EPA-540/1-86-028
Environmental
Agency
ice of Emergency and
^medial Response
Washington DC 20460
Superfund
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
HEALTH EFFECTS ASSESSMENT
FOR METHYLENE CHLORIDE
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EPA/540/1-86-028
September 1984
HEALTH EFFECTS ASSESSMENT
FOR METHYLENE CHLORIDE
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
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DISCLAIMER
This report has been funded wholly or In 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 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute 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 methylene
chloride. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data
bases. The basic literature searched supporting this document 1s current up
to September, 1984. Secondary sources of Information have also been relied
upon 1n 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 Halomethanes.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
400/5-80-051. NTIS PB 81-117624.
U.S. EPA. 1982. Addenda to Hazard Profiles on Halomethanes.
Environmental Criteria and Assessment Office, Cincinnati, OH.
Internal draft.
U.S. EPA. 1983b. Reportable Quantity for Olchloromethane. Pre-
pared by the Environmental Criteria and Assessment Office, Cincin-
nati, OH,, for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1985a. Health Assessment Document for Olchloromethane.
Environmental Criteria and Assessment Office, Research Triangle
Park, NC. EPA 600/8-82-004F. NTIS PB 85-191559.
U.S. EPA. 1985b Addendum to the Health Assessment Document for
Dlchloromethane/Methylene Chloride. Updated Carcinogen Assessment
of Dlchloromethane (Methylene Chloride). External Review Draft.
OHEA, Washington, DC. EPA 600/8-82-004FA.
The Intent 1n 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 1n
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 chemlcal(s) addressed.
111
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Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 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 In ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS 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.
The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). 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 Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s 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 noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983a).
For compounds for which there is sufficient evidence of carc1nogen1dty,
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 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n 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 Inter-
pretation and use of the quantitative estimates presented.
The major Issue of concern 1s the amply demonstrated cardnogenlcity of
methylene chloride. Human data that rule out cardnogenlcity to humans are
not available . Animal experiments have clearly demonstrated the cardno-
genlcity of methylene chloride In mice and strongly suggest cardnogenlcity
1n rats. Methylene chloride has been shown to be mutagenlc In Salmonella
and to Increase the number of chromosomal aberrations 1n cultured Chinese
hamster ovary cells. Negative results were obtained for mltotlc recombina-
tion 1n yeast, 1n mutagenldty tests 1n Drosophlla and evaluations of sister
chromatld exchange 1n cultured Chinese hamster ovary cells. A human q-|*
of 6.3xlO~4 (mg/kg/day)"1 has been estimated for Inhalation exposure
from a rat study which showed an Increased Incidence of salivary gland
sarcomas (U.S. EPA, 1985a). An evaluation of the draft results of the NTP
(1985) bloassay 1s currnetly 1n progress.
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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 1n 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:
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. . . .
3.3.1. 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. 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
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APPENDIX: Summary Table for Methylene Chloride ............ 48
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LIST OF TABLES
No. Title Page
2-1
4-1
4-2
4-3
4-4
5-1
Absorption of Methylene Chloride by Human Subjects
(Sedentary Conditions)
Summary of Salivary Gland Region Sarcoma Incidence In Male
Rats 1n a 2-Year Inhalation Study with Dlchloromethane. . . .
Tumor Incidence In Rats Treated with Methylene Chloride . . .
Tumor Incidence In Mice Treated with Methylene Chloride . . .
Mutagenldty and Genotoxlclty of Methylene Chloride .....
Regulatory Standards and Criteria for Methylene Chloride. . .
4
20
23
24
25
30
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF B1oconcentrat1on factor
bw Body weight
CS Composite score
EKG Electrocardiograph
LOAEL Lowest-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
SCE Sister chromatld exchange
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
methylene chloride (CAS No. 75-09-2), also known as methylene dlchlorlde and
dlchloromethane, are shown below.
Chemical class:
Molecular weight:
Vapor pressure:
Solubility 1n water:
Log octanol/water
partition coefficient:
Soil mobility:
(predicted as retardation
factor for a soil depth
of 140 cm and organic
carbon content of 0.087%)
BCF:
Half-life In air:
Half-life 1n water:
halogenated aliphatic hydrocarbon
(purgeable halocarbon)
84.93
362.4 mm Hg at 20°C
(Callahan et a!., 1979)
13,030 mg/!t at 25°C
(Horvath, 1982)
1.25 (Callahan et al., 1979)
<1.2 (estimated)
2.3 (estimated)
53-127 days (Singh et al., 1981;
Maklde and Rowland, 1981)
1-6 days (estimated)
30-40 days 1n lake water
(Zoeteman et al., 1980)
The soil mobility value has been estimated from a comparison of the
octanol/water partition coefficient values and the solubilities (Callahan et
al., 1979) of this compound with those for chloroform and the retardation
factor for chloroform given by Wilson et al. (1981).
The estimated half-life value for methylene chloride in water Is based
on the reaeratlon rate ratio of 0.650 and oxygen reaeratlon rate of
0.19-0.96 day'1 (Mabey et al., 1981). The difference between this
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estimated half-life value and the value given by Zoeteman et al. (1980) for
lake water 1s probably due to the retardation of volatility due to suspended
and sedlmentated particulated matter 1n the lake water, a factor not con-
sidered In estimating the half-life by the first method.
The BCF for methylene chloride has been estimated from Us octanol/water
partition coefficient value and the equation given by Velth et al. (1979).
The half-life of methylene chloride 1n soil could not be located 1n the
literature searched. However, evaporation Is expected to be the predominant
loss mechanism from the soil surface. In subsurface soil, blodegradatlon of
a chlorinated aliphatic hydrocarbon such as methylene chloride may be slow
(Wilson et al., 1983). Therefore, In subsurface soil, the nondegraded
methylene chloride 1s expected to leach Into groundwater.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
Pertinent data regarding the absorption of methylene chloride after oral
exposure could not be located 1n the available literature. Roberts and
Marshall (1976) Indicated that absorption through the Intestinal mucosa
appeared to be fairly rapid and complete. A number of reports of severe
toxldty following 1ngest1on (Llewellyn, 1966; Stewart and Hake, 1976;
FMedlander et al., 1978) also Imply that absorption following 1ngest1on
occurs.
2.2. INHALATION
The majority of data regarding absorption of methylene chloride pertains
to Inhalation exposure because that route 1s most likely to be Involved 1n
cases of occupational exposure. Several studies 1n both man and experi-
mental animals have, been performed. These data are summarized from U.S. EPA
(1981a).
R1ley et al. (1966) described the kinetics of absorption and excretion
1n a 70 kg man exposed for 2 hours to 100 ppm methylene chloride 1n air. As
absorption progressed, the concentration In alveolar air Increased, Indicat-
ing decreased absorption as a steady-state condition was achieved. In this
study, equilibrium had not been reached at the end of 2 hours. At this
time, exposure was discontinued and methylene chloride 1n exhaled air was
measured. The decline In concentration of methylene chloride 1n exhaled air
appeared to be exponential and roughly proportional to the amount absorbed
during the exposure period. The retention factors expressed as a percentage
of Inhaled dose 1n this and related studies are summarized 1n Table 2-1.
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TABLE 2-1
Absorption of Methylene Chloride by Human Subjects*
(Sedentary Conditions)
Inhalation
Concentration
(ppm)
50
100
150
200
662
806
1152
1181
44-680
100
100
200
250
500
750
Exposure
(hours)
7.5
7.5
7.5
7.5
0.30
0.50
0.50
0.50
2.00
2.00
4.00
2.00
0.50
0.50
1.00
Retention
(X)
70
60
63
60
74
75
72
70
31
53
41
51
55
55
34
Reference
DIVIncenzo and Kaplan, 1981
Lehmann and Schm1dt-Kehl, 1936
RHey et al., 1966
DIVIncenzo et al.. 1972
Astrand et al., 1975
Engstrom and Bjurstrom, 1977
*Source: U.S. EPA, 1981a
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The theoretical absorption of methylene chloride during short exposures
should be related directly to the concentration In Inhaled air. Although
the protocol that generated these data was not reported by U.S. EPA (1981a),
the data of Lehmann and Schmidt-Kehl (1936) confirm this hypothesis.
D1V1ncenzo and Kaplan (1981) exposed groups of 4-6 volunteers to 50,
100, 150 or 200 ppm methylene chloride for 7.5 hours. Serial breath excre-
tion curves were obtained. Pulmonary absorption was rapid during the first
hour, then began to decline as steady-state was approached. Postexposure
methylene chloride exposures 1n exhaled air dropped rapidly. By 7 hours
after treatment was terminated, expired air from those volunteers exposed to
50, 100 or 150 ppm contained <0.1 ppm methylene chloride. The concentration
In expired air from those exposed to 200 ppm declined to 1 ppm by 16 hours
post-treatment. Respiratory elimination consistently accounted for <5% of
the total amount of methylene chloride absorbed.
Astrand et al. (1975) stated that the amount absorbed Increased with
duration of exposure and physical activity (resulting in Increased venti-
lation and cardiac output). Astrand et al. (1975) found that physical
activity for 0.5 hours during exposure to 250 or 500 ppm methylene chloride
doubled absorption but decreased retention from 55 to 40% because of a
3-fold (6.9-22 8./m1nute) Increase 1n ventilation rate.
Engstrom and Bjurstrom (1977) demonstrated that methylene chloride
absorption was related directly to degree of obesity 1n human subjects.
Obese subjects (fat = 25% bw) absorbed 30% more methylene chloride than lean
subjects (fat = 8% bw) when exposed to 750 ppm for 1 hour. Biopsy and
analysis of subcutaneous fat revealed a substantial (10.2 and 8.4 mg/kg wet
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tissue) concentration 1n adlposa after 1 and 4 hours postexposure, respec-
tively. Although the concentrations 1n fat were somewhat lower 1n obese
than 1n lean subjects, the total amount of body fat resulted In greater
total methylene chloride absorption 1n obese subjects.
Savolalnen et al. (1977) exposed' rats to air containing 200 ppm methyl-
ene chloride 6 hours/day for 5 days. Tissue concentrations were measured In
brain, blood, liver and peMrenal fat on the 5th day of exposure after 0 (18
hours after exposure on day 4), 2, 3, 4 and 6 hours of exposure. Although
no absorption factors were discussed, the persistence In peMrenal fat
before exposure on the fifth day Indicated considerable retention In adlposa
relative to other tissues.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. No reports of subchronlc oral exposure of humans to methyl-
ene chloride have been located 1n the available literature. Only one study
of subchronlc oral toxldty of methylene chloride 1n animals was found.
Bornmann and Loeser (1967) exposed 30 male and 30 female Wlstar rats for 3
months to drinking water containing 0.125 g methylene chloride/1.
Although actual water Intake, hence amount of methylene chloride, was not
reported 1n the secondary source (U.S. EPA, 1983b), an Intake of 12.5 mg
methylene chlor1de/kg/day was estimated assuming rats weigh 0.35 kg and
drink 35 ml of water/day. No difference 1n behavior, appearance, body
weight or survival of treatment animals was observed compared with an equal
number of control animals. No significant differences In hematologlc
values, urlnalysls or plasma levels of nonesterlfled fatty adds were found
In 8-10 male rats from each group. Blood glucose levels 1n 10 treated males
were slightly elevated compared with 10 control males, but all values fell
within the normal range. Estrous cycles, as evaluated by microscopic exami-
nation of vaginal smears, Indicated no changes that were due to treatment.
Necropsy and histopathologlcal examination of -20 animals of each sex and
group revealed no lesions 1n any Internal organ examined. This study
defined a free-standing NOEL of 12.5 mg methylene chlorlde/kg/day In rats
whose exposure was from drinking water.
3.1.2. Inhalation. Inhalation exposure of humans to methylene chloride
1s likely to be a result of occupational exposure; consequently, long-term
exposure can be expected. Therefore, studies of repeated exposure of humans
to methylene chloride are discussed 1n Section 3.2.2. Subchronlc exposure
can be expected in the case of the use of consumer products containing
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methylene chloride, such as paint stripping products and various aerosol
cans containing the chemical. Historically, subchronlc Inhalation exposure
of humans to methylene chloride has been a concern In one particularly
high-risk occupation, astronauts exposed to vapors emanating from materials
used 1n the Interiors of spacecrafts. Consequently, several Investigators
(Thomas et al., 1972; Haun et a!., 1971, 1972; We1nste1n et al., 1972;
MacEwen et al., 1972) exposed laboratory animals to atmospheric methylene
chloride for up to 14 weeks. The U.S. EPA (1983b) summarized the results of
these studies as follows. Mice exposed to 25 or 100 ppm (87 or 348 mg/m3)
methylene chloride continuously for 14 weeks had an Increase 1n spontaneous
activity at the lower concentration but not at the higher one. No gross or
hlstologlcal lesions were found at autopsy, except that livers of the mice
exposed to 100 ppm stained positive for fat. HexobarbHal sleep time was
unaffected, but hepatic levels of cytochromes were somewhat altered. Rats
subjected to the same exposure regimens had nonspecific renal tubular degen-
eration and regeneration, and hepatic cytoplasmlc vacuollzatlon and positive
fat staining at both exposure levels. Rats appeared to be the more sensi-
tive species. No specific macro- or microscopic organ changes or changes 1n
hematologlc or clinical chemistry values were noted In the small number of
monkeys In this study. Carboxyhemoglobln levels, the result of metabolism
of methylene chloride to carbon monoxide and subsequent action on hemo-
globin, were elevated In monkeys at both exposure levels and 1n dogs only at
the higher exposure, but there was no cumulative Increase 1n carboxyhemo-
globln over the period of exposure. No overt signs of toxldty or changes
1n body weights relative to controls were noted 1n any of these four species.
Higher levels of continuous exposure were also Investigated. Exposure
of the same four species to 1000 or 5000 ppm (3480 or 17,400 mg/m3)
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resulted 1n signs of severe toxldty at the higher dose: narcosis for the
first 24 hours and pronounced lethargy for the remainder of the exposure
period, reduced food consumption, and high rates of mortality 1n mice, dogs
and monkeys. Rats were somewhat less sensitive; none died. Liver and
kidney damage were common findings 1n all species. At the lower exposure
level (1000 ppm), only the dogs were severely affected and died. Mice and
rats did not show overt signs of toxlclty, but body weight gain was slightly
depressed 1n the rats. Less severe hlstopathologlcal changes than had been
seen at 5000 ppm were noted 1n the livers of all four species and 1n the
kidneys of rats exposed to 1000 ppm. Monkeys had no significant changes 1n
hematologlc or clinical chemistry values.
Taken collectively, these studies seem to Indicate that subchronlc
exposure to methylene chloride causes effects on the Hver and kidneys of
exposed animals. Lesions In rats exposed to 25 or 100 ppm methylene
chloride appear to be more severe than lesions 1n mice exposed to the same
concentrations. Monkeys and 'dogs seem to be the species least affected. At
higher exposure concentrations (1000 ppm), dogs appear to be most sensitive
and to experience treatment-related mortality. A level of 25 ppm (87
mg/m3) 1n air seems to define a LOAEL In rats when the data from these
studies are considered collectively.
3.2. CHRONIC
3.2.1. Oral. No reports of chronic oral exposure of humans to methylene
chloride have been found 1n the available literature. The National Cancer
Institute has completed a 2-year study with rats and mice, In which the
animals were treated with methylene chloride by gavage. As of May 1985, the
study had been withdrawn pending further review.
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3.2.2. Inhalation. In humans mild Intoxication by methylene chloride re-
sults 1n somnolence, lassitude, anorexia and mild Ughtheadedness, followed
by greater degrees of disturbed central nervous system function and depres-
sion. Permanent disability has not been reported. When fatalities occur
the cause has been attributed to cardiac Injury and heart failure (NAS,
1978).
Further reports of human Intoxication from methylene chloride were pre-
sented by NIOSH (1976). Most of the case reports were concerned with acute
exposure and are not discussed here. Most of the epidemlologic studies
lack data on the concentration of methylene chloride In breathing space air
or they are complicated by exposure to other chemicals; therefore, they are
not suitable for risk assessment.
Weiss (1967) reported a case of toxic encephalosls 1n a chemist exposed
for several hours per day for 5 years to methylene chloride used In a salt-
recrystalUzatlon operation. Measurements revealed concentrations of
660-3600 ppm methylene chloride In workroom air with a mean of 900 ppm In
the breathing zone. This worker had physical contact with liquid methylene
chloride.
Recent ep1dem1olog1cal studies have not revealed adverse effects 1n
humans occupatlonally-exposed to methylene chloride. FMedlander et al.
(1978) reported an ep1dem1olog1cal study of male workers at Eastman Kodak
exposed primarily to methylene chloride. The workers had been exposed to
TWA concentrations of 30-125 ppm methylene chloride (estimated both from air
monitoring and blood carboxyhemoglobln levels) for ojp to 30 years. A
proportionate mortality study, using death certificates from 334 exposed
workers who died from 1956-1976, was performed. A cohort mortality study
Involving all 751 workers employed 1n the exposure area in 1964 and a
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separate analysis of a subgroup of 252 of these workers exposed for a mini-
mum of 20 years by 1964 were also performed. Data from this subgroup were
analysed separately to discuss effects requiring long latency periods. The
follow-up period 1n the cohort mortality study was 13 years. Control groups
consisted of other Eastman Kodak male employees working In production but
not exposed to methylene chloride, New York State male cause- and age-
specific mortality rates and United States male age-specific mortality
rates. Follow-up of workers aged >25 years was >97% as of 1964. None of
these studies revealed any Indication of Increased risk of death from circu-
latory disease Including 1schem1c heart disease, cancer or other causes.
More recently, Ott et al. (1983) Investigated mortality and current
cardiac health In workers from a fiber production plant In which methylene
chloride was used as a solvent. Reasoning that metabolism of methylene
chloride to carbon monoxide results 1n an Increase 1n percentage of carboxy-
hemoglobln with a commensurate decrease 1n the oxygen-carrying capacity of
the blood, these authors (Ott et al., 1983) suggested that exposure to
methylene chloride may lead to an Increase 1n the Incidence of 1schem1c
cardiac disease. Data on mortality were obtained from a cohort of workers
1n a fiber manufacturing plant exposed for at least 3 months between January
1, 1954 and January 1, 1977 to a TWA of -140 ppm methylene chloride. A
control cohort was composed of workers In another part of the plant not
exposed to methylene chloride. Another cohort was the expected death data
for 5-year Intervals matched by race (white and nonwhHe) and sex. Mortal-
ity data Indicated no Increase 1n deaths In either men or women from circu-
latory system diseases, Ischemlc heart disease as a separate category, or
malignant neoplasms associated with exposure to methylene chloride.
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In another study of cardiac function, these Investigators (Ott et al.,
1983} collected 24-hour EKG data from 50 workers from two fiber producing
plants. Data regarding 24 workers from the plant where exposure to TWA
concentrations of 60-475 ppm methylene chloride occurred were compared with
data from 26 workers from a similar plant not using methylene chloride. No
significant changes 1n ventricular or supraventrlcular ectoplc activity, nor
episodic ST segment depression were associated with exposure to methylene
chloride.
Burek et al. (1980) briefly discussed other epldemlologlc studies (Ott
et al., 1980a,b; Skory, 1980; Skory et al., 1980a,b) that apparently
revealed no adverse health effects attributable to methylene chloride. The
titles of some of these papers Indicated that more sensitive parameters of
toxldty were evaluated than those studied by FMedlander et al. (1978).
Exposure data from these studies were not available 1n the secondary source
from which this discussion was taken (Burek et al.-, 1980).
Cherry et al. (1981) reported that a group of 46 men occupationally
exposed to 75-100 ppm methylene chloride for an unspecified length of time
complained of excessive neurological symptoms. Clinical examinations, motor
conduction velocity measurements, EKGs and a battery of psychological tests
"designed to detect minimal brain damage" were administered to 29 of the
exposed men and an equal number of age-matched unexposed men employed at
similar jobs. The results revealed no evidence of cardiac abnormalities or
neurological or behavioral Impairment associated with exposure to methylene
chloride.
Burek et al. (1980, 1984) and Dow Chemical Co. (1980) studied chronic
Inhalation exposure of animals to methylene chloride. Sprague-Dawley rats
(SPF-der1ved, 129/sex/exposure concentration) and Golden Syrian hamsters
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(~108/sex/exposure concentration) were exposed to 0, 500, 1500 or 3500 ppm
(0, 1740, 5220 or 12,180 mg/m3) methylene chloride of >99% purity. Expo-
sures were for 6 hours/day, 5 days/week (excepting holidays) for up to 2
years. Rats were subjected to Interim kills at 6, 12, 15 or 18 months for
cytogenetlc or general chemical and histopathologlcal studies.
During the first week of exposure, rats 1n the high group exhibited a
slight decrease 1n physical activity, but appeared to return to normal
activity for the remainder of the trial. During the first 2 months, rats in
all groups suffered a disease believed to be sialodacryoadenitls, a tran-
sient viral Involvement of the salivary glands. No increased mortality was
associated with the disease. None of the exposure levels affected body
weights, clinical chemistries, or hematologic or urlnalysis values in rats.
Carboxyhemoglobln levels ranged from 0-5.3% 1n controls and 8.9-20.4% 1n
exposed rats but did not appear to be dose-related nor related to time of
exposure. Mortality was unaffected by treatment except that high-dose
females had a significantly elevated mortality rate starting at the 13th
month of exposure.
Mean Hver weights were increased in both male and female rats 1n the
high-dose group, which was first noticed at the 18-month Interim kill.
Histopathologically significant alterations related to methylene chloride
were found only 1n the liver. An increased incidence of hepatocellular
vacuolization indicative of fatty degeneration was noted In all exposed
groups of rats. Incidence and severity appeared to be dose-related. Multi-
nucleated hepatocytes, a spontaneous geriatric change in female rats, were
observed after 12 months in exposed and treated groups alike. A significant
Increase in the number of fod of altered hepatocytes was observed in high-
dose females. Males exposed to 1500 or 3500 ppm had an Increased incidence
-13-
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of hepatocellular necrosis and coagulation necrosis. Some females exposed
to 500 ppm for 12 months appeared to have slightly Increased hepatic hemo-
slderln. High-dose group female rats and middle- and high-dose male rats
had a decreased Incidence or severity of chronic progressive glomeruloneph-
ropathy, another normal geriatric change, compared with controls. High-dose
male rats, consequently, exhibited less severe nonrenal lesions (uremlc
pneumonHls, mineralization of organs and blood vessels, brain malaria,
myocardlal degeneration, etc.) associated with chronic progressive renal
disease.
In this study hamsters appeared to be less sensitive to methylene
chloride than did rats. Although carboxyhemoglobin levels were higher In
hamsters (0.3-4.0% 1n control groups, 22.2-34.6% 1n treatment groups) than
In rats, no clear evidence of toxldty was observed In hamsters. Methylene
chloride-exposed hamsters exhibited a decreased Incidence or severity of
amyloid deposition In their tissues, a normal geriatric change In hamsters,
compared with controls.
In rats, this study appeared to define a LOAEL of 500 ppm (1740
mg/m3), associated with mild hepatomegaly and mild hepatocellular vacuoll-
zatlon Indicative of fatty Infiltration. Assuming a body weight for rats of
0.35 kg and an Inhalation rate of 0.26 mVday, exposure for 6 hours/day, 5
days/week resulted 1n an Intake of 230.8 mg/kg/day.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data associating oral exposure of humans to
methylene chloride with terata or reproductive effects could not be located
1n the available literature. The estrous cycle In female rats was reported
to be unaffected by exposure to 0.125 g methylene chloride/1 1n their
drinking water for 3 months (Bornmann and Loeser, 1967).
-14-
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3.3.2. Inhalation. Pertinent data regarding teratogenldty or reproduc-
tive dysfunction In humans exposed by Inhalation to methylene chloride could
not be located 1n the available literature. Schwetz et al. (1975) exposed
Swiss-Webster mice and Sprague-Dawley rats to 1250 ppm (-4350 mg/m3)
methylene chloride for 7 hours/day on days 6-15 of gestation. House fetuses
were collected and examined on day 18 and rat fetuses were collected and
examined on day 21 of gestation. Dams of both species were minimally
affected; slightly Increased carboxyhemoglobln formation was the only effect
reported. Delayed development (manifestations unspecified) was the only
effect noted 1n rat fetuses; 1n mouse fetuses, slightly advanced ossifica-
tion of the sternebrae were noted, suggesting accelerated development.
The teratogenic effect of methylene chloride 1n rats was also Investi-
gated by Hardin and Manson (1980). Groups of 26-28 Long-Evans hooded rats
were exposed to 4500 ppm (-15,600 mg/m3) methylene chloride for 6 hours/
day (group one before -and during gestation, group two- before gestation and
group three during gestation). "Before gestation" exposures were the 3
weeks Immediately preceding mating and "during gestation" exposures Included
the first 17 days of gestation. Gravlda from 16-18 dams/group were examined
on day 20 of gestation.
A slight but significant decrease 1n fetal body weight occurred 1n
groups exposed during gestation compared with controls and the group exposed
only before gestation. No other abnormalities were reported. Bornscheln et
al. (1980) reported on the behavioral effects on the pups of 10 dams from
each group allowed to deliver. No statistically significant differences 1n
body weight were noted In any of the treatment groups compared with
controls, up to 400 days of age. Treatment appeared to have no effects on
food and water consumption, wheel running activity or avoidance learning.
-15-
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The minor and reversible effects on fetal development 1n mice exposed to
1250 ppm (-4350 mg/m3) methylene chloride reported by Schwetz et al.
(1975) appeared to be a LOAEL 1n this study. Exposure for 7 hours/day,
assuming mice Inhale 0.05 mVday and weigh 0.03 kg, resulted 1n an Intake
of 2114.6 mg methylene chlor1de/kg/day. This Intake 1s more than 50 times
greater than the Intake (26.6 mg/kg/day) 1n humans associated with occupa-
tional exposure to 261 mg/m3 (10 m3 Inhaled/day, human body weight of 70
kg) 1n the study by Cherry et al. (1981). Hence, these data will not Impact
risk assessment.
3.4. TOXICANT INTERACTIONS
No studies of toxic Interactions of methylene chloride with other xeno-
blotlcs have been found 1n the available literature. Some Interesting case
histories 1n humans, however, suggest that Interactions with other compounds
may occur. Functional circulatory disorders 1n workers exposed for >3 years
to methylene chloride and other organochlqrlne compounds at "permlssable"
levels have been reported (Dunavsk11, 1972). The symptoms, Including chest
pain, EK6 Irregularities, bradycardla, decreased myocardlal contractility
and altered adaptation to physical stress, were not attributed to methylene
chloride alone.
The metabolism of methylene chloride to carbon monoxide forms the basis
for concern about combined exposure to methylene chloride and carbon monox-
ide. Fodor and Roscovanu (1976) reported that exposure of human subjects to
500 ppm of methylene chloride (for an unspecified duration) resulted In
levels of carboxyhemoglobln 1n blood comparable with those produced by the
TLV for carbon monoxide, 50 ppm. Mixed exposures could pose a serious
threat to the well being of occupatlonally-exposed workers, smokers or
cardloresplratory patients.
-16-
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Savolalnen et al. (1977) expressed concern about exposure to methylene
choMde and other lypophHlc solvents resulting 1n enhanced danger of marked
central nervous system and metabolic effects.
Chrlstenson and Hu1z1nga (1971) reported the case of a 17-year-old male
found dead 1n a turret where he had been using a mixture of 80% methylene
chloride and 14.9% methanol to remove paint. Barbiturate derivatives were
found 1n the blood, brain, urine and stomach contents. Death was ascribed
to the combination of methylene chloride and barbiturates. This report sug-
gested the ability of barbiturates to potentiate the toxldty of methylene
chloride.
Finally, two reports of phosgene poisoning related to methylene chloride
(GerrHsen and Buschmann, 1960; English, 1964) point out that phosgene, a
combustion product of methylene chloride, is highly toxic. Both cases
Involved the use of methylene chloride as a paint remover In an enclosed
area heated with a portable kerosene heater. One case (GerrHsen and
Buschmann, 1960) Involved a woman who was exposed for a 3-hour period during
1 day when she was 7 months pregnant; that evening, she expectorated blood-
tinged sputum and felt a tightness 1n her chest. The next day she was hos-
pitalized with dyspnea, cyanosis, and elevated pulse and body temperature.
She was treated and discharged 8 days later. She gave birth to a healthy
infant 2 months later.
The second case (English, 1964) Involved a 67-year-old Interior
decorator exposed for 8 hours to methylene chloride 1n a small unventilated
room heated with a portable kerosene heater. He experienced breathlessness,
headache, giddiness and a tightness across the chest. Upon hospitaHzatlon
the next day he was cyanotic, sweating, and tachypneic with extensive coarse
rales in both lungs. He was discharged after 5 weeks but experienced lassi-
tude, weakness and hypochondriosis for an additional 3 months.
-17-
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the carc1nogen1dty In humans associated with
methylene chloride could not be located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. An NCI bloassay of methylene chloride has been conducted on
rats and mice, exposed by gavage, but as of May, 1985, the study had been
withdrawn pending further review.
The National Coffee Association performed a 24-month toxldty and
cardnogenldty bloassay In F344 rats (NCA, 1982a,b) and B6C3F1 mice (NCA,
1983). In the rat study, groups of 85 males and 85 females were adminis-
tered drinking water that provided methylene chloride at 0, 5, 50, 125 or
250 mg/kg bw/day for 24 months. A second control group of 50 rats/sex and a
high dose group (250 mg/kg bw/day) of 25 rats/sex were added to undergo
treatment for 78 weeks followed by a 26-week recovery period. The only
tumor that occurred at Increased Incidences was combined neoplastlc nodules
and hepatocellular carcinoma 1n female rats (p>0.05). These Incidences
(0/134, 1/85, 4/83, 1/85, 6/85 1n combined control, 5, 50, 125 and 250 mg/kg
bw/day groups, respectively), however, were within those observed 1n theo-
retical controls and the U.S. EPA (1985a) concluded that methylene chloride
showed "borderline" cardnogenldty In F344 rats.
In the mouse experiment, groups of 50 females and 60-200 males were
treated with drinking water that provided 0, 60, 125, 185 or 250 mg methyl-
ene chloride/kg bw/day for 24 months. A marginally significant (p<0.05)
Increase 1n the combined Incidence of hepatocellular adenoma and carcinoma
was recorded 1n male mice (24/125, 51/200, 30/100, 31/99 and 35/125 In
combined control, 60, 125, 185 and 250 mg/kg bw/day groups, respectively).
-18-
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The U.S. EPA (1985a) considered the evidence for the cardnogenldty of
methylene chloride 1n mice to be "borderline".
4.2.2. Inhalation. Burek et al. (1980, 1984) and Dow Chemical Co. (1980)
studied the cardnogenldty of methylene chloride from chronic (2-year)
Inhalation exposure. Sprague-Dawley rats and golden Syrian hamsters were
exposed to methylene chloride at 0, 500, 1500 or 3500 ppm for 6 hours/day, 5
days/week for up to 2 years. As was mentioned previously, hamsters seemed
to be less sensitive to the systemic toxic effects of methylene chloride
than were rats. No exposure-related differences 1n the Incidences of benign
or malignant tumors were observed 1n male hamsters. There was a statisti-
cally significant Increase 1n the Incidence of benign tumors In female
hamsters exposed to 3500 ppm methylene choMde, but this Increase was
attributed to Increased longevity enjoyed by that group as a result of
delayed diseases of aging.
In female rats, an Increase 1n the number of benign mammary tumors per
tumor-bearing rat (but not 1n the number of tumor-bearing rats) was observed
at all dose levels. An Increase 1n the number of benign mammary tumors 1n
tumor-bearing rats was also noted In males 1n the high-dose group. More
Importantly, a dose-related Increase 1n sarcomas Involving the salivary
gland became statistically significant at the high-dose exposure level In
male rats (Table 4-1). These tumors appeared to arise from mesenchymal
rather than epithelial tissue. Interpretation of these findings Is diffi-
cult, according to the Investigators (Burek et al., 1984). Studies of
chronic methylene chloride exposure at high levels 1n a wide variety of
laboratory spedes have established the liver as the primary target organ.
-19-
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TABLE 4-1
Summary of Salivary Gland Region Sarcoma Incidence 1n Male
Rats 1n a 2-Year Inhalation Study with D1chloromethanea
Dose
(ppm)
0
500
1500
3500
Incidence^
1/93
0/94
5/91
11/88
(15)
(0%)
(5.5%)
(12.5%)
Fisher's Exact Test
NA
NA
(p=0.10, NS)
(p=0.002)
aSource: Burek et al., 1980, 1984; Dow Chemical Co., 1980
bCochran-Arm1tage test for linear trend, p<0.0001.
NS = Not significant; NA = not applicable
-20-
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The present Indication of an apparent relationship between methylene
chloride and the salivary gland was unusual and appeared to be Inconsistent
with previously reported data. Early 1n the course of treatment, these rats
had apparently contracted a viral disease, s1alodacryoaden1t1s, 1n the
salivary glands. It was suggested that the combination of the virus with
methylene chloride may have Increased the Incidence of salivary gland
neoplasla. The fact that these sarcomas appeared to arise from mesenchymal
tissue rather than from epithelial (glandular) tissue added to the confu-
sion. The authors (Burek et al., 1984) expected primary salivary gland
neoplasms to arise from epithelial cells.
More recently, Dow Chemical Co. (1982) conducted a 2-year Inhalation
toxldty and oncogenldty study 1n rats exposed to 0, 50, 200 or 500 ppm, 6
hours/day, 5 days/week for 20 (males) or 24 months (females). Interim
necropsies were performed at 6, 13, 15 and 18 months. No treatment-related
Increase 1n tumor Incidence was observed. This study has been criticized
for using doses too low to elicit a positive response. Consequently, the
National Toxicology Program has performed another Inhalation study 1n rats
and mice (NTP, 1985). The board draft of this study has been released 1n an
unaudited form. In this experiment, 50 male and 50 female F344/N rats were
exposed to air containing 0 (chamber controls), 1000, 2000 or 4000 ppm, 6
hours/day, 5 days/week for 102 weeks. Concurrently, 50 male and 50 female
B6C3F1 mice were exposed by the same schedule to air containing 0, 2000 or
4000 ppm methylene chloride. During week 3 of treatment, rats of both sexes
1n the 1000 ppm group were exposed to 2000 ppm and rats of both sexes 1n the
2000 ppm group were exposed to 1000 ppm.
In rats, a significant positive trend (p<0.001) for mammary tumors
(fIbroadenoma, adenoma, fibroma: combined Incidence) was observed in both
-21-
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sexes (Table 4-2). The Incidence 1n high group males and females was sig-
nificantly greater than in control rats (p<0.001). Similarly, the Incidence
of subcutaneous fibroma or sarcoma (combined) 1n male rats was higher In
high group males than controls (p<0.05) and a positive trend (p=0.008) was
observed. The Incidence of these tumors was combined because they all
occurred 1n the mammary chain and were considered to be of the same etio-
loglc origin. Other tumor types also occurred with a significant positive
trend by life table analysis, but were not significant in treated vs.
control groups. These included the combined incidence of neoplastlc nodules
and hepatocellular carcinomas in female rats, adrenal gland pheochromocytoma
and interstitial cell tumors 1n males, squamous cell metaplasia in females,
pituitary gland adenoma or carcinoma and mononuclear cell leukemlas in both
sexes. In male rats, the incidence of mesothelioma derived from the tunica
vaglnalls was found to be significantly higher 1n both the high and inter-
mediate groups than 1n controls, but the incidence in controls In this
experiment was unusually low compared to'hlstorical controls.
The most striking observation 1n the mice was the incidence of lung
tumors (p=0.0001) 1n treated mice (Table 4-3). The period of latency was
significantly reduced in treated mice and lung tumors were believed to be
responsible for the reduced survival observed 1n high-dose group males and
females. Also noteworthy was the Incidence of liver tumors in treated mice
(see Table 4-3).
4.3. OTHER RELEVANT DATA
The available literature contains sufficient information on the muta-
genldty of methylene chloride; several experiments are summarized in Table
4-4. Simmon et al. (1977) reported that methylene chloride was mutagenic to
Salmonella typhimurium strain TA100 when assayed 1n a desslcator whose atmo-
sphere contained the test compound. Metabolic activation was not required.
-22-
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TABLE 4-2
Tumor Incidence 1n Rats Treated with Methylene Chloride3
Tumor Type
Control 1000 ppm 2000 ppm 4000 ppm
MALES
Fibroadenoma, adenoma, 0/50
fibroma of mammary gland
Subcutaneous (combined) 1/50
tumors of mammary area
0/50
1/50
2/50
4/50
5/50b
9/50c
FEMALES
Fibroadenoma, adenoma, 7/50
fibroma of mammary gland
13/50
14/50
23/50b
aSource: NTP, 1985
bp<0.001
cp=0.002
-23-
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TABLE 4-3
Tumor Incidence In Mice Treated with Methylene Chloride3
Tumor Type
MALES
Alveolar/bronchlolar adenomas
Alveolar/bronchlolar carcinomas
Multiple lung tumors
Hepatocellular adenoma and carcinoma
Hepatocellular carcinoma
Multiple liver tumors
FEMALES
Alveolar/bronchlolar adenomas
Alveolar/bronchlolar carcinomas
Multiple lung tumors
Hepatocellular adenoma and carcinoma
Hepatocellular carcinoma
Multiple liver tumors
Control
3/50
2/50
0/50
22/50
13/50
2/50
2/50
1/50
0/50
2/50
1/50
0/50
2000 ppm
19/50
10/50
10/50
24/49
15/49
11/49
23/48
13/48
11/48
6/48
11/48
3/48
4000 ppm
24/50b
28/50b
28/50
33/49c
26/49d
16/46
28/48b
29/48b
29/48
22/48e
32/48e
28/48
aSource NTP, 1985
bp=0.0001
cp=0.016
dp=0.005
-24-
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TABLE 4 4
Nutagenlclty and Genotoxlclty of Methylene Chloride*
1
INJ
-------
TABLE 4-4 (cont.)
Assay
Rec assay
Nilotic
recombination
Nltotlc
recombination
Sex-linked
recessive
lethal
Sex-linked
recessive
lethal
Sex-linked
• recessive
o? lethal
i
Nutations In
cell-culture
Chromosomal
aberration
Chromosomal
abberatlon
Chromosomal
aberration
Slster-
chromatld
exchange
Slster-
chromatld
exchange
Indicator
Organism
Bacillus
subtllls
Saccharomyces
cerevlstae 07
S. cerevlslae
03
Drosophlla
Drosophlla
Panagrelus
redlvlvus
CHO and V79
cells
rat bone
marrow cells
CHO cells
NMRI mice/bone
marrow
SCE/V79 cells
CHO cells
Application
NR
NR
NR
fed or
Injected
fed
NR
cell culture
Inhalation
cell culture
l.p.
Injection
cell culture
cell culture
Concentration
or Dose
NR
0-209 mN
NR
NR
0-620 mN
10"» to 10«
mol/l
0-SX
0-3500 ppra
0-10 pi/ml
0-3400 mg/kg bw
0-4. OX
0-10 tit/ml
Activating
System
NR
NA
NR
NA
NA
NA
NA
NA
NA
NA
NA
NA
Response Comments 1
Data available only In abstract form
* D7 strain metabolizes methylene
chloride to active Intermediates
Minimal data presented
Votallzatton not prevented
«- Conclusion; methylene chloride Is
mutagenlc to sperm
* Equivocal positive results
Equivocal negative results
NC
f Similar results In three replications
v Results equivocal
4- Positive dose-response
* Marginal but not significant response
Reference
Kanada and
Uyeta, 1978
Callen et al.,
1980
Simmon et al..
1977
Abrahamson and
Valencia, 1980
Gocke et al.,
1981
Samolloff
et al.. 1980
Jongen et al . ,
1981
Dow Chemical
Co.. 1980
Thllagar and
Kumar oo, 1983
Gocke et al.,
1981
Jongen et al..
1981
Thllagar and
Kumar oo, 1983
*Compound and/or purity not reported
NR = Not reported; NA = not applicable; NC - no comment
-------
The response was strongly dose-related. This is typical of the response of
many strains of £. typhimurium to methylene chloride (see Table 4-4). In S.
cerevisiae D3, however, mitotic recombination was not increased by methylene
chloride (Simmon et a!., 1977) although positive results were obtained in S.
cerevisiae 07 (Callen et al., 1980). Additionally, Filippova et al. (1967)
reported that methylene chloride was negative when tested for sex-linked
recessive lethals in Drosophlla melanogaster although positive results were
obtained by Gocke et al. (1981).
Thilagar and Kumaroo (1983) investigated the ability of methylene chlo-
ride to induce SCE and chromosomal aberrations in cultured Chinese hamster
ovary cells. They observed extensive chromosomal aberrations, both with and
without Aroclor 1242- and !254-1nduced rat S-9 fraction activation.
Negative results were reported 1n the SCE assay. These authors discovered
that running the tests in plastic rather than glass markedly reduced the
magnitude of the positive response, indicating the likely adsorption of
methylene chloride to the plastic.
4.4. WEIGHT OF EVIDENCE
Pertinent data regarding carcinogenicity 1n humans associated with
methylene chloride could not be located in the available, literature.
Although an NCI bloassay has been conducted In rats and mice using gavage
administration, the data are not yet available. Burek et al. (1980, 1984)
demonstrated that sarcomas of the salivary gland In male rats are associated
with inhalation exposure to high levels (3500 ppm) of methylene chloride.
Interpretation of the biological significance of these results is rendered
difficult for the reasons discussed in Section 4.2. Another NCI bloassay
involving inhalation exposure has recently been performed (NTP, 1985). The
results Indicate that methylene chloride 1s probably carcinogenic to rats
(mammary tumors) and clearly carcinogenic to mice (lung and liver tumors).
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Applying the criteria for evaluating the overall weight of evidence of
carc1nogen1c1ty to humans proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register, 1984), methylene chloride 1s most appropriately
classified a B2 - Probable Human Carcinogen.
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5. REGULATORY STANDARDS AND CRITERIA
Pertinent regulatory standards and criteria for methylene chloride are
summarized 1n Table 5-1. According to the ACGIH (1981) the TLV committee
adopted a criteria of 500 ppm In the Industrial workplace. Subsequent dis-
coveries that exposures approaching this magnitude resulted 1n substantially
elevated blood levels of carboxyhemoglobln led to a modification of the TLV
to 100 ppm; a STEL of 500 ppm has been proposed. In 1983, the ACGIH (1983)
had recommended reducing the STEL to 350 ppm.
The NIOSH (1976) criteria for methylene chloride was set at a TWA of 75
ppm for a 10-hour workday, 40-hour workweek. Recognizing the relationship
between methylene chloride and carbon monoxide, a formula has been derived
to deal with methylene chloride when carbon monoxide concentrations are >9
ppm. The formula 1s [C(CO) * L(CO)] + [C(DCM) * L(DCM)] <1 where:
C(CO) = TWA concentration of carbon monoxide ppm
L(CO) = 35 ppm, the recommended TWA limit for carbon monoxide
C(DCM) = TWA concentration of methylene chloride, ppm
L(DCM) = 75 ppm, the recommended TWA limit for methylene chloride.
As an oil and fat solvent, methylene chloride Is allowed In spice oleo-
reslns at concentrations up to 30 mg/kg and 1n decaffeinated coffee at
concentrations up to 10 mg/kg, according to NIOSH (1976).
OSHA (1976) has established occupational exposure standards as follows:
8-hour TWA, 1737 mg/m3; acceptable celling concentration, 3474 mg/m3;
acceptable maximum peak > celling (5 minutes In any 3 hours), 6948 mg/m3.
The U.S. EPA (1980b) has set the ambient water quality criterion at 6
vg/l on the basis of qualitative but not quantitative data concerning
the carclnogenldty of methylene chloride. They felt that the median con-
centration found In ambient water should not be exceeded until more defini-
tive data quantifying cancer risk to oral exposure have been generated.
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TABLE 5-1
Regulatory Standards or Criteria for Methylene Chloride
Standard or Criteria Value Reference
TLV
STEL
TWA*
TLV
STEL
100
500
75
100
350
ppm
ppm
ppm
ppm
ppm
(-360 mg/m3)
(-1700 mg/m3)
ACGIH,
NIOSH,
ACGIH,
1981
1976
1983
Level In spice oleo- 30 mg/kg NIOSH, 1976
resins
Level 1n decaffeinated 10 mg/kg
coffee
8-hour TWA 1737 mg/m3 OSHA, 1976
Acceptable celling 3474 mg/m3
Maximum peak 6948 mg/m3
Ambient water quality 6 jag/a U.S. EPA, 1980
criterion
1-Day SNARL 13 mg/a U.S. EPA, 1981b
10-Day SNARL 1.3 mg/a
Longer SNARL 0.15 mg/a
*See discussion In text for concurrent exposure to carbon monoxide.
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Based on data from acute and subacute toxldty studies, the Office of
Drinking Water Advisory Opinion for methylene chloride (U.S. EPA, 1981b) has
made Suggested No Adverse Response Level (SNARL) recommendations for methyl-
ene chloride as follows: 1-day exposure, 13 mg/fc; 10-day exposure, 1.3
mg/8,; and for longer exposures, 0.15 mg/8..
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Methylene chloride has been demonstrated to be carcinogenic In both rats
and mice. Data are sufficient for estimating carcinogenic potency; there-
fore, 1t 1s Inappropriate to derive an AIS for this chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Methylene chloride has been demonstrated to be carcinogenic In both rats
and mice. Data are sufficient for estimating carcinogenic potency; there-
fore, 1t 1s Inappropriate to derive an AIC for this chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The NCI has performed an oral exposure bloassay of methyl-
ene chloride 1n rats and mice. These data are not available, as this study
has been withdrawn pending further audit.
The U.S. EPA (1985a) reviewed an oral bloassay conducted by the National
Coffee Association (NCA, 1982a,b). This study provided suggestive evidence
of a treatment-associated Increased Incidence of hepatocellular carcinomas/
adenomas 1n male mice. In female rats the Incidence of neoplastlc nodules/
hepatocellular carcinomas was Increased with respect to matched but not
historical controls. U.S. EPA (1985a) felt this study was Inadequate for
quantitative risk assessment.
6.3.2. Inhalation. The study by Burek et al. (1980, 1984) associated the
Incidence of salivary gland sarcomas 1n male rats with exposure to methylene
chloride (see Sections 3.2. and 4.2.). The Incidence of tumors (control,
1/124; 500 ppm, 0/124; 1500 ppm, 5/124; 3500 ppm, 11/124) was significantly
different from matched controls at the highest dosage level. The Cancer
Assessment Group (U.S. EPA, 1985a) has used these data to calculate a human
q.* of 6.3xlO~4 (mg/kg/day)'1.
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More recently, the results of the NTP (1985) bloassay have become avail-
able 1n draft form. The U.S. EPA (1985b) Is in the process of Devaluating
the carclnogenlcHy of methylene chloride 1n the context of these more
recent results. However, an assessment In final quotable form 1s still
pending.
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7. REFERENCES
Abrahamson, S. and R. Valencia. 1980. Evaluation of substances of Interest
for genetic damage using Drosophlla melanogaster. Prepared for FDA Contract
233-77-2119. (Cited 1n U.S. EPA, 1985a).
ACGIH (American Conference of Governmental and Industrial Hyg1en1sts).
1981. Documentation of the Threshold Limit Values for Substances 1n Work-
room A1r. Cincinnati, OH. (Cited 1n U.S. EPA, 1980b)
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1983.
Threshold Limit Values for Chemical Substances and Physical Agents In the
Workroom Environment with Intended Changes for 1984. Cincinnati, OH.
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APPENDIX
Summary Table for Methylene Chloride
00
Carcinogenic
Potency
Inhalation
Oral
Species/Sex Experimental
Dose/Exposure
rats 12,159 mg/m3
6 hours/day,
5 days/week
for 2 years
NA NA
Effect
salivary gland
sarcomas
carcinoma
NA
q-|* Reference
6.3xlO~4 Burk et al.,
(mg/kg/day)"1 1980, 1984
ND NA
NA = Not available
ND = Not derived
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