EPA-540/1-86-010
I wi iinci uol
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Superfund
&EPA
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
HEALTH EFFECTS ASSESSMENT
FOR CHLOROFORM
-------
EPA/540/1-86-010
September 1984
HEALTH EFFECTS ASSESSMENT
FOR CHLOROFORM
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
-------
DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and It has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constlti/te endorse-
ment 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 chloro-
form. All estimates of acceptable Intakes and carcinogenic potency present-
ed 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 Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. 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. 1980b. Ambient Water Quality Criteria for Chloroform.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-033. NTIS PB 81-117442. (Cited 1n U.S. EPA, 1982}
U.S. EPA. 1982. Hazard Profile for Chloroform. Prepared by the
Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA
for the Office of Solid Waste and Emergency Response, Washington,
DC.
U.S. EPA. 1983b. Review of Toxlcological Data 1n Support of
Evaluation for Carcinogenic Potential of Chloroform. Prepared by
the Carcinogen Assessment Group, OHEA, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1984. Health Assessment Document for Chloroform.
Environmental Criteria and Assessment Office, Research Triangle
Park, NC. EPA 600/8-84-004A. NTIS PB 84-195163.
The Intent in these assessments 1s 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. Never-
theless, 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 sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronic, 1s 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 Hfespan). 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 1n ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronic human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
-------
The AIC, acceptable Intake chronic, Is similar 1n concept to the ADI
(acceptable dally Intake). It 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 [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC Is route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development Is explained 1n U.S. EPA (1983a).
For compounds for which there Is sufficient evidence of cardnogenldty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context, the
reader Is referred to the preface of this document. The preface outlines
limitations applicable to all documents of this series as well as the appro-
priate Interpretation and use of the quantitative estimates.
Chloroform has been shown to be carcinogenic by the oral route in
rodents 1n several independent investigations. Human data are limited, but
suggestive. The Carcinogen Assessment Group (U.S. EPA, 1984) has used the
following data: liver tumors in female mice (NCI, 1976); liver tumors 1n
male mice (NCI, 1976); kidney tumors in male rats (NCI, 1976); and kidney
tumors in male mice (Roe et al., 1979). There was no compelling reason to
select any one of these data sets over the others; therefore, the geometric
mean of the slope (q-j*), 7xlO~2 (mg/kg/day)"1, was used.
Data are not available which would allow an assessment of the carcino-
genic potential of chloroform following inhalation exposure.
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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 Helen Ball 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 Air 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:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
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. . . .
3.4. TOXICANT INTERACTIONS
CARCINOGENICLTY
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
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. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.3. CARCINOGENIC POTENCY (q-j*)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
Page
1
. . . 2
. . . 2
2
3
3
. . . 3
. . . 3
5
. . . 5
, , 5
. . . 6
, , 6
7
7
. . . 7
7
7
. . . 7
10
. . . 10
11
. . . 12
13
. . . 13
. . . 13
13
. . . 13
. . . 13
. . . 14
APPENDIX: Summary Table for Chloroform 23
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LIST OF ABBREVIATIONS
ADI Acceptable daily Intake
AIC Acceptable Intake chronic
AIS Acceptable intake subchronic
bw Body weight
CAS Chemical abstract service
CS Composite score
LOAEL . Lowest-observed-adverse-effect level
ppm Parts per million
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
viil
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
chloroform (CAS No. 67-66-3) are as follows:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
halogenated aliphatic hydrocarbon
(purgeable halocarbon)
119.38 (Callahan et a!., 1979)
150.5 mm Hg at 20°C (Callahan et al.,
1979)
8200 mg/8, at 20°C (Callahan et al.,
1979)
Octanol/water partition
coefficient:
Soil mobility:
(predicted as retardation factor
for a soil depth of 140 cm and
organic carbon content of 0.087%)
B1oconcentrat1on factor:
(1n bluegUl, Lepomis macrochlrus)
Half-life 1n air:
Half-life in water:
93 (Callahan et al., 1979)
1.2 (Wilson et al., 1981)
6 (Barrows et al., 1978)
80 days (U.S. EPA, 1982)
0.3-3 days In rivers (Zoeteman et
al., 1980)
3-30 days in lakes (Zoeteman et al.,
1980)
The half-life of chloroform 1n soil could not be located in the litera-
ture searched. However, evaporation is expected to be the predominant loss
mechanism from the soil surface. The half-life for soil evaporation should
be longer than its evaporation half-life from water. In subsurface soil,
blodegradatlon of chloroform Is likely to be a weak, very slow process (no
degradation in 27 weeks) (Wilson et al., 1983). Therefore, 1n subsurface
soil, chloroform Is expected to remain stable enough to leach Into ground-
water.
-1-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Evidence from human assays (Fry et al., 1972), as well as from animal
experiments (Brown et al., 1974; Taylor et al., 1974), indicates that -100%
of Ingested chloroform is absorbed from the gastrointestinal tract.
2.2. INHALATION
From 49-77% of the chloroform present 1n the inspired air 1s absorbed by
the lungs (U.S. EPA, 1980b).
-2-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
Table 3-1 presents a summary of the effects of subchronlc chloroform
exposure.
3.1.1. Oral. DeSalva et al. (1975) reported that chloroform at dose
levels of 1.0 and 2.5 mg/kg/day for a 1-year period produced no effects on
the functioning of the human liver and kidney.
No effects 1n rats were reported at dose levels of 15 and 30 mg/kg/day
(Palmer et al., 1979). However, dose levels of 150 and 410 mg/kg/day
produced severe toxic effects, such as necrosis of the liver and dysfunction
of the gonads (Palmer et al., 1979).
3.1.2. Inhalation. Torkelson et al. (1976) exposed rats, guinea pigs and
rabbits to 25, 50 and 80 ppm (122, 244 and 415 mg/m3, respectively) for 7
hours/day, 4 days/week for 6 months (Table 3-1). Exposure to 25 ppm chloro-
form produced hlstopathologlcal changes 1n the Hvers and kidneys of male
but not female rats. At higher doses, lobular granular degeneration and
focal necrosis were Increased 1n the liver, and cloudy swelling of epithe-
lial cells was Increased In the kidney. These changes were reported to be
reversible after 6 weeks. Hematologlcal, clinical chemistry and urinalysls
values were "within normal limits." The results obtained from chloroform
exposure In guinea pigs and rabbits are difficult to Interpret because
adverse effects are seen at the low dose (25 ppm) and high dose (85 ppm)
levels, but no effects are reported at the Intermediate dose level (50 ppm).
Ep1dem1olog1cal studies of humans exposed to chloroform 1n the workplace
at levels ranging from 22-237 ppm have Indicated that depression, gastro-
intestinal disturbances (e.g., flatulence, nausea), headache and frequent
and scalding urination are the primary symptoms (Challen et al., 1958;
-3-
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TABLE 3-1
Subchronlc Toxtclty of Chloroform
Route Dose or Exposure
Inhalation 0 ppm
25 ppm (122 mg/m»)
50 ppm (244 mg/m»)
85 ppm (415 mg/m»)
25 ppm (122 mg/m')
Inhalation 0 ppra
25 ppm (122 mg/n»)
50 ppm (244 mg/m*)
85 ppm (415 mg/m")
i Inhalation 0 ppm
•f 25 ppm (122 mg/m»)
50 ppm (244 mg/m»)
85 ppm (415 mg/m»)
Oral 0
1.0 mg/kg/day
2.5 rag/kg/day
Oral 0
15 mg/kg/day
30 mg/kg/day
150 mg/kg/day
410 mg/kg/day
Duration of
Treatment
7 hours/day,
5 days/week
for 6 months
4 hours/day.
5 days/week
7 hours/day,
5 days/week
up to 203 days
7 hours /day.
5 days/week
up to 203 days
1 year
13 weeks
Species/Strain Sex
rats/NR N/f
H/F
H/F
H/F
H/F
guinea plgs/NR H/F
H/F
H/F
H/F
rabblts/NR H/F
H/F
H/F
H/F
human NR
rats/ H/F
Sprague-Dawley
Number
Treated
10-12
10-12
10-12
10-12
10
16-24
16-24
16-24
16-24
4-6
4-6
4-6
4-6
NR
20
20
20
20
20
Effect
Exposure to chloroform at 25 ppm for 4
hours/day had no effect on male mice; at 25
ppm for 7 hours/day, hlstopathologlc changes
In the liver were present In males but not
females; at higher doses. Increasingly pro-
nounced changes were present In the liver and
kidneys of both sexes.-
Pneumonltls was seen In females exposed to
85 ppm, and hlstopathologtcal changes were
observed In the livers and kidneys of both
sexes exposed to 25 ppm but not 50 ppm.
Hepatic and renal pathology was seen In fe-
males exposed to 85 ppm, and pneumonltls and
hepatic necrosis In males exposed to 85 ppm.
Hlstopathologlcal changes were observed In
the livers and kidneys of both sexes exposed
to 25 ppm but not 50 ppm.
Liver and kidney function tests Indicated
that there were no statistically significant
differences between chloroform-treated Indi-
viduals and controls.
Increased liver weight with fatty necrosis,
gonadal atrophy and cellular proliferation
In the bone marrow occurred at 410 and 150
mg/kg/day. No effects were reported for
dose levels of 30 and 15 mg/kg/day.
Reference
Torkelson
et al., 1976
Torkelson
et al., 1976
Torkelson
et al., 1976
DeSalva
et al., 1975
Palmer
et al., 1979
NR = Not reported
-------
Bomskl et al. 1967). Regarding long-term effects, Challen et al. (1958)
reported that there was no evidence of any organic lesion attributable to
chloroform, based on physical exams and liver function tests. Bomskl et al.
(1967) reported that chloroform exposure may result 1n an Increased Inci-
dence of viral hepatitis, splenomegaly and hepatomegaly, although no statis-
tical analysis was presented.
3.2. CHRONIC
3.2.1. Oral. Several chronic oral studies (NCI, 1976; Palmer et al.,
1979; Roe et al., 1979) were designed to test the cardnogenlclty of chloro-
form (see Chapter 4). However, depression of body weight was observed at
chloroform doses >60 mg/kg/day 1n rats (NCI, 1976; Palmer et al., 1979) and
mice (Roe et al., 1979). Decreased relative liver weight and serum cholin-
esterase levels were reported In female mice treated with 60 mg/kg/day
chloroform (Palmer et al., 1979.) Higher chloroform doses (90 and 180
mg/kg/day) resulted 1n an Increased Incidence of noncancerous respiratory
diseases 1n rats (NCI, 1976), and a dose of 477 mg/kg/day resulted In
decreased female survival time In mice (NCI, 1976). A dose level of 165
mg/kg/day caused liver necrosis and gonadal atrophy In rats (Palmer et al.,
1979). No effects were reported to occur 1n rats at a dose of 15 mg/kg/day
(Palmer et al., 1979).
Chronic exposure of humans to chloroform appears to result in adverse
effects on the central nervous system (NIOSH, 1974), although there are no
data on the dose relation of the effects. In addition, chloroform affects
the liver, kidneys and heart in humans (NIOSH, 1974). The potential for
chronic human oral exposure to chloroform has increased because of the wide-
spread practice of chlorinating drinking water (U.S. EPA, 1980b).
3.2.2. Inhalation. Pertinent data regarding the carcinogenicity of
chloroform Inhalation in humans were not located in the available literature.
-5-
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3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
Teratogenlc effects (acaudla, Imperforate anus, decreased crown-rump
length, missing ribs and delayed skeletal ossification) were seen in
Sprague-Dawley rats {Schwetz et a!., 1974) that inhaled chloroform for 7
hours/day on days 6-15 of gestation at dose levels of 30, 100 and 300 ppm
(147, 489 and 1466 mg/m3, respectively). When CF/1 mice (Murray et a!.,
1979) were exposed to 100 ppm chloroform for 7 hours/day on days 6-15 of
gestation, there was a significantly increased incidence of cleft palate.
When pregnant mice and rats were exposed to 100 ppm chloroform, their food
consumption and body weight decreased, but their relative liver weight
Increased (U.S. EPA, 1982). Ingestion of chloroform caused fetotoxldty but
not teratogenicity, and only at levels that also produced severe maternal
toxicity (Thompson et al., 1974).
3.4. TOXICANT INTERACTIONS
The substances that potentiate the toxic effects of chloroform, are
methyl n-butyl ketone (Branchflower and Pohl, 1981), alcohol (Kutob and
Plaa, 1961), carbon tetrachloride (Harris et al., 1982), chlordecone (Iljima
et al., 1983), DOT and phenobarbital (McLean, 1970). Methyl n-butyl ketone
Increases the toxlcity of chloroform by lowering glutathione levels and by
Increasing the levels of hepatic cytochrome P-450, which, in turn, Increases
the metabolism of chloroform to phosgene (Branchflower and Pohl, 1981).
Harris et al. (1982) reported that carbon tetrachloride potentiated the
toxic effects of chloroform, because of Increased phosgene formation and the
initiation of lipid peroxldation. The mechanism of interaction for alcohol,
chlordecone, DDT and phenobarbital was not discussed, von Oettlngen (1964)
reported that high-fat/low-protein diets potentiated the hepatotoxic effects
of chloroform in animals.
-6-
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Although chloroform has not unequivocally been shown to
cause human cancer, ecological and case control studies (Alavanja et a!.,
1978; Cantor et a!., 1978; Brennlman et a!., 1978; Hogan et al., 1979;
Struba, 1979; Gottlieb et al., 1981; Young et al., 1981) have consistently
supported the association of Increased risk of bladder, colon and rectal
cancer with exposure to chloroform, which 1s the predominant trlhalomethane
contaminating chlorinated drinking water (U.S. EPA, 1983b).
4.1.2. Inhalation. Although exposure to airborne chloroform 1n the work-
place may have caused toxic effects (Challen et al., 1958; Bomski et al.,
1967), and although Inhalation of chloroform was teratogenlc In rats
(Schwetz et al., 1974), pertinent data regarding an association between
chloroform Inhalation and an Increased Incidence or risk of cancer were not
located In the available literature.
4.2. 8IOASSAYS
4.2.1. Oral. Table 4-1 summarizes the available data from oral bloassays
of chloroform cardnogenlcity. Eschenbrenner and Miller (1945) emphasized
that a dose level of chloroform that caused hepatic necrosis when given once
would cause hepatic carcinoma when given repeatedly. The NCI (1976) found a
dose-related Increase In hepatomas in both sexes when mice received chloro-
form in corn oil by gavage, and an increase in renal epithelial tumors 1n
males when rats received chloroform in corn oil by gavage (Table 4-1). The
Increased incidence of hepatic and renal tumors was statistically signifi-
cant (p<0.05). Palmer et al. (1979) criticized the NCI" study because rats
being treated with other volatile carcinogenic substances were housed 1n the
same room as the chloroform-treated rats.
-7-
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TABLE 4-1
Oral Bloassays of Chloroform Carclnogenlclty
Vehicle Dose
NR 150 mg/kg bw
200 mg/kg bw
600 mg/kg bw
1200 mg/kg bw
2400 mg/kg bw
Corn oil 0 mg/kg/day
138 mg/kg/day
277 mg/kg/day
238 mg/kg/day
477 mg/kg/day
0 mg/kg/day
00
i
Corn oil 0 mg/kg/day
90 mg/kg/day
180 mg/kg/day
100 mg/kg/daya
200 mg/kg day a
0 mg/kg day
Toothpaste0 0 mg/kg/day
IS mg/kg day
75 mg/kg/day
165 mg/kg day
Toothpaste*1 0 mg/kg/day
15 mg/kg day
75 mg/kg day
165 mg/kg day
Duration of Duration Species/Strain
Treatment of Study
once every 4 NR mice/
days for a (strain A)
total of 30
doses
S days/week 92-93 weeks m1ce/B6C3Fl
for 78 weeks
5 days/week 111 weeks rats/
for 78 weeks Osborne-Hendel
6 days/week 52 weeks rats/
for 52 weeks Sprague-Dawley
6 days/week 52 weeks rats/
for 52 weeks Sprague-Dawley
Sex
NR
N
N
N
F
F
F
M
N
N
F
F
F
H
N
N
H
F
F
F
F
Number Target
Treated Organ
NR liver
18 liver
50
45
45
41
20
19 kidney
50
50
49
48
20
75 none
25
25
25
75 none
25
25
25
Effects
Doses of 150 and 300 mg/kg bw
produced neither necrosis nor
carcinoma In the liver. Doses
of 600-2400 mg/kg bw produced
necrosis when given once, and
hepatomas when given repeatedly.
All females at the highest dose
and all males at the three
highest doses died early In the
experiment.
Hepatocellular carcinomas were
found In 1/18 (6X) control
males. 18/50 (36X) low-dose
males and 44/45 (98X) high-dose
males; In 0/20 control females,
36/45 (BOX) low-dose females and
39/41 (95X) high-dose females.
Renal carcinomas and adenomas
were found In 0/19 control
males, 4/50 (6X) low-dose males
and 12/50 (24X) high-dose males;
0/20 control females, 0/49 low-
dose females and 2/48 (4X) high-
dose females. Thyroid tumors
were found In 1/20 control
females, 8/49 low-dose females
and 10/48 high-dose females.
No treatment-related neoplastlc
effects were seen In comparison
with controls; however, all
groups had a high Incidence
of pulmonary and renal hlsto-
pathology.
Same as above
Reference
Eschenbrenner
and Miller.
1945
NCI, 1976
NCI. 1976
Palmer
et al.. 1979
Palmer
et al.. 1979
-------
TABLE 4-1 (cont.)
Vehicle
Toothpaste0
Toothpaste0
Dose
0 mg/kg/day
60 mg/kg day
0 mg/kg/day
60 mg/kg day
0 mg/kg day
17 mg/kg day
60 mg/kg day
0 mg/kg day
17 mg/kg day
60 mg/kg day
Duration of Duration
Treatment of Study
6 days/week 95 weeks
for 80 weeks
6 days/week 96 weeks
for 96 weeks
Species/Strain Sex
rats/ N
Sprague-Dawleyc N
F
F
rats/NR M
N
N
F
F
F
Number
Treated
50
50
50
50
104
52
52
104
52
52
Target
Organ
none
mammary
gland
kidney
none
Effects
No treatment-related neoplastlc
effects.
Mammary tumors were present In
16/20 control females and 21/50
treated mice; however, there were
significantly more malignant
tumors In the chloroform-exposed
mice (p=0.056)d
Several mice had lymphomas. but
the Incidence was not related
to chloroform exposure. Renal
tumors appeared In the high-dose
males, but In no other group.
Reference
Palmer
et al.. 1979
Roe et al.,
1979
aTMA dose reflecting Initial dose levels of 250 and 125 mg/kg/day that were lowered to 180 and 90 mg/kg/day after 22 weeks In the high- and low-dose
female groups, respectively.
"Toothpaste formulation Included peppermint oil and eucalyptol (essential oils) as flavor components
cCaesar1an-de!1vered, specific-pathogen-free rats
dS1gn1Mcance of Fischer exact test as reported by U.S. EPA (1982)
-------
Presumably because chloroform has been a contaminant 1n toothpaste,
British scientists treated rats (Palmer et al., 1979), mice (Roe et al.,
1979) and dogs (Heywood et al, 1979) with chloroform In a toothpaste base
Including essential oils as flavor components. Range-finding studies were
performed 1n all experiments. No effects at dose levels of 15, 17 and 165
mg/kg/day for 52 weeks were reported 1n rats. When female rats were treated
with 60 mg/kg/day for 96 weeks, however, there was an Increase (p=0.056) In
malignant mammary gland tumors 1n the chloroform-treated group, although the
untreated group developed benign mammary tumors (Palmer et al., 1979).
There was an Increased Incidence of kidney tumors 1n the high dose (60
mg/kg/day) level 1n male mice (Roe et al., 1979). The females had no
Increased Incidence of cancer, but there appeared to be some confounding
Influence because of the vehicle. The authors addressed, but did not
resolve, the problem of the effect produced by different vehicles (Roe et
al., 1979).
4.2.2. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled chloroform were not located In the available literature.
4.3. OTHER RELEVANT DATA
Chloroform was not mutagenlc In Escher1ch1a coll strains K12, WP2p and
WP2uvrA~p or 1n Salmonella typhlmurlum strains TA98, TA100, TA1535, TA1537
and TA1538 (Klrkland et al., 1981), with and without metabolic activation
(S-9). Chloroform was not mutagenlc In cultured Ch'lnese hamster lung flbro-
blasts at the 8-azaguan1ne locus (Sturrock, 1977), nor did chloroform
Increase sister chromatld exchanges 1n cultured Chinese hamster ovary cells
or human lymphocytes (White et al., 1979; Uehleke et al., 1977). In a
recent experiment 1n which chloroform was used at a higher concentration, 1t
was found to Induce sister chromatld exchange 1n cultivated human lympho-
cytes (Morimoto and Koizumi, 1983). In the presence of metabolic activation
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(S-9), chloroform was reported to be weakly positive or "suggestive" 1n
mutagenlclty assays In Saccharomyces cerevlsjae D7 and DrosophlHa. In a
host-mediated assay with S. typhlmuMum, 1n the murlne bone marrow micro-
nucleus test and 1n the Induction of murlne sperm head abnormalities
(Agustln and L1m-Syl1anco, 1978; Callen et al., 1980; Land et al., 1981;
Topham, 1980; Gocke et al., 1981).
4.4. WEIGHT OF EVIDENCE
Oral exposure to chloroform has caused hepatic carcinomas 1n male and
female B6C3F1 mice (NCI, 1976), renal carcinomas and adenomas 1n male
Osborne-Mendel rats (NCI, 1976) and 1n male ICI mice (Roe et al., 1979),
thyroid tumors 1n female Osborne-Mendel rats (NCI, 1976) and an Increased
Incidence of malignant mammary gland tumors after chronic exposure In
Sprague-Oawley rats (Palmer et al., 1979). Evidence 1s sufficient to
classify chloroform as an animal carcinogen. Although some association
between oral exposure to chloroform (presumably as a result of chlorinating
drinking water) and human bladder, Intestinal and rectal cancer has been
reported (see Section 4.1.1.), the evidence for human cardnogenldty Is
best designated as limited. Applying the criteria for evaluating the
overall weight of evidence of cardnogenldty to humans proposed by the
Carcinogen Assessment Group of the U.S. EPA (Federal Register, 1984),
chloroform 1s most appropriately classified as a Group 82, a probable human
carcinogen.
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1983) recommends a TWA-TLV of 10 ppm (50 mg/m3} and a STEL
of 50 ppm (225 mg/m3) for chloroform exposure, and also notes that chloro-
form has Induced cancer In animals by the oral route at high and Interme-
diate dose levels and 1s a suspected carcinogen for humans.
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Chloroform 1s known to be carcinogenic to animals and Is suspected of
being carcinogenic to humans. Data are sufficient for derivation of a
q,*; therefore, It 1s Inappropriate to derive an AIS for this chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Chloroform 1s known to be carcinogenic to animals and 1s suspected of
being carcinogenic to humans. Data are sufficient for derivation of a
q *; therefore, 1t 1s Inappropriate to derive an AIC for this chemical.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. The Carcinogen Assessment Group (U.S. EPA, 1984) used the
following data: liver tumors In female mice (NCI, 1976); liver tumors 1n
male mice (NCI, 1976); kidney tumors 1n male rats (NCI, 1976); and kidney
tumors 1n male mice (Roe et al., 1979). There was no compelling reason to
select any one of these data sets over the others; therefore, the geometric
mean of the slopes (q,*). 7xlO~2 (mg/kg/day)"1, was selected. The
Health Assessment Document on Chloroform (U.S. EPA, 1984) contains a
complete discussion of the calculation of the q *.
6.3.2. Inhalation. Pertinent data regarding the derivation of a q,*
for chloroform Inhalation were not located 1n the available literature.
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