EPA/600/8-89/092
August, 1989
HEALTH EFFECTS ASSESSMENT
FOR METHYLENE CHLORIOE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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EPA/600/8-89/092
August, 1989
HEALTH EFFECTS ASSESSMENT
FOR METHYLENE CHLORIDE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U S ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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_ TECHNICAL REPORT DATA
Iter rwd /rutncfions o* the revert* before completing)
1 E^7?(5,(5>/8-89/092
2.
3. RECIPIENT'S ACCESSION NO
PR90-142449/AS
4. title ano SUBTITLE
Updated Health Effects Assessment for Methylene
S. REPORT DATE
Chloride
B. PERFORMING ORGANIZATION CODE
7. AUTMOHIJI
B. PERFORMING ORGANIZATION REPORT NO
9. '»"»OR*IINO ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
Environmental Criteria and Assessment Office
13. TYPE Of REPORT ANO PERIOD COVERED
Office of Research and Development
U-S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
is supplementary notes
16. abstract
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 32991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
t.his document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
•
17.
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Public
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UnrlMsifipd
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1. EPA Report No.
EPA/600/8
ECAO-Cin-H028a
« Copyright Permission
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5a. Original Document Tttie ""
Updated Health Effects Assessment for Methylene Chloride
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£PA ¦362fCinKR*v,3/t?i
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review pdHcles and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with methylene
chloride. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary and reflect
limited resources allocated to this project, Pertinent toxicologic and
environmental data were located through on-line literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic litera-
ture searched supporting this document Is current up to May, 1987. Secon-
dary 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. 1980a. Ambient Water Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA-440/5-80-051. NTIS PB 81-117624.
U.S. EPA. 1982. Errata: Halomethanes Ambient Water Quality
Criteria for the Protection of Human Health. Prepared by the
Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Water Regulations and Standards, Washington, DC.
U.S. EPA. 1983. Reportable Quantity for Dlchloromethane.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985a. Health Assessment Document for Dlchloromethane
(Methylene Chloride). Office of Health and Environmental Assess-
ment, 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). Office of Health and
Environmental Assessment, Carcinogen Assessment Group, Washington,
DC.
U.S. EPA. 1986c. Integrated Risk Information System (IRIS).
Carcinogenicity Assessment for Lifetime Exposure to Methylene
Chloride. Online. (Verification date 12/04/86.) Office of Health
and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH.
111
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The Intent In these assessments Is to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived nor were
larger uncertainty factors employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 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 lifespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD§ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (Rf0§o)
exposures.
The RfO (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the lifespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDq) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1984).
For a discussion of risk assessment methodology for carcinogens refer to
U.S. EPA (1980b). Since cancer 1s a process that Is not characterized by a
threshold, any: exposure contributes an Increment of risk. For carcinogens,
q-j*s have been computed, 1f appropriate, based on oral and Inhalation data
1f available.
1 v
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ABSTRACT
In order to place the risk assessment evaluation in proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
The major Issue of concern Is the amply demonstrated carcinogenicity of
methylene chloride. Although human data are lacking, animal experiments
have clearly demonstrated the carcinogenicity of methylene chloride In mice
and strongly suggest carcinogenicity In rats. Methylene chloride has been
shown to be mutagenic 1n Salmonella and to Increase the number of chromoso-
mal aberrations In cultured Chinese hamster ovary cells.
The U.S. EPA (1985b, 1986c) reported an oral unit risk slope estimate of
7. 5xl0"3 (mg/kg/day)"1 based on the arithmetic mean of slope factors
derived from the NTP (1985) Inhalation data and the NCA (1983) oral data
The U.S. EPA (1985b, 1986c) also reported an Inhalation unit risk slope
estimate of 1.4x10"* (mg/kg/day)-* based on the combined Incidence of
carcinomas and adenomas of the lung or liver 1n B6C3F1 mice from the ?-vear
NTP (1985)_ Inhalation study. The corresponding unit risk for air 1s given
as 4.1x10"* jjg/m3. In all of these analyses methylene chloride has
been classified In weight of the evidence category B2, probable human
carcinogen. A potential revision to the unit risk estimate has been
proposed based upon the application of pharmacokinetic modeling fU S EPA
1987). Adoption of a unit risk estimate based upon pharmacokinetic modeling
could lead to an estimate 1 to 2 orders of magnitude lower than that
currently proposed.
v
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under' Contract No. 68-03-3112 for EPA1s Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and.Helen Ball was the Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington. DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Grouo
Office of Air Quality Planning and standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series, was provided by the
following:
Bette Zwayer, Trlna Porter
Environmental Criteria and Assessment 0f„fIce
Cincinnati, OH
vl
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 4
2.1. ORAL 4
2.2 INHALATION 5
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 8
3.1. SUBCHRONIC 8
3.1.1. Oral 8
3.1.2. Inhalation 9
3.2. CHRONIC 12
3.2.1. Oral 12
3.2.2. Inhalation 12
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 18
3.3.1. Oral 18
3.3.2. Inhalation 18
3.4. TOXICANT INTERACTIONS. 19
4. CARCINOGENICITY 22
4.1. HUMAN DATA 22
4.2. BIOASSAYS 22
4.2.1. Oral 22
4.2.2. Inhalation 23
4.3. OTHER RELEVANT DATA 28
4.4. WEIGHT OF EVIDENCE 34
5. REGULATORY STANDARDS AND CRITERIA 36
6. RISK ASSESSMENT 40
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 40
6.2. REFERENCE OQSE (RfO) 40
6.3. CARCINOGENIC POTENCY (q-j*) 40
6.3.1. Oral 40
6.3.2. Inhalation 41
7. REFERENCES 43
APPENDIX: Summary Table for Methylene Chloride 62
vl 1
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LIST OF TABLES
No. Title £age
2-1 Absorption of Methylene Chloride by Human Subjects
{Sedentary Conditions). ... 6
4-1 Sunmary of Salivary Gland Region Sarcoma Incidence in Male
Rats In a 2-Year Inhalation Study with Olchloromethane. ... 25
4-2 Tumor Incidence In Rats Treated with Methylene Chloride ... 27
4-3 Tumor Incidence In Mice Treated with Methylene Chloride ... 29
4-4 Mutagenicity and Senotoxlclty of Methylene Chloride ..... 31
5-1 Regulatory Standards and Criteria for Methylene Chloride. . . 37
v111
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LIST OF ABBREVIATIONS
ADI
Acceptable dally Intake
CAS
Chemical Abstract Service
CS
Composite score
EKG
Electrocardiogram
*oc
Soil sorption coefficient
Kow
Log octanol/water partition coefficient
LOAEL
Lowest-observed-adverse-effect level
MED
Minimum effective dose
NOAEL
No-observed-adverse-effect level
ppm
Parts per million
RfD
Reference dose
RfDj
Inhalation reference dose
RfD0
Oral reference dose
RFDS
Subchronlc reference dose
RFD$i
Subchronlc Inhalation reference dose
RfD§0
Subchronlc oral reference dose
RVd
Dose-rat1ng value
RVe
Effect-rating value
SCE
Sister chromatid exchange
SNARL
Suggested no-adverse-response level
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 at 20°C:
Water solubility at 25°C:
Density at 20°C (reference
water 4°C)
Vapor density
Log
K0c:
K0c:
Bloconcentratlon factor:
Half-Hves 1n air:
water:
Tropospherlc lifetime
Evaporation half-life
halogenated aliphatic
hydrocarbon (purgeable
halocarbon)
84.93
362.4 mm Hg
13,030 mg/l
1.3225
2.93 (alr-1)
1.25
27.5
8.8 g/mi
2.3 [estimated from
log Kow and the
equation given by
Velth et al. (1979)]
5.25 [estimated from
equation given by
Velth et al. (1979)
53-127 days
1-6 days (estimated)
1.4 yrs (calculated)
18-25 m1n (experimental)
20.7 mln (theoretical)
0.9*0.3 yrs (calculated)
0.3~~yrs (calculated)
0.39 yrs (calculated)
Callahan et al., 1979
Horvath, 1982
W^ndholz, 1983
U.S. EPA. 1985a
Hansch and Leo, 1985
Sabljlc, 1984
U.S. EPA, 1986b
Velth et al., 1979
U.S. EPA, 1985a
Singh et al., 1981;
Maklde and Rowland, 1981
Altshuller, 1980
01ll1ng, 1977
Singh et al., 1983
Cox et al., 1976
Davis et al., 1976
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Loss of methylene chloride from water will be due primarily to volatili-
zation (Dllllng, 1977; NLM, 1987). The aquatic half-life listed above was
estimated from a reaeratlon rate ratio of 0.650 and oxygen reaeratlon rate
constants of 0.19-0.96 day"1 (Mabey et al., 1981). On prolonged contact
with water, DCM hydrolyzes very slowly, forming HC1 as the primary product
(Fells and Moelwyn-Hughes, 1958). Adsorption to suspended solids and
sediments and bloaccumulatlon In aquatic organisms will not be significant
fate processes.
The half-life of methylene chloride 1n soil was not found In the
available literature. Evaporation Is expected to be the predominant loss
mechanism from the soil surface. The evaporation half-life from soil would
be expected given Its larger surface area to be shorter than Its evaporation
half-life from water. The aqueous solubility and relatively low KQC value
of this compound suggest that In cases where DCM Is not volatilized quickly,
leaching would also play a role In determining the fate of this compound 1n
soils (NLM, 1987). In subsurface soil and sediment sampling detected DCM In
60 of 118 cases. Concentrations were from 427 to 433 ppb. Ambient soil
concentrations of DCM are unknown (U.S. EPA, 1981). Blodegradatlon of
chlorinated aliphatic hydrocarbons such as methylene chloride may be slow
(Wilson et al., 1983); therefore, under conditions In which methylene
chloride leaches Into soil, 1t may leach Into groundwater. "Recent evidence
Indicates that DCM is biodegradable under both aerobic and anaerobic
conditions. Brunner and Lelslnger (1978) first reported the Isolation of a
facultatue methylotroph with the ability to utilize DCM as a sole carbon
source for growth." Wood et al. (1978) also has been able to demonstrate
the degradation of DCM under anaerobic conditions. Detection of this
compound In groundwater supplies supports this prediction (Page, 1981).
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However, these results are equivocal as Page (1981) does not give adequate
details pertaining to the methodology used. The methodology used varies
greatly and can Influence the limit of detection (LOO) and accuracy and bias
of results. "Contamination, absorption, and adsorption are common problems
of the methods used to analyze air and water for DCM content (National
Academy of Science, 1978)." However, DCM has been detected at 32 of 204
surface water sites from which samples were collected (Ewlng et al., 1977).
In the atmosphere, reaction with photochemically generated hydroxy!
radicals Is expected to be the predominant removal mechanism (NLM, 1987; Cox
et al., 1976; Davis et al., 1996). This compound may travel long distances
from Its emission sources because of Us relatively long lifetime In the
atmosphere. Based on a tropospherlc to stratospheric turnover time of 30
years and a half-life of 53-127 days for methylene chloride, <1% of the
tropospherlc methylene chloride is expected to diffuse Into the strato-
sphere. However, there 1s a great disparity 1n the reported residence time
of DCM In the atomosphere. Cox et al. (1976) argues conunlclngly for a
o
residence time or only 0.3 years based on photo klnetlz studies. Values,
however, range from the Cox et al. (1976) figure of 0.3 years to the
Altoherller (1980) estimate of 1.4 years.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. . ORAL
Absorption through the Intestinal mucosa appears to be fairly rapid and
complete In humans {Roberts and Marshall, 1976). Prlchard and Angelo (1982)
have described a physiologically based pharmacokinetic model {B1shoff model)
for mice and have used 1t to simulate the distribution, metabolism and
elimination of OCM after both acute and chronic dosing. Preliminary results
Indicate that the kinetics depend on route and vehicle used for administra-
tion. Administration of DCM 1n water by oral gavage orby Intravenous
Injection yields similar blood and tissue profiles; administration In 50%
polyethylene glycol/water shows a rapid blood elimination and a slow Hver
elimination, while oral gavage with corn oil as a vehicle. In subsequent
and more extensive Investigations, Angelo et al. (1986a) administered gavage
doses of 14C-methylene chloride at 50 mg/kg/day In water or 50 or 1000
mg/kg/day In corn oil once dally on 14 consecutive days to groups of six
young adult male B6C3F1 mice. Angelo et al. (1986b) also treated groups of
six young adult male F344 rats were treated by gavage with 14C-methylene
chloride at 50 or 200 mg/kg/day 1n water for 14 consecutive days. Cumula-
tive 24-hour recovery of exhaled radioactivity exceeded 90* of the admin-
istered dose In both species at all dose levels, measured on days 1, 7 and
14 of treatment. These data Indicate that methylene chloride Is almost
completely absorbed from the gastrointestinal tracts of both rats and mice.
Yesalr et al. (1977) administered single gavage doses of 14C-methylene
chloride In water or corn oil to mice and followed the appearance of radio-
activity In the plasma for the following 96 hours. Plasma levels of radio-
activity peaked later and higher, remaining higher throughout the experiment
when the test chemical was administered In corn oil rather than in water.
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WHhey et al (1983) have Investigated the absorption of DCM 1n fasting rats
following oral gavage of equivalent doses (125 mg/kg) 1n 4 ml of water or
corn oil. The post-absorption peak blood concentration averaged three times
higher for a water vehicle than for com oil (121 yg/mi versus 44
yg/mi), while the time to peak blood concentration averaged 3 times
longer for corn oil than for the water vehicle (16.3 vs. 5.2 minutes).
These observations suggests that gastrointestinal absorption may be greater
when water 1s used as the vehicle. No differences In absorption rates
between corn oil and water were discussed by Angelo et al. (1986a).
2.2. INHALATION
Riley et al. (1966) described the kinetics of absorption and excretion
In a 70 kg man exposed for 2 hours to 100 ppm methylene chloride In air. As
exposure progressed, the concentration In alveolar air Increased, suggesting
approach to steady state conditions. However, equilibrium had not been
reached after 2 hours and exposure was discontinued and methylene chloride
In exhaled air was monitored. The postexposure decline In concentration of
methylene chloride in 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.
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 concentrations 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.
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TABLE 2-1
Absorption of Methylene Chloride by Human Subjects*
(Sedentary conditions)
Inhalation
Concentration
Exposure
Retention
Reference
(ppro)
(hours)
(*)
50
7.5
70
DIVIncenzo and Kaplan, 1981
100
7.5
60
150
7.5
63
200
7.5
60
662
0.30
74
Lehmann and Schmldt-Kehl, 1936
806
0.50
75
1152
0.50
72
1181
0.50
70
44-680
2.00
31
Riley et al., 1966
100
2.00
53
01V1ncenzo et al., 1972
100
4.00
41
200
2.00
51
250
0.50
55
Astrand et al., 1975
500
0.50
55
750
1.00
34
Engstrom and Bjurstrom, 1977
~Source: U.S. EPA, 1985a
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The concentration In expired air from those exposed to 200 ppm declined to 1
ppm 16 hours after treatment. Exposure and post-exposure blood concentra-
tions of DCM were directly proportional to the magnitude of exposure (01
Vlncenzo and Kalplan, 1981a),
Absorption of methylene chloride Increased with duration of exposure and
physical activity (presumably due to an increase In ventilation, and cardiac
output) and with duratln of exposure (Astrand et al.t 1975). Elevated
ventilation doubled absorption but decreased retention from 55 to 40% of
Inhaled dose.
Engstrom and Bjurstrom (1977) demonstrated that methylene chloride
absorption was related directly to degree of obesity in human subjects.
Obese subjects (fat - 25% of body weight) absorbed 30% more methylene
chloride than lean subjects (fat - 8% of body weighty when exposed to 750
ppm for 1 hour. Biopsy and analysis of subcutaneous fat revealed a substan-
tial (10.2 and 8.4 mg/kg wet tissue) concentration In adlposa 1 and 4 hours
postexposure, respectively. Although the concentrations in fat were
somewhat lower In obese than In lean subjects, the total amount of body fat
resulted In greater total methylene chloride absorption in obese subjects.
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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
methylene chloride have been located In the available literature. Bornmann
and Loeser (1967) exposed 30 male and 30 female Wlstar rats for 3 months to
drinking water containing 0.125 g methylene chlor1de/i (125 ppm).
Assuming rats drink 0.049 l/day and that their average body weight 1s 0.35
kg, this dose corresponds to 17.5 mg/kg bw/day. No differences In behavior,
appearance, body weight or survival of treated rats were observed compared
with an equal number of control rats. No significant differences 1n
hematologic values, urinalysis or plasma levels of nonesterlfled fatty acids
were found 1n 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 w1th1n the normal range. Estrous cycles, as evaluated by
microscopic examination of vaginal smears, Indicated no changes that were
due to treatment. Necropsy and hlstopathologlcal examination of -20 animals
of each sex and group revealed no lesions In any Internal organ examined.
Recently, Klrschman et al. (1986) reported on groups of 20 male and 20
female Fischer 344 rats and Identical numbers of B6C3F1 mice provided with
drinking water containing 0, 0.15, 0.45 or 1.596 (0, 1500, 4500 or 15,000
ppm) methylene chloride for 90 days. Assuming rats drink 0.049 l/day and
that their average body weight Is 0.35 kg, these doses corresponds to 0,
210, 630 or 2100 mg/kg bw/day. Assuming mice drink 0.0057 l/day and that
their average body weight 1s 0.03 kg, these doses correspond to 0, 285, 855
or 280 mg/kg bw/day. Slightly decreased water Intake was observed 1n
treated rats along with a slight decrease in body weights 1n middle-dose
males and high-dose females. Minor hematological changes were observed 1n
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rats at >4500 ppm and clinical chemistry parameters that reflected poten-
tially compromised liver function were observed sporadically In all treated
groups. Urinary pH was reduced in all treated groups of rats In a dose-
related manner and high-dose females had elevated kidney weights. No histo-
pathologic changes were observed In rats at an Interim kill after 1 month of
treatment. At termination, however, high-dose rats of both sexes and some
middle-dose females had centrllobular necrosis. Dose-related Increased
hepatocellular vacuolization occurred 1n all treated groups.
Treated mice also had depressed fluid Intake, and slightly reduced body
weights were observed 1n both sexes at >855 mg/kg/day. There was no histo-
pathologic evidence of toxicity In mice at an Interim sacrifice performed at
1 month. At termination, a mild centrllobular fatty change, which was more
apparent In males, was observed 1n mice at >855 mg/kg/day.
3.1.2. Inhalation. Inhalation exposure of humans to methylene chloride
Is likely to be a result of occupational exposure; consequently, long-term
exposure can be expected. Studies of occupational exposure of humans to
methylene chloride are discussed In Section 3.2.2. Subchronlc exposure can
be expected the use of consumer products containing methylene chloride, such
as aerosol cans and paint stripping products. Historically, subchronlc
Inhalation exposure of astronauts to methylene chloride vapors emanating
from materials used In the Interiors of spacecrafts has been a concern.
Consequently, several Investigators (Thomas et al., 1972; Haun et al., 1971,
1972; We1nste1n et al., 1972; HacEwen et al., 1972) exposed several species
of laboratory animals to atmospheric methylene chloride for up to 14 weeks.
The U.S. EPA (1983) summarized results of these studies follows. Mice
exposed to 25 or 100 ppm (112.9 or 451.6 mg/kg bw/day) methylene chloride
continuously for 14 weeks had Increases 1n spontaneous locomotor activity at
0026H
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112.9 but not 451.6 mg/kg/day. No gross or histological lesions were found
at necropsy, except that livers of mice exposed to 451.6 mg/kg/day stained
positive for fat. Hexobarbltal sleep time was unaffected, but hepatic
levels of cytochromes were somewhat altered. Rats subjected to the same
exposure regimens had nonspecific renal tubular degeneration and regenera-
tion, and hepatic cytoplasmic vacuolization and positive fat staining at
both exposure levels (55.3 and 221.3 mg/kg/day). Rats appeared to be the
more sensitive species. No specific macro- or microscopic organ changes or
changes In hematologic or clinical chemistry values were noted 1n a small
number of monkeys In these studies (58.6 and 234.5 mg/kg/day). Carboxyhemo-
globln levels, the result of metabolism of methylene chloride to carbon
monoxide and subsequent action on hemoglobin, were elevated 1n monkeys at
both exposure levels (58.6 and 234.5 mg/kg/day) and 1n dogs only at the
higher exposure of 117.6 mg/kg/day but not at 29.4 mg/kg/day. There was no
cumulative Increase In carboxyhemoglobln over the period of exposure. No
overt signs of toxicity or changes 1n body weights relative to controls were
noted In any of these four species.
Higher levels of continuous exposure were also Investigated. Exposure
of the same four species to 1000 or 5000 ppm (mice; 4516.2 or 22,581.2
mg/kg/day rats; 2213 or 11,067.3 mg/kg/day dog; 1176.2 or 5881.2 mg/kg/day
monkeys; 2344.9 or 11,724.9 mg/kg/day) resulted 1n signs of severe toxicity
at 5000 ppm: 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 (22,581.2 mg/kg/day), dogs (5881.2 mg/kg/day) and
monkeys. Rats were somewhat less sensitive; none died. Liver and kidney
damage were common findings In all species. At 1176.2 mg/kg/day dogs were
severely affected and died. Mice and rats did not show overt signs of
0028H
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toxicity, but body weight gain was slightly depressed In the rats. Less
severe hlstopathologlcal changes than had been seen at the highest dose were
noted 1n the Hvers of all four species and In the kidneys of rats exposed
to 2213.5 rag/kg/day. Honkeys showed no significant changes In hematologic
or clinical chemistry values.
Hale SPF Wlstar rats exposed to 500 ppm (1106.7 mg/kg/day) vapors of
methylene chloride for 10 days had significantly elevated liver cytochrome
P-450 levels (Norpoth et al., 1974). However, this effect was not seen 1n
animals exposed to 5000 ppm. Likewise, Welnsteln et al. (1972) reported no
changes In liver enzymes In mice after 28 days of exposure to 250 ppm
(1129.1 mg/kg/day) methylene chloride.
Longer-term exposures to methylene chloride produces liver toxicity.
ICR mice exposed to 100 ppm (451.6 mg/kg/day) methylene chloride for 10
weeks had centrllobular fat accumulation and decreased glycogen levels
(Welnsteln and Olamond, 1972). Inhalation of 451.6 mg/kg/day methylene
chloride for 100 days produced cytoplasmic vacuolization and positive fat
staining 1n mice (Haun et al., 1972). These effects were also observed m
the liver of rats and dogs exposed to 25-100 ppm (rats; 55.3-221.3
mg/kg/day. dogs; 29.4-117.6 mg/kg/day) for 100 days. Kidney damage was also
reported 1n this study. Rats exposed to 55.3 and 221.3 mg/kg/day methylene
chloride had nonspecific renal tubular degenerative and regenerative changes.
Taken collectively, these studies suggest that subchronlc exposure to
methylene chloride produces behavioral effects 1n animals. The liver and
kidneys of animals are also likely target organs for methylene chloride
toxicity. Lesions in rats exposed to 25 or 100 ppm methylene chloride
appear to be more severe than lesions 1n mice exposed to the same concentra-
tions. Monkeys and dogs seem to be the least affected of those species
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studied. At higher exposure concentrations (1176.2 mg/kg/day), dogs appear
to be most sensitive and to experience treatment-related mortality.
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. Currently a 2-year
gavage study with rats has been sponsored by NTP (1988), but results are not
yet available.
A 24-month toxicity and carcinogenicity bloassay was performed In F344
rats and B6C3F1 mice (NCA, 1982a,b, 1983; Serota et al., 1986a,b). Details
of the experiments are discussed In Section 4.2.1. of this document. Rats
and mice received doses of 0.5, 50, 125 and 250 mg/kg/day methylene chloride
1n their drinking water for 2 years. In rats, a statistically significant
reduction In body weight, water consumption and food consumption were noted
at dose levels of 125 and 250 mg/kg/day. Minimal effects were noted on the
hematological and serum chemistry parameters monitored 1n rats. Treatment-
related alterations In hlstomorphology were observed In rats of both sexes
at all^dose levels tested except the lowest. Increases In foci of cellular
alterations and fatty changes were most prominent.
In mice (NCA, 1983; Serota et al., 1986b), no treatment-related changes
were observed 1n survival, body weight, water consumption, clinical obser-
vation, leukocyte counts and gross necropsy findings. H1stomorpholog1c
alterations of the liver were observed 1n both male and female mice In the
high-dose group.
3.2.2. Inhalation. In humans, mild Intoxication by methylene chloride
results In somnolence, lassitude, anorexia and mild lightheadedness,
followed by greater degrees of disturbed central nervous system function and
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depression. Permanent disability has not been reported. When fatalities
have occurred the cause has been attributed to cardiac Injury and heart
failure (NAS, 1978).
Further reports of human Intoxication from methylene chloride were
presented by NIQSH (1976). Most of the case reports were concerned with
acute exposure and are not discussed here. Most of the epidemiologic
studies lack data on the concentration of methylene chloride In breathing
space air or they are complicated by exposure to other chemicals. Welch
(1987) reported that workers from several Industries, Including auto parts
production and plastic and prosthesis manufacturing, presented a variety of
CNS complaints, Including headaches, dizziness, nausea, memory loss,
parasthesla, tingling 1n the hands and feet, and loss of consciousness.
These effects occurred during certain painting and cleaning operations.
Methylene chloride levels up to 100 ppm were measured and the duration of
exposure was 6 months to 2 years. Assuming, a breathing rate of 20 mVday,
5-day workweek, an 8-hour workday exposure and a body weight of 70 kg, this
corresponds to a dose of 23.6 mg/kg/day. However, workers were also exposed
concommltantly to a mixture of other chemicals and as such, the behavioral
effects noted In this study cannot be unequivocally ascribed to methylene
chloride.
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-recrystallHatlon operation. Measurements revealed concentrations of
660-3600 ppm (2293-12,SOS mg/m») methylene chloride In workroom air with a
mean of 900 ppm (3126 mg/m>) in the breathing zone. Assuming a breathing
rate of 20 m'/day. 5 day workweek, an S hour workday exposure, and a body
weight of 70 kg, this dose corresponds to 212.7 mg/kg/day. This worker also
had physical contact with liquid methylene chloride.
QQ28H
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Exposure of 56 workers to 28-173 ppm methylene chloride (In a 9:1
methylene chlor1de:methanol atmosphere) resulted In statistically signifi-
cant changes In mental tiredness {p<0.05) and physical tiredness and sleepi-
ness (p<0.01) (Cherry et al., 1983). These paramenters were significantly
different only for the morning shift and correlated with blood carboxyhemo-
globln levels at the end of the shift. Furthermore, performance deteriora-
tion on the morning shift correlated (p<0.01) with the end-of-the-sh1ft
blood concentrations of methylene chloride.
Other epidemiological studies have not revealed adverse effects 1n
humans occupatlonally exposed to methylene chloride. Frledlander et al.
(1978) reported an epidemiological study of male workers at Eastman Kodak
exposed primarily to TWA concentrations of 30-125 ppm (104-434 mg/m»)
(Assuming a breathing rate of 20 ma/day a 5-day workweek, an 8-hour
workday, and a body weight of 70 kg, these doses correspond to 7.1 and 29.5
mg/kg/day) methylene chloride (estimated both from air monitoring and blood
carboxyhemoglobln levels) for up to 30 years. A proportionate mortality
study, where death certificates from 334 exposed workers who died from
1956-1976 were used. A cohort mortality study that Involved all 751 workers
employed In the exposure area In 1964 and a separate analysis of a subgroup
of 252 of these workers exposed for a minimum of 20 years by 1964 were also
performed. Data from this subgroup were analyzed separately to study
effects requiring long latency periods. The follow-up period 1n the cohort
roortallty 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
U.S. male age-spec1f1c mortality rates. Follow-up of workers aged >25 years
0028H
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was >97% as of 1964. None of these studies revealed any Indication of
Increased risk of death from circulatory disease Including Ischemic heart
disease, cancer or other causes.
Ott et al. (1983a) investigated mortality and current cardiac health 1n
workers from a fiber production plant 1n which methylene chloride was used
as a solvent. Given that metabolism of methylene chloride to carbon
monoxide results 1n an Increase In percentage of carboxyhemoglobln with a
commensurate decrease In the oxygen-carrying capacity of the blood, these
authors suggested that exposure to methylene chloride may lead to an
Increase In the Incidence of Ischemic cardiac disease. Data on mortality
were obtained In a fiber manufacturing plant from a cohort of workers who
were exposed for at least 3 months between January 1, 1954 and January 1,
1977 to a TWA of -140 ppm (-486 mg/ma) methylene chloride. Assuming a
breathing rate of 20 m'/day, a 5-day workweek, and 8-hour workday and a
body weight of 70 kg. this dose corresponds to 33.1 mg/kg/day. A control
cohort was composed of workers who were not exposed to methylene chloride.
Another control group provided the expected death data for 5-year intervals
matched by race (white and non-whUe) and sex. Mortality data indicated no
Increase 1n deaths In either men or women from circulatory system diseases,
ischemic heart disease as a separate category, or malignant neoplasms
associated with exposure to methylene chloride.
In another stud* of cardiac function, ott et al. (1983b) collected
24-hour EKGs on 50 workers fro. two fiber producing plants. Data regarding
24 workers fron the plant where exposure to TWA concentrations of 60-475 ppm
(208-1650 mg/m») (assuming a breathing rate of 20 mvday, 5-day work-
week. an 8-hour workday and a body weight of 70 kg. these doses correspond
to 14.2-112.3 mg/kg/day) methylene chloride occurred were compared with data
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from 26 workers from a similar plant not using methylene chloride. No
significant changes In ventricular or supraventricular ectopic activity, nor
episodic ST-wave segment depression were associated with exposure to
methylene chloride.
Other epidemiologic studies (Skory, 1980; Skory et al., 1980a,b)
apparently revealed no adverse health effects attributable to methylene
chloride; however, exposure data from these studies were not available 1n
the secondary source from which this discussion was taken.
Cherry et al. (1981) reported that a group of 46 men who were
occupatlonally exposed to 75-100 ppm (261-347 mg/m") (assuming a breathing
rate of 20 m3/day, a 5-day workweek, an 8-hour workday and a body weight
of 70 kg, these doses correspond to 17.7-23.6 mg/kg/day) 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-derived, 129/sex/exposure concentration) and golden Syrian hamsters
M08/sex/exposure concentration) were exposed to 0, 500, 1500 or 3500 ppm
(rats: 0, 197.6, 592.9 and 1383.4 mg/kg/day; hamster: 0, 288.0, 864.1 and
2016.2 mg/kg/day) methylene chloride of >99% purity. Exposures were for 6
hours/day, 5 days/week (except "holidays") for up to 2 years. Rats were
subjected to Interim kills at 6, 12, 15 or 18 months for cytogenetic or
general chemical and hlstopathologlcal examinations.
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During the first week of exposure, rats 1n the high concentration group
exhibited a slight decrease In 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 slalodacryoadenltls, a
transient 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 urinalysis values In rats.
Carboxyhemoglobln levels ranged from 0-5.3% in controls and 8.9-20.4X In
exposed rats but did not appear to be dose- or duration-related. Signifi-
cant increases 1n mortality occurred only in the high-dose females starting
at the 13th month of exposure.
Mean liver weights were Increased at the 18-month Interim kill, 1n both
male and female rats In the high-dose group. Histopathologic alterations
related to methylene chloride were found only in the liver. A dose-related
Increase In hepatocellular vacuolization, Indicative of fatty degeneration,
was noted In all exposed groups of rats. Kultlnucleated hepatoses, a
spontaneous geriatric change tn female rats, were observed after 12 months
In exposed and treated groups alike. A significant Increase tn the number
of foci of altered hepatoses was observed In high-dose females. Hales
exposed to 592.9 or 1383.4 mg/kg/day had an Increased Incidence of hepato-
cellular necrosis and coagulation necrosis. Some females exposed to 197.6
mg/kg/day ppm for 12 months appeared to have sllghtl, increased hepatic
hemosiderin. Female rats exposed to 1383.4 mg/kg/day and male rats exposed
to 592.9 mg/kg/day methylene chloride had a decreased Incidence or seventy
of chronic progressive glomerulonephropathy. another normal geriatric
change, compared with controls. Male rats exposed to 1383.4 mg/kg/da,
exhibited less sever, nonrenal lesion, (uremic pneumonitis, mineralization
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of organs and blood vessels, brain malacla, myocardial degeneration, etc.)
that were associated with chronic progressive renal disease.
In this study, hamsters appeared to be less sensitive than rats to
methylene chloride. Although carboxyhemoglobln levels were higher In
hamsters (0.3-4.0% In control groups, 22.2-34.6% 1n treatment groups) than
In rats, no clear evidence of toxicity was observed In hamsters. Methylene
chloride-exposed hamsters exhibited a decrease In the Incidence of age-
related amyloid deposition relative to controls.
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 were not located In
the available literature. The estrous cycle In female rats was reported to
be unaffected by exposure to 0.125 g methylene chlorlde/i In their drink-
ing water for 3 months (17.5 mg/kg/day) (Bornmann and Loeser, 1967).
3.3.2. Inhalation. Pertinent data regarding teratogenicity or reproduc-
tive dysfunction In humans exposed by Inhalation to methylene chloride were
not located In the available literature. Methylene chloride has been shown
to cross the placental barrier 1n laboratory animals (Anders and Sunram,
1982). Schwetz et al. (1975) exposed Swiss-Webster mice and Sprague-Dawley
rats to 1250 ppm methylene chloride for 7 hours/day on days 6-15 of
gestation (mice, 1646.5 mg/kg/day; rats, 806.9 mg/kg/day). Mouse 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. In mouse fetuses, slightly advanced ossifica-
tion of the sternebrae were noted, which suggested accelerated development.
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The teratogenic effect of methylene chloride In rats was also Investi-
gated by Hardin and Manson (1980). Groups of 26-28 Long-Evans hooded rats
were exposed to 4500 ppm mg/m3) methylene chloride for 6 hours/day (2490.1
mg/kg/day) (group 1, before and during gestation; group 2, before gestation;
group 3, during gestation). "Before gestation" exposures were the 3 weeks
Immediately preceding mating and "during gestation" exposures Included the
first 17 days of gestation. Gravida 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.
In a companion paper, Bornscheln et al. (1980) studied the behavioral
effects of methylene chloride on pups from 10 dams per group. Methylene
chloride had no effects on behavior, body weights, food and water consump-
tion, wheel running activity, and avoidance learning up to 400 days of age.
3.4. TOXICANT INTERACTIONS
No studies of toxic Interactions of methylene chloride with other xeno-
blotlcs have been found In the available literature. Some case histories 1n
humans, however, suggest that Interactions with other compounds may occur.
Functional circulatory disorders In workers exposed for >3 years to
methylene chloride and other organochlorlne compounds at "permissible-
levels have been reported (Dunavskll, 1972). The symptoms, Including chest
pain, EKG Irregularities, bradycardia, decreased myocardial 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
monoxide. Fodor and Roscovanu (1376) reported that exposure of human
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subjects to 500 ppm (assuming a breathing rate of 20 m3/day, with
continuous exposure, this dose corresponds to 496.3 mg/kg/day) of methylene
chloride (for an unspecified duration} resulted in levels of carboxyhemo-
globln In blood comparable with those produced by the TLV for carbon
monoxide, 50 ppm. Mixed exposures could pose a health threat to occupation-
ally exposed workers, smokers or cardiorespiratory patients. Savolalnen et
al. (1977) expressed concern that exposure to methylene chorlde In combina-
tion with other lipophilic solvents may result 1n enhanced central nervous
system and metabolic effects.
Chrlstenson and Hulzlnga (1971) reported the case of a 17-year-old male
who died after 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.
Two reports of phosgene poisoning related to methylene chloride
{Gerrltsen and Buschmann, 1960; English, 1964) pointed 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 (Gerrltsen and
Buschmann, 1960) Involved a woman who was exposed for a 3-hour period during
1 day when she was 7 months pregnant; she expectorated blood-tinged sputum
and felt tightness In her chest. The next day she was hospitalized 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.
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The second case (English, 1964) Involved a 67-year-old male who was
exposed for 8 hours to methylene chloride In a small unventllated room
heated with a portable kerosene heater. He experienced breathlessness,
headache, giddiness and a tightness across the chest. Upon hospitalization
the next day he was cyanotic, sweating, and tachypnelc with extensive coarse
rales In both lungs. He was discharged after 5 weeks but experienced
lassitude, weakness and hypochortdrlosls for an additional 3 months.
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4. CARCINOGENICITY
4.1. HUMAN DATA
Several epidemiological studies that were reviewed briefly 1n Section
3.2.2. examined the health effects associated with occupational exposure to
methylene chloride. Frledlander et al. (1978) and Ott et al. (1983a}
reported no excess cancer mortality In exposed cohorts compared with
controls. This study has been recently updated through 1984 (Hearne et al.,
1987). Workers were exposed to an average workplace concentration of 26 ppm
(assuming a breathing rate of 20 mVday, a 5-day workweek, an 8-hour
workday and a body weight of 70 kg, this dose corresponds to 6.1 mg/kg/day)
methylene chloride for an average of 22 years. Again, there was no Increase
In deaths from malignant neoplasms, respiratory cancer, or liver cancer 1n
exposed workers compared with the general population. An Increase In the
Incidence of deaths due to pancreatic cancer was observed but was not
statistically significant.
4.2. BIOASSAYS
4.2.1. Oral. An NTP-sponsored gavage bloassay of methylene chloride In
rats Is currently underway; results are not yet available (NTP, 1988).
A 24-month toxicity and carcinogenicity bloassay was performed In F344
rats (NCA, 1982a,b; Serota et al., 1986a) and B6C3F1 mice {NCA, 1983; Serota
et al., 1986b). In the rat study, groups of 85 males and 85 females were
administered methylene chloride In their drinking water. Target doses were
0, 5, 50, 125 or 250 mg/kg bw/day for 24 months. Consumption was monitored
and actual consumption closely paralleled target doses. A second control
group of 50 rats/sex and a high-dose group (250 mg/kg bw/day) of 25 rats/sex
were added for 78 weeks followed by a 26-week recovery period. There was a
statistically significant Increase (p<0.05) In the combination of neoplastic
nodules and hepatocellular carcinomas In female rats relative to controls.
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These Incidences {0/134, 1/85, 4/83, 1/85, 6/85 In combined control, 5, 50,
125 and 250 mg/kg bw/day groups, respectively), however, were within those
observed 1n historical controls. The U.S. EPA (1985a) concluded therefore,
that this study did not provide sufficient evidence for methylene chloride
carcinogenicity in F344 rats.
In the mouse experiment, groups of 50 females and 60-200 males were
treated with methylene chloride In the drinking water. Target doses were 0,
60, 125, 185 or 250 mg/kg bw/day for 24 months. Dally consumption was
monitored and showed that consumed dose was similar to target dose. A
significant (p<0.05) Increase In the combined Incidence of hepatocellular
adenoma and carcinoma was recorded in 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). This data 1s not considered to be sufficient
evidence of carcinogenicity of methylene chloride In mice.
4.2.2. Inhalation. Burek et al. (1980, 1984) and Dow Chemical Co. (1980)
evaluated the carcinogenicity of methylene chloride based on a chronic
(2-year) Inhalation exposure regimen. Sprague-Dawley rats and golden Syrian
hamsters were exposed to methylene chloride at 0, 500, 1500 or 3500 ppm 6
hours/day, 5 days/week for up to 2 years (assuming rats have a breathing
rate of 0.223 mVday and a body weight of 0.35 kg these doses correspond
to 0, 197.6, 592.9 and 1383.4 mg/kg/day. Assuming a hamster has a breathing
rate of 0.13 mVday and a body weight of 0.149 kg, these doses correspond
to 0,288.0, 864.1 and 2016.2 mg/kg/day. No exposure-related differences In
the incidences of benign or malignant tumors were observed In male hamsters.
There was a statistically significant increase (p-0.032) 1n the incidence of
benign tumors In female hamsters exposed to 2016.2 mg/kg/day ppm methylene
chorlde. However, this Increase was attributed to Increased longevity 1n
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that group and subsequently, a higher probability of developing these
tumors. After corrections for survival differences between the groups, the
data Is not statistically significant.
An Increase 1n the number of benign mammary tumors per tumor-bearing rat
(but not In the number of tumor-bearing rats) was observed at all dose
levels In females and In males In the high dose group. There was a statis-
tically significant increase
-------
TABLE 4-1
Summary of Salivary Gland Region Sarcoma Incidence In Hale
Rats 1n a 2-Year Inhalation Study with D1chloromethanea
Dose
(mg/kg/day)
Incidence15
Fisher's Exact Test
0
1/93 (15)
NA
197.6
0/94 (OX)
NA
592.9
5/91 (5.5%)
(p-0.10, NS)
1383.4
11/88 (12.5X)
Cochran-Arm1tage test for linear trend, p<0.0001
NS » Not significant; NA « not applicable
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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 an Inhalation study In rats and
mice (NTP, 1985). The final draft of this study has been released (NTP,
1986). In this experiment, 50 male and 50 female F344/N rats were exposed
to air containing 0 (chamber controls), 1000, 2000 or 4000 ppm (0, 3474,
6947 or 13,894 mg/ma), 6 hours/day, 5 days/week for 102 weeks. Concur-
rently, 50 male and 50 female B6C3F1 mice were exposed by the same schedule
to air containing 0, 2000 or 4000 ppm methylene chloride (0, 1612.9 or
3225.9 mg/kg/day). During week 3 of treatment, rats of both sexes In the
395.3 mg/kg/day group were exposed to 790.5 mg/kg/day and rats of both sexes
In the 790.5 mg/kg/day group were exposed to 395.3 mg/kg/day.
In rats of both sexes, a significant Increase (p<0.05 males; p<0.001
females) In mammary tumors (fibroadenoma, adenoma, fibroma: combined
Incidence) was observed 1n the high-dose groups (Table 4-2). Similarly, the
Incidence of subcutaneous fibroma or sarcoma (combined) according to
authors, In male rats was significantly higher In the high-dose group than
In controls (p<0.01). The Incidence of these tumors was combined because
they all occurred In the mammary chain and were considered to be of the same
etlologlc origin. However, combining tumor incidences 1s not a valid
statistical procedure. Furthermore, historical Incidence of these tumors,
which are generally much higher than experimental controls, are generally
ignored in NTP's discussion. In light of these facts the results and
conclusions of the NTP (1985, 1986) bloassay are equivocal. The Incidence
of other tumor types were also Increased although not statistically signifi-
cant. These Included the combined Incidence of neoplastic nodules and
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TABLE 4-2
Tumor Incidence In Rats Treated with Methylene Chloride3
Tumor Type Historical Control 395.3 790.5 1581.0
Controls®
HALES
Fibroadenoma, adenoma, >3*3X 0/50 (OX) 0/50 (OX) 2/50 (4%) 5/50b (10X)
fibroma of mannary
gland
Subcutaneous (combined) >5±3X 1/50 (2X) 1/50 (2X) 4/50 (8X) 9/50c (18%)
tumors of manmary area
FEMALES
Fibroadenoma, adenoma, >28±10X 7/50 (14X) 13/50 (26%) 14/50 (28%) 23/50* (46%)
fibroma of mammary gland
^Source: NTP, 1986; percentages based on animal groups of 50 each.
bp<0.05; Fisher's exact Test as compared to control Incidences.
cp<0.01 as compared to control Incidences.
dp
-------
hepatocellular carcinomas In female rats, adrenal gland pheochromocytoma and
Interstitial cell tumors In males, squamous cell metaplasia In females,
pituitary gland adenoma or carcinoma and mononuclear cell leukemlas 1n both
sexes. In male rats, the Incidence of mesothelioma derived from the tunica
vaginalis was found to be significantly higher In both the high and
intermediate groups than In controls, but the incidence 1n controls In this
experiment was unusually low compared with historical controls thereby
making Interpretation of these results equivocal.
An Increase 1n the Incidence of lung tumors 1n treated mice was highly
significant (p<0.001) (Table 4-3). The latency period was significantly
reduced in treated mice. Lung tumors were believed to be responsible for
the reduced survival observed In high-dose group males and females. Also
noteworthy was the incidence of liver tumors 1n treated mice (p«0.014 males;
p<0.001 females) (see Table 4-3).
The results of the NTP (1985) bloassay were used 1n combination with
data from the drinking water mouse study (NCA, 1983) by the U.S. EPA (1985b)
to derive cancer potency estimates for oral and Inhalation exposure to
methylene chloride (Section 6.3.). Subsequent to the U.S. EPA (1985b)
analysis, the NTP study was finalized and became available 1n a published
form (NTP, 1986). The relevant tumor Incidence data had not changed between
the 1985 and 1986 versions of the study and publication of the more recent
version 1s not expected to alter the quantitative estimation of carcinogenic
potency.
~•3. OTHER RELEVANT DATA
Several experiments regarding the mutagenicity of methylene chloride are
summarized In Table 4-4. Simmon et al. (1977) reported that methylene
chloride was mutagenic to Salmonella tvphlmurlum strain TA100 when assayed
In a desiccator 1n which the atmosphere contained the test compound.
0028H -28- 08/14/89
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TABLE 4-3
Tumor Incidence In Nice Treated with Methylene Chloride3
Tumor Type
Historical®
Control
1612.9
3225.9
Controls
mg/kg/day
mg/kg/day
MALES
Alveolar/bronchlolar adenomas
17+8%f
3/50 (6%)
19/50b (38X)
24/50b (48X)
Alveolar/bronchlolar carcinomas
17±8%f
2/50 (4X)
10/50c (20X)
28/50b (56X)
Multiple lung tumors
0/50 (OX)
10/50 (20X)
28/50 (56X)
Hepatocellular adenoma and carcinoma
30+8%
22/50 (44X)
24/49 (49X)
33/49c (67%)
Hepatocellular carcinoma
13/50 (26X)
15/49 (31X)
26/49d (53%)
Multiple liver tumors
21/50 (4X)
11/49 (22X)
16/49c (33%)
FEMALES
Alveolar/bronchlolar adenomas 7+4%f
Alveolar/bronchlolar carcinomas 7+4Xf
Multiple lung tumors
Hepatocellular adenoma and carcinoma 30+8%
Hepatocellular carcinoma
2/50 (4X)
1/50 (2X)
0/50 (OX)
3/50 (6%)
1/50 <2X)
23/48b (48X)
13/48b [21%)
11/48 (23X)
16/48b (33X)
11/48b (23X)
28/48b (58X)
29/48b (60X)
29/48 (60%)
40/48b (83X)
32/48b (67%)
-------
TABLE 4-3 (con't)
Tumor Type
Historical6
Control
1612.9
3225.9
Controls
mg/kg/day
mg/kg/day
Multiple liver tumors
0/50 (0%)
3/48 (6%)
28/48 (58%)
^Source NTP. 1986
bp
-------
TABLE 4-4
Mutagenicity and Genotoxtclty of Methylene Chloride*
Assay
Indicator
Organtsa
Application
Concentration
or Oose
Activating
Systea
Response Coments
Reference
Reverse
autatton
Salaonella
tvohtaurtua
TA1S35, TA1537,
TA1S38, TA98,
TAJOO
yfpor
ttposure
0-800 vt/9 t
desiccator
~S-9
~ Oata reported only for TA100;
~ positive with or without S-9
activation
Staaon et al.,
1977
Reverse
autatton
S. tvohtaurtua
TA100
vapor
exposure
0-1 at/9 ft
desiccator
~S-9
~ S-9 aay enhance, hut not
~ required for autagenlctty
Staaon and
Kauhanen. 1978
Reverse
autatton
S. tvohtaurtua
TA153S. TA100
vapor
exposure
0-8.3X In atr
~S-9
~ S-9 enhanced autagenlctty;
~ dose-response was evident
In TA100
Green, 1983
Reverse
Mutation
S. tvohtaurtua
vapor
exposure
0-10* theo-
retical In atr
none
~ Clear-cut dose-response
clearly evident
McGregor, 1979
Reverse
autatton
S. tvohtaurtua
TA1535, TA1537,
TA1S36, TA98,
TA100
vapor
exposure
NR
~S-9
~ Positive result only when
conducted tn gas tight chaaber
Nestaann
et al.. 1980
Reverse
autatton
S. tvohlaurtua
TA98, TA100
vapor
fxposure
0-1 al/
chaaber
~S-9
~ Positive in both TA98, TA100
~
Snow et al.,
1979
Reverse
Mutation
S. tvohtaurtua
TA98. TA100
NR
MR
S-9
~ Data available tn abstract
fora only
Kanada and
Uyeta, 1978
Reverse
autatton
S. tvohtaurtua
?AM. TA10D
vapor
exposure
0-57.000 ppa
~S-9
~ Response positive and dose-
~ related
Jongen et al.,
1978
Reverse
autatton
S. tvohtaurtua
TA153S, TA98.
TA100
vapor
exposure
0-10,000 ppa
~ Positive dose-related response
~ only In air tight chaaber
Sarber et al.,
1981
Reverse
autatton
S. tvohtaurtua
TA100
vapor
•xposure
0-8.4%
~S-9
~ Positive dose-related
~ response, S-9 activation did
not enhance response
Green, 1980
Reverse
autatton
S. tvohtaurtua
TA1535, TA1S37.
TA153S, TA98.
TAIOO
vapor
exposure
0-750 at/
desiccator
~S-9
~ Weak positive response
~
Gocke et al.,
1981
Reverse
autatton
S. tvohtaurtua
TA100
vapor
exposure
0-1.4%
~S-9,
cytosal,
atcrosoaes
~ Activation with cytosol
~ yielded aaxtaua response
Jongen et al.,
1982
-------
TABLE 4-4 (cont.)
Assay
Indicator
Organise
Application.
Concentration
or Oose
Activating
Systea
Response
Coeaents
Reference
Roc assay
Bacillus
fll^tlllS
MR
NR
NR
-
Data available only In
abstract fora
Kanada and
Uyeta. 1970
Mitotic
recombination
Saccharoavces
f en vis la* B7
NR
0-209 aM
NA
~
07 strain aetabollies
¦ethylene chloride to active
Interaedlates
Callen et al..
1980
Mitotic
recombination
|-
M
NR
NR
-
Ntnlaal data presented
Simon et al.,
1977
Sex-llnfced
recessive
lethal
frf?oph1J4
fed or
Injected
NR
NA
-
(totalization not prevented
Abrahaason and
Valencia, I960
Sex-linked
recessive
lethal
frWiMH
fed
0-620 «N
NA
~
Conclusion; aethylene chloride
Is autagenlc to spera
fiocke et al.,
1981
Sex-linked
recessive
lethal
fanaorelus
MR
10"* to 10«
aol/i
NA
~
Equivocal positive results
Saaolloff
et al., 7980
Mutations In
cell -cult lire
CHO and V79
cells
cell culture
0-5*
NA
-
Equivocal negative results
Jongen et al.,
1981
Chroaosoaal
aberration
rat bone
•arrow cells
Inhalation
0-3500 ppa
NA
-
NC
Oow Chealcal
Co., 1980
Cbroaoseaal
aberration
JMRI alee/bone
•arrow
l.p.
VOectloa
0-3400 ag/kg bw
NA
~
Results equivocal
Gocke et al.,
1981
Sister-
chroaatld
exchange
SCl/m cells
coll culture
0-4.OX
NA
4
Positive dose-response
Jongen et al.,
1981
Chroaosoaal
abberatlon
CUD cells
cell culture
0-10 pt/aL
~ S-9
~
Slallar results In three
replications
Thllagar and
Kuaaroo, 1903
Slster-
chroaattd
exchange
CHO cells
-------
Metabolic activation was not required. The response was strongly dose-
related. This 1s typical of the response of many strains of S. typhlmurlum
to methylene chloride {see Table 4-4). In S. cerevlslae 03, however,
mitotic recombination was not Increased by methylene chloride {Simmon et
al., 1977) although positive results were obtained In S. cerevlslae D7
(Callen et al., 1980). Additionally, Abrahamson and Valencia (1960)
reported that methylene chloride was negative when tested for sex-1Inked
recessive lethals In Drosophlla melanogaster. although positive results were
obtained by Gocke et al. {1981).
Thllagar and Kumaroo (1983) Investigated the ability of methylene
chloride to Induce SCE and chromosomal aberrations In cultured Chinese
hamster ovary cells. They observed extensive chromosomal aberrations, both
with and without Aroclor 1242- and 1254-lnduced rat S-9 fraction activation.
Negative results were reported In the SCE assay. These authors discovered
that uslpg plastic rather than glass for the tests markedly reduced the
magnitude of the positive response. This observation suggests that
methylene chloride may bind to plastic, decreasing its effective
concentration 1n these assays.
In general, methylene chloride Is mutagenic to several strains of
Salmonella typhlmurlum. Metabolic activation with S-9 Is not required but
may enhance mutagenicity. Five studies reported a dose-response relation-
ship (Green, 1980, 1983; McGregor, 1979; Jongen et al., 1978; Barber et al.,
1981). The evidence for mutagenicity In other test systems Is not so clear
cut however. In Saccharomvces cerevlslae. an Increase 1n mitotic recombina-
tions were observed In the 07 strain (Callen et al., 1980) but not In the D3
strain (Simmon et al., 1977). Likewise, 1n Drosophlla. positive (Gocke et
al., 1981) and negative (Abrahamson and Valencia, 1980) results have been
reported.
0028H
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The mammalian cells, Jjn vitro exposure to methylene chloride produces an
Increase In chromosome abberatlons 1n CHO cells (Thllagar and Kumaroo, 1983)
and 1n sister-chromatid exchange 1n SCE/V79 cells (Jongen et al., 1981).
However, other reports are negative or equivocal (Jongen et al., 1981; Dow
Chemical Co., 1980; Goche et al., 1981; Thllagar and Kumaroo, 1983).
The in vivo Interaction of methylene chloride and Its metabolites with
F344 rat and B6C3F1 mouse lung and liver DNA was measured after Inhalation
of 4000 ppm 14C-methylene chloride for 3 hours (CEFIC, 1986). The DNA was
Isolated from the tissue 6, 12 and 24 hours after the start of exposure and
then analyzed for total radioactivity and the distribution of radioactivity
1n enzymatlcally hydrolyzed DNA samples. Low-levels of radioactivity were
found In DNA from the lungs and livers of both rats and mice. Higher levels
were found 1n mouse DNA and protein than In the rat. The radioactivity was
found to be associated with normal constituents of DNA. Under the condi-
tions of this study, there was no evidence for alkylatlon of DNA by
methylene chloride and 1t was concluded that methylene chloride was not
genotoxlc (CEFIC, 1986).
There Is clear evidence of mutagenicity 1n yeast. Results are mixed for
DrosophUa and mammalian cells in cultures, and were largely negative In
mammalian cells in vivo. Given this evidence 1t was concluded that
methylene chloride may be a weak mutagen In mammalian systems (U.S. EPA,
1987).
4.4. HEIGHT OF EVIDENCE
Pertinent data regarding carcinogenicity of methylene chloride in humans
were not located 1n the available literature. An NTP-sponsored gavage study
In rats is currently underway, but results are not yet available (NTP,
1988). Burek et al. (1980, 1984) was unable to demonstrate carcinogenicity
0028H
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In rats with chronic Inhalation exposure to high levels 1383.4 mg/kg/day
methylene chloride. Another NCI bloassay that involved Inhalation exposure
has recently been published (NTP, 1985, 1986). The results Indicate that
methylene chloride 1s may be carcinogenic to rats (mammary tumors) and mice
(lung and liver tumors). However, questionable statistical assumptions used
1n deriving carcinogenic Incidences makes the NTP (1985, 1986) conclusions
equivocal. Applying the criteria for evaluating the overall weight of
evidence of carcinogenicity to humans adopted by the Carcinogen Assessment
Group of the U.S. EPA (1986a), methylene chloride 1s most appropriately
classified a B2 - Probable Human Carcinogen. This classification Is
consistent with the current analysis of the U.S. EPA (1985a, 1986c).
QQ28H
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5. REGULATORY STANDAROS AND CRITERIA
Pertinent regulatory standards and criteria for methylene chloride are
summarized In Table 5-1. According to the AC6IH (1986) the TIV committee
adopted a TLV-TWA of 100 ppm In the workplace. The committee recoimiends the
elimination of the STEL until additional toxlcologlcal data and Industrial
hygiene experience become available.
The NIOSH (1976) occupational criteria for methylene chloride was set at
a TWA of 75 ppm for a 10-hour workday, 40-hour workweek. Recognizing the
additional relationship between methylene chloride and carbon monoxide, a
formula has been derived to relate methylene chloride toxicity and carbon
monoxide toxicity with concentrations that are >9 ppm.
[C(C0) * L(CO)] * [C(DCM) + L(DCM)] <1
where
C(CO) - TWA concentration of carbon monoxide (ppm)
t(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
The carcinogenic response to methylene chloride has been documented In
several studies of chronic effects In animals, (see Section 4.2.1.).
Consequently, a recent report by NIOSH (1986) recommends that methylene
chloride be regarded as a "potential occupational carcinogen". Therefore,
NIOSH (1986) recommends that occupational exposure to methylene chloride be
controlled to the lowest feasible limit.
The U.S. EPA (1986c) has verified an oral slope factor of 7.5xlQ~a
(mg/kg/day)"1 and a drinking water unit risk of 2.1x10"' (wg/t). An
Inhalation slope factor of 1.4x10"* (mg/kg/day)"1 and an Inhalation unit
risk of 4.1x10"* tiigW1. These values were derived using a
linearized multistage procedure.
QG28H
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08/14/89
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TABLE 5-1
Regulatory Standards or Criteria for Methylene Chloride3
Standard or Criteria
Value
Reference
TLV-TWA
Level In spice oleo-reslns
Level In decaffeinated
coffee
B-hour PEL-TWA
Acceptable celling
Maximum peak
Ambient water quality
criterion
Ingesting water and organisms
Ingesting organisms only
Health advisories (HAs)
1-day (child)
10-day (child)
DWELb
Suggested no adverse response
level (SNARL)
1-day
7-day
100 ppm (~360 mg/m3)
30 mg/kg
10 mg/kg
500 ppm (1737 mg/m®)
1000 ppm (3474 mg/m')
2000 ppm (6948 mg/m3)
0.19 yg/l
15.7 jig/l
13.3 mg/l
1.5 mg/l
1.75 mg/l
45.5 mg/l
6.5 mg/l
ACGIH, 1986
NI0SH, 1976
0SHA, 1986
U.S. EPA, 1980a
U.S. EPA, 1985c
U.S. EPA, 1985c
NAS, 1980
aSee discussion 1n text for concurrent exposure to carbon monoxide.
b0WEL * drinking water equivalent level.
0028H
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08/07/89
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As an oil and fat solvent, methylene chloride Is allowed In spice
oleoreslns at concentrations up to 30 mg/kg and In decaffeinated coffee at
concentrations up to 10 mg/kg (NIOSH, 1976).
OSHA (1986) has established Permissible Exposure Limits (PELs) for
occupational exposures to methylene chloride as follows: 8-hour TWA, 500
ppm; acceptable celling concentration, 1000 ppm; acceptable maximum peak >
celling (5 minutes 1n any 2 hours), 2000 ppm.
The U.S. EPA (1980a) has set the ambient water quality criterion for
Ingesting water and organisms at 0.19 yg/i and for Ingesting organisms
only at 15.7 vg/t.
The U.S. EPA Office of Drinking Water (00W) has prepared health
advisories (HAs) for a number of drinking water contamlnents. The HAs
describe concentrations of contamlnents In drinking water at which non-
carclnogenlc effects would not be anticipated to occur and would provide a
margin of safety to protect sensitive members of the population. The 1-day
and 10-day HAs are calculated for exposure of children; for methylene
chloride these values are 13.3 and 1.5 mg/i, respectively (U.S. EPA,
1985c). Adequate data for calculating a longer-term HA were not available,
however, IRIS reports a modified DWEL value of 0.5 mg/l as the longer-term
HA. Since methylene chloride 1s classified by EPA is a B2 carcinogen, a
lifetime HA value 1s not recommended. However, a drinking water equivalent
level (DUEL) of 1.75 mg/l 1s recommended.
The U.S. EPA (1985c) has recalculated previously published 1- and 7-day
suggested-no-adverse-response level (SNARL) data (MAS, 1980). These values
are 45.5 and 6.5 mg/l, respectively. Because of a lack of suitable data,
a chronic SNARL was not calculated.
0028H
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The U.S. EPA (1985d) has verified a chronic RfDg of 6xlQ~2 mg/kg/day
for methylene chloride based on NOAELs of 5.85 and 6.47 mg/kg/day for male
and female rats, respectively. The data was derived from a 2-year drinking
water bloassay (NCA, 1983; Serota et al., 1986a,b). However, since the
supporting data base 1s limited, the confidence In the RfDg 1s only medium.
0028H
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD<.)
Methylene chloride has been demonstrated to probably be carcinogenic In
both rats and mice. Data are sufficient for estimating carcinogenic potency.
6.2. REFERENCE DOSE (RfD)
Methylene chloride has been demonstrated to probably be carcinogenic In
both rats and mice. Data are sufficient for estimating carcinogenic potency.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. In the 2-year NCA studies (NCA, 1982a,b, 1983; Serota et
al., 1986a,b), F344 rats and B6C3F1 mice were administered" methylene
chloride in the drinking water. Female rats had an' Increased Incidence of
neoplastic nodules or hepatocellular carcinomas, which was significant when
compared with matched but not historical controls. No Increased Incidence
of liver tumors was reported In male rats. Male mice had Increased
Incidences of combined neoplastic nodules and hepatocellular carcinomas;
however, these Increases were not statistically significant or dose-related.
_ U.S. EPA (1985b) derived a drinking water unit risk estimate of
2.1x10"' (ug/ft)"x based on extrapolation using the linearized
multistage model. The slope factor 1s an arithmetic mean of slope factors
derived from the NTP (1985) Inhalation study and the NCA (1983) oral data.
This value was verified by the U.S. EPA (1986c) and Is available on IRIS.
This analysis of the NTP Inhalation study Is discussed more fully in Section
6.3.2. According to the analysis presented by U.S. EPA (1986c), methylene
chloride is absorbed rapidly following either Inhalation or oral exposure.
Therefore, use of Inhalation data for calculation of risk from oral exposure
Is possible If lung tumor data are omitted. Further details of the assump-
tions and derivation of the oral unit risk for humans are presented In the
0028H
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09/01/89
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U.S. EPA (1986c) summary. Methylene chloride was considered to be a well
absorbed vapor at low doses. The unit risk should not be used 1f the water
concentration exceeds 5xl04 *»g/l, because above this concentration the
slope factor may differ from that stated.
Subsequent to the derivation of the U.S. EPA (1985b) analysis, the NTP
data became available In a final form (NTP, 1986). The NTP (1986) data did
not differ from the 1985 version and there has been no modification of the
risk assessment. The value of 2.1x10"' (wg/l)~x is equivalent to
7.5x10""3 (mg/kg/day)"1, which 1s adopted as the estimate of the carcino-
genic potency to orally exposed humans for the purposes of this document.
6,.3.2. Inhalation. The U.S. EPA (1985b) used the data from the 2-year
inhalation study reported by NTP (1985) for combined carcinomas and adenomas
of the lung or liver In B6C3F1 mice for derivation of the Inhalation unit
risk of 4.1x10"* (yg/m3). Details of the NTP (1985) study, as well as
other Inhalation studies are discussed In Section 3.2.2. of this document,
and assumptions and derivation of the inhalation unit risk are presented In
the U.S. EPA (1985b) document. As discussed In Section 6.3.1., the NTP data
are available In a final form (NTP, 1986), which does not differ substan-
tially from the 1985 version and there 1s no modification to this risk
assessment based upon this final NTP report. The above value Is equivalent
to 1.4xl0~a (mg/kg/day)"1 and Is verified and available on IRIS (U.S.
EPA, 1986c). The value of 1.4xl0~2 (mg/kg/day)"1 is adopted for the
purposes of this document as the estimate of the carcinogenic potency of
methylene chloride to humans exposed by Inhalation. The unit risk should
not be used Af the air concentration exceeds 2x10* |ig/ma because above
this concentration the slope factor may differ from that stated.
0028H
-41-
09/01/89
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After critical analysis of the evidence, EPA has concluded that
methylene chloride may be a weak genotoxlcant 1n manmals {U.S. EPA, 1987).
Current evidence Is not sufficient to Identify the mechanism of action or to
Indicate that this mechanism would not be expected In humans. Indeed, It
seems reasonable to assume that humans metabolize methylene chloride via the
glutathlon-s-transferase pathway as do rats and mice, albeit at a much
slower rate. U.S. EPA (1987) suggests that since some data exist on the
pharmacokinetics and metabolic pathways of methylene chloride, it may be
more appropriate to use a physlolglcally based, pharmacokinetic model
(Andersen et al., 1987). However, this model has not been fully validated.
Nevertheless, using the pharmacokinetic model with its original kinetic
parameters to estimate the Internal dose of the glutathione-transferase
metabolite, and correcting Internal dose for Interspecies differences 1n
sensitivity by using the surface area correction factor, leads to a unit
risk estimate for continuous Inhalation exposure to 1 „g/m» of
4.7xl0"7. This factor 1s -8.7-fold lower than the Inhalation unit risk of
4.1x10"* derived from the 2-year NTP (1986) bloassay. This difference, 1n
light of the uncertainties of the model mentioned above, are not, In prac-
tical terms, very distinct. In this case, pharmacokinetic considerations
have not revealed a great error Inherent In using applied dose as a
surrogate for Internal or delivered dose.
0028H
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7. REFERENCES
Abrahamson, S. and R. Valencia. 1980. Evaluation of substances of Interest
for genetic damage using Drosophlla melanoqaster. Prepared for FDA Contract
233-77-2119. (Cited In U.S. EPA, 1985a)
ACGIH (American Conference of Governmental and Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological Exposure
Indices for Substances In Workroom Air, 5th ed. Cincinnati, OH.
Ahshuller, A.P. 1980. Lifetimes of organic molecules 1n the troposphere
and lower atmosphere. Adv. Environ. Sc 1. Technol. 10: 181-219. (Cited 1n
U.S. EPA, 1985a)
Andersen, M.E., H.J. Clewell, III., H.l. Gargas, F.A. Smith and R.H. Reltz.
1987. Physiologically based pharmacokinetics and the risk assessment
process for methylene chloride. Toxicol. Appl. Pharmacol. 87: 185-205.
Angelo, M.J., A.B. Prltchard, D.R. Hawkins, A.R. Mailer and A. Roberts.
1986a. The pharmacokinetics of dlchloromethane. I. Disposition 1n B6C3F1
mice following Intravenous and oral administration. Food Chem. Toxicol.
24(9): 965-97*.
Angelo, M.J., A.B. Prltchard, D.R. Hawkins, A.R. Waller and A. Roberts.
1986b. The pharmacokinetics of dlchloromethane. II. Disposition in Fischer
344 rats following Intravenous and oral administration. Food Chem. Toxicol.
24(9): 975-980.
0028H
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Anders, M.W. and J.M. Sunram. 1982. Transplacental passage of dlchloro-
methane and carbon monoxide. Toxicol. Lett. 12(A): 231-234. (Cited In
ATSDR, 1987)
Astrand, I.» P. Ovrum and A. Carlsson. 1975. Exposure to methylene
chlor1de--I. Its concentration In alveolar air and blood during rest and
exercise and 1t metabolism. Scand. J. Work Environ. Health. 1: 78-94.
(Cited In U.S. EPA, 1985a)
ATSDR (Agency for Toxic Substances and Disease Registry). 1987. Toxlco-
loglcal Profile for Methylene Chloride. Draft.
Barber, E.D., W.H. Donlsh and K.R. Mueller. 1981. A procedure for the
quantitative measurement of volatile liquids In the Hlnes Salmonella/micro-
some assay. In: 11th Ann. Meeting Environ. Mutagen. Soc. p. 39. (Cited 1n
U.S. EPA, 1985a)
Bornmann, 6. and A. Loeser. 1967. Zur Frage wlner Cron1sch-Tox1chen
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APPENDIX
Summary Table for Methylene Chloride
Carcinogenic Experimental qj* or
Potency Species/Sex Dose/Exposure Effect Unit Risk Slope Reference
(rag/kg/day)~l
Inhalation
mouse/female
<4000 ppm (13.894
mg/a"), 6 hours/
day, 5 days/week
for 2 years
combined carcinomas
and adenomas of the
lung and liver
1.4xl0~a
NTP. 1985;
U.S. EPA.
1985b, 1986c
Oral
mouse/male
and female
Inhalation
<4000 ppm (13,894
mg/ma), 6 hours/
day, 5 days/week
for 2 years and
drinking water
study: <250
ng/kg/day for 2
years
hepatocellular
adenomas or
carcinomas
7.5xl0~s+
NTP, 1985;
NCA, 1983;
U.S. EPA,
1985b, 1986c
tAMthmetlc mean of slope factors derived from NTP (1986) and the NCA (1983) data.
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