TECHNICAL REPORT DATA
(Pleat reed li*a\icnons on the reverie before completing/
1. REPORT NO.
EPA/600/8-88/044
2.
3. RECIPIENT'S ACCESSION NO
PB88-179916/AS
4. TITLE AND SUBTITLE
5. REPORT DATE
Health Effects Assessment for Isophorone
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME ANO ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT ANO PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is sn estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The .RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data If available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENOE D TERMS c. COSATI Field/Croup
8. DISTRIBUTION STATEMENT
19. SECURITY CLAS> (Thu Report!
21. NO. OF PAGES
Public
20. SECURITY CLASS
Unclassified
22. PRICE
EPA Farm 2220-1 (R«». 4-77) PKCVIOUB EDITION n OBSOLETE
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EPA/600/8-88/044
May, 1987
HEALTH EFFECTS ASSESSMENT
FOR ISOPHORONE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
U.S. Environmental Protection Agency
R3gion 5, Library (5PL-16)
?-'/0 £- Dearborn Sr.'.-.et, Hocm 1670
Chicago, IL 60004
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DISCLAIMER
This document has been reviewed In accordance with the U S
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with Isopho-
rone. All estimates of acceptable Intake and carcinogenic potency presented
1n this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-Hne literature searches of the TOXLINE,
CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature
searched supporting this document 1s current up to May, 1986. Secondary
sources of Information have also been relied upon In the preparation of this
report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Isophorone. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 400/5-80-056. NTIS P881-117673.
U.S. EPA. 1980b. Hazard 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, Washington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for
Isophorone. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Integrated Risk Information System (IRIS).
Reference Dose (RfD) for Oral Exposure for Isophorone. Online
(verification date 11/16/86). Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,
C1nc1rnat1, OH.
The Intent In these assessments Is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the llfespan).
111
-------
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants in ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD^j) and oral (RfD$0)
exposures.
The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980c) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfOrj) or Inhalation (RfOi) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of carclnogenlclty
RfD$ and RfO values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980c). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data if available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The U.S. EPA (1986a) computed a q-|* for human oral exposure to
Isophorone of 4.1xlO~3 (mg/kg/day)"1 based on the Increased Incidence of
kidney and preputlal gland tumors 1n male rats In a 2-year gavage study
(NTP, 1986). In the same study. Increased Incidence of liver tumors and
tumors of the skin were observed In male mice.
No data concerning the potential carclnogenlclty of Isophorone following
Inhalation exposure were located 1n the literature. Therefore, an Inhala-
tion q-j* was not calculated.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
,PPE
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA. ...
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) AND REFERENCE
DOSE (RfD)
6.2. CARCINOGENIC POTENCY (qi*)
6.2.1. Oral
6.2.2. Inhalation. . .
REFERENCES. . ,
NDIX: Oral Summary Table for Isophrone 1n the Male Rat ....
Page
1
3
... 3
... 3
4
4
... 4
... 5
... 5
. . . 5
6
6
. . . 6
7
. . . 8
. . . 9
. . . 9
. . . 9
. . . 9
. . . 12
. . . 12
. . . 12
. . . 13
14
. . . 14
. , , 14
. . . 14
. . . 14
. . . 16
. . . 21
V11
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LIST OF ABBREVIATIONS
AOI Acceptable dally Intake
CAS Chemical Abstract Service
CS Composite score
ONA Deoxyrlbonuclelc acid
Koc Soil sorptlon coefficient
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PEL Permissible exposure limit
ppm Parts per million
RfD Reference dose
RfD$ Subchronlc reference dose
RVj Dose-rating value
RVe Effect-rating value
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
Isophorone are presented In Table 1-1.
In the atmosphere, Isophorone should exist primarily 1n the vapor phase
and 1s expected to react with ozone and photochemically generated HO radi-
cal. The atmospheric half-life listed In Table 1-1 has been based on the
contribution of both ozone and HO radical reactions. It Is also estimated
using an estimated ozone reaction rate constant of S.OxlO-16 cmVmole-
cule-sec at 25°C, an ambient ozone concentration of IxlO12 molecules/
cm3, an estimated hydroxyl reaction rate constant of 8.14X10-11 cm3/
molecule-sec at 25°C and an ambient hydroxyl concentration of 8.0x10*
molecule/cm3 (U.S. EPA, 1986c). Considering Us relatively high water
solubility, dissolution of Isophorone Into clouds and removal 1n rainfall
may be significant fate processes. The half-life of Isophorone In water and
soil was not located In the literature searched; however, blodegradatlon may
be an Important fate process both In water and soil (Tabar et a!., 1981).
Adsorption to suspended solids and sediments In water and b1oaccumulat1on In
aquatic organisms are not expected to be significant fate processes. Based
on Us estimated K value of 25, Isophorone should be highly mobile 1n
soil (Swann et al., 1983) and leaching Into ground water may occur.
0084h -1- 01/26/87
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TABLE 1-1
Selected Chemical and Physical Properties
and Environmental Fate of Isophorone
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
B1oconcentrat1on factor:
Soil adsorption
coefficient:
Half-lives:
A1r
Water
Soil
78-59-1
unsaturated monocycllc
ketone
138.2
0.38 mm Hg at 20°C
0.44 mm Hg at 25°C
12.000 mg/i at 20°C
2.22 (estimated)
1.7 (estimated)
7, bluegUl sunflsh
(Lepomls macrochlrus)
25 (estimated)
32 minutes (estimated)
NA
NA
Verschueren, 1983
U.S. EPA, 1980a
U.S. EPA, 1976
U.S. EPA, 1986b
Callahan et al., 1979
U.S. EPA, 1980a
Lyman et al., 1982
U.S. EPA, T986c
NA
NA
NA = Not available
0084h
-2-
01/26/87
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2. ABSORPTION IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Quantitative data regarding the absorption of Isophorone from the oral
route of administration could not be located In the available literature.
Isophorone Is absorbed by the gastrointestinal tracts of rats and rabbits as
Indicated In a study by Dutertre-Catella et al. (1978), where unchanged
Isophorone and metabolites were detected In the urine of rats and rabbits 24
hours after oral dosing with Isophorone.
2.2. INHALATION
Quantitative data regarding the absorption of Isophorone from the Inha-
lation route could not be located 1n the available literature. Absorption
of Isophorone after Inhalation can be Inferred from studies by Smyth et al.
(1942) and Hazelton Labs, Inc. (1968) that show systemic toxldty following
Inhalation exposure to Isophorone.
0084h -3- 09/04/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SU8CHRONIC
3.1.1. Oral. AME, Inc. (1972a) fed groups of 20 male and 20 female CFE
weanling rats Isophorone In their diets at 0, 750, 1500 or 3000 ppm for 90
days (TWA doses of 0, 61.1, 123.1 or 250.5 mg/kg/day, males; 0, 82.7, 170.4
or 323.8 mg/kg/day, females). The only effect observed was a significant
(p<0.01) decrease In mean body weight gain after 6 weeks In males receiving
250.5 mg/kg/day. The parameters examined were appearance, behavior,
hematology, clinical chemistry, urlnalysls, organ weights, and gross and
hlstopathologlcal examination of major organs.
AME, Inc. (1972b) dosed groups of four male and four female beagle dogs
orally with Isophorone 1n gelatin capsules at 0, 35, 75 or 150 mg/kg/day for
7 days/week for 90 days. Dogs treated with 75 or 150 mg/kg/day had soft and
loose stools. No effects on appearance, behavior, hematology, clinical
chemistry, urlnalysls, organ weights and pathology of organs were noted at
any dose level.
NTP (1986) conducted a 13-week study, 1n which groups of 10 male and 10
female Fischer 344/N rats and equal numbers of B6C3F1 mice received Isopho-
rone 1n corn oil by gavage. Hats and mice received doses of 0, 62.5, 125,
500 or 1000 mg/kg/day, 5 days/week. Hlstopathologlcal examination was
performed only on controls anc high-dose rats and mice. Rats treated with
1000 mg/kg/day were lethargic after dosing. In addition, deaths of one
female rat and three female ir.lce at 1000 mg/kg/day were considered to be
compound-related. There were no effects or gross appearance at necropsy or
hlstologlcal appearance of a comprehensive selection of organs and tissues
from high-dose rats and mice, when compared with controls.
0084h -4- 01/26/87
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3.1.2. Inhalation. In a study by Hazelton Labs, Inc. (1968), groups of
10 male and 10 female young adult Charles River CD rats were exposed to
Isophorone at average dally air concentrations of 0 or 0.208 mg/i (208
mg/m3), 6 hours/day, 5 days/week for 4 weeks. The effects observed 1n the
exposed rats were transient nasal bleeding. Increased percentages of lympho-
cytes, decreased percentages of neutrophlls and Increased hemoglobin concen-
tration In males and females. Significantly lower terminal body weights and
significantly decreased absolute and relative liver weights of exposed
males, as compared with controls, were also observed.
An earlier subchronlc Inhalation study, using commercial samples of
Isophorone, with rats and guinea pigs, was conducted by Smyth et al. (1942).
The U.S. EPA (1980a) has stated that 1f pure Isophorone had been used 1n
this study, the air concentrations of Isophorone reported by Smyth et al.
(1942) could not have been attained under the conditions employed. Because
the results of the Smyth et al. (1942) study are seriously compromised,
details of this study will not be reviewed here. Effects observed 1n rats
and guinea pigs exposed to Isophorone at unspecified concentrations were
pale or brown kidneys, pale livers, congested spleens and lungs, and
discolored bile.
3.2. CHRONIC
3.2.1. Oral. In the NTP (1986) study, groups of 50 male and 50 female
F344 rats and equal numbers of B6C3F1 mice were dosed with 0, 250 or 500
mg/kg Isophorone In corn oil by gavage.'S days/week for 103 weeks. During
the study, body weights were recorded and clinical signs were noted. At 103
weeks, survivors were necropsled, organs were examined for gross lesions and
examined microscopically. Tumor Incidences are presented 1n Section 4.2.1.
0084h -5- 09/04/86
-------
In rats, mean body weights of high-dose males averaged -5% lower than
vehicle controls after 1 week. Mean body weights of high-dose females
averaged -8% lower than vehicle controls after week 43. No compound-related
clinical signs were noted. Survival of the high-dose group of male rats was
significantly lower than vehicle controls after 196 weeks.
In the kidneys of dosed male rats, tubular cell mineralization was
Increased. This lesion, characterized by basophlUc aggregates of mineral,
was often found In medullary collecting ducts and occurred colnddentally
with lesions of chronic nephropathy. Fatty metamorphosis of the adrenal
cortex was observed to Increase In dosed male but not female rats; this
lesion was most often observed tn the zona fasclculata.
In mice, mean body weights of high-dose females averaged 5/4 lower than
vehicle controls during the second year of the study. No body weight
differences were noted between male treated and control mice. No compound-
related clinical signs were noted. Survival of treated female mice was
significantly (p<0.005) greater than vehicle controls. In males, survival
was adversely affected by fighting. H1stopatholog1cal examination of the
kidneys of male mice revealed a dose-related Increase In chronic focal
Inflammation.
3.2.2. Inhalation. Ware (1973) Indicated that workers exposed to Isopho-
rone at levels of 5-8 ppm for 1 month complained of fatigue and malaise.
When levels were reduced to 1-4 ppm, the complaints ceased.
Further Information regarding the effects of chronic Inhalation exposure
to Isophorone could not be located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.T. Oral. No pertinent data regarding teratogenlc and reproductive
effects after oral exposure were located 1n the available literature.
0084h -6- 01/26/87
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3.3.2. Inhalation. The CMA sponsored two Inhalation teratogenicHy
studies. In the first study, groups of 12 pregnant Fischer 344 rats and 12
GDI mice were exposed to Isophorone at 0, 50, 100 or 150 ppm (0, 141, 283 or
848 mg/m3) 6 hours/day, on days 6-15 of gestation (B1o Dynamics, Inc.,
1984). The animals were weighed and examined externally on gestation days
3, 6, 9, 12 and 16. On day 16, the animals were killed, the number of live
and dead fetuses were counted and the fetuses were examined for abnormal-
ities.
The results Indicated no consistent changes 1n body weights of dams.
Food consumption for rats exposed to 150 ppm Isophorone was lower than food
consumption for controls. Food consumption for mice was not reported.
Signs of toxldty observed 1n rat dams, especially those exposed to 100 and
150 ppm, were alopecia, excessive lacrlmatlon, yellow stains In the
ano-gen1tal area and tan, yellow or red material around the mouth, eyes or
lower jaw. At least one of these signs was observed In all rats exposed to
100 or 150 ppm Isophorone. Similar toxic signs were observed In only two
mice exposed to 100 ppm and two mice exposed to 150 ppm Isophorone. The
only fetal effect noted In rats was a late resorptlon In one 150 ppm Utter
1n which one rat had brain tissue protruding from the cranium. In mice,
exencephaly was observed In two 150 ppm Utters. In one of those Utters
exencephaly was observed 1n a later resorptlon, and 1n the other Utter, the
same abnormality was observed In two live fetuses. No abnormalities were
observed 1n control Utters.
0084h -7- 01/26/87
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3.4. TOXICANT INTERACTION
Smyth et al. (1969, 1970) studied the toxldty of all possible pairs of
27 Industrial chemicals. Including Isophorone. Female albino rats were
given the chemicals by gavage and LD5Qs were determined. Isophorone,
paired with the other chemicals, did not cause the LD5Q to deviate greatly
from predicted.
0084h -8- 01/26/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data concerning cardnogenldty of Isophorone In humans by
either oral or Inhalation routes could not be located In the available
literature.
4.2. BIOASSAYS
4.2.1. Oral. In an NTP (1986) study, groups of 50 male and 50 female
Fischer 344/N rats and equal numbers of B6C3F1 mice were treated by gavage
with Isophorone (94-97% pure) In corn oil at doses of 250 or 500 mg/kg/day,
5 days/week for 103 weeks. Control groups of rats and mice received corn
oil. At 105 weeks, surviving animals were sacrificed; complete necropsies
and comprehensive hlstologlcal examinations were performed on all rats and
mice that died during the study (unless precluded by advanced autolysls or
cannibalism), that were moribund and killed during the study or that were
killed at the end of the study.
After 96 weeks,the survival of the high-dose male rats was significantly
reduced. This decline occurred late enough In the study so that late
developing tumors could be detected. Results (Table 4-1) showed that male
rats had an Increased Incidence (adjusted for Intercurrent mortality) of
tubular cell adenoma or adenocardnoma (combined.) of the kidney. These
effects on the kidney were significant for the high-dose group by the life
table test and significant for dose-related trend by the life table and
incidental tumor tests, but not significant by the Cochran-Armltage or
Fisher Exact tests. The occurrence of kidney tumors 1s noteworthy .In that
kidney tumors are rarely observed In this strain of rats; comparison of
Incidence In the low-dose group and high-dose group with historical controls
(0.4X) showed a significant Increase (p=0.002) by the Fisher Exact test.
0084h -9- 01/26/87
-------
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-------
In male rats, the Increased Incidence of carcinoma of the preputial gland
showed a significant dose-related trend by all statistical methods. Tumors
of this type have been observed at a very low Incidence (12/1094) In
historical corn oil vehicle control rats; therefore NTP (1986) stated that
carcinoma of the preputlal gland may be compound-related. A significantly
higher Incidence of adnar cell carcinoma of the pancreas was also observed
1n the high-dose male rats as compared with controls. Because the histori-
cal Incidence of adnar cell tumors In corn oil treated rats 1s relatively
high, NTP (1986) suggested that Isophorone was possibly acting as a co-
cardnogen or promoter of the effect of corn oil. There were no signifi-
cantly Increased Incidences of tumors observed In female rats. From the
results of this study, NTP (1986) concluded that there was some evidence of
cardnogenlclty In rats as a result of the Increased Incidence of renal
tubular cell adenomas and adenocarclnomas In male rats treated with 250 or
500 mg/kg/day and of the Increased Incidence of preputlal gland carcinomas
1n males treated with 500 mg/kg/day.
Results 1n male mice (see Table 4-1) showed an Increase 1n the Incidence
of hepatocellular adenoma or carcinoma (combined), and an Increase In
flbromas, sarcomas, flbrosarcomas or neuroflbrosarcomas (combined) of the
Integumentary system as compared with controls. These Increases were
significant when analyzed by the Incidental tumor, the Cochran-ArmHage and
the Fisher Exact tests. The Incidence of lymphoma Ini male mice was
Increased significantly In the low-dose group, but not In the high-dose
group. There were no significant Increases 1n tumor Incidence observed In
female mice. From these results, NTP (1986) concluded that there was
equivocal evidence of cardnogenldty 1n male mice.
0084H -11- 01/26/87
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4.2.2. Inhalation. No pertinent data regarding the cardnogeniclty of
Isophorone after Inhalation exposure were located In the available
literature.
4.3. OTHER RELEVANT DATA
Isophorone has been examined for mutagenldty and genotoxldty by CHA
(1984) and NTP (1986). Isophorone was negative In reverse mutation assays,
with and without S-9 metabolic activation, using Salmonella typhlmurlum
TA100, TA1535, TA1537 and TA98 (NTP. 1986). CMA (1984) found Isophorone to
be negative In a forward mutation assay using L5178Y/TKf " mouse lymphoma
cells 1n the presence and absence of S-9 metabolic activation at concentra-
tions of 0.06-9 ng/mi. At higher concentrations (400-1200 mg/mi), NTP
(1986) found a slightly positive response In the absence of S-9 1n the mouse
lymphoma assay. Isophorone was negative In the mlcronucleus test In male
and female mice, for unscheduled DNA synthesis In rat primary hepatocytes
(CMA, 1984) and for chromosome aberrations 1n Chinese hamster ovary cells
with and without S-9 metabolic activation (NTP, 1986). NTP (1986) found a
positive response for sister chromatld exchange In Chinese hamster ovary
cells In the absence of S-9.
4.4. HEIGHT OF EVIDENCE
The NTP (1986) study Is the only available one concerning the cardno-
genldty of Isophorone. In this study, kidney tumors and preputlal gland
carcinomas 1n male rats and hepatic and Integumentary system tumors 1n male
mice showed a significant Increase above controls. This evidence 1s suffi-
cient to place Isophorone 1n IARC Group C and, according to the EPA classi-
fication scheme (U.S. EPA, 1986d), Isophorone can be placed 1n Group C,
Possible Human Carcinogen.
0084h -12- 01/26/87
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5. REGULATORY STANDARDS AND CRITERIA
The Interim ambient water quality criteria Is 5.2 mg/i (U.S. EPA,
1980a). This value Is based on an oral ADI of 0.15 mg/kg/day that was
calculated from a 90-day study using dogs that determined a NOAEL of 150
mg/kg/day (U.S. EPA, 1980a). This criterion was based on Ingestlon of 2 I
of water and 6.5 g of fish and shellfish/day.
NIOSH (1978) has recommended a PEL for Isophorone of 4 ppm (23 mg/m3)
as a TWA concentration for up to a 10-hour workshlft. The ACGIH (1986)
celling limit Is 5 ppm (-25 mg/m3) for occupational exposure. Both the
NIOSH PEL and ACGIH celling limit are based on a report by Ware (1973),
which Indicates that workers at Western Electric Co. complained of fatigue
and malaise at 5-8 ppm (28-45 mg/m3) but not at 1-4 ppm (6-23 mg/m3).
The OSHA standard for occupational exposure to Isophorone Is 25 ppm (140
mg/m3) as an 8-hour TWA concentration limit In workroom air (OSHA, 1981).
The Federal Food, Drug and Cosmetic Act exempts Isophorone from the
requirement of a tolerance when It Is used as a solvent and cosolvent for
pesticide formulation used before crops emerge from soil, and for post-
emergent use on rice before the rice begins to head, and on sugar and table
beets (U.S. EPA, 1974).
0084h -13- 01/26/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD.) AND REFERENCE DOSE (RfO)
O
Isophorone has been shown to be a carcinogen 1n animals; therefore, 1t
Is not appropriate for the purposes of this document to derive acceptable
Intake values.
6.2. CARCINOGENICITY POTENCY (q^)
6.2.1. Oral. In a recent U.S. EPA (1986a) analysis, a q,* has been
calculated using the data from the NTP (1986) study, which showed an
Increase In kidney tubular cell adenomas and carcinomas and preputlal gland
carcinomas 1n male rats, and 1n liver and Integumentary system tumors 1n
male B6C3F1 mice. Although the Increased Incidence of tumors 1n the male
mice was statistically significant, the Incidence of liver tumors In male
mice may be highly variable and judged by NTP (1986) to represent
"equivocal" evidence of carclnogenlclty. NTP (1986) judged the Incidence of
kidney and preputlal gland tumors In treated male rats to represent "some
evidence of carclnogenlclty" because of the absence of these tumors 1n
matched contemporary controls and the very low Incidence In historical
controls. The U.S. EPA (1986a) combined the Incidences of kidney and
preputlal gland tumors 1n male rats to calculate a human q * for oral
exposure to Isophorone of 4.1xlO~3 mg/kg/day, using the multistage model
of Howe and Crump (1982). The data used In this, computation are presented
1n Table 6-1.
6.2.2. Inhalation. No pertinent data concerning the potential carclno-
genlclty of Isophorone were located 1n the literature; therefore, an Inhala-
tion q,* will not be calculated.
0084h -14- . . 05/14/87
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TABLE 6-1
Cancer Data Sheet for Derivation of q-|*
Compound: Isophorone
Reference: NTP, 1986
Specles/straln/sex: rat, Fischer 344/N, male
Route/vehicle: gavage, corn oil
Length of exposure (le) = 103 weeks
Length of experiment (LE) = 105 weeks
Llfespan of animal (L) * 105 weeks
Body weight = 0.'40 kg (measured)
Tumor site and type: kidney (tubular cell) adenoma or carcinoma; preputlal
gland carcinoma
Experimental Doses
or Exposures
(mg/kg/day, 5 days/week)
0
250
500
Transformed Dose
(mg/kg/day)
0
175
350
Incidence
No. Responding/No.
0/48
3/50
8/50
Examined
Unadjusted q-j* * 7.33x10-* (mg/kg/day)-*
Human q-j* = 4.1xlO-3 (mg/kg/day)-1
0084h -15- . 01/26/87
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Documentation of Threshold Limit Values and Biological Exposure Indices, 5th
ed. Cincinnati, OH. p. 333.
AHE, Inc. (Affiliated Medical Enterprises, Inc.). 1972a. 90-Day subchronlc
toxlclty of Isophorone In the rat. Final Report. Prepared for Rohm and
Haas Co. OTS 8d submission Doc. ID 87812179. Microfiche No. 205975.
AME, Inc. (Affiliated Medical Enterprises, Inc.). 1972b. 90-Day subchronlc
toxlclt.y of Isophorone 1n the dog. Final Report. Prepared for Rohm and
Haas Co. OTS 8d submission Doc. ID 87812178. Microfiche No. 205975.
81o Dynamics, Inc. 1984. Inhalation teratogenldty probe study In rats and
mice. Final Report. Prepared for Exxon Blomedlcal Sciences. Inc. QTS
Submission, Microfiche No. 0507219.
Callahan, M.A., M.W. SUmak, II.U. Gabel, et al. T979. Water-related
environmental fate of 129 priority pollutants. Vol. II. EPA 440/4-79-029B.
U.S. EPA, Washington, DC.
CMA (Chemical Manufacturers Association). 1984. Voluntary Testing Program
under Section 4 of the Toxic S.ubstance Control Act. Submission of Test
Data. Vol. III. Isophorone Mutaoenldty Studies, FYI-OTS-1084-0355.
0084h -16- . 01/26/87
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Outertre-Catella, H., P.L. Nguyen, Q.Q. Dang and R. Truhaut. 1978.
Metabolic transformations of the 3,5,5-2-cyclohexene-l-one tMmethyl
(Isophorone). Toxlcol. Eur. Res. 1(4): 209-216.
Hazelton Labs, Inc. 1968. Assessment and comparison of subacute Inhalation
toxldtles of three ketones. Final Report. Prepared for Exxon Chem. Amers.
OTS 8d Submission Doc ID 878210935. Microfiche No. 206267.
Howe, R.B. and K.S. Crump. 1982. GLOBAL 82, a Computer Program to Extrapo-
late Quanta! Animal Toxldty Data to Low Doses. Prepared for Office of Car-
cinogen Standards, OSHA, U.S. Dept. of Labor under Contract No. 41USC252C3.
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Chemical Property
Estimation Methods. McGraw-Hill Book Co., New York.
NIOSH (National Institute for Occupational Safety and Health). 1978.
Criteria for Recommended Standard...Occupational Exposure to Ketones. U.S.
DHEH, PHS, CDC, Rockvllle, MD. Publ. No. 78-173.
NTP (National Toxicology Program). 1986. Toxicology and carc^nogenesls
studies of Isophorone 1n F344/N rats and B6C3F1 mice (gavage studies).
National Toxicology Program Tech. Rep. Ser. No. 291. (Also pub!. as DHHS
(NIH) 86-2547) 189 p.
OSHA (Occupational Safety and Health Administration). 1981. OSHA Safety
and Health Standards. Code of Federal Regulations. 29 CFR 1910.1000.
0084h -17- 01/26/87
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Smyth, H.F., Jr., J. Seaton and L. Fischer. 1942. Response of guinea pigs
and rats to repeated Inhalation of vapors of mesltyl oxide and Isophore. J.
Ind. Hyg. Toxlcol. 24: 46-50.
Smyth, H.F., Jr., C.S. Well, J.S. West and C.P. Carpenter. 1969. Explora-
tion of joint toxic action: Twenty-seven Industrial chemicals Intubated In
rats In all possible pairs. Toxlcol. Appl. Pharmacol. 14(2): 340-347.
Smyth, H.F., Jr., C.S. Well, J.S. West and C.P. Carpenter. 1970. An
exploration of Joint toxlcatlon II equltoxlc versus equlvolume mixtures.
Toxlcol. Appl. Pharmacol. 17: 498-503.
Swann, R.L., D.A. laskowskl, P.J. McCall, K. VanderKuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio, and water solubility. Res. Rev. 85: 17-28.
Tabar, H.H., S.A. Quave, C.I. Mashnl and E.F. Barth. 1981. B1odegradab1l-
1ty studies with priority pollutant compounds. J. Water Pollut. Control
Fed. 5.3: 1503-1518.
U.S. EPA. T974. Tolerances and exemptions from tolerances for pesticide
chemicals In or on raw agricultural commodities. Office of Pesticide
Program, U.S. EPA. Federal Register. 39: 37195.
U.S. EPA. 1976. Investigation of selected potential anvlronmental contami-
nants: Ketontc solvents. U.S. EPA, Office of Toxic Substances, Washington,
DC. EPA 560/2-76-003.
0084h -18- 01/26/87
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U.S. EPA. 1980a. 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 Regu-
lations and Standards, Washington, DC. EPA 440/5-80-056. NTIS PB81-117673.
U.S. EPA. 1980b. Hazard 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, Washington, DC.
U.S. EPA. 1980c. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. 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.
U.S. EPA. 1986a. 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.
U.S. EPA. 1986b. MedChem Software Release 3.32, CLogP3 Graphical Exposure
Modeling System (GEMS). U.S. EPA, Office of Toxic Substances, Washington,
DC.
0084h . -19- 02/13/87
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U.S. EPA. 1986c. Graphical Exposure Modeling System (GEMS). Fate of
Atmospheric Pollutants (FAP). U.S. EPA, Office of Toxic Substances.
U.S. EPA. 1986d. Guidelines for Carcinogenic Risk Assessment. Federal
Register. 51(185): 33992-34003.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Relnhold Co., New York.
Ware, G.D. 1973. Communication to chairman TLV committee from Western
Electric Co., Kearny, PA. (CUed In ACGIH, 1986)
0084H . -20- 01/26/87
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APPENDIX
Oral Summary Table for Isophorone In the Male Rat*
Experimental Effect
Exposure
qi*
0, 250, 500. kidney (tubular 4.1xlO-3
mg/kg/day^ cell) adenoma
5 days/week or carcinoma
for 103 weeks and preputlal
gland carcinoma
*Source: NTP, 1986; U.S. EPA, 1986a
U.S. Environmental Protection Agency
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0084h -21- 01/26/87
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