0013
J
January "1992
t
FINAL
QUANTIFICATION OF TOXICOLOGICAL EFFECTS
FOR
DICHLOROMETHANE
Health and Ecological Criteria Division
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC.
HEADQUARTERS LIBRARY
ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
-------
January 1992
FINAL
QUANTIFICATION OF TOXICOLOGICAL EFFECTS
FOR
DICHLOROMETHANE
Health and Ecological Criteria Division
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC.
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TABLE OF CONTENTS
Page
LIST OF TABLES vi
FOREWORD vii
A. PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS 2
1. Noncarcinoyenic Effects 2
2. Carcinogenic Effects 4
B. QUANTIFICATION OF NONCARCINOGENIC EFFECTS FOR DICHLOROMETHANE. . 7
1. Toxic Effects in Humans ^
a. Short-term Exposure 7
b. Long-term Exposure 8
2. Toxic Effects in Animals 8
a. Short-term Exposure 8
b. Long-term Exposure 11
3. Development of Health Advisories 16
a. One-day Health Advisory 17
b. Ten-day Health Advisory IB
c. Longer-term Health Advisory 18
d. Reference Dose and Drinking Water Equivalent Level ... 21
C. QUANTIFICATION OF CARCINOGENIC EFFECTS FOR DICHLOROMETHANE ... 23
1. Categorization of Carcinogenic Potential 23
2. Quantitative Carcinogenic Risk Estimates 30
D. EXISTING GUIDELINES AND STANDARDS 30
E. SPECIAL CONSIDERATIONS 32
F. SUMMARY 32
G. REFERENCES ' . . 34
APPENDIX
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LIST OF TABLES
Table No.
1
2
3
4
b
6
7
8
9
10
Summary of Hepatocellular Findings in the Livers of
Rats Given DCM in Drinking Water for 90 Days
Incidence of Liver Foci/Areas of Alteration in Rats
Given DCM in Drinking Water for 78 or 104 Weeks ....
Summary of Subchronic Oral Toxicity Studies Considered
for the Development of the Longer-term HA . .
Summary of Chronic Oral Toxicity Studies Considered for
the Development of the Reference Dose and Drinking Water
Summary of Findings for Liver Tumors in Rats Given DCM
in Drinking Water for 2 Years
Summary of Findings for Liver Lesions /Tumors in Male
Mice Given DCH in Drinking Water for 2 Years
Summary of Findings for Mammary and Subcutaneous Tumors
in Rats Exposed via Inhalation to DCM for 2 Years . . .
Summary of Findings for Lung and Liver Tumors in Mice
Summary of Findings for Mammary and Ventral Cervical
Tumors in Rats Exposed via Inhalation to DCM for
2 Years '
Summary of Quantification of Toxicological Effects for
Page
1 7
15
10
oo
cc.
•Jf.
26
28
OQ
33
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FOREWORD
Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended in 1986,
requires the Administrator of the Environmental Protection Agency to publish
Maximum Contaminant Level Goals (MCLGs) and promulgate National Primary Drinking
Water Regulations for each contaminant, which, in the judgment of the
Administrator, may have an adverse effect on public health and which is known or
anticipated to occur in public water systems. The MCLG is nonenforceable and is
set at a level at which no known or anticipated adverse health effects in humans
occur and which allows for an adequate margin of safety. Factors considered in
setting the MCLG include health effects data and sources of exposure other than
drinking water.
This document provides the health effects basis to be considered in
establishing the MCLG. To achieve this objective, data on pharmacokinetics,
human exposure, acut? and chronic toxicity to animals and humans, epidemiology,
and mechanisms of toxicity were evaluated. Specific emphasis is placed on
literature data providing dose-response information. Thus, while the literature
search and evaluation performed in support of this document was comprehensive,
only the reports considered most pertinent in the derivation of the MCLG are
cited in the document. The comprehensive literature data base in support of this
document includes information published up to April 1987; however, more recent
data have been added during the review process and in response to public
comments.
When adequate health effects data exist, Health Advisory values for less-
than-lifetime exposures (One-day, Ten-day, and Longer-term, approximately 10% of
an individual's lifetime) are included in this document. These values are not
used in setting the MCLG, but serve as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.
James R. Elder
Director
Office of Ground Water and Drinking Water
Tudor T. Davies
Director
Office of Science of Technology
vii
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QUANTIFICATION OF TOXICOLOGICAL EFFECTS FOR DICHLOROMETHANE
The source documents for background information used to develop this
report on the quantification of toxicological effects for dichloromethane are
the health assessment document (HAD) for dichlormethane (U.S. EPA, 1985a) and a
subsequent addendum to the HAD (U.S. EPA, 1985b). In addition, some references
published since 1985 are discussed.
The quantification of toxicological effects of a chemical consists of
/
separate assessments of noncarcinogenic and carcinogenic health effects.
Chemicals that do not produce carcinogenic effects are believed to have a
threshold dose below which no adverse, noncarcinogenic effects occur, while
carcinogens are assumed to act without a threshold.
To summarize the results of the quantification of toxicological effects, a
One-day Health Advisory of 10,000 ug/L for a 10-kg child was calculated, based
on an acute oral study in rats reported by Kimura et al. (1971). No suitable
data for the derivation of a Ten-day Health Advisory were found in the avail-
able literature. A Longer-term Health Advisory of 2,000 was developed for a
10-kg child, based on a 90-day drinking water study in rats (Kirschman et al.,
1986). A Drinking Water Equivalent Level (DWEL) of 2,000 ug/L for a 70-kg
adult was calculated based on a 2-year drinking water study in rats (Serota et
al., 1986). The DWEL is used as a conservative estimate for the Longer-term
HA for an adult. Caution must be exercised when considering the risk of lifetime
exposure to dichloromethane because, based on a 2-year inhalation study in rats
(NTP, 1986), this chemical 1s classified as a Probable Human Carcinogen (Group
B2). The estimated excess cancer risk associated with lifetime exposure to
drinking water containing 1,750 ug/L of dichloromethane is 4 x 10~4 based on
the upper 95% confidence limit of the linearized multistage model.
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A. . PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS
1. Noncarcinogem'c Effects
In the quantification of noncarcinogenic effects, a Reference Dose {RfD),
formerly termed the Acceptable Daily Intake (ADI), is calculated. The RfD is
an estimate of a daily exposure to the human population that is likely to be
without appreciable risk of deleterious effects, even if exposure occurs over a
lifetime. The RfD is derived from a No-Observed-Adverse-Effect Level (NOAEL),
• f
or Lowest-Observed-Adverse-Effect Level (LOAEL), identified from a subchronic
or chronic study, and divided by an uncertainty factor. The RfD is
calculated as follows:
RfD = (NQAEL or LOAEL)
Uncertainty factor
mg/kg bw/day
Selection of the uncertainty factor to be used in the calculation of the
RfD is based on professional judgment while considering the entire data base of
toxicological effects for the chemical. To ensure that uncertainty factors are
selected and applied in a consistent manner, the Office of Drinking Water (ODW)
emplpys a modification to the guidelines proposed by the National Academy of
Sciences (NAS, 1977, 1980), as follows:
o An uncertainty factor of 10 is generally used when good chronic or
subchronic human exposure data identifying a NOAEL are available and
are supported by good chronic toxicity data in other species.
o An uncertainty factor of 100 is generally used when good chronic
toxicity data identifying a NOAEL are available for one or more animal
species (and human data are not available), or when good chronic or
subchronic toxicity data identifying a LOAEL in humans are available.
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o An uncertainty factor of 1,000 is generally used when limited or
incomplete chronic or subchronic toxicity data are available, or when
good chronic or subchronic toxicity data identify a LOAEL, but not
a NOAEL, for one or more animal species.
The uncertainty factor used for a specific risk assessment is based prin-
cipally upon scientific judgment rather than on scientific fact and accounts for
possible intra- and interspecies differences. Additional considerations not -
incorporated in the NAS/ODW guidelines for selection of an uncertainty factor
include the use of a less-than-lifetime study for deriving an RfD, the signifi-
cance of the adverse health effect, and the counterbalancing of beneficial
effects.
From the RfD,.a Drinking Water Equivalent Level (DUEL) can be calculated.
The DWEL represents a medium-specific (i.e., drinking water) lifetime exposure,
at which adverse, noncarcinogenic health effects are not expected to occur. The
DWEL provides the noncarcinogenic health effects basis for establishing a
drinking water standard. For ingestion data, the DWEL is derived as follows:
DWEL ~ {RfD)(body weight in kg)
Drinking water volume in L/day
f
TL
mg/L (.
ug/L)
where:
Body weight - assumed to be 70 kg for an adult.
Drinking water volume - assumed to be 2 L per day for an adult. •
In addition to the RfD and the DWEL, Health Advisories (HAs) for exposures
of shorter duration (One-day, Ten-day, and Longer-term) are determined. The HA
values are used as informal guidance to municipalities and other organizations
when emergency spills or contamination situations occur. The HAs are calculated
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using a similar equation to the RfD and DWEL; however, the NOAELs or LOAELs are
identified from acute or subchronic studies. The HAs are derived as follows:
HA = (NOAEL or LOAEL)(bw) = mg/L ( ug/L)
( L/dayJW)
Using the above equation, the following drinking water HAs are developed
for honcarcinogenic effects:
1. One-day HA for a 10-kg child ingesting 1 L water per day.
t
2. Ten-day HA for a 10-kg child ingesting 1 L water per day.
3. Longer-term HA for a 10-kg child ingesting 1 L water per day.
4. Longer-term HA for a 70-kg adult ingesting 2 L water per day.
The One-day HA calculated for a 10-kg child assumes a single acute
exposure to the chemical and is generally derived from a study of less than 7
days' duration. The Ten-day HA assumes a limited exposure period of 1 to 2
weeks and is generally derived from a study of less than 30 days' duration.
A Longer-term HA is derived for both a 10-kg child and a 70-kg adult and
assumes an exposure period of approximately 7 years (or 10% of an individual's
lifetime). A Longer-term HA is generally derived from a study of subchronic
duration (exposure for 10% of animal's lifetime).
2. Carcinogenic Effects
The EPA categorizes the carcinogenic potential of a chemical, based on the
overall weight of evidence, according to the following scheme:
o Group A: Known Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support a causal association between exposure
to the chemical and human cancer.
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o Group B: probable Human Carcinogen. Sufficient evidence of carcino-
genicity in animals with limited (Group Bl) or inadequate (Group 82)
evidence in humans.
o Group C: Possible Human Carcinogen. Limited evidence of carcinogeni-
city in animals in the absence of human data.
o Group D: Not Classified as to Human Carcinogenicity. Inadequate human
and animal evidence of carcinogenicity or for which no data are
/
available.
o Group E; Evidence of Noncarcinogenicity for Humans. No evidence of
carcinogenicity in at least two adequate animal studies in different
species or in both adequate epidemiologic and animal studies.
If toxicological evidence leads to the classification of the contaminant
as a known, probable, or possible human carcinogen, mathematical models are used
to calculate the estimated excess cancer risk associated with the ingestion of
the contaminant in drinking water. The data used in these estimates usually
come from lifetime exposure studies in animals. To predict the risk for
humans from animal data, animal doses must be converted to equivalent human
doses. This conversion includes correction for noncontinuous exposure, less-
than-lifetime studies, and for differences in size. The factor that compen-
sates for the size difference is the cube root of the ratio of the animal and
human body weights. It is assumed that the average adult human body weight is
70 kg and that the average water consumption of an adult human is 2 liters of
water per day.
For contaminants with a carcinogenic potential, chemical levels are corre-
j
lated with a carcinogenic risk estimate by employing a cancer potency (unit
-5-
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risk) value together with the assumption for lifetime exposure via inyestion of
water. The cancer unit risk is usually derived from a linearized multistage
model, with a 95% upper confidence limit providing a low-dose estimate; that
is, the true risk to humans, while not identifiable, is not likely to exceed
the upper limit estimate and, in fact, may be lower. Excess cancer risk esti-
mates may also be calculated using other models such as the one-hit, Weibull,
logit, and probit. There is little basis in the current understanding of the
biological mechanisms involved in cancer to suggest that any one of these
models is able to predict risk more accurately than any others. Because each
model is based upon differing assumptions, the estimates that are derived for
each model can differ by several orders of magnitude.
The scientific data base used to calculate and support the setting of
cancer risk rate levels has an inherent uncertainty due to the systematic and
random errors in scientific measurement. In most cases, only studies using
laboratory animals have been performed. Thus, there is uncertainty when the
data are extrapolated to humans. When developing cancer risk rate levels,
several other areas of uncertainty exist such as the incomplete knowledge
concerning the health effects of contaminants in drinking water; the impact of
the laboratory animal's age, sex, and species; the nature of the target organ
system(s) examined; and the actual rate of exposure of the internal targets in
laboratory animals or humans. Dose-response data usually are available only
for high levels of exposure, not for the lower levels of exposure closer to
where a standard may be set. When there is exposure to more than one contami-
nant, additional uncertainty results from a lack of information about possible
synergistic or antagonistic effects.
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B. QUANTIFICATION OF NONCARCINOGENIC EFFECTS FOR DICHLOROMETHANE
Exposure to dichloromethane (OCM) has resulted in hepatic, renal, cardiac,
and central nervous system (CNS) toxicity in a variety of species. DCM vapors
are irritating to the lungs, mucous membranes, eyes, and skin. The most serious
effects of DCM (i.e., severe CNS depression/death) occur following exposure to
high vapor concentrations or when large doses are administered via gavage or
injection. Such severe effects are unlikely to occur in humans or laboratory
animals by exposure to DCM via drinking water.
1. Toxic Effects in Humans
a. Short-term jxposure
Toxicity studies on DCM in humans are limited to inhalation exposure.
Behavioral and neurological symptoms such as light-headedness (Stewart et al.,
1973), reduced scores on sensory/motor tests (Fodor and Winneke, 1971), and
eye/hand coordination depression (Putz et al., 1976) have been observed at
levels of 800 ppm for 1 hour, 300 ppm for 3 hours, and 200 ppm for 4 hours,
respectively. These exposures correspond to approximate doses of 12 to 14
mg/kg (see Appendix for calculation).
Reports of serious health effects from accidental/occupational exposure to
DCM (Moskowitz and Shapiro, 1952; Bonventre et al., 1977; Stewart and Hake,
1976) have not adequately determined the circumstances of exposure or quanti-
fied airborne DCM concentrations.
After carbon monoxide was found to be a metabolite of DCM, Stewart et al.
(1972b) expressed concern that individuals with advanced cardiovascular disease (j
may suffer severe effects from DCM exposure. Elevated carboxyhemoglobin levels
-7-
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followiny DCM exposure have been implicated in exacerbation of cardiovascu-lar
effects (Welch, 1987), but no conclusive evidence linking DCM to cardiotoxicity
in humans has been shown.
b. Long-term exposure^
*
Hepatotoxicity and possible hematopoietic effects have been implicated in
chronic occupational exposure studies. Ott et al. (1983c) studied 83 men and
183 women occupationally exposed to DCM levels of 60 to 475 ppm (approximately
t
7.2 to 57 mg/kg/day; see Appendix). Red blood cell counts were increased in
women, but not in men, exposed to approximately 475 ppm DCM, compared with no
increase among unexposed controls.
Welch (1987) analyzed 141 cases of adverse health effects in workers
occupationally exposed to DCM. Effects included neurotoxicity, respiratory
irritation, cardiotoxicity, and hepatitis. Although the author linked these
effects to UCM, in none of these cases could it be conclusively demonstrated
that the effects were due to DCM exposure. Confounding variables included
exposure to other solvents and cigarette smoking. In addition, data on DCM
concentrations in workplace air and data on the carboxyhemoylobin levels in the
blood of exposed individuals were incomplete.
2. Toxic Effects in Animals
a. Short-term exposure
The only acute oral toxicity study found was that reported by Kimura et
al. (1971). In this study, 14-day-old (16 to 50 g), young adult (80 to 160 g),
and older adult (300 to 470 g) Sprague-Dawley rats were given single oral doses
of DCM (undiluted) and observed for 1 week for mortality and signs of toxicity.
-8-
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LU50 values and 95% confidence limits for 14-day-old, young adult, and older
adult rats were 1.8 (1.3 to 2.3), 1.6 (1.3 to 1.9), and 2.3 (1.7 to 3.2) ml/kg,
respectively. Although few details were given, the authors report that the
lowest dose causing observable effects (i.e., dyspnea, ataxia, cyanosis, and/or
coma} was 1 ml/kg (equivalent to 1,326 mg/kg, based on a density of 1.326
g/mL).
Short-term DCM exposure has also been shown to cause a variety of neuro-
toxic effects in laboratpry animals. At concentrations of 17,000 ppm for 6
hours, or 27,QUO ppm for 1.5 hours (approximately equivalent to 5,600 and 2,200
mg/kg/day; see Appendix), DCM induced coma and death in rats (Thomas et al.,
1971). Rats developed symptoms of depressed activity after 3 hours of exposure
to concentrations of 1,000 ppm (approximately 165 mg/kg; see Appendix).
Other neurotoxic effects have resulted from exposure to DCM via inhalation
or ip injection. Effects on sleeping behavior such as reduced rapid eye move-
ment (REM) sleep were observed in rats (strain not specified) exposed continu-
ously for 24 hours to concentrations as low as 500 ppm (approximately equiva-
lent to 660 mg/kg; see Appendix; Berger and Fodor, 1968). Other neurological
effects include edema of the meninges of the brains of female beagles exposed
continuously to 5,000 ppm DCM for 17 to 23 days (MacEwen et al., 1972), and a
decrease in sciatic nerve conduction velocity in Wistar rats exposed to 85 and
510 mg/kg via ip injection (Pankow et al., 1979).
Hepatotoxic effects of short-term inhalation exposure to DCM have been
demonstrated in several species. Morris et al..(1979) observed increased
hepatic triglyceride and phospholipid levels in guinea pigs exposed to 5,200
ppm for 6 hours (approximately 1,400 mg/ky; see Appendix). Male Hartley guinea
pigs exposed via inhalation to 11,100 ppm for 6 hours, or 5,000 ppm for 6
-9-
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hours/day for 5 days, also developed a variety of hepatic histopathological
lesions such as fatty livers and vacuolization (Balmer et al., 1976). Hepatic
fatty changes were also reported by Balmer et al. (1976) Jn three of five male
Hartley guinea pigs exposed to DCM at levels of 552 to 679 ppm for 6 hours/day
for 5 days (approximately 188 mg/kg; see Appendix).
Female mice (ICR strain) exposed continuously via inhalation to 5,000 ppm
of technical grade DCM (12,000 mg/kg/day; see Appendix) for 7 days exhibited
increased liver-to-body'weight ratios, increased liver triglyceride levels, and
decreased glycogen and protein synthesis. A variety of histopathological
effects including breakdown of the endoplasmic reticulum in hepatocytes,
referred to as balloon degeneration, were also observed. Liver lesions were
initially noted after 12 hours of exposure or 6,000 mg/kg/day (Weinstein et
al., 1972). Male Wistar rats, exposed to 500 ppm for 5 hours/day for 10 days
(approximately 140 mg/kg/day; see Appendix), exhibited microsomal enzyme induc-
tion (Norpoth et al., 1974).
Klaassen and Plaa (1966) detected minor inflammatory changes to the liver
(no details were specified) in male Swiss-Webster mice given a single intraperi-
toneal (ip) injection of 2,519 mg/kg DCM in corn oil; no histopathological
changes were reported for mice administered 1,459 mg/kg. In addition, no
changes in SPGT activity were noted at either dose level. Mongrel .dogs appeared
to be more sensitive to DCM exposure, displaying slight hepatic changes such as
subcapsular necrosis, moderate neutrophilic infiltration, and organ dysfunction
characterized by increased serum glutamic-pyruvic transaminase (SGPT) activity
24 or 48 hours after receiving a single ip injection of 663 or 995 mg/kg DCM in
corn oil. The effective dose at which a 50% increase in organ dysfunction
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occurred was estimated to be 796 mg/kg, based on increased SGPT activity
(Klaassen and Plaa, 1967).
Cornish et al. (1973) also reported elevated serum glutamic-oxaloacetic
transaminase (SCOT) levels in groups of four Sprague-Dawley rats administered ip
injections of 265, 663, and 1,326 mg/lcg DCM in peanut oil.
b. Long-term exposure
Long-term exposure to DCM has been shown to cause a variety of hepatotoxic
effects including carcinogenesis, which will be discussed in detail in Section C
In a 90-day study conducted at Bio/dynamics, Inc. (Kirschman et al., 1986),
Fischer 344 rats were given DCM in the drinking water at target concentrations
of 0.15, 0.45, or 1.50%, which are equivalent to doses of 166, 420, or 1,200
mg/kg/day, respectively, in male rats, and 209, 607, or 1,469 mg/kg/day, respec-
tively, in female rats, based on water consumption measurements. Several
hepatocellular changes were observed after 90 days of exposure to DCM (Table 1).
A dose-related increase in the incidence of hepatocyte vacuolization (lipid
accumulation) was found. Centrilobular necrosis, granulomatous foci, and some
evidence of ceroid and lipofuscin accumulation were noted in mid- and high-dose
animals, particularly females. Slight decreases in body weight were noted in
mid-dose males and high-dose females, and several changes in clinical chemistry
parameters, such as increased SGPT, SGOT, and lactic dehydrogenase levels and
decreased serum protein levels, were noted, particularly in mid- and high-dose
females. The NOAELs for male and female rats were 166 and 209 mg/kg/day,
respectively.
Similarly, hepatocellular changes were observed in a companion study in
B6C3Fi mice (Kirschman et al., 1986). DCM concentrations of 0.15, 0.45, or
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Table 1. Summary of Hepatocel lular Findings in the Livers
of Rats Given DCM in Drinking Water for 90 Days
Liver response
Number examined
Normal
Hepatocyte vacuolization
Hepatocyte degeneration
Pigment, Kupffer cells
Granuloma (focal)
Eosinophilic cytoplasmic
bodies {hepatocytes)
No. of
0
M
15
11
1
0
0
1
0
rats affected at DCM concentrations (%)a
F
15
4
6
0
0
0
0
0.
M
15
3
10
0
0
0
0
15
F
15
1
13
0
0
0
0
0
M
15
6
9
0
0
0
0
.45
F
15
0
15
0
0
4
0
1.
M
15
7
7
2
1
1
2
of:
50
F
15
0
.15
12
13
6
4
aihese concentrations correspond to doses of approximately 0, 166, 42U, or 1,200
my/kg/day for males and 0, 209, 607, or 1,469 mg/kg/day for females, based on
daily water consumption and body weights,
SOURCE: Adapted from Kirschman et al. (1986).
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1.50% in drinking water, equivalent to doses of 226, 587, or 1,911 mg/kg/day,
respectively, in males, and 231, 586, or 2,030 rag/kg/day, respectively, in
females, were administered in mice for 90 days. Livers from the mid- and
high-dose males and females exhibited subtle centrilobular fatty changes. In
addition, slight decreases in body weights were noted in mid- and high-dose
animals during the second half of the study. Unlike rats, male mice appeared
to be more sensitive to hepatocellular change compared to females. The NOAELs
for this study were 226 and 231 mg/kg/day for male and female mice, respec-
f
tively.
Bornmann and Loeser (1967) reported that no adverse effects occurred in
male and female Wistar rats after administration of 125 mg/L or 15 mg/kg/day
(assuming daily consumption of 12 nt/100 g body weight) of DCM in the drinking
water for 13 weeks. The urine albumin test was frequently positive, but no bio-
logical significance was attached to this observation. Only one dose level was
tested, and this was identified as the NOAEL for this study.
Weinstein and Diamond (1972) observed increased triglyceride levels, cen-
trilobular fat accumulation, and decreased glycogen content in livers of female
ICR mice exposed continuously to 100 ppm for up to 10 weeks. Histologic effects
were first observed after 7 days (approximately 240 mg/kg/day; see Appendix).
Haun et al. (1972) observed vacuolization in the livers of rats, dogs, and
monkeys (strain not specified) exposed to 100 ppm for 100 days (estimated to be
equivalent to doses of 130, 84, and 42 mg/kg/day for rats, dogs, and monkeys,
respectively). In this study, rats receiving 25 or 100 ppm exhibited some renal
tubular degeneration, but this effect appeared to be transient with subsequent
regeneration.
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In a chronic study reported by Serota et al. (1986a) and conducted by
Hazleton Laboratories, Fischer 344 rats were given DCM in drinking water at
target doses of 0, 5, 50, 125, and 250 mg/kg/day for 104 weeks. At 50, 125,
or 250 mg/kg/day, an increased incidence of foci/areas of cellular alteration
(Table 2) and fatty change were observed in the liver. These hepatic effects
were noted at 78 and 104 weeks of the study. An increased incidence of hepatic
tumors (neoplastic nodules, and neoplastic nodules and hepatoce!lular carcino-
mas combined) occurred in females receiving 50 or 250 mg/kg/day, but not 125
t
mg/kg/day (see Section C). In addition to hepatocellular effects, statisti-
cally significant decreases (p <0.05) in body weight, and in water and food con-
sumption, were observed in animals receiving 125 or 250 mg/kg/day compared with
controls. Because the increased incidence of hepatic tumors noted in females
was within the range of historical controls, and in the absence of a dose-related
effect, i.e., increased incidence in the 125-mg/kg/day group, this was not
considered to be attributable to DCM administration. A NOAEL of 5 mg/kg was
identified.
Mice appeared to be less sensitive to oral DCM exposure. In a study in
which B6C3Fi mice were given 0, 60, 125, 185, and 250 mg/kg/day DCM in drinking
water for 104 weeks, an increase in hepatocellular alterations consisting of
slight increases in the amount of Oil Red-0 positive material (consistent with
increased fat content in the liver) was noted in high-dose males and females.
A NOAEL of 185 mg/kg/day was identified (Serota et al., 1986b). Increased
incidence of combined heptocellular adenomas/carcinomas was noted in male mice
given DCM at concentrations of 125 or 185 mg/kg/day but not at 250 mg/kg/day
(see Section C). The authors considered this increase marginal because there
was no dose-related response, and the incidence was within the historical
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Table 2. Incidence of Liver Foci/Areas of Alteration in Rats
. Given DCM in Drinking Water for 78 or 104 Weeks
Sex
Males
Females
Males
Females
Incidence^
0
7/20
3/2U
t
27/36
17/31
of lesion
5
3/20
11/20
22/34
12/29
at DCM dose
50
78 weeks
15/20
14/20
104 weeks
35/38
30/41
(mg/kg/day)
12b
13/20
16/20
34/35
34/38
of:
2bO
20/20
17/20
40/41
31/34
"Number of rats affected/number examined.
SOURCE: Adapted from Serota et al. (1986a).
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control range of 5 to 34% (mean 16.1%) for this tumor type in B6C3Fi mice at t
Hazleton Laboratories (Serota et al., 19865). 1
The National Toxicology Program (NTP, 1986) reported that inhalation
exposure to 1,000, 2,000, or 4,000 ppm DCM, 6 hours/day, 5 days/week for 102
weeks, resulted in increased incidences of hepatic hemosiderosis, cytomegaly,
cytoplasmic vacuolization, necrosis, granulomatous inflammation, and bile duct
fibrosis in both male and female F344/N rats. In addition, increased inci-
dences of benign mammary tumors (primarily fibroadenomas) were noted in both
male and female rats exposed to 4,000 ppm DCM (see Section C, Table 7). In a
companion study {NTP, 1986), 2-year exposure to 2,000 or 4,000 ppm DCM 6 hours/
day, 5 days/week, resulted in hepatic cytologic degeneration in B6C3Fi mice.
Dose-related increases in the incidence of alveolar/bronchial adenomas and/or
carcinomas, and in the number of treated mice bearing multiple pulmonary tumors
or hepatocellular adenomas/carcinomas, were also noted (see Section C).
In another chronic inhalation study, 2-year exposure of Sprague-Oawley rats
to 500, 1,500, or 3,500 ppm DCM, 6 hours/day, 5 days/week, resulted in hepatic
lesions characterized by increased vacuolization in males and females at the 500-
ppm level (approximately 165 mg/kg/day; see Appendix). Increases in sarcomas
in and around the salivary glands were observed in male rats at the 1,500- or
3,500-ppm exposure levels. Also, female rats exhibited a dose-related increase
in total numbers, but not incidence, of benign mammary tumors (see Section C).
No effects were noted in Golden Syrian hamsters exposed for 2 years to 500 to
3,500 ppm DCM, 6 hours/day, 5 days/week (Burek et al., 1984).
3. Development of Health Advisories
The limited studies performed to date may not have identified the most
sensitive endpoint of DCM toxicity. Available studies on human occupational
-16-
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inhalation exposure focus primarily on behavioral/neurological effects; possible
toxicity to other tissues has not been investigated in detail. Hepatotoxicity
from short-term ingestion and inhalation exposure has been observed in mice,
guinea pigs, and rats, but behavioral/neurotoxic effects have not been well
studied at similar exposure levels. The only report on the acute oral toxicity
of DCM is the study of Kimura et al . (1971). Details of the toxic effects and
doses tested were not provided.
Long-term ingestion and inhalation studies of DCM in rats have identified
the liver as a target organ. In addition, chronic occupational inhalation
exposure has been linked to increased bilirubin levels (Ott et al., 1983c),
which is suggestive of hepatotoxicity. Oral and inhalation exposures have also
been found to cause kidney and CNS effects in laboratory animals.
a. One-day Health Advisory
The study by Kimura et al . (1971) was selected for derivation of the One-
day HA for DCM in a 10-kg child because no other adequate acute oral studies of
appropriate duration or design were found in the literature. This study identi-
fied a LOAEL of 1.0 ml/kg (1,326 mg/kg) in young adult Sprague-Dawley rats on
the basis of gross signs of toxicity (i.e., dyspnea, ataxia, cyanosis, and/or
coma) following the administration of a single oral dose of DCM. The authors
implied that multiple dose levels were administered to define dose response,
although details' were not reported. The calculations for a One-day "HA for a
10-kg child are given below:
One-day HA = t1*?2^ m&W. (.1U ^ * 13.3 mg/L (rounded to 10,000 ug/L)
j (I L/day)
-17-
-------
where:
1,326 mg/kg
10 kg
1,000
LOAEL, based on gross signs of toxicity in rats.
assumed body weight of a child.
uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
1 L/day « assumed daily water consumption of a child.
b. Ten-day Health Advisory
/
The March 31, 1987, HA for dichloromethane gives a value for the Ten-day
HA of 1,500 mg/L, based on the study of Bornmann and Loeser (1967). With the
availability of a more recent study, Kirschman et al. (1986), the Ten-day HA
value has been revised and is based on the Longer-term HA of 2,000 ug/L for a
10-kg child.
c. Longer-term Health Advisory
Three studies were considered for the calculation of the Longer-term HA
(Table 3}. In two studies conducted at Bio/dynamics, Inc., and reported by
Kirschman et al. (1986), Fischer 344 rats and B6C3Fi mice were given nominal
concentrations of 0.15, 0.45, and 1.50% DCH in the drinking water for 90 days.
These levels are equivalent to doses of 166, 420, or 1,200 mg/kg/day, respec-
tively, for male rats, and 209, 607, or 1,469 mg/kg/day, respectively, for
female rats; and 226, 587, or 1,911 mg/kg/day, respectively, for male mice, and
231, 586, or 2.U30 ing/kg/day, respectively, for female mice. Based on dose-
related increases in hepatocyte vacuolization in both males and females and a
variety of histopathological changes at the mid- and high-dose levels, a LOAEL
of 166 mg/kg/day was identified. In addition, slight decreases were observed
in body weights of mid-dose males and high-dose females, and degenerative changes
were observed in the hepatocytes of high-dose females. The authors reported a
-18-
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Table 3. Summary of Subchronic Oral Toxicity Studies Considered for the
Development of the Longer-term HA
Reference Species Duration
Dose
Percent (mg/kg/day)
(v/v) Males Females
Effects
Ki rschman
et al.
(1986)
Rat
90 days
Ki rschman
et al.
(1986}
Bornmann
and Loeser
(1967)
Mouse
Rat
90 days
13 weeks
0.15
0.45
1.50
0.15
0.45
1.50
0.013
166 209
420 607
1,200 1,469
226
587
1,911
15
231
586
2,030
15
LOAEL
Dose-related increases
in hepatocyte vacuoliza-
tion; slight decreases
in body weight. In females,
hepatocellular degeneration
and increases in serum
glutamic-pyruvic transami-
nase, serum glutamic-oxalo-
acetic transaminase, total
serum protein, and lactic
dehydrogenase.
NOAEL
Centrilobular fatty
change in liver.
NOAEL
No effects noted.
-19-
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NUAEL for mice of approximately 231 mg/kg/day, based on slight centrilobular
fatty changes in the livers of mid- and high-dose animals.
Bornmann and Loeser (1967) exposed Wistar rats to DCM in drinking water
for 13 weeks and reported a NOAEl of 125 mg/L. This is equivalent to a dose of
approximately 15 mg/kg/day» based on daily water consumption of 12 mL/100 g
body weight.
The 9U-day study reported by Kirschman et al. (1986), in which DCM was
administered in drinking water at doses of 166 to 1,469 mg/kg/day to Fischer
344 rats, has been selected as the basis for the Longer-term HA because rats
proved to be slightly more sensitive to DCM administration than mice. This
study was selected over the Bornmann and Loeser study primarily because a range
of doses was used to demonstrate a toxic effect, and a detailed description of
the study methods and results was provided.
The Longer-term HA for a 10-kg child is calculated as follows:
(166 mg/ky/day)(10 kg) * 1.7 my/L (pounded to 2,UOO ug/L)
(1 L/day)(1,000)
where:
166 my/kg/day = LOAEL, based on dose-related increased histopathological
changes in the livers of rats.
10 kg = assumed body weight of a child.
1 L/day = assumed daily water consumption of a child.
1,000 » uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
-20-
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d* Reference Dose and Drinking Vlater Equivalent Level
Caution must be exercised in deciding how to consider possible lifetime
exposure to this substance because, based on the available carcinogenicity data,
dichloromethane may be classified in Group B2 {Probable Human Carcinogen), accord-
iny to the EPA guidelines for assessment of carcinogenic risk (U.S. EPA, 1986).
Consequently, the assessment of carcinogenic potential must be balanced against
the likelihood of occurrence of health effects related to noncarcinogenic end-
/
points of toxicity.
The two chronic oral toxicity studies reported by Serota et al. (1986a,b)
were considered as the basis for calculation of the Reference Dose (RfD) and
Drinking Water Equivalent Level (DUEL) (Table 4). Although both studies were
adequate, the study with rats is most appropriate for derivation of the DWEL
because rats are the more sensitive species. A NOAEL of 5 mg/kg/day was iden-
tified in this study. Effects on body weight, hematological parameters, and
histopathological changes in the liver (incidence of foci/areas of cellular
alteration and/or fatty changes) were observed at higher doses.
The DWEL for a 70-kg adult is calculated as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (5 mg/kg/day) = 0.05 mg/kg/day
where:
5 my/kg/day « NOAEL based on the absence of liver and blood effects in
rats.
1UU = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
-21-
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Table 4. Summary of Chronic Oral Toxicity Studies Considered for the
Development of the Reference Dose and Drinking Water Equivalent
Level
Reference
Serota et
al. (1986a)
Species
(sex)
Rat
(M/F)
Duration
Route (weeks)
Oral 104
Dose
(mg/kg/day)
5
50
Effect
NOAEL
Hepatic fatty change,
125
250
Serota et
al. (1986b)
Mouse
(M/F)
Oral
104
60
125
185
250
hepatic tumors.
Hepatic fatty change,
decreased body weight
and food consumption.
Hepatic fatty change,
hepatic tumors,
decreased body weight
and food consumption.
NOAEL
Hepatic lesions.
-22-
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Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DUEL = (O.U5 mg/kg/day)(70 kg) - ^75 mg/L (pounded to 2,000 ug/L)
2 L/day
where:
0.05 mg/kg/day = RfD.
7U kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption by an adult.
C. QUANTIFICATION OF CARCINOGENIC EFFECTS FOR OICHLOROMETHANE
1. Categorization of Carcinogenic Potential
DCM has been shown to be mutagenic in numerous test systems, including
Salmonella reversion assays using JS. typhimuriurn strains TA100, TA1535, and
TA98 (U.S. EPA, 1985a). The epidemiologic studies (Friedlander et al., 1978;
Hearne and Friedlander, 1981; and Ott et al., 1983a,b,c,d,e) have not demon-
strated any excessive cancer risk 1n occupationally exposed workers. However,
because of the limitations of these studies (e.g., insufficient followup
time), these findings were judged to be inconclusive (U.S. EPA, 1985b).
Three groups have reported results of DCM carcinogenic!ty bioassays:
Scrota et al. (1986a,b, conducted by Hazleton Laboratories); the National
Toxicology Program (NTP, 1986); and Dow Chemical Company (Burek et al., 1984;
Dow, 1982). The results of these bioassays were considered in evaluating the
carcinogenic potential of DCM.
Serota et al. (1986a,b) describe studies in which Fischer 344 rats and
B6C3Fj mice were exposed to DCM in drinking water at concentrations equivalent
to doses of 0, 5, 5U, 125, or 2bO mg/kg/day (rats) and 0, 60, 125, 185, or 25U
-23-
-------
my/kg/day (mice). A significant increase (p <0.05) in the incidence of neo-
plastic nodules/hepatocellular carcinomas was observed in female rats exposed
to 50 and 250 mg/kg/day compared to matched controls (Table 5). These increases
were within the range of historical controls and were considered marginal.
Similarly, increases in combined hepatocellular adenomas/carcinomas in male
mice were also considered borderline with increases significantly different (p
<0.05) from controls in the 125- and 185-mg/kg/day, but not the 2bO-mg/kg/day,
>
dose groups (Table 6). Based on the incidence of hepatocellular adenomas/car-
cinomas in male mice, an upper-bound risk estimate for ingestion of DCM in
drinking water was calculated (U.S. EPA, 1985b). Using the multistage model,
the incremental unit risk estimate for drinking water was estimated to be 3.5 x
10-7
An inhalation study conducted by NTP (1986) serves as the basis for both
the qualitative ranking (Group B2, Probable Human Carcinogen) and the quantita-
tive risk assessment. In this study, Fischer 344/N rats and B6C3Fi mice of both
sexes were exposed to DCM concentrations of 0, 1,000, 2,000, or 4,000 ppm
(rats) and 0, 2,000, or 4,000 ppm (mice) for 6 hours/day, 5 days/week, for 2
years. Significant increases in the benign mammary tumors (primarily fibro-
adenomas) were observed in high-dose male and female rats from all DCM-dosed
groups (Table 7). Significant positive trends for mammary adenoma or fibroade-
noma were also noted in male and female groups. The significance of other tumor
incidence increases (combined hepatocellular neoplastic nodules/carcinomas,
mononuclear cell leukemia, mesotheliomas, adrenal pheochromocytomas and intersti-
tial cell tumors, and combined pituitary glarid adenomas/carcinomas) varied with
the type of statistical analysis used to evaluate the results. For mice, increasecL
incidences of al veolar/bronchiolar adenonomas and/or carcinomas as well as signifiu
cant positive trends were found for both sexes (Table 8), and the number of
-24-
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Table 5. Summary of Findings for Liver Tumors in Rats Given DCM in
Drinking Water for 2 Yearsa
Dose (mg/kg/day)
Lesion
50
125
250
25U&
Males
Neoplastic nodules
Hepatocellular carcinomas
Combined nodules/
carcinomas
Females
Neoplastic nodules
Hepatocellular carcinomas
Combined nodules/
carcinomas
4(S)c
2(2)
6(7)
0(0)
0(0)
0(0}
5(10)
2(4}
7(14)
0(0)
0(0)
0(0)
2(2)
0(0)
2(2)
KD
0(0)
KD
3(4)
0(0)
3(4)
2(2)
2(2)
4(5)*
3(3)
0(0)
3(4)
1(1)
0(0)
KD
HD
KD
2(2)
4(5)
2(2}
6(7)*
4(16}
0(0)
4(16)
2(8)
0(0}
2(8)*
aLifetime totals.
bRecovery group, exposed to DCM for 78 weeks followed by a recovery period of
26 weeks.
CNumber of animals affected (percent incidence).
*Significantly different from controls (p <0.05) using a combined control
incidence of 0/134.
SOURCE: Adapted from Serota et al. (1986a).
-25-
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Table 6. Summary of Findings for Liver Lesions/Tumors in
Male Mice Given DCM in Drinking Water for 2 Yearsa
Lesion
Dose (mg/ky/day)
60
185
ZbU
Focal hyperplasia
4(7)a 6(9) 14(7) 4(4) 10(10) 13(10)
Hepatocellular adenoma 6(10) 4(6) 20(10) 14(14) 14(14) 15(12) I
Hepatocellular carcinoma 5(8) ;9(14) 33(17) 18(18) 17(17) 23(18) .
Hepatocellular adenoma
and/or carcinoma
11(18) 13(20) 51(26) 30(30)* 31(31)* 35(28)
aNumber of animals affected (percent incidence).
*Significantly different from controls (p <0.05) using a combined incidence of
24/25.
SOURCE: Adapted from Serota et al. (1986b).
-26-
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Table 7. Summary of Findings for Mammary and Subcutaneous Tumors
in Rats Exposed via Inhalation to DCM for 2 Years
Dose (ppm)
Site/tumor
Hales
Mammary gland: adenoma or fibroadenoma
Subcutaneous tissue: ftbroma
Mammary yland or subcutaneous tissue:
adenoma, fibroadenoma, or fibroma
Fema 1 es
Mammary gland: fibroadenoma
Mammary gland: adenoma or fibroadenoma
0
0(0)a*
1(2)
1(2)*
5(10)*
5(10)*
1,000
0(0)
1(2}
1(2)
11(22)*
11(22)*
.2,000
2(4)
2(4)
4(8)
' 13(26}*
13(26)*
4,000
5(10)*
4(8)
9(18)*
22(44)**
23(46)**
^Number of animals affected (percent incidence),
*Significant1y different from controls (p <0.05).
**Significant1y different from controls (p <0.01).
Note: A positive trend denoted at control level by an asterisk using incidental
tumor tests (actual tests used were not reported).
SOURCE: Adapted from NTP (1986).
-------
Table 8. Summary of Findings for Luny and Liver Tumors in
Mice Exposed via Inhalation to DCM for 2 Years
1
Site/ tumor
Males
Alveolar/bronchiolar adenoma
Alveolar/bronchiolar carcinoma
t
Alveolar/bronchiolar adenoma or carcinoma
Hepatocellular adenoma
Hepatocellular carcinoma
Hepatocellular adenoma or carcinoma
Females
Alveolar/bronchiolar adenoma
Alveolar/bronchiolar carcinoma
Alveolar/bronchiolar adenoma or carcinoma
Hepatocellular adenoma
Hepatocellular carcinoma
Hepatocellular adenoma or carcinoma
0
3(6)a*
2(4)*
5(10)*
10(20)
13(26)*
22(44)* -
2(4)*
1(2)*
3(6)*
2(4.)*
1(2)*
3(6)*
Dose (£pm)
2,000
19(38)**
10(20)*
27(54)**
14(29)
15(31)
22(49)
23(48)**
13(27)**
30(63)
6(13)
11(23)**
16(33)**
4,000 i
;
1
24(48)** j
i
28(56)**
\
40(80)** |
14(29) j
26(53)* j!
33(67)* |!
,!
i
28(58)** I
29(60)** ;
41(85)
22(46)** jl
32(67)**
40(83)** i
i
I
t
aNumber of animals affected (percent incidence).
*Significantly different from controls (p <0.05)
**Significant1y different from controls (p <0.01).
Note: A positive trend denoted at control level by an asterisk using incidental
tumor tests (actual tests used were not reported).
SOURCE: Adapted from NTP (1986).
-28-
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treated animals bearing multiple pulmonary tumors was also increased over controls.
In addition, the incidence of mice with multiple hepatocellular adenomas/carci-
nomas increased significantly in a dose-related matter. On the basis of these
results, NTP concluded that there was some evidence of the carcinogenicity of
DCM for male Fischer 344/N rats as shown by an increased incidence of benign
neoplasms of the mammary gland; there was sufficient or clear evidence of the
carcinogenicity of OCM for female Fischer 344/N rats as shown by an increased
incidence of benign neoplasms of the mammary gland; and there was clear evidence
of carcinoyenicity in male and female B6C3Fi mice as shown by increased incidence
of lung and liver tumors. The increased incidence of hepatocellular adenomas/
carcinomas was used as the basis for computing the unit risk estimate for
inhalation of UCM: .7.5 x 10-8 (ug/l)-l (U.S. EPA, 19855).
In the study described by Burek et al. (Dow Chemical, 1983), Sprague-
Dawley rats and Golden Syrian hamsters (both sexes) were exposed via inhalation
to levels of 0, 500, 1,500, or 3,500 ppm DCM, 6 hours/day, 5 days/week, for 2
years. No effects were noted in hamsters. Increases in two tumor types were
observed in rats: (1) ventral cervical sarcomas, probably of the salivary
gland (male rats only, 1,500- and 3,500-ppm dose groups); and (2) benign mammary
tumors (female rats only, increase in total number of tumors, not incidence)
(Table 9). In a second study (Dow, 1982), Sprague-Dawley rats were exposed to
0, 50, 200, and SOU ppm DCM. No significant Increase in tumor incidence was
found.
2. Quantitative Carcinogenic Risk Estimates
The two risk estimates based on hepatocellular adenomas/carcinomas in mice
(Serota et al., 1986a,b; NTP, 1986) are similar, with a mean value of 2.1 x 10-7
(ug/L)-l (U.S. EPA, 1985b). The estimated excess cancer risk associated with
-29-
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Table 9. Summary of Findings for Mammary and Ventral Cervical
Tumors in Rats Exposed via Inhalation to OCM for 2 Years
Site/tumor
Mal_es
Mammary tumor (benign)
Total number benign mammary tumors
Ventral cervical sarcoma
Females
.Mammary tumor (benign)
Total number benign .mammary tumors
Ventral cervical sarcoma b
Dose (ppm)
0 500 1,500
7{8)a 3(3) 7(7)
8 6 11
1(1} 0(0) 5(5)
79(82) 81(85) 80(83)
165 218 245
-_
3,500
14(14)
17
11(11)*
83(86)
287
--
aNumber of animals affected (percent incidence).
bNot reported.
*Significantly different from controls (p <0.05).
SOURCE: Adapted from Burek et al. (1984). .
-30-
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lifetime exposure to drinking water containing DCM at 1,750 ug/L (the OWEL) is
approximately 3.7 x 10-4. This estimate represents the upper 95% confidence
I
limit from extrapolations prepared by the U.S. EPA Carcinogen Assessment Group
using the linearized, multistage model. The actual risk is unlikely to exceed
this value, but there is considerable uncertainty as to the accuracy of risks
calculated by this methodology.
0. EXISTING GUIDELINES AND STANDARDS
/
The U.S. EPA (1980a) criterion for DCM in drinking water is 12.4 mg/L
based on noncarcinogenic risk. The original U.S. EPA (1980b) Suggested-No-
Adverse-Response Levels (SNARLS, presently referred to as Health Advisories)
in drinking water were calculated as 13, 1.5, and 0.150 mg/L for One-day, Ten-
day, and Longer-term exposures, respectively. The National Academy of Sciences
(HAS, 198U) reported One- and Seven-day NAS-SNARLS of 35 and 5 mg/L, respec-
tively, for DCM in drinking water. Recalculation of these data resulted in
One- and Seven-day values of 45.5 and 6.5 mg/L, respectively (U.S. EPA, 1987).
The American Conference of Governmental Industrial Hygienists (ACGIH,
1984} recommended a Time-Weighted Average-Threshold Limit Value (TWA-TLV) of
100 ppm (360 my/m3) in the absence of exposure to carbon monoxide and a short-
term exposure level of 500 ppm. The Occupational Safety and Health Administra-
tion (OSHA, 1979) established an occupational exposure standard of 1,737 mg/m3
for 8 hours (TWA) with a 3,474 mg/m3 ceiling concentration (5 minutes in any 2
hours). The National Institute of Occupational Safety and Health (NIOSH, 1976)
recommended an exposure limit of 261 mg/m^ for.10 hours (TWA).
-31-
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E. SPECIAL CONSIDERATIONS
High-Risk Populations
Carbon monoxide is a known metabolite of DCM, causing elevated carboxyhemo-
globin levels in humans (Ott et al., 1983c,e). The increased concentrations of
carboxyhemoglobin may compound cardiovascular effects as suggested by Welch
(1987). Thus, although there is no conclusive evidence linking DCM to cardio-
t
toxicity in man, those suffering from advanced cardiovascular disease may con-
stitute a potential high-risk population (Stewart et al., 1972).
!
F. SUMMARY
The recommended One-day, Ten-day, and Longer-term HA values, the DWEL, and
the estimated excess cancer risks are summarized in Table 10.
-32-
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Table 1U. Summary of Quantification of lexicological
Effects for Dichloromethane
Drinking water
concentration
(ug/L)
Reference
One-day HA for 10-kg child
Ten-day HA for 10-kg child
Longer-term HA for 10-kg child
Longer-term HA for 70-kg adult
DWEL (100% from drinking
water)
Excess cancer risk
.10-4
10-5
10-6
10,000
a
2,000
b
2,000
476
48
5
Kimura et al. (1971)
Kirschman et al. (1986)
Kirschman et al. (1986)
Kirschman et al. (1986)
Scrota et al. (1986)
U.S. EPA (1985b)
U.S. EPA (19855)
U.S. EPA (1985b)
aThe Longer-term HA is used as a conservative estimate of the Ten-day HA.
bThe OWEL value is used as a conservative estimate of the Longer-term HA value
for a 70-kg adult.
-------
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Berger M, Fodor GG. 1968. CNS disorders under the influence of air mixtures
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Bonventre S, Brennan 0, Jason D, Henderson A, Bastos ML. 1977. Two deaths
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Bornmann G, Loeser A. 1967. Zur frage einer chronisch-toxischen wirkung von
dichloromethan. Z. Lebensm.-Unters. Forsch, 136:14-18.
Burek JU, Nitschke KD, Bell TJ, Wackerle DL, Childs RC, Beyer JE, Dittenber DA,
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Hearn FT, Friedlander BR. 1981. Follow-up of methylene chloride study. J.
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Kimura ET, Ebert DM, Dodge PW. 1971. Acute toxicity and limits of solvent
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Klaassen CD, Plaa GL. 1966. The relative effects of various chlorinated
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Klaassen CO, Plaa GL. 1967. Relative effects of various chlorinated hydro-
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Krischman SC, Brown NM, Coots RH, Morgareidge K. 1986. Review of investiga-
tions of dichloromethane metabolism and subchronic oral toxicity as the basis
for the design of chronic oral studies in rats and mice. Food Chem. Toxicol.
24:943-949.
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APPENDIX?
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Estimations of Dose From Studies of Inhalation Exposure to Dlchloromethane
Species
Concen-
tration
(pom)
Duration of
exposure
(hr/day)
Estimated
absorbed dose
(mg/kg/day)a
Reference
Human: (70 kg; U.6 m3/hr)
Controlled
exposures
Occupational
exposures
2UO
300
800
6U
475
4
3
1
8
8
Rat: (0.25 ky; 0.0792 m3/hr)
Mouse; (0.025 kg; 0.0144 m3/hr)
5,000
100
12
24
Guinea pig; (0.50 kg; 0.133 m3/hr)
5,200 6
Dog; (10 kg; 0.20 m3/hr)
100 24
Monkey; (10 kg; 0.1 m3/hr)
100 24
Hamster: (0.10 kg; 0.0366 m3/hr)
500 6
12
14
12
7.2
57
25
100
500
500
500
1,000
17,000
27,000
24
24
5
6
24
3
6
1.5
33
130
140
165
660
165
5,600
2,200
6,000
240
14,400
84
42
1,900
Putz et al. (1976)
Fodor and Winneke (1971)
Stewart et al. (1973b)
Ott et al. (1983a,c)
Ott et al. (1983a,c)
Haun et al. (1972)
Haun et al. (1972)
Norpoth et al. (1974)
Dow (1980)
Berger and Fodor (1968)
Thomas et al. (1971)
Thomas et al. (1971)
Thomas et al. (1971)
Weinstein et al. (1972)
Weinstein and Diamond (1972)
Morris et al. (1979)
Haun et al. (1972)
Haun et al. (1972)
Dow (1980)
Estimated absorbed dose was calculated as follows:
Dose *
[Conc.(ppm) x 3.47 mg/m3 ppm-l][Exposure(hr)][Resp.
rate(mg/m3)][50% absorption]
body weignt (kg)
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