% of the females treated with 25,000 ppm cyclohexanone survived beyond 1
year. Based on these effects, the 3300 ppm cyclohexanone (converted to 462
mg/kg/day) in rats is considered the NOAEL, whereas the high dose (6500 ppm or
910 mg/kg/day) that causes decreased body weight gain was considered the LOAEL
in rats.
__I.A.3. Uncertainty and Modifying Factors (Oral RfD)
UF — An uncertainty factor of 100 was applied; 10 for interspecies
extrapolation and 10 for intraspecies variability among the human population.
MF — None
__I.A.4. Additional Comments (Oral RfD)
In a French study by Gondry (1973), pregnant mice were administered a diet
containing 1% (approximately 1300 mg/kg/day) cyclohexanone throughout their
gestation and lactation period. An increased rate of neonatal mortality was
observed during the first 21 days of life. Details of this study were
unavailable. Schroeder (1984) evaluated the embryotoxic and teratogenic
effects of cyclohexanone in rats exposed through inhalation at 0, 320, 680,
and 1430 ppm levels during 9-16 days of gestation. Evaluation of teratologic
data showed no incidence of teratogenicity in rats treated with any of the
above doses, whereas the high dosage caused significant depression of both
maternal and fetal body weights. Therefore, the high dose, 1430 ppm (457
mg/kg/day) was a LOAEL and the mid dose, 686 ppm (219 mg/kg/day) was
considered to be a NOEL for maternotoxicity and fetotoxicity in rats.
The National Cancer Institute conducted subchronic toxicity studies of 95 to
175 days duration in mice and rats, respectively (NCI, 1979). The doses were:
0, 200, 425, 850, 1700, 3500, 5000, or 7000 ppm for rats; and 0, 425, 2400,
7000, 14,000, 26,000, 36,000, or 50,000 ppm for mice. The toxicologic
endpoints in this study included mortality, body and organ weight changes,
clinical observations, and histopathologic evaluations of the target organs.
The results of the rat study indicated no effect on survival in either sex at
any of the dosage levels, but a depression of body weight was seen in both
sexes exposed to 7000 ppm cyclohexanone. The study with mice indicated
depression of weight gain at 14,000 ppm or higher levels in males, at 36,000
ppm or higher levels in females, and decreased survival in both sexes at the
high-dose level (50,000 ppm). Cyclohexanone was administered in water (v/v).
Assuming a 0.35 kg rat drinks 49 mL water/day, and applying a correction
factor of 0.95 (to account for the specific gravity), 5000 ppm cyclohexanone
dosage was converted to 665 mg/kg/day. This dose was considered to be the
highest NOEL. However, this dose is higher than the dose of 457 mg/kg/day
(LOAEL), which produced fetal and maternal weight gain depression in the
inhalation study of Schroeder (1984). Furthermore, the derivation of an oral
RfD using inhalation data may present uncertainties associated with route-to-
route extrapolation. Therefore, the NOAEL (462 mg/kg/day) from the Lijinsky
and Kovatch (1986) study is preferred as the basis for RfD derivation.
__I.A.5. Confidence in the Oral RfD
Study — High
Database — Medium
RfD — Medium
The principal study was based on an NCI cancer bioassay oral study with adequate toxicologic endpoints where mice and rats were used; high confidence is assigned. Adequate supporting subchronic studies and other reproductive studies were available in the database to warrant medium confidence. Therefore, the RfD is assigned a medium confidence level.
__I.A.6. EPA Documentation and Review of the Oral RfD
Source Document — This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation — None
Agency Work Group Review — 06/11/1986, 09/02/1986
Verification Date — 09/02/1986
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Cyclohexanone conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.
__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Substance Name — Cyclohexanone
CASRN — 108-94-1
Not available at this time.
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name — Cyclohexanone
CASRN — 108-94-1
This substance/agent has not undergone a complete evaluation and determination
under US EPA's IRIS program for evidence of human carcinogenic potential.
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_VI. Bibliography
Substance Name — Cyclohexanone
CASRN — 108-94-1
Last Revised — 08/01/1989
_VI.A. Oral RfD References
Gondry, E. 1973. Toxicity of cyclohexylamine, cyclohexanone, and
cyclohexanol and metabolites of cyclamate. J. Environ. Toxicol. 5: 227-238.
Lijinsky, W. and M. Kovatch. 1986. A chronic toxicity study of cyclohexa-
none in rats and mice (NCI study). J. Natl. Cancer Inst. 77(4): 941-949.
NCI (National Cancer Institute). 1979. Summary and experimental design of
subchronic studies of cyclohexanone. Final Report.
Schroeder, R.E. 1984. An inhalation teratology study in rats with
cyclohexanone. Bio/Dynamics, Division of Biology and Safety Evaluation.
Submitted to Industrial Health Foundation, Pittsburgh, PA. Final report.
Project No. 83-2719.
_VI.B. Inhalation RfD References
None
_VI.C. Carcinogenicity Assessment References
None
_VII. Revision History
Substance Name — Cyclohexanone
CASRN — 108-94-1
Date |
Section |
Description |
---|---|---|
08/01/1989 | VI. | Bibliography on-line |
01/01/1992 | I.A.7. | Secondary contact changed |
01/01/1992 | IV. | Regulatory actions updated |
04/01/1997 | III., IV., V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
12/03/2002 | I.A.6. | Screening-Level Literature Review Findings message has been added. |
_VIII. Synonyms
Substance Name — Cyclohexanone
CASRN — 108-94-1
Last Revised — 09/30/1987
- 108-94-1
- ANONE
- CICLOESANONE
- CYCLOHEXANON
- Cyclohexanone
- CYKLOHEKSANON
- HEXANON
- HYTROL O
- KETOHEXAMETHYLENE
- NADONE
- NCI-C55005
- PIMELIC KETONE
- PIMELIN KETONE
- RCRA WASTE NUMBER U057
- SEXTONE
- UN 1915